Novel GSPT1 compounds and methods of using such novel compounds

Abstract

Provided herein are compounds of Formula I for treating, preventing, or managing cancer. Also provided are pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions. In certain embodiments, the methods include treating, preventing, or managing cancer, including solid tumors and blood-borne tumors, using the compounds provided herein. JPEG2025513877000109.jpg38116

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 USC §119(e) of U.S. Provisional Patent Application No. 63 / 331,193, filed April 14, 2022; the disclosure of which is incorporated herein by reference.

[0002] FIELD OF THEINVENTION Provided herein are compounds for treating, preventing or managing cancer.Also provided are pharmaceutical compositions comprising the compounds, and methods for using the compounds and compositions.In certain embodiments, the methods include treating, preventing or managing cancer (including solid tumors and blood-borne tumors) with the compounds provided herein. [Background technology]

[0003] Cancer Pathobiology Cancer is primarily characterized by an increase in the number of abnormal cells derived from a given normal tissue, invasion of these abnormal cells into adjacent tissues, or lymphatic or blood-mediated spread of malignant cells to regional lymph nodes and distant sites (metastasis). Clinical data and molecular biological studies indicate that cancer is a multistep process that begins with minor preneoplastic changes and can progress to tumor formation under certain conditions. Neoplastic lesions may evolve clonally and develop enhanced capacities to invade, proliferate, metastasize, and become heterogeneous, especially under conditions where neoplastic cells escape host immune surveillance. See Roitt, I., Brostoff, J, and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

[0004] A wide variety of cancers are described and explained in detail in medical literature. Examples include lung cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, brain cancer, and intestinal cancer. With the aging of the general population, the occurrence of new cancers, and the increase in susceptible populations (e.g., people infected with AIDS or people overexposed to sunlight), the incidence of cancer continues to rise.Therefore, there is a great demand for new methods and compositions that can be used to treat cancer patients.

[0005] Many types of cancer are associated with the formation of new blood vessels, a process known as angiogenesis. Several mechanisms of action involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms of action is the secretion of cytokines with angiogenic properties by tumor cells. Examples of these cytokines include acidic and basic fibroblast growth factors (a, b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cells may release angiogenic peptides through the production of proteases and subsequent degradation of the extracellular matrix in which several cytokines (e.g., b-FGF) are stored. Angiogenesis may also be induced indirectly through the recruitment of inflammatory cells (especially macrophages) and the subsequent release of angiogenic cytokines (e.g., TNF-α, b-FGF).

[0006] Lymphoma refers to cancer originating from the lymphatic system. Lymphoma is characterized by malignant tumors of lymphocytes-B lymphocytes and T lymphocytes (i.e., B-cells and T-cells). Lymphoma generally develops in lymph nodes, or collections of lymphatic tissue in organs, including but not limited to the stomach or intestines. Lymphoma can affect bone marrow and blood in some cases. Lymphoma can spread from one part of the body to another.

[0007] Treatment of various forms of lymphoma is described, for example, in U.S. Patent No. 7,468,363, the entire contents of which are incorporated herein by reference. Such lymphomas include, but are not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, activated B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular center lymphoma, transformed lymphoma, intermediate lymphocytic lymphoma, intermediate grade lymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL), central cell lymphoma, diffuse small cleaved cell lymphoma (DSCCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma and mantle zone lymphoma, and low grade follicular lymphoma.

[0008] Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer in both men and women in the United States, with an estimated 63,190 new cases and 18,660 deaths in 2007. See Jemal A et al., CA Cancer J Clin 2007;57(1):43-66. The probability of developing NHL increases with age, and the incidence of NHL in older adults has increased steadily over the past decade, raising concerns about the aging trend of the U.S. population. Ibid. See Clarke CA et al., Cancer 2002;94(7):2015-2023.

[0009] Diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of non-Hodgkin's lymphomas. Some DLBCL patients are cured with classical chemotherapy, but the rest die from the disease. Anticancer drugs rapidly and persistently deplete lymphocytes, presumably by directly inducing apoptosis in mature T and B cells. See K. Stahnke. et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count (ALC) has been shown to be a prognostic factor in follicular non-Hodgkin's lymphoma, and recent results suggest that ALC at diagnosis is an important prognostic factor in diffuse large B-cell lymphoma. See D. Kim et al., Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Suppl), 2007:8082.

[0010] Leukemia refers to a malignant tumor of the hematopoietic tissues. Various forms of leukemia are described, for example, in U.S. Patent No. 7,393,862 and U.S. Provisional Patent Application No. 60 / 380,842, filed May 17, 2002, the entire contents of which are incorporated herein by reference. Although viruses have been reported to cause several types of leukemia in animals, the causes of human leukemia are largely unknown. See The Merck Manual, 944-952 (17th ed. 1999). Transformation to a malignant tumor typically occurs in a single cell through two or more steps, followed by proliferation and clonal expansion. In certain leukemias, specific chromosomal translocations have been identified that have consistent leukemic cell morphology and special clinical features (e.g., translocations 9 and 22 in chronic myeloid leukemia and translocations 15 and 17 in acute promyelocytic leukemia). Acute leukemias are predominantly undifferentiated cell populations, whereas chronic leukemias are more mature cell morphology.

[0011] Acute leukemias are divided into lymphoblastic (ALL) and nonlymphoblastic (ANLL) types. See The Merck Manual, 946-949 (17th ed. 1999). Acute leukemias may be further subdivided according to their morphological and cytochemical appearance, according to the French-American-British (FAB) classification, or according to their type and degree of differentiation. The use of specific B-cell and T-cell and myeloid antigen monoclonal antibodies is most helpful in classification. ALL is predominantly a pediatric disease, established by laboratory findings and bone marrow examination. ANLL, also known as acute myeloid leukemia or acute myeloblastic leukemia (AML), is an acute leukemia that can occur at any age and is more common in adults; it is the form that is usually associated with radiation as the causative agent.

[0012] Chronic leukemias are described as being lymphocytic (CLL) or myeloid (CML). See The Merck Manual, 949-952 (17th ed. 1999). CLL is characterized by the appearance of mature lymphocytes in the blood, bone marrow, and lymphoid organs. CLL is characterized by a persistent absolute lymphocytosis (>5,000 / μL) and an increase in lymphocytes in the bone marrow. Most CLL patients also have a clonal expansion of lymphocytes with B-cell characteristics. CLL is a disease of middle age or old age. In CML, the defining feature is the predominance of granulocytic cells at all stages of differentiation in the blood, bone marrow, liver, spleen, and other organs. In symptomatic patients at the time of diagnosis, the total white blood cell (WBC) count is usually about 200,000 / μL but can reach 1,000,000 / μL. CML is relatively easy to diagnose because of the presence of the Philadelphia chromosome.

[0013] In addition to the classification of acute and chronic, tumors are also classified into precursor tumors or peripheral tumors based on the cell that causes such disorders. See, for example, U.S. Patent Publication No. 2008 / 0051379 (this publication is incorporated herein by reference in its entirety). Precursor tumors include ALL and lymphoblastic lymphoma, which arise in lymphocytes before differentiating into either T or B cells. Peripheral tumors are tumors that arise in lymphocytes that have differentiated into either T or B cells. Such peripheral tumors include, but are not limited to, B-cell CLL, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma, follicular lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, plasmacytoma, diffuse large B-cell lymphoma, and Burkitt's lymphoma. In more than 95% of CLL cases, the clonal expansion is of B-cell lineage. See Cancer: Principles & Practice of Oncology (3rd Edition) (1989) (pp. 1843-1847). In less than 5% of CLL cases, the tumor cells have a T-cell phenotype. However, regardless of these classifications, pathological disturbance of normal hematopoiesis is a feature of all leukemias.

[0014] Multiple myeloma (MM) 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 proliferation of these cells can result in bone pain and fractures, anemia, infections, and other complications. Although the exact cause of multiple myeloma remains unknown, it is the second most common hematologic malignancy. Multiple myeloma produces 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 myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.

[0015] Skeletal symptoms, including bone pain, are among the most clinically significant manifestations of multiple myeloma. Malignant tumor cells release osteoclast stimulating factors (including IL-1, IL-6, and TNF), which leach calcium from bone and cause lytic lesions; hypercalcemia is another manifestation. Osteoclast stimulating factors, also called cytokines, may prevent apoptosis or death of myeloma cells. Fifty percent of patients have radiologically detectable myeloma-associated skeletal lesions at the time of diagnosis. Other common clinical manifestations of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal failure.

[0016] Solid tumors are abnormal masses of tissue that may, but usually do not, contain cysts or liquid areas. Solid tumors may be benign (non-cancerous) or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of types of solid tumors include, but are not limited to, malignant melanoma, adrenal carcinoma, breast cancer, renal cell carcinoma, pancreatic cancer, non-small cell lung cancer (NSCLC), and cancer of unknown primary. Drugs that are commonly administered to patients with various types or stages of solid tumors include, but are not limited to, Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or combinations thereof.

[0017] Patients who achieve a complete remission with initial therapy have a high chance of cure, but of patients who do not respond or who relapse, less than 10% achieve a cure or have a response lasting longer than 3 years. See Cerny T et al., Ann Oncol 2002;13 Suppl 4:211-216. Rituximab is known to deplete normal host B cells. See M. Aklilu et al., Annals of Oncology 15:1109-1114, 2004. The long-term immunological effects of B cell depletion with rituximab and the characteristics of the reconstituted B cell pool in patients with lymphoma are not well defined, despite the widespread use of this therapy. See Jennifer H. Anolik et al., Clinical Immunology, vol. 122, issue 2, February 2007, pages 139-145.

[0018] Solutions for patients with relapsed or refractory disease rely heavily on experimental therapies followed by stem cell transplantation, which may not be feasible for patients with poor performance status or elderly patients.Therefore, there is a great demand for novel approaches that can be used to treat patients with NHL. The link between cancer and altered cellular metabolism is well established. Cairns, RA et al., Nature Rev., 2011, 11:85-95. Understanding tumor cell metabolism and associated genetic changes can lead to the identification of improved methods for cancer treatment. Ibid. For example, tumor cell survival and proliferation via increased glucose metabolism is linked to the PIK3 pathway, whereby mutations in tumor suppressor genes such as PTEN activate tumor cell metabolism. Ibid. AKT1 (aka PKB) stimulates glucose metabolism associated with tumor cell proliferation through various interactions with PFKFB3, ENTPD5, mTOR and TSC2 (aka tuberin). Ibid.

[0019] The transcription factors HIF1 and HIF2 are largely responsible for the cellular response to hypoxic conditions that often accompany tumors. Ibid. Once activated, HIF1 promotes the ability of tumor cells to carry out glycolysis. Ibid. Thus, inhibition of HIF1 can slow or reverse tumor cell metabolism. Activation of HIF1 is associated with PI3K, tumor suppressor proteins such as VHL, succinate dehydrogenase (SDH) and fumarate hydratase. Ibid. The oncogenic transcription factor MYC is also associated with tumor cell metabolism, particularly glycolysis. Ibid. MYC also promotes cell proliferation through the glutamine metabolic pathway. Ibid.

[0020] AMP-activated protein kinase (AMPK) functions as a metabolic checkpoint that tumor cells must overcome in order to proliferate. Ibid. Several mutations have been identified that suppress AMPK signaling in tumor cells. See Shackelford, DB & Shaw, RJ, Nature Rev. Cancer, 2009, 9:563-575. STK11 has been identified as a tumor suppressor gene implicated in a role for AMPK. See Cairns, RA et al., Nature Rev., 2011, 11:85-95. The tumor suppressor transcription factor p53 also plays an important role in regulating cellular metabolism. Ibid. Loss of p53 in tumor cells may be a significant factor in shifting tumor cell metabolism toward the glycolytic pathway. Ibid. Another potential chemotherapy target, the OCT1 transcription factor, may cooperate with p53 in regulating tumor cell metabolism. Ibid.

[0021] Pyruvate kinase M2 (PKM2) promotes changes in cellular metabolism that confer a metabolic advantage to cancer cells by supporting cell proliferation. Ibid. For example, lung cancer cells expressing PKM2 over PKM1 have been found to have such an advantage. Ibid. In the clinic, PKM2 has been identified as overexpressed in many types of cancer. Ibid. Thus, PKM2 may be a useful biomarker for early detection of tumors. Mutations in isocitrate dehydrogenase IDH1 and IDH2 are associated with tumorigenesis, particularly in glioblastoma and acute myeloid leukemia. See Mardis, ER et al., N. Engl. J. Med., 2009, 361:1058-1066; Parsons, DW et al., Science, 2008, 321:1807-1812.

[0022] The incidence of cancer continues to rise, as does the aging of the general population, the occurrence of new cancers, and an increase in susceptible populations (e.g., AIDS-infected people, the elderly, and people with excessive sun exposure).Therefore, there is a tremendous demand for novel methods, treatments, and compositions that can be used to treat cancer patients, including, but not limited to, those with lymphoma, NHL, multiple myeloma, AML, leukemia, and solid tumors. Thus, compounds that can modulate and / or inhibit unwanted angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful in treating and preventing various forms of cancer.

[0023] Cancer Treatment Methods Current cancer treatments may include surgery, chemotherapy, hormone therapy, and / or radiation therapy to eradicate tumor cells in the patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy may also include biological therapy or immunotherapy. All of these solutions may have significant drawbacks for the patient. For example, surgery may be contraindicated due to the patient's health or may be unacceptable to the patient. In addition, surgery may not completely remove the tumor tissue. Radiation therapy is only effective if the tumor tissue is more sensitive to radiation than normal tissue. Radiation therapy may also cause severe side effects. Hormonal therapy is rarely given as a single agent. Although hormone therapy can be effective, it is often used to prevent or delay the recurrence of cancer after other treatments have removed the majority of the cancer cells. Certain biologic and other therapies have a limited number of side effects that can cause heartburn or swelling, flu-like symptoms such as fever, chills, and fatigue, gastrointestinal problems, or allergic reactions.

[0024] Regarding chemotherapy, there are various chemotherapeutic agents available for the treatment of cancer. Many cancer chemotherapeutics work by either directly or indirectly preventing the biosynthesis of deoxyribonucleotide triphosphate precursors, thereby inhibiting DNA synthesis and preventing DNA replication and therefore cell division. Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York).

[0025] Despite the 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, often dangerous, side effects, such as severe nausea, bone marrow suppression, and immunosuppression. In addition, many tumor cells are resistant or develop resistance to chemotherapeutic agents, even when administered in combination. In fact, those cells that are resistant to a particular chemotherapeutic agent used in a treatment protocol often become resistant to other drugs, even if these agents act by a different mechanism of action than the drug used in the particular treatment. This phenomenon is called multidrug resistance. Because of drug resistance, many cancers are resistant to standard chemotherapy treatment protocols.

[0026] There is a significant need for safe and effective compounds and methods for treating, preventing and managing cancer, including cancers that are refractory to standard treatments such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicity and / or side effects associated with conventional therapies. Summary of the Invention

[0027] Provided herein are compounds, pharmaceutical compositions containing the compounds, and methods of their use in the treatment of cancer, including solid and blood-borne tumors.

[0028] 1. In a first embodiment, the present invention provides a compound of formula (I): [ka] [In formula: A is independently selected from an unsubstituted or substituted 3- to 12-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3- to 12-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring; X is O or -NR 11 More independently selected; R 1 are independently selected from hydrogen, halogen, -C1-C6 alkyl, or 3- to 6-membered cycloalkyl; R 2 are independently selected from hydrogen, halogen, -C(O), -C1-C6 alkyl, and 3- to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl is optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 3 is hydrogen, halogen, -OR 11 , -N(R 11 R 11 ), -NHR 11 , -C1-C6 alkyl, a 3- to 6-membered cycloalkyl, a 4- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 4 are independently selected from hydrogen, halogen, -C1-C6 alkyl, a 3- to 6-membered cycloalkyl, a 4- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -NHR 11 -OR 11 may be substituted with; R 5are independently selected from hydrogen, -C1-C6 alkyl, a 3- to 6-membered cycloalkyl, a 4- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 6 are independently selected from hydrogen, -C1-C6 alkyl, a 3- to 6-membered cycloalkyl, a 4- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; Here, two R 5 and R 6 The substituents, together with the carbon atoms to which they are attached, may be bonded to form a 5- or 6-membered ring, which may be saturated or partially saturated, and further, optionally, one or two R 11 may be optionally substituted with a substituent; R 7 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -NHR 11 , -N(R 11 R 11 ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C2-C6 alkenyl, -O-(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(R 11 ), -C(=O)N(R 11 R 11 ), -S(O)2R11 , -S(=O)R 11 , -SR 11 , -S(=O)2NH2, -S(=O)2NH(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl); wherein the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is optionally selected from the group consisting of -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 8 is hydrogen, halogen or -C1-C6 alkyl (optionally -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 (which may be substituted with ) independently selected from; R 9 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -NHR 11 , -N(R 11 R 11 ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C2-C6 alkenyl, -O-(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(R 11 ), -C(=O)N(R 11 R 11 ), -S(O)2R 11 , -S(=O)R 11 , -SR 11 , -S(=O)2NH2, -S(=O)2NH(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl); wherein the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is optionally selected from the group consisting of -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 10 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -NHR 11 , -N(R 11 R 11 ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C2-C6 alkenyl, -O-(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(R 11 ), -C(=O)N(R 11 R 11 ), -S(O)2R 11 , -S(=O)R 11 , -SR 11 , -S(=O)2NH2, -S(=O)2NH(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl); wherein the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is optionally selected from the group consisting of -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 11 are independently selected from hydrogen, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 haloalkyl, 3- to 12-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring; Here, R 11The alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, aryl or heteroaryl rings in 12 is substituted with a substituent; R 12 is independently selected at each occurrence from hydrogen, -C1-C6 alkyl, halogen, -OH, -O-(C1-C6 alkyl)-, -NH2, a 3- to 12-membered alkyl, a 5- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring; where R 12 The alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, aryl or heteroaryl rings in 13 is replaced by; R 13 is independently substituted with hydrogen, halo, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxyalkyl, oxo, hydroxyl, or -C1-C6 alkoxy; where two R on adjacent carbon atoms of A or B group 9 and R 10 may be linked to form a 5- or 6-membered ring which is saturated, partially saturated or aromatic; Further optionally, one or two R 13 may be substituted with substituents and, if the ring is not aromatic, may contain oxo substituents; Here, each A, B, R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 and R 13 The heterocyclic and heteroaryl rings in may contain 1, 2 or 3 heteroatoms independently selected from O, N or S. or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0029] In one embodiment, the compounds provided herein are of Formula I: In one embodiment, the compounds provided herein are pharma- ceutically acceptable salts of the compounds of Formula I. In one embodiment, the compounds provided herein are solvates of the compounds of formula I. In one embodiment, the compounds provided herein are hydrates of the compounds of formula I. In one embodiment, the compounds provided herein are clathrates of the compounds of formula I.

[0030] Also provided are pharmaceutical compositions containing an effective concentration of one or more compounds provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, formulated to be administered by a suitable route and means, and optionally containing at least one pharmaceutical carrier.

[0031] In one embodiment, the pharmaceutical composition provides an effective amount for the treatment of cancer, including solid and blood borne tumors. In one embodiment, the pharmaceutical composition provides an amount effective for the prevention of cancer, including solid and blood-borne tumors. In one embodiment, the pharmaceutical composition provides an amount effective to ameliorate cancer, including solid and blood-borne tumors.

[0032] Also provided is a combination therapy using one or more of the compounds or compositions provided herein, or their enantiomers or mixtures of enantiomers, or their diastereomers or mixtures of diastereomers, or their pharma- ceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs, in combination with a therapy, for example, another pharmaceutical agent active against cancer or its symptoms. Examples of therapies within the scope of the method include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biochemical therapy, immunotherapy, and combinations thereof. The compounds or compositions provided herein, or pharma- ceutically acceptable derivatives thereof, can be administered concomitantly with, prior to, or after one or more of the above-mentioned therapies. Pharmaceutical compositions containing the compounds provided herein and one or more of the above-mentioned agents are also provided.

[0033] In certain embodiments, the compounds of the invention may be formulated into antibody-drug conjugates, or ADCs, which are highly targeted biopharmaceuticals that combine a monoclonal antibody specific for a surface antigen present on certain tumor cells with a highly potent anti-cancer drug linked via a chemical linker. In certain embodiments, provided herein are methods of treating, preventing, or ameliorating cancer, including solid tumors and blood-borne tumors, or one or more symptoms or etiology thereof. In certain embodiments, provided herein are methods of preventing cancer, including solid tumors and blood-borne tumors, or one or more symptoms or causes thereof. In certain embodiments, provided herein are methods of ameliorating cancer, including solid tumors and blood-borne tumors, or one or more symptoms or etiology thereof.

[0034] In certain embodiments, the blood-borne tumor is leukemia. In certain embodiments, the methods provided herein include methods for treating various forms of leukemia, such as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. In certain embodiments, the methods provided herein include methods for preventing various forms of leukemia, such as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. In certain embodiments, the methods provided herein include methods for managing various forms of leukemia, such as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia.

[0035] The methods provided herein encompass the treatment of leukemia that is relapsed, refractory or resistant. The methods provided herein encompass the prevention of leukemia, which is relapsed, refractory or resistant. The methods provided herein encompass the management of leukemia, which is relapsed, refractory or resistant.

[0036] In one embodiment, the methods provided herein include methods of treating acute myeloid leukemia. In one embodiment, the methods provided herein include a method of preventing acute myeloid leukemia. In one embodiment, the methods provided herein include methods of managing acute myeloid leukemia.

[0037] In practicing the method, an effective amount of a compound, or a composition containing a therapeutically effective concentration of a compound, is administered to an individual exhibiting symptoms of the disease or disorder to be treated, the amount being effective to ameliorate or eliminate one or more symptoms of the disease or disorder.

[0038] Additionally, pharmaceutical packs or kits are provided that contain one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally, such containers may bear a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of drugs or biological products, which notice may reflect approval by the agency for manufacture, use, or sale for administration to humans. The packs or kits may be labeled with information regarding the mode of administration, the drugs and the order in which they are to be administered (e.g., separately, sequentially, or simultaneously), etc. These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Provided herein are compounds of formula I: Enantiomers of compounds of formula I are provided herein. Mixtures of enantiomers of compounds of Formula I are provided herein. Pharmaceutically acceptable salts of the compounds of formula I are provided herein. Pharmaceutically acceptable solvates of the compounds of Formula I are provided herein. Pharmaceutically acceptable hydrates of the compounds of Formula I are provided herein. Pharmaceutically acceptable co-crystals of compounds of formula I are provided herein. Pharmaceutically acceptable clathrates of compounds of formula I are provided herein. Pharmaceutically acceptable polymorphs of compounds of Formula I are provided herein.

[0040] Further provided are methods for treating cancer, including solid tumors, blood-borne tumors, and pharmaceutical compositions and dosage forms useful in such methods. Further provided are methods for preventing cancer, including solid tumors, blood-borne tumors, as well as pharmaceutical compositions and dosage forms useful in such methods. Additionally provided are methods for ameliorating cancer, including solid tumors and blood-borne tumors, as well as pharmaceutical compositions and dosage forms useful in such methods. The compounds, methods and compositions are described in detail in the sections below.

[0041] A.Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications are incorporated in their entirety by reference. In the event that there are multiple definitions for terms used herein, the definitions in this section prevail unless otherwise specified.

[0042] Definition abbreviations: The following abbreviations may be used herein: [Table 1] [Table 2] [Table 3]

[0043] The use of the words "a", "an", "the" and similar referents in the context of describing the present invention (particularly in the context of the claims) should be construed to cover both the singular and the plural unless otherwise specified. The recitation of a range of values ​​herein is intended merely to serve as a shorthand method of referring individually to each separate value within the range, unless otherwise specified herein, and each separate value is incorporated herein as if the value were recited herein. The use of any and all exemplary or exemplary language (e.g., "etc.") provided herein is intended to better illustrate the invention and is not intended to limit the scope of the invention, unless otherwise specified. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0044] "Alkyl" refers to a straight or branched hydrocarbon chain consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms and attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. "Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain, consisting only of carbon and hydrogen, containing no unsaturation, having from 1 to 8 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may be attached to the remainder of the molecule through any two carbons within the chain.

[0045] "Alkenylene" or "alkenylene chain" refers to a straight or branched, unsaturated divalent group consisting solely of carbon and hydrogen atoms, having 2 to 8 carbon atoms, where the unsaturation is present only as double bonds, which can be between any two carbon atoms in the chain, e.g., ethenylene, prop-1-enylene, but-2-enylene, etc. The alkenylene chain may be attached to the remainder of the molecule through any two carbons within the chain. "Alkoxy" refers to a group of the formula -OR where R is alkyl or haloalkyl. "Optionally substituted alkoxy" refers to a group of the formula -OR where R is alkyl, optionally substituted as defined herein.

[0046] "Amino" refers to a group of the formula -NR'R'', where R' and R'' are each independently hydrogen, alkyl, or haloalkyl. "Optionally substituted amino" refers to a group of the formula -NR'R'', where one or both of R' and R'' are optionally substituted alkyl as defined herein. "Aryl" refers to a group of carbocyclic ring systems, including monocyclic, bicyclic, tricyclic, and tetracyclic C6-C18 ring systems, where at least one of the rings is aromatic.Aryl may be completely aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl, and pyrenyl.Aryl may also contain aromatic rings in combination with non-aromatic rings, examples of which are acenaphene, indene, and fluorene.

[0047] "Cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms and being saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl, and bicyclo[2.2.2]octane. "Halo", "halogen" or "halide" refers to F, Cl, Br or I. "Haloalkyl" refers to an alkyl group, and in certain embodiments, a C1-6 alkyl group in which one or more hydrogen atoms are replaced with halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,3-difluoro-2-methylpropyl, 2,2-difluorocyclopropyl, (trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl, and 2,2,2-trifluoro-1,1-dimethylethyl.

[0048] "Heterocycle" or "heterocyclyl" refers to a stable 3- to 15-membered non-aromatic ring group consisting of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In one embodiment, the heterocyclic ring system group can be a monocyclic, bicyclic, or tricyclic ring or a tetracyclic ring system, which may include fused or bridged ring systems; the nitrogen or sulfur atoms of the heterocyclic ring system group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl group may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound. Exemplary heterocyclic groups include morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl, indolinyl, and the like.

[0049] "Heteroaryl" refers to a heterocyclyl group as described above that is aromatic. Heteroaryl groups include, but are not limited to, monocyclyl, bicyclyl, and tricyclyl groups and may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound. Examples of such heteroaryl groups include, but are not limited to, furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, and the like.

[0050] "EC 50 " refers to the amount, concentration or dosage of a particular test compound that achieves 50% efficacy or effectiveness of a maximal response, such as cell culture or proliferation, as measured via any in vitro or cell-based assay described herein. "I C 50" refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of a maximal response, such as cell culture or proliferation, as measured via any in vitro or cell-based assay described herein.

[0051] Pharmaceutically acceptable salts include, but are not limited to, amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts such as potassium and sodium; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc; other metal salts including, but not limited to, sodium hydrogen phosphate and disodium phosphate; salts of mineral acids including, but not limited to, hydrochlorides and sulfates; and salts of organic acids including, but not limited to, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

[0052] As used herein, and unless otherwise specified, the term "hydrate" refers to a compound provided herein or a salt thereof that further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein, unless otherwise specified, the term "solvate" refers to a solvate formed when one or more solvent molecules are combined with a compound provided herein. The term "solvate" includes hydrates (e.g., monohydrates, dihydrates, trihydrates, tetrahydrates, etc.).

[0053] Unless stated otherwise specifically in the specification, it is understood that substitution may occur at any atom of an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group. When the number of any given substituent (e.g., haloalkyl) is not limited, one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0054] When a group described herein is referred to as being "substituted," with the exception of an alkyl group, the group may be substituted with any suitable substituent. Specific examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl (monocyclic); or heterocyclyl (which may be a monocyclic ring or a fused or non-fused polycyclic ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or heterocyclyl (which may be a monocyclic ring or a fused or non-fused polycyclic ring, for example, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (for example, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.When alkyl groups as described herein are referred to as "substituted," they may be substituted with any of the substituents found in the exemplary compounds and embodiments disclosed herein, including halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0055] Unless otherwise specified, where a compound can assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers are intended to be included within the scope of the claimed subject matter. For example, if a compound is described in one of two tautomeric forms, both tautomers are intended to be included herein. Thus, the compounds provided herein may be enantiomerically pure, or may be stereoisomeric or diastereomeric mixtures.

[0056] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or a mixture thereof. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one of skill in the art will recognize that administering a compound in its (R) form is equivalent to administering a compound in its (S) form, in the case of compounds that undergo epimerization in vivo. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on chiral stationary phases.

[0057] In the present description, if there is any discrepancy between a chemical name and a chemical structure, the structure shall prevail. As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" refer to alleviating or reducing the severity of symptoms associated with the disease or condition being treated. The term "prevention" includes inhibiting the symptoms of a particular disease or disorder. In some embodiments, patients with a family history of cancer, including solid and blood-borne tumors, are candidates for a preventative regimen. In general, the term "preventing" refers to administering a drug to a patient at risk of cancer, particularly including solid and blood-borne tumors, before symptoms develop.

[0058] As used herein, unless otherwise specified, the term "managing" includes preventing the recurrence of a particular disease or disorder in a patient suffering from the disease or disorder, increasing the time a patient is in remission from the disease or disorder, reducing the patient's mortality rate, and / or maintaining a reduction in the severity of or avoidance of symptoms associated with the disease or condition being managed. A "subject" as used herein is typically an animal, including a human, such as a human patient.

[0059] The term "tumor" as used herein refers to all neoplastic cells, whether malignant or benign, that grow and proliferate, and all pre-cancerous and cancerous cells and tissues. As used herein, "neoplastic" refers to any form of irregular or disorganized cell growth, whether malignant or benign, that results in abnormal tissue growth. Thus, "neoplastic cells" include malignant or benign cells that have undergone irregular or disorganized cell growth. "Hematologic malignancies" as used herein refers to cancers of the body's blood-forming and immune systems - bone marrow and lymphatic tissues. Such cancers include leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma.

[0060] The term "leukemia" refers to a malignant tumor of the hematopoietic tissue. Leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. Leukemia may be relapsed, refractory, or resistant to conventional treatment. As used herein, "promyelocytic leukemia" or "acute promyelocytic leukemia" refers to a malignant tumor of the bone marrow in which there is a deficiency of mature blood cells in the myeloid lineage and an excess of immature cells called promyelocytes. It is usually characterized by the exchange of regions of chromosome 15 and chromosome 17.

[0061] As used herein, "acute lymphocytic leukemia (ALL)," also known as "acute lymphoblastic leukemia," refers to a malignant disease caused by the abnormal growth and development of primary nongranular white blood cells or lymphocytes. "T-cell leukemia" as used herein refers to a disease in which certain cells of the lymphatic system, called T lymphocytes or T cells, are malignant. T cells are white blood cells that can normally attack virus-infected cells, foreign cells, and cancer cells and produce substances that control the immune response. The term "relapse" refers to a situation in which a patient who has been in remission from leukemia after treatment experiences a reappearance of white blood cells in the bone marrow and a decrease in normal blood cells.

[0062] The term "refractory or resistant" refers to the situation where a patient has persistent leukemia cells in their bone marrow, even after intensive treatment. As used herein, unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease and to delay or minimize one or more symptoms associated with the disease or disorder being treated. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or pathogenesis of a disease or disorder, or enhances the therapeutic effect of another therapeutic agent.

[0063] The terms "co-administration" and "combination" include administration of two therapeutic agents (e.g., a compound provided herein and another anti-cancer agent) simultaneously, concurrently, or sequentially, without particular time limitations. In one embodiment, both agents are present in a cell or in the patient's body at the same time, or exert their biological or therapeutic effects at the same time. In one embodiment, the two therapeutic agents are combined in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are combined in separate compositions or unit dosage forms.

[0064] The term "supportive care agents" refers to any substances that treat, prevent, or manage side effects resulting from treatment with a compound of Formula I. The term "biologic therapy" refers to the administration of biological therapeutic agents such as cord blood, stem cells, growth factors, and the like. In this specification, unless otherwise specified, the term "about" refers to a value that does not exceed ±10% of the value modified by the term. For example, "about 10 mg / m 2 " is 9 mg / m 2 ~11mg / m 2 This means the range.

[0065] "Anti-cancer drug" refers to metabolic inhibitors (e.g., 5-fluoro-uracil, methotrexate, fludarabine), microtubule inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, and the like; taxanes such as paclitaxel, docetaxel, and the like), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosourea and hydroxyurea, and the like), platinum agents (e.g., cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), anthracyclines (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosourea and hydroxyurea, and the like), anthracyclines (e.g., cyclophosphamide, melphalan, carmustine, bischloroethylnitroso ... These include cyclophosphamide, cyclosporine ... As used herein, abbreviations for any protecting groups, amino acids and other compounds are in accordance with their common usage, accepted abbreviations, or those of the IUPAC-IUB Biochemical Nomenclature Commission (Biochem. 1972, 11: 942-944), unless otherwise specified.

[0066] B. Compound Embodiment The embodiments listed below are presented in numbered form for convenience and for ease of reference and clarity when referring back to multiple embodiments.

[0067] 1. In a first embodiment, the present invention provides a compound of formula (I): [ka] [In formula: A is independently selected from unsubstituted or substituted 3- to 12-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl rings; B is independently selected from an unsubstituted or substituted 3- to 12-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring; X is O or -NR 11 More independently selected; R 1 are independently selected from hydrogen, halogen, -C1-C6 alkyl, or 3- to 6-membered cycloalkyl; R 2 are independently selected from hydrogen, halogen, -C(O), -C1-C6 alkyl, and 3- to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl is optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 3 is hydrogen, halogen, -OR 11 , -N(R 11 R 11 ), -NHR 11 , -C1-C6 alkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 4 are independently selected from hydrogen, halogen, -C1-C6 alkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl rings, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -NHR 11 -OR11 may be substituted with; R 5 are independently selected from hydrogen, -C1-C6 alkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl rings, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 6 are independently selected from hydrogen, -C1-C6 alkyl, 3- to 6-membered cycloalkyl, 4- to 12-membered heterocycle, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl rings, wherein the alkyl, cycloalkyl, heterocycle, and heteroaryl are optionally selected from -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; Here, two R 5 and R 6 The substituents, together with the carbon atoms to which they are attached, may be bonded to form a 5- or 6-membered ring, which may be saturated or partially saturated, and further, optionally, one or two R 11 may be optionally substituted with a substituent; R 7 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -NHR 11 , -N(R 11 R 11 ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C2-C6 alkenyl, -O-(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(R 11), -C(=O)N(R 11 R 11 ), -S(O)2R 11 , -S(=O)R 11 , -SR 11 , -S(=O)2NH2, -S(=O)2NH(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl); wherein the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is optionally selected from the group consisting of -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 8 is hydrogen, halogen or -C1-C6 alkyl (optionally -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 (which may be substituted with ) independently selected from; R 9 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -NHR 11 , -N(R 11 R 11 ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C2-C6 alkenyl, -O-(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(R 11 ), -C(=O)N(R 11 R 11 ), -S(O)2R 11 , -S(=O)R 11 , -SR 11 , -S(=O)2NH2, -S(=O)2NH(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl); wherein the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is optionally selected from the group consisting of -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 10 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -NHR 11 , -N(R 11 R 11 ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C2-C6 alkenyl, -O-(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(R 11 ), -C(=O)N(R 11 R 11 ), -S(O)2R 11 , -S(=O)R 11 , -SR 11 , -S(=O)2NH2, -S(=O)2NH(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl); wherein the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is optionally selected from the group consisting of -R 11 , -N(R 11 R 11 ), -NHR 11 -OR 11 may be substituted with; R 11 are independently selected from hydrogen, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 haloalkyl, a 3- to 12-membered cycloalkyl, a 4- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring; Here, R 11The alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, aryl or heteroaryl rings in 12 is substituted with a substituent; R 12 is independently selected at each occurrence from hydrogen, -C1-C6 alkyl, halogen, -OH, -O-(C1-C6 alkyl)-, -NH2, a 3- to 12-membered alkyl, a 5- to 12-membered heterocycle, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring; where R 12 The alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycle, aryl or heteroaryl rings in are each independently unsubstituted or 13 is replaced by; R 13 are independently hydrogen, halo, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 alkoxyalkyl, oxo, hydroxyl, or -C1-C6 alkoxy; where two R on adjacent carbon atoms of A or B group 9 and R 10 may be linked to form a 5- or 6-membered ring which is saturated, partially saturated or aromatic; Further optionally, one or two R 13 may be substituted with substituents and, if the ring is not aromatic, may contain oxo substituents; Here, each A, B, R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 and R 13 The heterocyclic and heteroaryl rings in may contain 1, 2 or 3 heteroatoms independently selected from O, N or S. or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0068] 2. A compound of formula I, wherein X is O, or a compound of embodiment 1, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer in any of the above forms, or a mixture thereof. 3. X is -NR 11 or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0069] 4. R with 1 or 2 As 7 A compound of formula I, substituted with a substituent, as defined in any one of embodiments 1-3, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 5. R 7 is selected from hydrogen, halogen, or -C1-C6 alkyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0070] 6. R 7is independently selected from hydrogen, F, Cl, or methyl, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 7. R 7 is hydrogen, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0071] 8. R 7 is F; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 9. R 7 is Cl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0072] 10. R 7 is methyl, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 11. A is phenyl, [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0073] 12. The compound according to any one of embodiments 1-11 or 9, wherein A is phenyl, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 13. A [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0074] 14. A [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 15. A [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0075] 16. A [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 17. A [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0076] 18. A [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 19. B is substituted or unsubstituted phenyl; [ka] A compound according to any one of embodiments 1-18, independently selected from: A pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0077] 20. B is one or more R 9A compound of formula I, substituted with a substituent, as defined in any one of embodiments 1-19, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 21. R 9 is hydrogen, halogen, -OR 11 , -C1-C6 alkyl, -(C1-C6 haloalkyl), -(C1-C6 alkyl)-NH2, -(C1-C6 alkyl)-OH, -CN, or 3- to 12-membered cycloalkyl, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0078] 22. R 9 is H, -OH, Cl, F, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)OH, -CH2NH2, -CN, -OCH3, -OCH(CH3)2, -OCHF2, [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 23. R 9 is H; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0079] 24. R 9is -OH; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 25. R 9 is Cl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0080] 26. R 9 is F; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 27. R 9 is -CH3, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0081] 28. R 9 is -CH2CH3, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 29. R 9 is -(CH2)2CH3, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0082] 30. R 9 is -CH(CH3)2, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 31. R 9 is -(CH2)OH, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0083] 32. R 9 is -CH2NH2, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 33. R 9 is -CN, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0084] 34. R 9 is -OCH3, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 35. R 9is -OCH(CH3)2, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0085] 36. R 9 is -OCHF2, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 37. R 9 but [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0086] 38. R 9 but [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 39. B is one or more R 10 A compound of formula I, substituted with a substituent, as described in any one of embodiments 1-38, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0087] 40. R 10 Hydrogen, halogen, -CN, -OR 11 , -(C1-C6 alkyl), -NH2, -CH2NH2, -CH2OH, -OH, 3-12 membered cycloalkyl, or 4-12 membered heterocycle, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 41. R 10 is hydrogen, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0088] 42. R 10 is halogen; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 43. R 10 is -CN; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0089] 44. R 10 -OR 11 or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 45. R 10A compound according to any one of embodiments 1-40, wherein is -(C1-C6 alkyl), or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0090] 46. ​​R 10 is -NH2, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 47. R 10 is -CH2NH2, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0091] 48. R 10 is -CHOH; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 49. R 10 is -OH; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0092] 50. R 10is 3-12 membered cycloalkyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 51. R 10 is a 4-12 membered heterocycle, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0093] 52. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0094] 53. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 54. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0095] 55. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 56. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0096] 57. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 58. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0097] 59. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 60. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0098] 61. B [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 62. R 1 is selected from hydrogen or -C1-C6 alkyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0099] 63. R 1 is hydrogen, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 64. R 1is -C1-C6 alkyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0100] 65. R 1 is methyl, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 66. R 2 , R 3 and R 4 is hydrogen, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0101] 67. R 6 is selected from hydrogen or -C1-C6 alkyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 68. R 6 is hydrogen; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0102] 69. R 6is -C1-C6 alkyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 70. R 6 is methyl, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0103] 71. R 8 is methyl; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof. 72. R 8 is hydrogen, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0104] 73. In another embodiment, the present invention provides a compound of formula II: [ka] [In formula: R 1 is independently selected from hydrogen or methyl; R 14 teeth, [Table 4] [Table 5] [Table 6] more independently selected] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0105] 74. 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea, 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea, 1-(4-((2-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, 1-(4-((3-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, 1-(4-((3-aminobenzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, 1-[4-(benzyloxy)phenyl]-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((3-(hydroxymethyl)benzyl)oxy)phenyl)urea, 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((2-(hydroxymethyl)benzyl)oxy)phenyl)urea, 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((2-hydroxybenzyl)oxy)phenyl)urea, 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((2-hydroxybenzyl)oxy)phenyl)urea, 1-(4-{[4-(aminomethyl)-2-fluorophenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-methylphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[5-(aminomethyl)pyridin-2-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[6-(aminomethyl)pyridin-3-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[5-(aminomethyl)pyrimidin-2-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[6-(aminomethyl)pyridazin-3-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}-3-methylphenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}-3-fluorophenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(6-{[4-(aminomethyl)phenyl]methoxy}pyridazin-3-yl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(6-{[4-(aminomethyl)phenyl]methoxy}pyridin-3-yl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-ethylphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-n-propylphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-methoxyphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-(propan-2-yloxy)phenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-chlorophenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-(oxetan-3-yloxy)phenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-cyclopropylphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-((2-aminobenzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, 1-(4-((4-(aminomethyl)benzyl)oxy)-3-chlorophenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea, 1-(4-{[4-(aminomethyl)-2-i-propylphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-difluoromethoxyphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3S)-3-methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3R)-3-methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea, 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-1-(4-{[(1r,4r)-4-(aminomethyl)cyclohexyl]methoxy}phenyl)urea, or 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0106] 75. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0107] 76. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0108] 77. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0109] 78. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0110] 79. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0111] 80. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0112] 81. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0113] 82. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0114] 83. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0115] 84. In another aspect, the present invention provides a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, polymorph or tautomer thereof, a pharma- ceutically acceptable salt of the polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

[0116] 85. In another aspect, the invention includes a compound according to any one of embodiments 1-84 for use as a medicament. 86. A compound according to any one of embodiments 1-85 for use in a method for treating cancer, the method comprising administering to a mammal with cancer a therapeutically effective amount of the compound. 87. The compound for use according to embodiment 86, wherein the cancer is leukemia.

[0117] 88. The compound for use according to embodiment 87, wherein the leukemia is chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, or acute myelogenous leukemia. 89. The compound for use according to embodiment 88, wherein the leukemia is acute myeloid leukemia. 90. A compound for use in any one of embodiments 1-89, wherein the leukemia is relapsed, refractory or resistant to conventional therapy.

[0118] 91. A compound for use in any one of embodiments 86-89, wherein the method further comprises administering a therapeutically effective amount of another second active agent or a supportive care agent. 92. A compound used according to embodiment 91, wherein the other second active agent is a therapeutic antibody that specifically binds to a cancer antigen, a hematopoietic growth factor, a cytokine, an anti-cancer drug, an antibiotic, a cox-2 inhibitor, an immunomodulatory agent, an immunosuppressant, a corticosteroid, or a pharmacologically active variant or derivative thereof.

[0119] In one embodiment, the compounds provided herein are compounds of Table 1. In another embodiment, X=NR 11 The compound is the following compound: [ka] Includes.

[0120] Compounds where X=NH can be synthesized by one skilled in the art using routes similar to those described herein. Also provided herein are isotopically enriched analogs of the compounds provided herein. Isotopically enriching (e.g., subjecting a compound to deuteration) has previously been demonstrated for several classes of drugs to improve their pharmacokinetic ("PK"), pharmacodynamic ("PD"), and toxicity profiles. See, e.g., 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).

[0121] Without being limited to a particular theory, isotopically enriching a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of administrations needed to achieve a desired effect, (4) reduce the dosage needed to achieve a desired effect, (5) increase the formation of active metabolites, if formed, and / or (6) reduce the production of harmful metabolites in certain tissues, and / or create more effective drugs and / or safer drugs for use in combination therapy, whether the combination therapy is intended or not.

[0122] Substituting an atom with one of its isotopes will often result in a change in the 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 the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), substituting deuterium for the hydrogen will cause a decrease in the reaction rate, slowing down the process. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE"). (See, for example, 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)).

[0123] The magnitude of the DKIE can be expressed as a ratio between a given reaction in which a C-H bond is broken and the same reaction in which deuterium is used instead of hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers such as 50 or more, meaning that a reaction can be 50 times slower or more when deuterium is used instead of hydrogen. Without being limited to a particular theory, high DKIE values ​​can be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling occurs because the hydrogen atom has a low mass, and transition states involving protons can form in the absence of the required activation energy. Deuterium is more massive than hydrogen, and therefore is statistically much less likely to undergo this phenomenon.

[0124] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic weight close to 3. It exists in very low concentrations in the natural environment, most commonly seen as T2O. Tritium decays slowly (half-life = 12.3 years), emitting low-energy beta particles that cannot penetrate the outer layer of human skin. The main hazard associated with this isotope is internal exposure, but even then large amounts must be ingested to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before it reaches dangerous levels. Substitution of hydrogen with tritium ("T") creates an even stronger bond than deuterium, resulting in a numerically larger isotope effect.

[0125] Similarly, but not limited to, with respect to carbon 13 C or 14 C and sulfur 33 S, 34 S, or 36 Regarding S and nitrogen 15 Regarding N and oxygen 17 O or 18 Substitution of other elements for the isotope, including substitution for O, will result in similar kinetic isotope effects.

[0126] Animal bodies express a variety of enzymes to eliminate foreign substances, such as therapeutic agents, from their circulatory system. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to either carbon-oxygen (CO) or carbon-carbon (CC) pi bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles compared to the parent compound. For many drugs, such oxidation is rapid. As a result, these drugs often require multiple administrations or high daily doses.

[0127] Isotopically enriching specific positions of the compounds provided herein may produce detectable KIEs that affect the pharmacokinetic, pharmacological, and / or toxicity profiles of the compounds provided herein compared to similar compounds with natural isotopic composition. In one embodiment, deuterium enrichment is performed at sites where C-H bonds are cleaved during metabolism.

[0128] C. Treatment and Prevention Methods In one embodiment, provided herein is a method for treating and preventing cancer comprising administering to a patient a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In another embodiment, provided herein is a method of managing cancer comprising administering to a patient a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0129] Also provided herein are methods for treating patients who have been previously treated for cancer but do not respond to standard therapy, as well as previously untreated humans. The present invention encompasses methods for treating patients regardless of the age of the patient, although some diseases or disorders are more prevalent in certain age groups. The present invention further encompasses methods for treating patients who have undergone surgery to treat the disease or disorder in question, as well as humans who have not undergone surgery. Because cancer patients have heterogeneous clinical symptoms and various clinical outcomes, the treatment given to a patient may vary depending on the prognosis of the patient. Those skilled in the art will be able to easily determine the specific second agent, type of surgery, and non-drug-based standard therapy that can be effectively used to treat an individual cancer patient without undue experimentation.

[0130] As used herein, the term "cancer" includes, but is not limited to, solid tumors and blood-borne tumors. The term "cancer" refers to diseases of the skin tissue, organs, blood and blood vessels, including, but not limited to, bladder cancer, bone cancer, blood cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, pharyngeal cancer, and uterine cancer. Specific cancers include, but are not limited to, aggressive malignancies, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, malignant brain tumors with poor prognosis, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, rectal adenocarcinoma, Dukes C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, malignant melanoma, malignant mesothelioma, Includes malignant pleural effusion melanoma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone refractory prostate cancer, amputated high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenström's macroglobulinemia, smoldering myeloma, low-grade myeloma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent non-metastatic stage IV prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, urachal carcinoma, papillary thyroid carcinoma, follicular thyroid cancer, medullary thyroid cancer, and smooth muscle tumors.

[0131] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer or glioblastoma. In certain embodiments, the cancer is a blood borne tumor. In certain embodiments, the blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant. In certain embodiments, the cancer is leukemia.

[0132] In one embodiment, the methods provided herein include treating, preventing or managing various types of leukemia, such as chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and acute myeloblastic leukemia (AML), by administering a therapeutically effective amount of a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0133] In some embodiments, the methods provided herein encompass treating, preventing or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), including but not limited to anaplastic AML (M0), acute myeloblastic leukemia (M1), acute myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In one embodiment, the acute myeloid leukemia is anaplastic AML (M0). In one embodiment, the acute myeloid leukemia is acute myeloblastic leukemia (M1). In one embodiment, the acute myeloid leukemia is acute myeloblastic leukemia (M2). In one embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In one embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with neutrophilia [M4E]). In one embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In one embodiment, the acute myeloid leukemia is erythroleukemia (M6). In one embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, a method of treating, preventing, or managing acute myeloid leukemia in a subject comprises administering to the subject an amount of a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, alone or in combination, effective to treat, prevent, or manage acute myeloid leukemia. In some embodiments, the methods include administering to the subject a compound provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with a second active agent in an amount effective to treat, prevent, or manage acute myeloid leukemia.

[0134] In some embodiments, the methods provided herein include treating, preventing, or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia originating from blast cells (B-cells) of the bone marrow, the thymus (T-cells), and lymph nodes. Acute lymphocytic leukemia can be classified according to the French-American-British (FAB) morphological classification system as L1-mature-appearing lymphoblasts (T-cells or precursor B-cells), L2-immature, pleomorphic (variably shaped) lymphoblasts (T-cells or precursor B-cells), and L3-lymphoblasts (B-cells; Burkitt cells). In one embodiment, the acute lymphocytic leukemia originates from blast cells (B-cells) of the bone marrow. In one embodiment, the acute lymphocytic leukemia originates from the thymus (T-cells). In one embodiment, the acute lymphocytic leukemia originates from lymph nodes. In one embodiment, the acute lymphocytic leukemia is of the L1 type, characterized by mature-appearing lymphoblasts (T cells or precursor B cells). In one embodiment, the acute lymphocytic leukemia is of the L2 type, characterized by immature, pleomorphic (variably shaped) lymphoblasts (T cells or precursor B cells). In one embodiment, the acute lymphocytic leukemia is of the L3 type, characterized by lymphoblasts (B cells; Burkitt cells). In a particular embodiment, the acute lymphocytic leukemia is T cell leukemia. In one embodiment, the T cell leukemia is peripheral T cell leukemia. In another embodiment, the T cell leukemia is T cell lymphoblastic leukemia. In another embodiment, the T cell leukemia is cutaneous T cell leukemia. In another embodiment, the T cell leukemia is adult T cell leukemia. Thus, a method for treating, preventing or managing acute lymphocytic leukemia in a subject includes the step of administering to the subject a compound provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, alone or in combination with a second active agent, in an amount effective to treat, prevent, or manage acute lymphocytic leukemia.In some embodiments, the method includes administering to the subject a compound provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with a second active agent in an amount effective to treat, prevent, or manage acute lymphoblastic leukemia.

[0135] In some embodiments, the methods provided herein include treating, preventing, or managing chronic myelogenous leukemia (CML) in a subject. The methods include administering to the subject a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in an amount effective to treat, prevent, or manage chronic myelogenous leukemia. In some embodiments, the methods include administering to the subject a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with a second active agent, in an amount effective to treat, prevent, or manage chronic myelogenous leukemia.

[0136] In some embodiments, the methods provided herein include treating, preventing, or managing chronic lymphocytic leukemia (CLL) in a subject. The methods include administering to the subject a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in an amount effective to treat, prevent, or manage chronic lymphocytic leukemia. In some embodiments, the methods include administering to the subject a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in combination with a second active agent, in an amount effective to treat, prevent, or manage chronic lymphocytic leukemia.

[0137] In certain embodiments, provided herein are methods of treating, preventing, or managing disease in patients with impaired renal function. In certain embodiments, provided herein are methods of treating, preventing, or managing cancer in patients with impaired renal function. In certain embodiments, provided herein are methods of providing appropriate dose adjustments to patients with impaired renal function due to, but not limited to, disease, aging, or other patient factors. In certain embodiments, provided herein are methods of treating, preventing, or managing lymphoma, including non-Hodgkin's lymphoma. In some embodiments, provided herein are methods of treating, preventing, or managing non-Hodgkin's lymphoma (NHL), including but not limited to diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

[0138] In certain embodiments, provided herein is a method for treating, preventing, or managing multiple myeloma, including relapsed / refractory multiple myeloma, in patients with or symptoms of renal impairment, comprising administering to a patient with relapsed / refractory multiple myeloma with renal impairment a therapeutically effective amount of a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof.

[0139] In certain embodiments, the therapeutically or prophylactically effective amount of the compound is about 0.005 to about 1,000 mg / day, about 0.01 to about 500 mg / day, about 0.01 to about 250 mg / day, about 0.01 to about 100 mg / day, about 0.1 to about 100 mg / day, about 0.5 to about 100 mg / day, about 1 to about 100 mg / day, about 0.01 to about 50 mg / day, about 0.1 to about 50 mg / day, about 0.5 to about 50 mg / day, about 1 to about 50 mg / day, about 0.02 to about 25 mg / day, about 0.05 to about 10 mg / day, about 0.05 to about 5 mg / day, about 0.1 to about 5 mg / day, or about 0.5 to about 5 mg / day.

[0140] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg / day. In some embodiments, the therapeutically or prophylactically effective amount is about 2, about 3, about 4, about 5, about 6, or about 7 mg / day.

[0141] In one embodiment, the recommended daily dose range for the compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, for the conditions described herein is in the range of about 0.5 mg / day to about 50 mg / day, preferably administered as a single dose once a day or in divided doses throughout the day. In some embodiments, the dosage ranges from about 1 mg / day to about 50 mg / day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg / day. Specific daily doses include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg / day.

[0142] In certain embodiments, the recommended starting dose may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, or 50 mg / day. In another embodiment, the recommended starting dose may be 0.5, 1, 2, 3, 4, or 5 mg / day. The dose may be increased to 15, 20, 25, 30, 35, 40, 45, and 50 mg / day. In certain embodiments, the compound may be administered to a patient with leukemia, including AML, in an amount of about 25 mg / day. In certain embodiments, the compound may be administered to a patient with leukemia, including AML, in an amount of about 10 mg / day. In certain embodiments, the compound may be administered to a patient with leukemia, including AML, in an amount of about 5 mg / day. In certain embodiments, the compound may be administered to a patient with leukemia, including AML, in an amount of about 4 mg / day. In certain embodiments, the compound may be administered to a patient with leukemia, including AML, in an amount of about 3 mg / day.

[0143] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.001 to about 100 mg / kg / day, about 0.01 to about 50 mg / kg / day, about 0.01 to about 25 mg / kg / day, about 0.01 to about 10 mg / kg / day, about 0.01 to about 9 mg / kg / day, 0.01 to about 8 mg / kg / day, about 0.01 to about 7 mg / kg / day, about 0.01 to about 6 mg / kg / day, about 0.01 to about 5 mg / kg / day, about 0.01 to about 4 mg / kg / day, about 0.01 to about 3 mg / kg / day, about 0.01 to about 2 mg / kg / day, about 0.01 to about 1 mg / kg / day, or about 0.01 to about 0.05 mg / kg / day.

[0144] Dosages may be expressed in units other than mg / kg / day. For example, parenteral doses may be expressed in mg / m 2 Doses can be expressed as mg / kg / day to mg / m2 / day. One of skill in the art can determine dosages based on either a given height or weight, or both, of a subject. 2It will be easy to see how this is converted to a dose of 1 mg / kg / day (see www.fda.gov / cder / cancer / animalframe.htm). For example, in a 65 kg human, a dose of 1 mg / kg / day is approximately 38 mg / m 2 / day.

[0145] In certain embodiments, the amount of compound administered is sufficient to provide a steady state plasma concentration of the compound in the range of about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM. In other embodiments, the amount of compound administered is sufficient to provide a steady state plasma concentration of the compound in the range of about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM, or about 50 to about 100 nM.

[0146] As used herein, the term "steady state plasma concentration" refers to the concentration achieved after a period of administration of a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof. When steady state is reached, there are small peaks and troughs on the time-dependent curve of the plasma concentration of the compound.

[0147] In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound in the range of about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM.

[0148] In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound in the range of about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0.01 to about 25 μM, about 0.01 to about 20 μM, about 0.02 to about 20 μM, about 0.02 to about 20 μM, or about 0.01 to about 20 μM. In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound in the range of about 100 to about 100,000 ng*hr / mL, about 1,000 to about 50,000 ng*hr / mL, about 5,000 to about 25,000 ng*hr / mL, or about 5,000 to about 10,000 ng*hr / mL.

[0149] In certain embodiments, a patient who can be treated with one of the methods provided herein has not been treated with an anti-cancer therapy prior to administering a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, a patient who can be treated with one of the methods provided herein has been treated with an anti-cancer therapy prior to administering a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma-ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, a patient who can be treated with one of the methods provided herein has developed drug resistance to the anti-cancer therapy.

[0150] The methods provided herein encompass treating patients regardless of their age, although some diseases or disorders are more prevalent in certain age groups. Depending on the disease to be treated and the condition of the subject, the compound of formula I, or its enantiomer or mixture of enantiomers; or its pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. The compound of formula I, or its enantiomer or mixture of enantiomers; or its pharma-ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, may be formulated in suitable dosage units, alone or with pharma-ceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each administration route.

[0151] In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered orally. In another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered parenterally. In yet another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered intravenously.

[0152] The compound of formula I, or its enantiomer or mixture of enantiomers; or its pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, can be delivered as a single dose, such as, for example, a single bolus injection, or an oral tablet or pill; or as a dose over time, such as, for example, a continuous infusion over time or a divided bolus dose over time. If necessary, the compound can be repeatedly administered, for example, until the patient experiences disease stability or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, in the case of solid tumors, stable disease generally means that the vertical diameter of measurable lesions has not increased by more than 25% since the last measurement. See Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205-216(2000). Disease stability or lack thereof is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor imaged using X-ray, CAT, PET or MRI scans, and other commonly accepted evaluation methods.

[0153] The compound of formula I, or its enantiomer or mixture of enantiomers; or its pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph may be divided into multiple daily administrations, such as once a day (QD), twice a day (BID), three times a day (TID), and four times a day (TID). In addition, administration may be continuous (i.e., for consecutive days or every day), intermittent, e.g., cyclic (i.e., with rest periods of several days, weeks, or months without drug). The term "daily" as used herein is intended to mean that the therapeutic compound, such as the compound of formula I, is administered, for example, once or more times every day for a period of time. The term "continuously" is intended to mean that the therapeutic compound, such as the compound of formula I, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term "intermittent" or "intermittently" as used herein means to stop or start at either regular or irregular intervals. For example, intermittent administration of a compound of formula I can be administration for 1-6 days per week, administration in cycles (e.g., daily administration for 2-8 consecutive weeks followed by a rest period of up to 1 week without administration), or administration on alternate days. The term "cycle" as used herein means that a therapeutic compound, such as a compound of formula I, is administered daily or consecutively, but without a rest period. In some such embodiments, 2-6 days are administered once a day, with the remaining period being a rest period of 5-7 days without administration.

[0154] In some embodiments, the frequency of administration ranges from once a day to once a month. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered once a day. In another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered twice a day. In yet another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered three times per day. In yet another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered four times per day.

[0155] In certain embodiments, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered once a day for 1 day to 6 months, 1 week to 3 months, 1 week to 4 weeks, 1 week to 3 weeks, or 1 week to 2 weeks. In certain embodiments, the compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, is administered once a day for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered once a day for 4 days. In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once a day for five days. In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once a day for six days. In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once a day for one week. In another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once a day for two weeks. In yet another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once daily for three weeks. In yet another embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once daily for four weeks.

[0156] C-1. Combination therapy with a second active agent The compounds of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, may be combined or used in combination with other therapeutic agents that are useful in the treatment and / or prevention of cancer as described herein.

[0157] In one embodiment, provided herein is a method of treating, preventing or managing cancer comprising administering to a patient a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in combination with one or more second active agents, optionally in combination with radiation therapy, blood transfusion, or surgery. Examples of second active agents are disclosed herein (see, e.g., Section 5.4).

[0158] The term "in combination" as used herein includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein, including, for example, a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours) the administration of a second therapy (e.g., a prophylactic or therapeutic agent). The second therapy is administered to the subject at the same time or later (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), at the same time as the second therapy, or later (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after).Third therapy is also considered herein.

[0159] The administration of the compound of formula I and one or more second active agents to a patient can be performed simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration utilized for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without being degraded prior to entering the bloodstream) and on the cancer being treated.

[0160] The route of administration of the compound of formula I is independent of the route of administration of the second therapy. In one embodiment, the compound of formula I is administered orally. In another embodiment, the compound of formula I is administered intravenously. Thus, according to these embodiments, the compound of formula I is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, by liposomes, by inhalation, intravaginally, intraocularly, by local delivery by catheter or stent, subcutaneously, intraadipose, intraarticularly, intrathecally, or in sustained release form. In one embodiment, the compound of formula I and the second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the compound of formula I is administered by one mode of administration, for example by IV, while the second agent (anticancer agent) is administered by another mode of administration, for example orally.

[0161] In one embodiment, the second active agent is administered intravenously or subcutaneously once or twice daily in an amount of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or 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 the disease, and the amount of the compound of Formula I provided herein and any additional active agents being co-administered to the patient.

[0162] One or more second active ingredients or agents may be used in the methods and compositions provided herein together with the compounds of Formula I. The second active agent can be a large molecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

[0163] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, especially therapeutic antibodies against cancer antigens. Exemplary large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins. Proteins that are particularly useful in the methods and compositions provided herein include proteins that stimulate the survival and / or proliferation of hematopoietic precursor cells and immunologically active hematopoietic cells in vitro or in vivo. Other useful proteins stimulate the division and differentiation of intracellularly committed erythroid progenitor cells in vitro or in vivo. Particular proteins include, but are not limited to, interleukins such as IL-2 (recombinant IL-II (including "rIL2" and canarypox IL-2), IL-10, IL-12, and IL-18; interferons such as interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

[0164] In certain embodiments, GM-CSF, G-CSF, SCF or EPO is administered at a dose of about 1 to about 750 mg / m 2 / day, about 25~500mg / m 2 / day, about 50~250mg / m 2 / day, or about 50 to about 200 mg / m 2 In certain embodiments, GM-CSF is administered subcutaneously in an amount ranging from about 60 to about 500 mcg / m2 / day for about 5 days in a 4- or 6-week cycle. 2 intravenously over 2 hours, or about 5 to about 12 mcg / m 2In certain embodiments, G-CSF may be administered subcutaneously in an amount of about 1 mcg / kg / day initially, and can be adjusted as the total number of granulocytes increases. Maintenance doses of G-CSF may be administered subcutaneously in an amount of about 300 mcg (in smaller patients) or 480 mcg. In certain embodiments, EPO may be administered subcutaneously in an amount of 10,000 units three times a week.

[0165] Particular proteins that may be used in the methods and compositions include, but are not limited to, filgrastim, available in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.); sargramostim, available in the United States under the trade name Leukine® (Immunex, Seattle, Wash.); and recombinant EPO, available in the United States under the trade name Epogen® (Amgen, Thousand Oaks, Calif.).

[0166] Recombinant and mutant forms of GM-CSF can be produced as described in U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496, all of which are incorporated herein by reference. Recombinant and mutant forms of G-CSF can be produced as described in U.S. Patent Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755, all of which are incorporated herein by reference.

[0167] Also provided are native, naturally occurring, and recombinant proteins for use in combination with the compounds provided herein, or their enantiomers or mixtures of enantiomers, or their pharma- ceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs. Also included are mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit at least some of the pharmacological activity of the protein on which they are based in vivo. 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 form of the protein. The term "mutant" also includes proteins that lack carbohydrate moieties normally present in the naturally occurring form (e.g., non-glycosylated 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 a protein or to an active portion of a protein of interest. See, e.g., Penichet, ML and Morrison, SL, J. Immunol. Methods 248:91-101 (2001).

[0168] The antibody that can be used in combination with the compounds provided herein, or their enantiomers or enantiomeric mixtures, or their pharma- ceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs, includes monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin®), pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®), and G250. The compounds provided herein or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, may be combined or used in combination with an anti-TNF-α antibody, such as, for example, Erbitux® or panitumumab, and / or an anti-EGFR antibody.

[0169] Further anti-cancer drugs that can be included in the present invention are antibody-drug conjugates (ADCs). Antibody-drug-conjugates consist of three components: antibody, payload, and linker. The antibody targets the ADC and may trigger a therapeutic response. The payload triggers the desired therapeutic response. The linker binds the payload to the antibody and should be stable in circulation and release the payload only at the desired target. The anti-cancer drug (payload) is coupled to an antibody via a linker that specifically targets a particular tumor antigen (e.g., a protein that is ideally only present in or on tumor cells). The antibody itself binds to the antibody on the surface of the cancer cell. The biochemical reaction between the antibody and the target protein (antigen) causes signaling in the tumor cell, which then absorbs or internalizes the antibody together with the attached payload. When the ADC is internalized, the payload kills the cancer. This targeting limits side effects and confers a larger therapeutic window than other chemotherapeutic agents. In certain embodiments, the compound of formula I can be incorporated as a payload that is attached to the antibody.

[0170] Large molecule active agent can be administered in the form of anti-cancer vaccine.For example, the vaccine secretes or causes the secretion of cytokines such as IL-2, G-CSF, and GM-CSF can be used in the provided methods and pharmaceutical compositions.See, for example, Emens, LA et al., Curr. Opinion Mol. Ther. 3(1):77-84(2001).

[0171] Small molecule second active agents can also be used to reduce side effects associated with administration of the compounds provided herein, or their enantiomers or enantiomeric mixtures, or their pharma- ceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs. However, as with some large molecules, many are believed to be capable of providing synergistic effects when administered together (e.g., before, after, or simultaneously) with the compounds provided herein, or their enantiomers or enantiomeric mixtures, or their pharma-ceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs. Examples of small molecule second active agents include, but are not limited to, anticancer drugs, antibiotics, immunosuppressants, and steroids.

[0172] In certain embodiments, the second agent is an HSP inhibitor, a proteasome inhibitor, an FLT3 inhibitor, a TOR kinase inhibitor, an anti-tumor agent, a tyrosine kinase inhibitor, a Hedgehog pathway inhibitor, a Bcl-2 inhibitor, or an isocitrate dehydrogenase (IDH) inhibitor.

[0173] Examples of anti-cancer drugs that may be used in the methods or compositions described herein include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropyrifos amine;busulfan;cactinomycin;calsterone;caracemide;carbetimer;carboplatin;carmustine;carubicin hydrochloride;carzelesin;cedefingol;celecoxib (COX-2 inhibitor);cerbidine;chlorambucil;cinoremycin;cisplatin;cladribine;clofarabine;crisnatol mesylate;cytarabine;cyclophosphamide;Ara-C;dacarbazine;dactinomycin;daunorubicin hydrochloride;daunorubicin hydrochloride and cytarabine liposome;daurismo;decitabine;dexorumaplatin;dexa Methasone;Dezaguanine;Dezaguanine mesylate;Diaziquone;Docetaxel;Doxorubicin;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enasidenib mesylate;Enloplatin;Enpromate;Epipropizine;Epirubicin hydrochloride;Elburozole;Esorubicin hydrochloride;Estramustine;Estramustine sodium phosphate;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fa hydrochloride Drozole;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Flurocitabine;Fosquidone;Fostriecin sodium;Gemcitabine;Gemcitabine hydrochloride;Gemtuzumab ozogamcin;Hydroxyurea;Ibrutinib;Idarubicin hydrochloride;Ifosfamide;Irmofosine;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;Mitocalcine;Mitochromine;Mitogillin;Mitomalcin;Mitomycin;Mitospar;Mitotane;Mitoxantrone hydrochloride;Mycophenolic acid;Nocodazole;Nogalamycin;Omacetaxine;Ormaplatin;Oxisuran;Paclitaxel Xel;Pegaspargase;Periomycin;Pentamustine;Peplomycin sulfate;Perfosfamide;Pipobroman;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porpheromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Riboprin;Safingol;Safingol hydrochloride;Semustine;Simtrazene;Sorafenib;Sparfosartonate lium;sparsomycin;spirogermanium hydrochloride;spiromucin;spiroplatin;streptonigrin;streptozocin;sulfenur;tallysomycin;tacogalan sodium;taxotere;tegafur;taloxantrone hydrochloride;temoporfin;teniposide;teroxylon;testolactone;thiamiprine;thioguanine;thiotepa;tiazofurin;tirapazamine;toremifene citrate;trestrone acetate;triciribine phosphate;trimethoprim These include: Rexate; Trimetrexate glucuronate; Triptorelin; Tubrozole hydrochloride; Uracil mustard; Uredepa; Vapreotide; Venetoclax; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Binepidine sulfate; Vingrisinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrocidine sulfate; Vinzolidine sulfate; Vorozole; Zeniplatin; Dinoplatin; and Zorubicin hydrochloride.

[0174] Other anti-cancer agents that may be included in the method or composition 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-angiogenesis tannins. Peptide-1;Antiandrogens, prostate cancer;High estrogen;Antineoplastic drugs;Antisense oligonucleotides;Aphidicolin glycinate;Apoptosis gene modulators;Apoptosis regulators;Apurinic acid;ara-CDP-DL-PTBA;Arginine deaminase;Arsenic trioxide;Asulaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azacitidine;Azasetron;Azatoxin;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists ;Benzochlorins;Benzoylstaurosporines;Beta-lactam derivatives;Beta-arretin;Beta-chlamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizelesin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcipotriol;Calfostin C;Camptothecin derivatives;Capecitabine;Carboxamide-amino-triazoles;Carboxamide triazoles;CaRestM3;CARN700;Cartilage derived inhibitors;Carzeresi ;Casein kinase inhibitors (ICOS);Castanospermine;Cecropin B;Cetrorelix;Chlorins;Chloroquinoxaline sulfonamides;Cicaprost;Cis-porphyrins;Cladribine;Clomiphene analogs;Clotrimazole;Colismycin A;Colismycin B;Combretastatin A4;Combretastatin analogs;Conagenin;Crambecidin 816;Crysnatol;Cryptophycin 8;Cryptophycin A derivatives;Cracin A;Cyclopentane thraquinone;Cyclophosphamide;Cycloplatam;Cypemycin;Ara-C oxyphosphate;Cytolytic factors;Cytostatin;Dacliximab;Decitabine;Dehydrodidemnin B;Deslorelin;Dexamethasone;Dexyphosphamide;Dexrazoxane;Dexverapamil;Diaziquone;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;9-Dihydrotaxol;Dioxamycin;Diphenylspiromustine;Docetaxel;Docosanol;Dolasetron;Doxifluridine;Doxorubicin;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edrecolomab;Eflornithine;Elemene;Emiteflu;Enasidenib;Epirubicin;Epristeride;Estramustine analogs;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrazole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flazelastine;Fluasterone;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriecin;Fu Otemustine;Gadolinium texaphyrin;Gallium nitrate;Galocitabine;Ganirelix;Gelatinase inhibitors;Gemcitabine;Gemtuzumab;Gilteritinib;Glasdegib;Glutathione inhibitors;Hepsulfam;Helegri;Hexamethylene bisacetamide;Hypericin;Ibandronate;Idarubicin;Idoxifene;Idramantone;Ilmofosine;Ilomastat;Imatinib (e.g., Gleevec®);Imiquimod;Immunostimulating peptides;Insulin-like growth factor-1 receptor inhibitors;Interferon-agonist Nist;Interferon;Interleukin;Iobenguane;Iododoxorubicin;4-Ipomeanol;Ilopract;Irsogladine;Isobengazole;Isohomohalichondrin B;Itasetron;Ivosidenib;Jasplakinolide;Kahalalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Lentinan sulfate;Leptolstatin;Letrozole;Leukemia inhibitory factor;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone;Leuprorelin;Levamisole;Liarozole;Linear polyamine analogs;lipophilic disaccharide peptides;lipophilic platinum compounds;lysoclinamide 7;lobaplatin;lombricin;lometrexol;lonidamine;loxosantrone;loxoribine;lurtotecan;lutetium texaphyrin;lysofylline;lytic peptides;maytansine;mannostatin A;marimastat;masoprocol;maspin;matrilysin inhibitors;matrix metalloproteinase inhibitors;menogaril;merbarone;meterelin;methioninase;metoclopramide;midostaurin;MIF inhibitors;mifepristone;miltefosine;mirimostim;mitoguazone;mitolactol;mitomycin analogs;mitonaphide;mitoto xin fibroblast growth factor-saporin;mitoxantrone;mofalotene;molgramostim;mylotarg;erbitux, human chorionic gonadotropin;monophosphoryl lipid A+myobacillus cell wall sk;mopidamol;mustard anticancer drugs;mycaperoxide B;mycobacterial cell wall extract;myriaporone;N-acetyldinaline;N-substituted benzamides;nafarelin;nagressip;naloxone+pentazocine;napavine;naphterpine;nartograstim;nedaplatin;nemorubicin;neridronic acid;nilutamide;nisamycin;nitric oxide regulators;nitric oxide antioxidants;nitrulline;oblimersen (Genasense®);O; 6-Benzylguanine;Octreotide;Oxenone;Oligonucleotides;Onapristone;Ondansetron;Ondansetron;Oracin;Oral cytokine inducers;Ormaplatin;Osateron;Oxaliplatin;Oxaunomycin;Paclitaxel;Paclitaxel analogs;Paclitaxel derivatives;Palauamine;Palmitoyl rhizoxin;Pamidronic acid;Panaxytriol;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecine;Pentosan polysulfate sodium;Pentostatin;Pentrozole ol;perflubron;perphosphamide;perillyl alcohol;phenazinomycin;phenyl acetate;phosphatase inhibitors;picibanil;pilocarpine hydrochloride;pirarubicin;piritrexim;prasetin A;prasetin B;plasminogen activator inhibitors;platinum complexes;platinum compounds;platinum triamine complexes;porfimer sodium;porfiromycin;prednisone;propyl bis-acridone;prostaglandin J2;proteasome inhibitors;protein A-based immunomodulators;protein kinase C inhibitors;microalgae protein kinase C inhibitors;protein tyrosine phosphatase inhibitors;purine nucleoside phosphorylase inhibitors;purpurin;pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugates;raf antagonists;raltitrexed;ramosetron;ras farnesyl protein transferase inhibitors;ras inhibitors;ras-GAP inhibitors;demethylated reterliptin;relium Re186 etidronate;lidoxin;ribozyme;RII retinamide;rohitucine;romurtide;roquinimex;rubiginone B1;ruboxil;safingol;santopi ;SarCNU;Sarcophytol A;Sargramostim;Sdi1 mimetic;Semustine;Senescence induction inhibitor 1;Sense oligonucleotides;Signal transduction inhibitors;Sizofiran;Sobzoxane;Sodium borocaprate;Sodium phenylacetate;Sorberol;Somatomedin binding proteins;Sonermin;Sparfosic acid;Spicamycin D;Spiromustine;Splenopentin;Spongistatin 1;Squalamine;Stipiamide;Stromelysin inhibitors;Sulfinosine;Superactive vasoactive intestinal peptide antagonist;Sladista;Suramin;Swainsonine;Talimustine;Tamoxifen methiodide;Tauromustine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrylium;Telomerase inhibitors;Temoporfin;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thioguanine;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrin;Thyroid-stimulating hormone;Tin ethyl etiopurpurin;Tirapazamine;Titanocene dichloride;Topsentin;Toremifene;Translation inhibitors agents; 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; veraresol; veramine; verudin; verteporfin; vincristine sulfate; vinorelbine; vinxartin; vitaxin; vorozole; zanoteron; zeniplatin; zilascorub; and zinostatin stimalamer.

[0175] Certain second active agents that are particularly useful in the methods or compositions include, but are not limited to, rituximab, oblimersen (Genasense®), Remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temodromide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG-10 ... Intron-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, Ara-C, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonates, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramucin sodium phosphate (Emcyt®), sulindac, and etoposide.

[0176] In certain embodiments of the methods provided herein, the use of a second active agent in combination with a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, may be modified or delayed during or immediately following administration of a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, as deemed appropriate by one of skill in the art. In certain embodiments, subjects receiving a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, alone or in combination with other therapies, may receive supportive care, including antiemetics, myeloid growth factors, and platelet transfusions, as appropriate. In some embodiments, a subject receiving a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, may be administered a growth factor as a second active agent, according to the judgment of one of skill in the art. In some embodiments, administration of a compound provided herein, or an enantiomer or mixture of enantiomers thereof, or a pharma-ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in combination with erythropoietin or darbepoetin (Aranesp) is provided.

[0177] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered together with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.

[0178] In certain embodiments, the compounds provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, may be used in combination with a second active ingredient in the following: temozolomide for pediatric patients with recurrent or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide, and cyclophosphamide for recurrent or progressive CNS cancers; recurrent or progressive meningiomas, malignant meningiomas, hemangiopericytomas, multiple brain metastases, recurrent brain tumors, or newly diagnosed multiple myelomas. combinations such as temodar for patients with glioblastoma multiforme; irinotecan for patients with recurrent glioblastoma; carboplatin for children with brain stem gliomas; procarbazine for children with progressive malignant gliomas; cyclophosphamide for patients with poor prognosis malignant brain tumors, newly diagnosed, or recurrent glioblastoma multiforme; Gliadel® for high-grade recurrent malignant gliomas; temodromide and tamoxifen for anaplastic astrocytoma; or topotecan for glioma, glioblastoma, anaplastic astrocytoma, or anaplastic oligodendroglioma.

[0179] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with metastatic lung cancer along with methotrexate, cyclophosphamide, a taxane, abraxane, lapatinib, herceptin, an aromatase inhibitor, a selective estrogen modulator, an estrogen receptor antagonist, and / or PLX3397 (Plexxikon). In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered together with temozolomide to a patient with a neuroendocrine tumor.

[0180] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered together with gemcitabine to patients with recurrent or metastatic head and neck cancer. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered together with gemcitabine to a patient with pancreatic cancer.

[0181] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to a patient with colon cancer in combination with ARISA®, avastatin, taxol, and / or taxotere. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with capecitabine and / or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or to patients who have failed or have had a poor response to first-line treatment for colon or rectal adenocarcinoma.

[0182] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes' C&D colorectal cancer or to patients who have previously been treated for metastatic colorectal cancer. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with capecitabine, Xeloda, and / or CPT-11 to patients with refractory colorectal cancer.

[0183] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal adenocarcinoma. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular adenocarcinoma; or together with cisplatin and thiotepa to patients with primary or metastatic hepatocellular carcinoma.

[0184] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with pegylated interferon alpha to a patient with Kaposi's sarcoma. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fludarabine, carboplatin, and / or topotecan to patients with refractory or relapsed or high-risk acute myeloid leukemia.

[0185] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with liposomal daunorubicin, topotecan, and / or cytarabine to patients with unfavorable karyotype acute myeloblastic leukemia. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with gemcitabine, abraxane, erlotinib, geftinib, and / or irinotecan to patients with non-small cell lung cancer.

[0186] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with doxetazole to a patient with non-small cell lung cancer who has previously been treated with carbo / VP16 and radiation therapy.

[0187] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered to patients with non-small cell lung cancer in combination with carboplatin and / or taxotere, or in combination with carboplatin, paclitaxel, and / or thoracic radiation therapy. In certain embodiments, a compound provided herein, e.g., a compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.

[0188] In certain embodiments, a compound provided herein, e.g., a compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered in combination with oblimersen (Genasense®) to patients with non-small cell lung cancer. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with ABT-737 (Abbott Laboratories) and / or obatoclax (GX15-070) to patients with lymphoma and other vascular cancers.

[0189] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with a second active ingredient, such as vinblastine or fludarabine, to patients with various types of lymphoma, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, or relapsed or refractory low-grade follicular lymphoma.

[0190] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon), and / or dacarbazine to patients with various types or stages of melanoma. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered alone or in combination with vinorelbine to patients with malignant mesothelioma or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.

[0191] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulfan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonates, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof, to patients with various types or stages of multiple myeloma. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with doxorubicin (Doxil®), vincristine, and / or dexamethasone (Decadron®) to patients with relapsed or refractory multiple myeloma.

[0192] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof, to patients with various types or stages of ovarian cancer, such as peritoneal adenocarcinoma, papillary serous carcinoma, refractory ovarian cancer, or recurrent ovarian cancer.

[0193] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with Xeloda, 5 FU / LV, gemcitabine, irinotecan + gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, emcit, dendron, or a combination thereof, to patients with various types or stages of prostate cancer.

[0194] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof, to patients with various types or stages of renal cell carcinoma. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with a COX-2 inhibitor, such as IFN, Celebrex®, and / or Sulindac, to patients with various types or stages of gynecological, uterine, or soft tissue sarcoma cancer.

[0195] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof, to patients with solid tumors of various types or stages. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof to a patient with scleroderma or cutaneous vasculitis.

[0196] Also included herein is a method for increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, comprising administering to the patient (e.g., a human) a compound or its enantiomer or mixture of enantiomers; or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph. Patients that can benefit from this method are those who are likely to suffer from side effects associated with anti-cancer drugs for treating certain cancers of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal gland, kidney, prostate, breast, colorectum, or combinations thereof. Administering a compound provided herein, e.g., a compound of Formula I, or its enantiomer or mixture of enantiomers, or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, alleviates or reduces such severe side effects that would otherwise limit the amount of anti-cancer drug.

[0197] In one embodiment, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is orally administered daily in an amount ranging from about 0.1 to about 150 mg, about 1 to about 50 mg, or about 2 to about 25 mg, prior to, during, or after the onset of side effects associated with administering an anti-cancer drug to a patient. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma-ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with certain agents, such as heparin, aspirin, coumadin, or G-CSF, to avoid side effects associated with anti-cancer drugs, such as, but not limited to, neutropenia or thrombocytopenia.

[0198] In one embodiment, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with additional active ingredients, including, but not limited to, anti-cancer drugs, anti-inflammatory agents, antihistamines, antibiotics, and steroids, to patients with diseases and disorders associated with or characterized by unwanted angiogenesis.

[0199] In another embodiment, the present disclosure encompasses a method of treating, preventing and / or managing cancer, comprising administering a compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in combination with (e.g., before, during, or after) a conventional therapy, including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug-based therapy currently used to treat, prevent, or manage cancer. The combination of the compounds provided herein with conventional therapy may provide a unique therapeutic regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that the compound of formula I may provide additive or synergistic effects when given simultaneously with conventional therapy.

[0200] As described elsewhere herein, the present disclosure includes methods of reducing, treating and / or preventing side effects or undesirable effects associated with conventional therapies, including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy. Compounds provided herein, such as compounds of Formula I, or enantiomers or mixtures of enantiomers thereof, or pharma- ceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs thereof, and other active ingredients, can be administered to a patient before, during, or after the onset of side effects associated with conventional therapy.

[0201] In one embodiment, the compound of formula I may be administered orally daily in an amount ranging from about 0.1 to about 150 mg, about 1 to about 25 mg, or about 2 to about 10 mg, either alone or in combination with a second active agent disclosed herein (see, e.g., Section 5.4), before, during, or after the use of conventional therapy. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, and doxorubicin are administered to a patient with non-small cell lung cancer who has been previously treated with carbo / VP16 and radiation therapy.

[0202] C-2. Use in transplantation therapy The compounds of formula I provided herein, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can be used to reduce the risk of graft-versus-host disease (GVHD).Accordingly, included herein is a method of treating, preventing, and / or managing cancer, comprising administering a compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with transplantation therapy.

[0203] As recognized by those skilled in the art, cancer treatment is often based on the stage of the disease and the mechanism of action. For example, certain stages of cancer may develop unavoidable leukemic transformation, requiring transplantation of peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow. The combination of the compound of formula I provided herein, or its enantiomer or enantiomeric mixture, or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, with transplantation therapy provides unique and unexpected synergistic effects. In particular, the compound of formula I, or its enantiomer or enantiomeric mixture, or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, exhibits immunomodulatory activity that can provide additive or synergistic effects when given simultaneously with transplantation therapy in cancer patients.

[0204] The compound of formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, can act in combination with transplantation therapy to reduce the risk of complications and GVHD associated with invasive procedures of transplantation. Included herein is a method of treating, preventing, and / or managing cancer, comprising administering to a patient (e.g., a human) a compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, before, during, or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow. Some examples of stem cells suitable for use in the methods provided herein are disclosed in U.S. Patent No. 7,498,171, the entire contents of which are incorporated herein by reference.

[0205] In one embodiment, a compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to a patient with multiple myeloma before, during, or after autologous peripheral blood progenitor cell transplantation. In one embodiment, a compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to a patient with NHL (e.g., DLBCL) before, during, or after autologous peripheral blood progenitor cell transplantation.

[0206] C-3. Cycle therapy In certain embodiments, the prophylactic or therapeutic agents provided herein are cyclically administered to a patient. Cycling therapy involves administering an active agent for a period of time, followed by a period of rest, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce side effects of one therapy, and / or improve efficacy of the treatment.

[0207] As a result, in certain embodiments, the compound of formula I provided herein, or its enantiomer or enantiomeric mixture, or its pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, is administered daily in a single or divided dose in a cycle of 4 to 6 weeks, with a 1-week or 2-week break. The cycle method can also increase the frequency, number, and length of the cycle of administration. Thus, included herein in certain embodiments is the administration of a compound provided herein, for example, a compound of formula I, or its enantiomer or enantiomeric mixture, or its pharma-ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph, in more cycles than would be typical if it were administered alone. In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to a patient who is not also receiving a second active ingredient, for more cycles that would typically cause dose-limiting toxicity in the patient.

[0208] In one embodiment, the compound of formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered at a dose of about 0.1 to about 150 mg / day consecutively daily for three or four weeks, followed by one or two weeks off.

[0209] In another embodiment, the compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and the second active ingredient are administered orally, with administration of the compound of formula I occurring 30 to 60 minutes prior to administration of the second active ingredient during a cycle of 4 to 6 weeks. In certain embodiments, the combination of the compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma-ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and the second active ingredient is administered by intravenous infusion over about 90 minutes per cycle. In certain embodiments, one cycle comprises about 0.1 to about 150 mg / day of the compound of formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma-ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and about 50 to about 200 mg / m 2 / day of the second active ingredient daily for 3 to 4 weeks, followed by 1 or 2 weeks of rest. In certain embodiments, the number of cycles that the patient is administered the combination treatment ranges from about 1 to about 24 cycles, from about 2 to about 16 cycles, or from about 3 to about 4 cycles.

[0210] D. Patient Population In certain embodiments of the methods provided herein, the subject is an animal, preferably a mammal, more preferably a non-human primate. In certain embodiments, the subject is a human. The subject can be a male or female subject. Subjects particularly useful for the methods provided herein include human cancer patients, e.g., patients who have been diagnosed with leukemia, including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic myelogenous leukemia. In certain embodiments, the subject has not been diagnosed with acute promyelocytic leukemia.

[0211] In some embodiments, the subject has a blast population higher than normal. In some embodiments, the subject has a blast population of at least 10%. In some embodiments, the subject has a blast population between 10% and 15%. In some embodiments, the subject has a blast population of at least 15%. In some embodiments, the subject has a blast population between 15% and 20%. In some embodiments, the subject has a blast population of at least 20%. In some embodiments, the subject has a blast population of about 10-15%, about 15-20%, or about 20-25%. In other embodiments, the subject has a blast population of less than 10%. Useful subjects with a blast population of less than 10% in the context of the methods described herein include those subjects who, for any reason according to the judgment of one of skill in the art, require treatment with a compound provided herein, alone or in combination with a second active agent.

[0212] In some embodiments, the subject is treated based on the Eastern Cooperative Oncology Group (ECOG) performance status rating for leukemia. ECOG performance status can be scored on a scale of 0-5, with 0 meaning asymptomatic; 1 meaning symptomatic but fully ambulatory; 2 meaning symptomatic and bedbound <50% of the day; 3 meaning symptomatic and bedbound >50% of the day but not bedbound; 4 meaning bedbound; and 5 meaning death. In some embodiments, the subject has an ECOG performance status rating of 0 or 1. In some embodiments, the subject has an ECOG performance status rating of 0. In some embodiments, the subject has an ECOG performance status rating of 1. In other embodiments, the subject has an ECOG performance status rating of 2.

[0213] In certain embodiments, the methods provided herein encompass treating a subject who has not previously been treated for leukemia. In some embodiments, the subject has not undergone an allogeneic bone marrow transplant. In some embodiments, the subject has not undergone a stem cell transplant. In some embodiments, the subject has not undergone hydroxyurea treatment. In some embodiments, the subject has not undergone treatment with any investigational agent for leukemia. In some embodiments, the subject has not undergone treatment with systemic glucocorticoids.

[0214] In other embodiments, the method includes treating a subject who has previously been treated for leukemia or is currently being treated for leukemia. For example, the subject has previously been treated for leukemia or is currently being treated for leukemia. The subject may be treated for any standard leukemia treatment regimen known to those skilled in the art. In certain embodiments, the subject has previously been treated with at least one induction / re-induction or consolidation AML regimen. In some embodiments, the subject has undergone autologous bone marrow or stem cell transplantation as part of a consolidation regimen. In some embodiments, the bone marrow or stem cell transplantation occurred at least 3 months prior to treatment with the methods provided herein. In some embodiments, the subject has undergone hydroxyurea treatment. In some embodiments, the hydroxyurea treatment occurred up to 24 hours prior to treatment with the methods provided herein. In some embodiments, the subject has undergone induction or consolidation therapy with cytarabine (Ara-C). In some embodiments, the subject has undergone treatment with systemic glucocorticosteroids. In some embodiments, glucocorticosteroid treatment was administered up to 24 hours prior to treatment with the methods described herein. In other embodiments, the methods include treating a subject who has previously been treated for cancer, but is non-responsive to standard therapy.

[0215] Also included is a method for treating a subject with relapsed or refractory leukemia.In some embodiments, the subject is diagnosed with relapsed or refractory AML subtype as defined by the World Health Organization (WHO).Relapsed or refractory disease can be new AML or secondary AML, for example, therapy-related AML (t-AML).

[0216] In some embodiments, the methods provided herein are used to treat drug-resistant leukemia, such as chronic myeloid leukemia (CML). Thus, treatment with the compounds provided herein may provide an alternative for patients who do not respond to other treatment methods. In some embodiments, such other treatment methods include treatment with Gleevec® (imatinib mesylate). In some embodiments, provided herein are methods of treating Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML). In some embodiments, provided herein are methods of treating Gleevec® (imatinib mesylate) resistant Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML).

[0217] Also included are methods of treating subjects regardless of the subject's age, although some diseases or disorders are more prevalent in certain age groups. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years old. In other embodiments, the subject is under 65 years old. In some embodiments, the subject is under 18 years old. In some embodiments, the subject is under 18, 15, 12, 10, 9, 8, or 7 years old.

[0218] In some embodiments, the method finds use in subjects at least 50 years old, although younger subjects may benefit from the method as well. In other embodiments, the subject is at least 55 years old, at least 60 years old, at least 65 years old, and at least 70 years old. In another embodiment, the subject has a deleterious cytogenetic effect. "Detrimental cytogenetic effect" is defined as any non-diploid karyotype, or three or more chromosomal abnormalities. In another embodiment, the subject is at least 60 years old or older and has a deleterious cytogenetic effect. In another embodiment, the subject is 60-65 years old and has a deleterious cytogenetic effect. In another embodiment, the subject is 65-70 years old and has a deleterious cytogenetic effect.

[0219] In certain embodiments, the subject treated has no history of myocardial infarction within 3 months of treatment with the methods provided herein. In some embodiments, the subject has no history of cerebrovascular accident or transient ischemic attack within 3 months of treatment with the methods provided herein. In some embodiments, the subject has not suffered a non-thromboembolic event, including deep vein thrombosis or pulmonary embolism, within 28 days of treatment with the methods provided herein. In other embodiments, the subject has not experienced or has not experienced uncontrolled disseminated intravascular coagulation.

[0220] Because cancer subjects have heterogeneous clinical symptoms and various clinical outcomes, the treatment given to a patient may vary depending on the patient's prognosis. Those skilled in the art will be able to easily determine, without undue experimentation, the specific secondary agents, types of surgery, and non-drug-based standard therapies that can be effectively used to treat an individual subject with cancer. It will be understood that any suitable combination of a compound provided herein with one or more of the compounds described above, and optionally with one or more additional pharmacologically active substances, is contemplated herein.

[0221] E. Formulation of Pharmaceutical Compositions Pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein, and a pharma- ceutically acceptable carrier, diluent, or excipient. The compound can be formulated into suitable pharmaceutical preparations, such as solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release preparation or elixir for oral administration, or sterile solution or suspension for ocular or parenteral administration, as well as transdermal patch preparation and dry powder inhaler.Typically, the above-mentioned compound is formulated into pharmaceutical composition by using techniques and operations well known in the art (for example, see Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0222] In the composition, an effective concentration of one or more compounds or pharma- ceutically acceptable salts is mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective to deliver an amount that, when administered, treats, prevents or ameliorates one or more symptoms and / or progression of cancer, including solid tumors and blood-borne tumors.

[0223] Typically, the composition is formulated for administration in a single dosage form.To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in the selected vehicle at an effective concentration to relieve or improve the symptoms to be treated.The pharmaceutical carrier or vehicle suitable for administering the compound provided herein includes any such carrier known to those skilled in the art that is suitable for specific administration mode. In addition, the compound may be formulated in the composition as the only pharma- ceutically active ingredient or may be combined with other active ingredients. Liposomal suspensions, including tumor-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharma- ceutically acceptable carriers. They may be prepared according to methods known in the art. For example, liposomal formulations may be prepared as known in the art. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by drying egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) in a flask. A solution of the compound provided herein in phosphate buffered saline (PBS) without divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, centrifuged to pellet, and then resuspended in PBS.

[0224] The active compound is included in a pharma- ceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without causing undesirable side effects to the patient being treated. The therapeutically effective concentration is empirically determined by testing the compound in the in vitro and in vivo systems described herein, and the dosage for humans is extrapolated therefrom. The concentration of active compound in pharmaceutical composition will depend on the absorption, tissue distribution, inactivation and excretion rate of the active compound, the physicochemical properties of the compound, administration schedule and dosage, and other factors known to those skilled in the art.For example, the amount delivered is sufficient to improve one or more symptoms of cancer, including solid tumor and blood-borne tumor.

[0225] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of the active compound of about 0.1 ng / mL to about 50-100 μg / mL. In one embodiment, the pharmaceutical composition provides from about 0.001 mg to about 2000 mg of the compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg of the essential active ingredient or combination of essential active ingredients, and in certain embodiments, from about 10 to about 500 mg, per dosage unit form.

[0226] The active ingredient may be administered at once, or may be divided into smaller amounts to be administered at regular intervals. It is understood that the exact dosage and duration of treatment are a function of the disease being treated, and may be empirically determined using known testing protocols, or may be determined by extrapolating from in vivo or in vitro test data. It should also be noted that concentration and dosage values ​​may vary with the severity of the condition to be alleviated. Furthermore, for any particular subject, a particular dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and it should be understood that the concentration ranges set forth herein are merely illustrative and do not limit the scope or practice of the compositions described in the claims.

[0227] Thus, an effective concentration or amount of one or more compounds described herein or pharma- ceutical acceptable salts thereof is mixed with a suitable pharmaceutical carrier or vehicle for systemic, local or topical administration to form a pharmaceutical composition. The compound is formulated in an amount effective to alleviate, treat, slow or prevent one or more symptoms. The concentration of the active compound in the composition will depend on the absorption, tissue distribution, inactivation and excretion rate of the active compound, administration schedule, dosage, formulation characteristics, and other factors known to those skilled in the art.

[0228] The composition is to be administered by a suitable route, including but not limited to oral, parenteral, rectal, topical and local. For oral administration, it can be formulated into capsules and tablets. The composition is in liquid, semi-liquid or solid form and is formulated in a manner suitable for each administration route.

[0229] Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application can contain any of the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, dimethylacetamide or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates and phosphates; and tonicity adjusters such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, pens, disposable syringes, or single or multiple dose vials made of glass, plastic or other suitable material.

[0230] In cases where a compound exhibits insufficient solubility, methods of solubilizing the compound may be used, which are known to those skilled in the art and include, but are not limited to, using a co-solvent such as dimethylsulfoxide (DMSO), using a surfactant such as TWEEN®, or dissolving in sodium bicarbonate. Upon mixing or addition of the compound, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture will depend on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for alleviating the symptoms of the disease, disorder, or condition being treated and can be empirically determined.

[0231] The pharmaceutical composition is provided for administration to humans and animals in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, oil-in-water emulsions, containing an appropriate amount of the compound or its pharma-ceutically acceptable salts. The pharma-ceutically therapeutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms as used herein refer to physically separate units suitable for human and animal subjects and individually packaged as known in the art. Each unit dose contains a therapeutically active compound in a predetermined amount sufficient to produce the desired therapeutic effect, together with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dosage form may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container so that the unit dosage forms are administered separately. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dose form is a multiple of unit doses that are not segregated in packaging.

[0232] Sustained release formulations can also be produced. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds provided herein, which matrices are in the form of, for example, shaped articles such as films or microcapsules. Examples of sustained release matrices include iontophoretic patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and degradable lactic acid-glycolic acid copolymers such as poly-D-(-)-3-hydroxybutyric acid. Polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for over 100 days, while certain hydrogels release proteins for shorter periods of time. If encapsulated compounds remain in the body for a long period of time, they may denature or aggregate as a result of exposure to moisture at 37°C, leading to loss of biological activity and altering their structure. Depending on the mechanism of action involved, rational strategies can be devised for stabilization. For example, if the aggregation mechanism is found to be due to intermolecular SS bonds via thio-disulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, adjusting the moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0233] Dosage forms or compositions containing the active ingredient in the range of 0.005%-100%, with the remainder consisting of non-toxic carriers, may be prepared. For oral administration, pharma- ceutically acceptable non-toxic compositions may be prepared by blending with any commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained release formulations, such as, but not limited to, implants, and microencapsulated delivery systems, as well as biodegradable biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparing these compositions are known in the art. Contemplated compositions may contain about 0.001%-100% active ingredient, and in certain embodiments, about 0.1-85% or about 75-95% active ingredient.

[0234] The active compounds or pharma- ceutically acceptable salts may be prepared with carriers, such as time release formulations or coatings, that protect the compound against rapid elimination from the body. The composition may contain other active compounds to obtain a desired combination of properties. The compounds provided herein, or pharma- ceutically acceptable salts thereof described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the above-mentioned diseases or conditions, such as diseases associated with oxidative stress. It should be recognized that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

[0235] The lactose-free compositions provided herein may contain excipients that are well known in the art, for example, those listed in the United States Pharmacopoeia (USP) SP(XXI) / NF(XVI).In general, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in pharma- ceutically compatible and pharma-ceutically acceptable amounts.For example, lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0236] Also included are anhydrous pharmaceutical compositions and dosage forms that contain the compounds provided herein.For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means to simulate long-term storage to measure properties such as half-life or stability over time of formulations.See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp.379-80.In fact, water and heat accelerate the decomposition of some compounds.Thus, the effect of water on formulations can be very important, since moisture and / or humidity are generally relevant during the manufacture, handling, packaging, storage, shipping and use of formulations.

[0237] Anhydrous pharmaceutical compositions and dosage forms provided herein can be manufactured under low moisture or low humidity conditions using anhydrous or low moisture containing ingredients. Pharmaceutical compositions and dosage forms that include lactose and at least one active ingredient, including a primary or secondary amine, are anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is anticipated. Anhydrous pharmaceutical compositions must be prepared and stored so that their anhydrous nature is maintained.Therefore, anhydrous compositions are packaged using materials that prevent exposure to water so 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.

[0238] E-1. Oral dosage forms Oral pharmaceutical dosage forms are either solid, gel or liquid. Solid dosage forms are tablets, capsules, granules, and bulk powders. Oral tablet types include compressed chewable lozenges and tablets, which may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art.

[0239] In certain embodiments, the formulation is a solid dosage form such as a capsule or tablet. Tablets, pills, capsules, troches, etc. may contain any of the following ingredients, or compounds of a similar nature: binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents.

[0240] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any approved certified water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include artificial sweeteners such as sucrose, lactose, mannitol, saccharin, and numerous spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0241] When oral administration is desired, the compound can be provided in a composition that protects the compound from the acidic environment of the stomach.For example, the composition can be formulated with an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.The composition can also be formulated in combination with an antacid or other such ingredient. When the dosage unit is a capsule, it can contain liquid carriers such as fatty oils in addition to the above-mentioned type of materials.In addition, the dosage unit can contain various other materials that modify the physical form of the dosage unit, such as sucrose coating and other enteric agents.The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups can contain sucrose as a sweetener, and certain preservatives, dyes, and colorings and flavors in addition to the active compounds.

[0242] The active materials can be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a pharma-ceutically acceptable salt thereof. High concentrations of up to about 98% by weight of the active ingredient may be included.

[0243] The pharma- ceutical acceptable carriers incorporated in the tablet are binders, lubricants, diluents, disintegrants, colorants, flavorings, and wetting agents. Enteric-coated tablets, because of their enteric coating, resist the action of stomach acid and dissolve or disintegrate in neutral or alkaline intestines. Sugar-coated tablets are compressed tablets on which different layers of pharma- ceutical acceptable substances are applied. Film-coated tablets are compressed tablets that are coated with polymers or other suitable coatings. Multiple compressed tablets are compressed tablets that are produced by more than one compression cycle using the pharma- ceutical acceptable substances described above. Colorings may also be used in the above dosage forms. Flavorings and sweetening agents are used in compressed tablets, sugar-coated tablets, multiple compressed tablets, and chewable tablets. Flavorings and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0244] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs, and syrups. Emulsions are either oil-in-water or water-in-oil.

[0245] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of sucrose, e.g., and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use pharma- ceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules to reconstitute liquid oral dosage forms include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules to reconstitute liquid oral dosage forms include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in any of the above dosage forms.

[0246] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include surfactants such as gelatin, acacia, tragacanth, bentonite, and polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, and acacia. Diluents include lactose, and sucrose. Sweetening agents include sucrose, syrup, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic additives include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds producing a pleasant taste sensation.

[0247] For solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patents 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, the solution, for example in polyethylene glycol, can be diluted with a sufficient quantity of a pharma- ceutical acceptable liquid carrier, for example water, to be easily measured for administration.

[0248] Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, formulations containing a compound provided herein, dialkylated mono- or poly-alkylene glycols, including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0249] Other formulations include, but are not limited to, aqueous alcoholic solutions, including acetal that is pharmaceutically acceptable.The alcohol used in these formulations is any pharmaceutically acceptable water-miscible solvent with one or more hydroxyl groups, including, but are not limited to, propylene glycol and ethanol.Acetal includes, but is not limited to, the di(lower alkyl) acetal of lower alkyl aldehyde, such as acetaldehyde diethyl acetal.

[0250] In all embodiments, the tablet and capsule formulations may be coated as known to those skilled in the art to modify or maintain the solubility of the active ingredient. Thus, for example, the formulations may be coated with conventional enterically digestible coating agents such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0251] E-2. Injections, solutions and emulsions Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if necessary, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins. Implantation of a delayed or sustained release system is also contemplated herein, so that a constant level of dosage is maintained. Briefly, the compounds provided herein are dispersed in a solid internal matrix, e.g., hydrophilic polymers such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which are capable of being absorbed by body fluids. The compound is surrounded by an outer polymeric membrane that is insoluble, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubbers, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers. The compound diffuses through the outer polymeric membrane in a process that controls the release rate.The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[0252] Parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration.Preparations for parenteral administration include sterile solutions for injection, sterile dry solubilized products such as freeze-dried powders, including subcutaneous tablets, which are mixed with solvents immediately before use, sterile suspensions for injection, sterile dry insoluble products that are mixed with vehicles immediately before use, and sterile emulsions.Solutions can be either aqueous or non-aqueous.

[0253] For intravenous administration, suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof. Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetic agents, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharma- ceutically acceptable substances.

[0254] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents must be added to parenteral preparations packaged in multi-dose containers in bacteriostatic or fungistatic concentrations and include phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfite. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (TWEEN® 80). Sequestering or chelating agents of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles, sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0255] The concentration of the pharma- ceutical active compound is adjusted so that an injection provides an amount effective to produce the desired pharmacological effect. The exact dose depends on the age, weight, and condition of the patient or animal, as is known in the art. Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. All preparations for parenteral administration must be sterile, as known and practiced in the art.

[0256] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is the injection of a sterile aqueous or oily solution or suspension containing the active material, as needed, to produce the desired pharmacological effect.

[0257] Injectables are designed for local and systemic administration. Typically, therapeutically effective dosage forms are formulated to contain active compounds at concentrations of at least about 0.1% w / w to about 90% w / w or more relative to the tissue being treated, for example, greater than 1% w / w. The active ingredient may be administered once or divided into several smaller doses for administration at intervals. It is understood that the exact dosage and duration of treatment is a function of the tissue being treated and may be determined experimentally using known testing protocols or by extrapolation from in vivo or in vitro test data. It should also be noted that concentration and dosage values ​​may also vary with the age of the individual being treated. It should further be understood that for any particular subject, specific dosing regimes must be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[0258] The compound may be micronized or suspended in other suitable forms, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to alleviate the symptoms of the condition and may be empirically determined.

[0259] E-3. Freeze-dried powder Also of interest herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted or formulated as solids or gels.

[0260] The sterile lyophilized powder is prepared by dissolving a compound provided herein or a pharma- ceutically acceptable salt thereof in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Excipients that may be used may include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffers known to those skilled in the art, in one embodiment at about neutral pH. The solution is then subjected to sterile filtration, followed by lyophilization under standard conditions known to those skilled in the art to obtain the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dose (including but not limited to 10-1000 mg or 100-500 mg) or multiple doses of the compound. The lyophilized powder may be stored under suitable conditions, such as at about 4°C to room temperature.

[0261] The lyophilized powder is reconstituted with water for injection to provide a formulation for parenteral administration. For reconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg of lyophilized powder is added per mL of sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amounts can be empirically determined.

[0262] E-4. Local administration Topical mixtures are prepared as described for local or systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigate, spray, suppository, bandage, skin patch, or other preparation suitable for topical administration.

[0263] The compound or its pharma- ceutically acceptable salt may be formulated as an aerosol for local administration, such as by inhalation (see, for example, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids useful for treating inflammatory diseases, particularly asthma). These formulations for administration to the respiratory system are in the form of aerosols or solutions for nebulizers, alone or in combination with inert carriers such as lactose, or ultrafine powders for inhalation. In such cases, the particles of the formulation will be less than 50 microns or less than 10 microns in diameter.

[0264] The compound may be formulated for local or topical administration, such as topical application to the skin and mucous membranes (such as in the eye), in the form of gels, creams and lotions, and for application to the eye, or intracapsular or intrathecal application.Topical administration is also considered for transdermal delivery, and also for administration to the eye and mucous membranes, or inhalation therapy.Nasal solutions of the active compound alone or in combination with other pharma- ceutically acceptable excipients may also be administered. These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, with appropriate salts, and a pH of about 5-7.

[0265] E-5. Compositions for other routes of administration Other routes of administration, such as topical application, transdermal patches, and rectal administration, are also contemplated herein.

[0266] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets with systemic action. Rectal suppositories are used herein to mean solid objects for insertion into the rectum that melt or soften at body temperature and release one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles, and agents that raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), and appropriate mixtures of mono-, di- and tri-glycerides of fatty acids. Combinations of various bases may be used. Agents that raise the melting point of the suppository include spermaceti and wax. Rectal suppositories can be manufactured by either compressed or molded methods. The weight of a rectal suppository is illustratively about 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same pharma- ceutical acceptable substances and by the same methods as formulations for oral administration.

[0267] E-6. Sustained release composition The active ingredient provided herein can be administered by controlled release means or delivery devices known to those skilled in the art.For example, but not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5, Nos. 972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide delayed or controlled release of one or more active ingredients, for example, using hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or varying the proportions of combinations thereof to obtain the desired release profile. Suitable formulations known to those skilled in the art, including the controlled release formulations described herein, can be readily selected for use with the active ingredients provided herein.

[0268] All controlled-release pharmaceutical products have a common goal of improving drug therapy over the goal achieved by their non-controlled counterparts. In one embodiment, the medical use of an optimally designed controlled-release formulation is characterized by the minimal amount of drug being utilized in the minimal amount of time to cure or manage symptoms. In certain embodiments, the advantages of a controlled-release formulation include extended drug activity, reduced dosing frequency, and improved patient compliance. In addition, controlled-release formulations can also be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus affect the occurrence of side effects (e.g., adverse effects).

[0269] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that quickly produces the desired therapeutic effect, and then slowly and sustainably release another amount of drug to maintain this level of therapeutic or prophylactic effect over a long period of time.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 metabolized by the amount of drug excreted from the body.The controlled release of active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0270] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see Sefton, CRC Crit. Ref Biomed. Eng. 14:201(1987); Buchwald et al., Surgery 88:507(1980); Saudek et al., N. Engl. J. Med. 321:574(1989)). In another embodiment, a polymeric material may be used. In yet another embodiment, the controlled release system may be placed near the therapeutic target, i.e., requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138(1984)).

[0271] In some embodiments, the controlled release device is introduced into the subject near the site of inappropriate immune activation or near the tumor. Other controlled release systems are described in the journal Science 249:1527-1533 (1990) by Langer. The active ingredient is dispersed in a solid internal matrix, e.g., hydrophilic polymers such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which is insoluble in body fluids, and an external matrix. The composition is surrounded by a polymeric membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymer with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer.The active ingredient then diffuses through the outer polymeric membrane in a process that controls the release rate.The percentage of active ingredient contained in such parenteral compositions is highly dependent on its specific nature and the needs of the subject.

[0272] E-7. Targeted formulations The compounds provided herein, or their pharma- ceutically acceptable salts, may also be formulated to target specific tissues, receptors, or other areas of the body of the subject to be treated.Many such targeting methods are well known to those skilled in the art.All such targeting methods are contemplated herein for use in the compositions of the present invention. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0273] In one embodiment, liposomal suspensions, including tumor-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharma-ceutically acceptable carriers. They may be prepared according to methods known to those skilled in the art. For example, liposomal formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) in a flask. A solution of the compound provided herein in phosphate buffered saline (PBS) without divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, centrifuged to pellet, and then resuspended in PBS.

[0274] E-8. Manufactured products The compounds or pharma- ceutically acceptable salts can be packaged as an article of manufacture comprising packaging material, a compound provided herein or a pharma- ceutically acceptable salt thereof (for use in treating, preventing, or ameliorating one or more symptoms or progression of cancer, including solid tumors and blood borne tumors), and a label indicating that the compound or a pharma- ceutically acceptable salt thereof is used in treating, preventing, or ameliorating one or more symptoms or progression of cancer, including solid tumors and blood borne tumors.

[0275] The products provided herein contain packaging materials. Packaging materials used for packaging pharmaceutical products are well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for the selected formulation and intended administration and treatment mode. A wide range of formulations are contemplated for the compounds and compositions provided herein.

[0276] F. Compound Preparation The compounds provided herein can be prepared by methods known to those skilled in the art, following procedures similar to those described in the Examples section of this specification, with routine modifications thereto. Exemplary reaction schemes for preparing the compounds are shown below.

[0277] General synthesis including scheme The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, JP et al., Heterocycles, 16(1):35-37(1981)). General synthetic schemes for producing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art may use to produce the compounds disclosed herein. Different methods for producing antibody-drug conjugates will be apparent to those skilled in the art. In addition, various steps in the synthesis may be performed in alternative orders to obtain the desired compounds.

[0278] Examples of compounds of the invention prepared by the methods described in the general scheme are shown in the Intermediates and Examples sections described below. Preparation of homochiral examples can be carried out by methods known to those skilled in the art. For example, homochiral compounds can be prepared by separating racemic products by chiral phase preparative HPLC. Alternatively, example compounds can be prepared by methods known to obtain enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functional groups on racemic intermediates that serve to control the diastereoselectivity of the transformation, and cleavage of the chiral auxiliary to obtain enantiomerically enriched products.

[0279] The compounds of the present invention can be prepared in many ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods shown below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations to be carried out. Those skilled in the art will understand that the functional groups present on the molecule must remain consistent with the proposed transformations. This will sometimes require modifying the order of synthetic steps or choosing one particular process scheme over another to obtain the desired compounds of the present invention.

[0280] It will also be appreciated that another major consideration in planning any synthetic route in this field is the careful selection of protecting groups used to protect reactive functional groups present in the compounds described in this invention. An authoritative account describing many alternatives to those skilled in the art is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0281] Scheme I. General synthetic scheme [ka]

[0282] Scheme 1 shows the general synthesis of compound (I-7). Arylmethyl bromides or heteroarylmethyl bromides (I-1) can be reacted with nitrophenols or nitroheteroaryl alcohols (I-2) with a base such as potassium carbonate to give compound (I-3). The nitro group of (I-3) is reduced to give aniline (I-4), which is reacted with bis(2,5-dioxopyrrolidin-1-yl)carbonate and then coupled with isoindolinemethylamine (I-6) to give (I-7). The procedures described here can also be used for compounds in which the aryl and heteroaryl moieties are replaced with some modifications and 3- to 12-membered saturated ring systems, as shown in Examples 32 and 33.

[0283] Working Example: Example 1: 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea [ka]

[0284] Step 1-1: (4-((4-nitrophenoxy)methyl)phenyl)methanol [ka]

[0285] To a solution of (4-(bromomethyl)phenyl)methanol (0.500 g, 2.49 mmol, 1 equiv.) in DMF (10 mL), 4-nitrophenol (0.415 g, 2.98 mmol, 1.2 equiv.) and cesium carbonate (1.620 g, 4.97 mmol, 2 equiv.) were added and the reaction was then stirred at 25° C. for 12 h. TLC showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. It was then diluted with water (20 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. It was used directly in the next step without further purification. (2-((4-nitrophenoxy)methyl)phenyl)methanol (0.620 g, 2.39 mmol, 96.2% yield) was obtained as a white solid. 1 H NMR(400MHz DMSO-d6) δ 8.23-8.17(m,2H), 7.45-7.39(m,2H), 7.35-7.31(m,2H), 7.23-7.17(m,2H), 5.24(s,2H), 5.18(t,J=5.6Hz,1H), 4.49(d,J=5.6Hz,2H)

[0286] Step 1-2: 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline [ka]

[0287] To a solution of (3-((4-nitrophenoxy)methyl)phenyl)methanol (0.620 g, 2.39 mmol, 1 eq.) in DMF (15 mL), tert-butylchlorodimethylsilane (0.721 g, 4.78 mmol, 2 eq.) and 1H-imidazole (0.488 g, 7.17 mmol, 3 eq.) were added, and the reaction was then stirred at 25° C. for 12 h. TLC showed the reaction was complete. The reaction was dissolved in water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. It was used directly in the next step without further purification. tert-Butyldimethyl((4-((4-nitrophenoxy)methyl)benzyl)oxy)silane (0.800 g, 2.14 mmol, 89.6% yield) was obtained as a white oil.

[0288] To a solution of tert-butyldimethyl((4-((4-nitrophenoxy)methyl)benzyl)oxy)silane (0.800 g, 2.14 mmol, 1 equiv.) in water (5 mL), iron (0.598 g, 10.71 mmol, 5 equiv.), ammonium chloride (1.150 g, 21.42 mmol, 10 equiv.) and ethanol (10 mL) were added, and the reaction was then stirred at 80° C. for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. It was then diluted with water (20 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The reaction was purified by silica gel column chromatography (2-10% ethyl acetate in petroleum ether). There was obtained 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (0.500 g, 1.46 mmol, 68.0% yield) as a yellow solid.

[0289] Step 1-3: 1-(4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl) [ka]

[0290] To a solution of 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (0.209 g, 0.61 mmol, 1.5 eq.) and bis(2,5-dioxopyrrolidin-1-yl)carbonate (0.156 g, 0.61 mmol, 1.5 eq.) in acetonitrile (3 mL), N-ethyl-N-isopropylpropan-2-amine (0.105 g, 0.81 mmol, 2 eq.) was added and stirred at 0° C. for 0.1 h, after which 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate (0.150 g, 0.41 mmol, 1 eq., mesylate) was added to the reaction which was stirred at 25° C. for 11.9 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the residue was concentrated. It was used directly in the next step without further purification. 1-(4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.200 g, 0.31 mmol, 76.6% yield) was obtained as a white solid. LCMS (ESI) m / z: 643.2 [M+1] + , 1 H NMR(400MHz DMSO-d6) δ 10.98(s,1H), 8.47(s,2H), 7.69(d,J=7.6Hz,1H), 7.52(s,1H), 7.35-7.27(m,6 H), 6.89(d,J=8.8Hz,3H), 6.72-6.69(m,1H), 5.17-5.08(m,2H), 5.02(s,3H), 4. 71(s,2H), 4.52-4.30(m,7H), 2.90(d,J=12.0Hz,1H), 2.62(s,1H), 2.39(dd,J=4 .4, 13.2Hz,1H), 2.02-1.98(m,1H), 0.95-0.94(m,1H), 0.91(s,8H), 0.09(s,6H)

[0291] Step 1-4: 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea [ka]

[0292] A mixture of 1-(4-((3-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.150 g, 0.23 mmol, 1 eq) in hydrogen chloride / dioxane (3 mL, 4 M) was stirred at 25° C. for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The reaction was purified by semi-preparative reverse phase HPLC (25-55% acetonitrile in water + 0.225% formic acid over 10 min), then the fractions were collected and concentrated to remove most of the acetonitrile, which was lyophilized to give the desired compound. 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((3-(hydroxymethyl)benzyl)oxy)phenyl)urea (0.012 g, 0.02 mmol, 9.2% yield, 96.0% purity) was obtained as a white solid. LCMS (ESI) m / z: 529.2 [M+1] + , 1 H NMR(400MHz DMSO-d6) δ 10.97(s,1H), 8.41(s,1H), 7.69(d,J=7.6Hz,1H), 7.51(s,1H), 7.43(d,J=8 .0Hz,1H), 7.39-7.34(m,2H), 7.33-7.26(m,4H), 6.88(d,J=8.8Hz,2H), 6.6 2(t,J=5.6Hz,1H), 5.19-5.07(m,2H), 5.01(s,2H), 4.52-4.28(m,6H), 2.97 -2.85(m,1H), 2.60(d,J=16.0Hz,1H), 2.41-2.31(m,1H), 2.07-1.94(m,1H)

[0293] Example 2: 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea [ka]

[0294] Step 2-1: tert-Butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate [ka]

[0295] To a solution of tert-butyl N-[[4-(bromomethyl)phenyl]methyl]carbamate (10 g, 33.3 mmol) in MeCN (150 mL) was added 4-nitrophenol (4.82 g, 34.6 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 °C for 16 h. TLC (petroleum ether / ethyl acetate, 2:1, Rf#1=0.76 Rf#2=0.6) showed that the starting material was consumed and a new spot was formed. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate / H2O (200 mL / 200 mL) and the organic layer was washed with brine (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (12 g, crude) as a light yellow solid. 1 H NMR: (400MHz, DMSO-d6) δ 8.27(d,J=9.2Hz,2H), 7.48(d,J=7.6Hz,3H), 7.34-7.27(m,4H), 5.30(s,2H), 4.19(d,J=6.0Hz,1H), 1.45(s,9H)

[0296] Step 2-2: tert-Butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate [ka]

[0297] To a solution of tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (12 g, 33.5 mmol) in EtOH (150 mL) and HO (30 mL) was added Fe powder (9.35 g, 167 mmol) and NH4Cl (17.9 g, 335 mmol). The mixture was stirred at 80 °C for 2 h. TLC (2:1 petroleum ether / ethyl acetate) showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (400 mL) and the filtrate was combined and concentrated. The residue was diluted with water and ethyl acetate (400 mL / 400 mL), the organic layer was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (9 g, 81.9% yield) as a grey solid. This material was used in the next step without further purification.

[0298] Step 2-3: tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methylcarbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate [ka]

[0299] To a solution of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (5.65 g, 17.2 mmol) in MeCN (200 mL) was added bis(2,5-dioxopyrrolidin-1-yl)carbonate (5.64 g, 22.0 mmol) and Et3N (6.16 g, 60.9 mmol) at -20°C under nitrogen. The mixture was stirred at -20°C for 1 h. 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6.80 g, 18.4 mmol, MsOH salt) was added to the mixture. The mixture was stirred at 20°C for 15 h. TLC (2:1 petroleum ether / ethyl acetate) showed the reaction was complete. The reaction mixture was filtered and the filter cake was washed with MeCN (50 mL) and dried to give tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methylcarbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (9 g, crude) as a grey solid. 1 H NMR: (400MHz, DMSO-d6) δ 10.99(s,1H), 8.43(s,1H), 7.69(d,J=8.0Hz,1H), 7.53-7.23(m,9H), 6.88(d,J=8.8Hz,2H), 6.63(d,J=6.0Hz,1H), 5.14-5.09(m, 1H), 5.09(s,2H), 4.47-4.29(m,4H), 4.12(d,J=6.0Hz,2H), 2.92-2.91(m,1H), 2.62-2.51(m,1H), 2.41-2.37(m,1H), 1.40(s,9H)

[0300] Step 2-4: 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea [ka]

[0301] A solution of tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methylcarbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (9.0 g, 14.3 mmol) and HCl (30 mL, 12N in dioxane) was stirred at 0° C. for 1 h. LCMS showed the starting material was consumed. MeCN (500 mL) was added slowly to the mixture at 0-10° C. After stirring for 30 min, the resulting solid was filtered and dried to give 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea (7.12 g, 88.0% yield, HCl salt) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ 10.98(s,1H), 8.66(s,1H), 9.30(s,3H), 7.69(d,J=7.6Hz,1H), 7.51-7.43(m,6H), 7.31-7.29(m,2H), 6.89(d,J=2.0Hz,2H), 6.88(s,1H) , 5.13-5.07(m,3H), 4.47-4.29(m,4H), 4.01(t,J=5.6Hz,2H), 2.95-2.87(m,1H), 2.62-2.52(m,1H), 2.50-2.38(m,1H), 2.01-1.94(m,1H)

[0302] The examples listed in Table 1 were prepared from appropriate commercially available starting materials by following procedures similar to those described in Examples 1 and 2.

[0303] [ka] Table 1 [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21]

[0304] Example 32: 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3S)-3-methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea [ka]

[0305] Step 32-1: (S)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile [ka]

[0306] To a solution of methyl 2-(bromomethyl)-4-cyano-benzoate (1500 mg, 5.900 mmol, 1.00 equiv) in DMF (15.0 mL) was added (3S)-3-amino-3-methyl-piperidine-2,6-dione (839 mg, 5.900 mmol, 1.00 equiv) and TEA (2.0 mL). The mixture was stirred at 100° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give (S)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (1570 mg, 5.542 mmol, 93% yield) as a light yellow solid. LCMS (ESI, m / z): 284 [M+H] +

[0307] Step 32-2: tert-butyl (S)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate [ka]

[0308] To a solution of (S)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (780 mg, 2.750 mmol, 1.00 equiv.) in a mixture of DMF (10.0 mL) and THF (10.0 mL), di-tert-butyl dicarbonate (120 mg, 5.500 mmol, 2.00 equiv.) and 6.0 g of Raney nickel were added. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered and the filter cake was washed with 30.0 mL of MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give tert-butyl (S)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (247.0 mg, 0.637 mmol, 23% yield) as a white solid. LCMS (ESI, m / z): 388 [M+H] +

[0309] Step 32-3: (S)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione [ka]

[0310] To a stirred mixture of tert-butyl (S)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (247 mg, 0.640 mmol, 1.00 equiv) in 1,4-dioxane (3.0 mL) was added HCl in 1,4-dioxane (3.0 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give (S)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione (200 mg, crude, HCl salt) as a light yellow solid. LCMS (ESI, m / z): 288 [M+H] +

[0311] Step 32-4: 4-[(tert-butoxycarbonylamino)methyl]benzoic acid methyl ester [ka]

[0312] To a stirred mixture of methyl 4-(aminomethyl)benzoate (1000 mg, 6.050 mmol) in methanol (10.0 mL) was added di-tert-butyl dicarbonate (1387 mg, 6.360 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure to give methyl 4-[(tert-butoxycarbonylamino)methyl]benzoate (1640 mg, 5.810 mmol, 95% yield) as a light yellow solid. LCMS (ESI, m / z): 266 [M+H] +

[0313] Step 32-5: tert-Butyl N-[[4-(hydroxymethyl)phenyl]methyl]carbamate [ka]

[0314] To a stirred solution of methyl 4-[(tert-butoxycarbonylamino)methyl]benzoate (900 mg, 3.390 mmol, 1.00 equiv) in a mixture of 1,4-dioxane (5.0 mL) and water (5.0 mL) was added NaBH4 (645 mg, 17.000 mmol, 5.00 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with 50 mL of water. The resulting mixture was extracted with 50.0 mL of EtOAc. The organic phases were combined and dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using the following conditions (Spherial C18, 120 g, 20-40 μm; mobile phase A: water (0.05% NH4HCO3), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 0% B to 100% B in 20 min, 210 nm; RT: 9.0 min) to give tert-butyl N-[[4-(hydroxymethyl)phenyl]methyl]carbamate (400.0 mg, 1.685 mmol, 49% yield) as a light yellow solid. LCMS (ESI, m / z): 238 [M+H] +

[0315] Step 32-6: tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate [ka]

[0316] To a stirred mixture of tert-butyl N-[[4-(hydroxymethyl)phenyl]methyl]carbamate (400 mg, 1.690 mmol, 1.00 equiv) in DMF (8.0 mL) was added 1-fluoro-4-nitro-benzene (475 mg, 3.370 mmol, 2.00 equiv). To the above mixture was added K2CO3 (697 mg, 5.060 mmol, 3.00 equiv). The resulting mixture was stirred at 100° C. overnight. Filtration was performed and the filter cake was washed with 15.0 mL of MeCN. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash column chromatography using the following conditions (Spherical C18, 80 g, 20-40 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 0% B to 100% B in 20 min, 210 nm; RT: 8.5 min) to give tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (410.0 mg, 1.144 mmol, 67% yield) as a yellow solid. LCMS (ESI, m / z): 359 [M+H] +

[0317] Step 32-7: tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate [ka]

[0318] To a stirred mixture of tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (390 mg, 1.090 mmol, 1.00 equiv) in a mixed solvent of ethanol (5.0 mL) and water (1.0 mL) was added Fe (303 mg, 5.450 mmol, 5.00 equiv) and NH4Cl (587 mg, 10.880 mmol, 10.00 equiv). The above mixture was stirred at 80° C. for 2 h. 20 mL of ethanol was added to dilute the reaction and the solid was filtered. The filtrate was concentrated under reduced pressure. The residue was redissolved in 20.0 mL of EtOAc and filtered. The filtrate was concentrated in vacuo to give tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (342.0 mg, 1.041 mmol, 95% yield) as a brown solid. LCMS (ESI, m / z): 329 [M+H] +

[0319] Step 32-8: tert-butyl (S)-(4-((4-(3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate [ka]

[0320] To a stirred mixture of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (109 mg, 0.330 mmol, 1.00 equiv) in DCE (3.0 mL) was added carbonyldiimidazole (59 mg, 0.370 mmol, 1.12 equiv). The resulting mixture was stirred at 60° C. for 4 h. It was concentrated under reduced pressure and the residue was dissolved in 3.0 mL of MeCN. To the above mixture was added (S)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione HCl salt (107 mg, 0.330 mmol, 1.00 equiv) and 0.3 mL of TEA in 1.0 mL of DMF. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash column chromatography using the following conditions (Spherical C18, 40 g, 20-40 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 0% B to 100% B in 20 min, 210 nm; RT: 7 min) to give tert-butyl (S)-(4-((4-(3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (100.0 mg, 0.155 mmol, 46% yield) as a light brown solid. LCMS (ESI, m / z): 642 [M+H] +

[0321] Step 32-9: 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[1-oxo-2-[rac-(3S)-3-methyl-2,6-dioxo-3-piperidyl]isoindolin-5-yl]methyl]urea [ka]

[0322] To a stirred mixture of tert-butyl (S)-(4-((4-(3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (95 mg, 0.150 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) was added HCl in 1,4-dioxane (3.0 mL). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in 1.0 mL of ACN, then 1.0 mL of NaHCO3 saturated solution was added to adjust the pH value to 8. It was concentrated and the crude product was directly purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30*150mm 5μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B to 32%B in 10min, hold 32%B; Wavelength: 254nm; RT1(min): 9.32) to give 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3S)-3-methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea (40.0mg, 49% yield, TFA salt) as a white solid. LCMS (ESI, m / z): 542 [M+H] + ; 1 H NMR (400MHz, methanol-d4) δ 7.68(d,J=7.9Hz,1H), 7.57-7.42(m,6H), 7.28-7.20(m,2H), 6.93-6.87(m,2H), 5.09(s,2H), 4.68(s ,2H), 4.49(s,2H), 4.11(s,2H), 2.88-2.73(m,2H), 2.73-2.61(m,1H), 2.04-1.93(m,1H), 1.77(s,3H)

[0323] Example 33: 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3R)-3-methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea [ka]

[0324] Step 33-1: (R)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile [ka]

[0325] To a stirred solution of (3R)-3-amino-3-methyl-piperidine-2,6-dione·hydrogen bromide (1000 mg, 4.483 mmol, 1.00 equiv) in DMF (10.0 mL) was added 2-(bromomethyl)-4-cyano-methylbenzoate (1139 mg, 4.483 mmol, 1.00 equiv) and TEA (0.8 mL). The resulting mixture was stirred at 110° C. for 12 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20 / 1) to give (R)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (320.0 mg, 1.130 mmol, 25% yield) as a yellow solid. LCMS(ESI, m / z): 284[M+H] +

[0326] Step 33-2: tert-butyl (R)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate [ka]

[0327] To a stirred mixture of 2.0 g of Raney Ni and (R)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (200 mg, 0.706 mmol, 1.00 equiv.) in a mixed solvent of DMF (8.0 mL) and THF (12.0 mL), Boc2O (308 mg, 1.411 mmol, 2.00 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature under H2 atmosphere for 12 hours. The desired product could be detected by LCMS. The solid was filtered and the filter cake was washed with 60.0 mL MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC [MeOH / DCM (1 / 20)] to give tert-butyl (R)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (92.0 mg, 0.237 mmol, 34% yield) as a colorless oil. LCMS (ESI, m / z): 388 [M+H] +

[0328] Step 33-3: (R)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione [ka]

[0329] To a stirred mixture of tert-butyl (R)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (92 mg, 0.237 mmol, 1.00 equiv) in DCM (10.0 mL) was added TFA (3.0 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give (R)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione (107.0 mg, crude, TFA salt) as a yellow oil. LCMS (ESI, m / z): 288 [M+H] +

[0330] Step 33-4: (R)-1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea [ka]

[0331] To a stirred solution of (R)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione trifluoroacetate (100 mg, 0.249 mmol, 1.00 equiv.) and 0.5 mL of TEA in DCE (4.0 mL) was added carbonyldiimidazole (48 mg, 0.298 mmol, 1.20 equiv.) at room temperature. The resulting mixture was stirred at 60° C. for 1 h and then concentrated under reduced pressure. The residue was redissolved in 4.0 mL of MeCN and a solution of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (98 mg, 0.298 mmol, 1.20 equiv.) was added. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The above crude Boc-protected intermediate was dissolved in 5.0 mL of 1,4-dioxane and 5.0 mL of 4M HCl in dioxane, then stirred at room temperature for 2 h. After the mixture was concentrated under reduced pressure, the crude product was dissolved in 1.0 mL of ACN, and then 1.0 mL of NaHCO3 saturated solution was added to adjust the pH value to 8. The resulting solution of crude product was directly purified by preparative HPLC (column: X-select CSH C18 OBD column 30*150mm 5μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 2% B to 25% B in 10 min, hold 25% B; wavelength: 254nm; RT1(min): 9.37) to give (R)-1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (34.5mg, 0.054mmol, 15%, 100%ee) (TFA salt) as a white solid. LCMS (ESI, m / z): 542[M+H] + ; 1H NMR: (400MHz, methanol-d4) δ 7.68(d,J=7.9Hz,1H), 7.57-7.49(m,3H), 7.49-7.42(m,3H), 7.28-7.21(m,2H), 6.94-6.87(m,2H), 5.09(s,2H) ), 4.68(s,1H), 4.49(s,2H), 4.11(s,2H), 2.89-2.73(m,2H), 2.73-2.61(m,1H), 2.04-1.93(m,1H), 1.77(s,3H)

[0332] Example 34: 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-1-(4-{[(1r,4r)-4-(aminomethyl)cyclohexyl]methoxy}phenyl)urea [ka]

[0333] Step 34-1: tert-butyl N-[[4-[(4-nitrophenoxy)methyl]cyclohexyl]methyl]carbamate [ka]

[0334] To a stirred mixture of tert-butyl (((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)carbamate (300 mg, 1.234 mmol, 1.00 equiv) in THF (6.0 mL) was added 4-nitrophenol (171 mg, 1.230 mmol, 1.00 equiv) and triphenylphosphine (355 mg, 1.360 mmol, 1.10 equiv). To the above mixture was added DIAD (0.3 mL, 1.360 mmol, 1.10 equiv) dropwise at 0° C. and then stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography under the following conditions (Spherical C18, 120 g, 20-40 μm; mobile phase A: water (0.05% NH4HCO3), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 0% B to 100% B in 30 min, 210 nm; RT: 15.0 min) to give tert-butyl (((1r,4r)-4-((4-nitrophenoxy)methyl)cyclohexyl)methyl)carbamate (340.0 mg, 0.932 mmol, 75% yield) as a light yellow solid. LCMS (ESI, m / z): 365 [M+H] +

[0335] Step 34-2: tert-butyl (((1r,4r)-4-((4-aminophenoxy)methyl)cyclohexyl)methyl)carbamate [ka]

[0336] To a stirred solution of tert-butyl (((1r,4r)-4-((4-nitrophenoxy)methyl)cyclohexyl)methyl)carbamate (330 mg, 0.910 mmol) in a mixed solvent of ethanol (5.0 mL) and water (1.0 mL), NH4Cl (484 mg, 9.070 mmol, 10.00 equiv) and Fe (253 mg, 4.530 mmol, 5.00 equiv) were added. The resulting mixture was stirred at 80° C. for 2 h and then diluted with 20.0 mL of ethanol. The solid was filtered and the filtrate was concentrated under reduced pressure. 30.0 mL of EA was added to the above residue and filtered again once more. The filtrate was concentrated in vacuo to give tert-butyl (((1r,4r)-4-((4-aminophenoxy)methyl)cyclohexyl)methyl)carbamate (225.0 mg, 0.672 mmol, 74% yield) as a light brown solid. LCMS (ESI, m / z): 335 [M+H] +

[0337] Step 34-3: tert-butyl (((1r,4r)-4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)cyclohexyl)methyl)carbamate [ka]

[0338] To a stirred mixture of tert-butyl (((1r,4r)-4-((4-aminophenoxy)methyl)cyclohexyl)methyl)carbamate (50 mg, 0.150 mmol) in DCE (2.0 mL) was added carbonyldiimidazole (26 mg, 0.160 mmol, 1.07 equiv). The resulting mixture was stirred at 60 °C for 2 h. The resulting mixture was concentrated under reduced pressure. To the above residue was added 2.0 mL MeCN, followed by a solution of 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione trifluoroacetate (58 mg, 0.1500 mmol, 1.00 equiv) and TEA (0.5 mL) in DMF (1.0 mL). The resulting mixture was stirred at room temperature for another 2 h. This was purified by reverse phase flash chromatography under the following conditions (Spherical C18, 80 g, 20-40 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 0% B to 100% B in 10 min, 210 nm; RT: 12 min) to give tert-butyl (((1r,4r)-4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)cyclohexyl)methyl)carbamate (33.0 mg, 0.052 mmol, 34% yield) as a light yellow solid. LCMS (ESI, m / z): 634 [M+H] +

[0339] Step 34-4: 1-(4-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea [ka]

[0340] To a stirred mixture of tert-butyl (((1r,4r)-4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)cyclohexyl)methyl)carbamate (28 mg, 0.040 mmol) in 1,4-dioxane (2.0 mL) was added dropwise HCl in 1,4-dioxane (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The crude product was dissolved in 1.0 mL of ACN, and then 1.0 mL of NaHCO3 saturated solution was added to adjust the pH value to 8. The resulting solution was purified by preparative HPLC under the following conditions (column: X-select CSH C18 OBD column 30*150mm 5μm, n; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 2% B to 20% B in 10 min, hold 20% B; wavelength: 254nm; RT1(min): 10.57) to give 1-(4-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (12.0mg, 0.022mmol, 50% yield) as a white solid. LCMS (ESI, m / z): 534[M+H] + ; 1 H NMR (300MHz, methanol-d4) δ 8.85(s,1H), 7.77(d,J=7.9Hz,1H), 7.58-7.45(m,2H), 7.24(d,J=9.0Hz,2H), 7.00 (s,1H), 6.82(d,J=9.0Hz,2H), 5.14(dd,J=13.3, 5.2Hz,1H), 4.58-4.39(m,4H), 3. 77(d,J=6.2Hz,2H), 3.00-2.90(m,1H), 2.70-2.60(m,4H), 2.59-2.40(m,2H), 2.00 (m,1H), 1.99-1.75(m,4H), 1.70-1.55(s,1H), 1.50-1.42(s,1H), 1.10-0.85(m,4H)

[0341] Example 35: 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea [ka]

[0342] Step 35-1: (1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexan-1-ol [ka]

[0343] To a stirred solution of (1r,4r)-4-aminocyclohexan-1-ol (240 mg, 2.080 mmol, 1.00 equiv) in methanol (5.0 mL) was added hexane-2,5-dione (0.3 mL, 2.080 mmol, 1.00 equiv). To the above mixture was added p-toluenesulfonic acid (86 mg, 0.500 mmol, 2.40 equiv) and stirred at 60° C. for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50.0 mL of EA and washed with 15 mL of 1 M HCl aq. followed by 15 mL of saturated NaHCO3 aq. After drying over anhydrous Na2SO4 and filtration, the filtrate was concentrated under reduced pressure to give (1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexan-1-ol (230 mg, 1.189 mmol, 57% yield) as a yellow solid. LCMS (ESI, m / z): 194 [M+H] +

[0344] Step 35-2: 1-((1r,4r)-4-((4-bromobenzyl)oxy)cyclohexyl)-2,5-dimethyl-1H-pyrrole [ka]

[0345] To a stirred solution of (1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexan-1-ol (332 mg, 1.720 mmol, 1.00 equiv) in THF (5.0 mL) was added NaH (82 mg, 3.440 mmol, 2.00 equiv) portionwise at room temperature. To the above mixture was added a solution of 1-bromo-4-(bromomethyl)benzene (430 mg, 1.720 mmol) in THF (5.0 mL). The resulting mixture was stirred at 60° C. overnight. The reaction was quenched with 20.0 mL of H2O. The resulting mixture was extracted with 50.0 mL×3 of EA. The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography under the following conditions (Spherical C18, 80 g, 20-40 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 0% B to 100% B in 10 min, 210 nm; RT: 6 min) to give 1-((1r,4r)-4-((4-bromobenzyl)oxy)cyclohexyl)-2,5-dimethyl-1H-pyrrole (420.0 mg, 1.159 mmol, 67% yield) as a yellow solid. LCMS (ESI, m / z): 362 [M+H] +

[0346] Step 35-3: tert-butyl (4-((((1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexyl)oxy)methyl)benzyl)carbamate [ka]

[0347] To a stirred mixture of 1-((1r,4r)-4-((4-bromobenzyl)oxy)cyclohexyl)-2,5-dimethyl-1H-pyrrole (420 mg, 1.160 mmol, 1.00 equiv) in a mixture of 1,4-dioxane (3.0 mL) and water (0.3 mL) was added potassium N-Boc-aminomethyl trifluoroborate (273 mg, 1.160 mmol, 1.16 equiv). To the above mixture was added Cs2CO3 (1130 mg, 3.480 mmol, 3.48 equiv) and XPhos Pd G3 (106 mg, 0.120 mmol, 0.12 equiv). The resulting mixture was stirred at 110 °C overnight under nitrogen atmosphere. The reaction was quenched with 10.0 mL of water and then extracted with 40.0 mL x 3 of EtOAc. The organic phases were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions (Spherical C18, 80 g, 20-40 μm; mobile phase A: water (0.05% NH4HCO3), mobile phase B: ACN; flow rate: 70 mL / min; gradient: 0% B to 100% B in 20 min, 210 nm; RT: 10 min) to give tert-butyl (4-((((1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexyl)oxy)methyl)benzyl)carbamate (125.0 mg, 0.303 mmol, 26% yield) as a yellow oil. LCMS (ESI, m / z): 413 [M+H] +

[0348] Step 35-4: tert-butyl (4-((((1r,4r)-4-aminocyclohexyl)oxy)methyl)benzyl)carbamate [ka]

[0349] To a stirred mixture of tert-butyl (4-((((1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexyl)oxy)methyl)benzyl)carbamate (102 mg, 0.250 mmol, 1.00 equiv) in IPA (4.3 mL) and water (1.1 mL) was added hydroxylamine; hydrochloride (257 mg, 3.710 mmol, 1.50 equiv). To the above mixture was added TEA (0.4 mL) and then stirred at 80° C. overnight. The crude product was purified by flash chromatography using the following conditions (Spherical C18, 80 g, 20-40 μm; mobile phase A: water (0.05% NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 0% B to 100% B in 10 min, 210 nm; RT: 9 min) to give tert-butyl (4-((((1r,4r)-4-aminocyclohexyl)oxy)methyl)benzyl)carbamate (65.0 mg, 0.194 mmol, 78% yield) as a yellow solid. LCMS (ESI, m / z): 335 [M+H] +

[0350] Step 35-5: tert-butyl (4-((((1r,4r)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)cyclohexyl)oxy)methyl)benzyl)carbamate [ka]

[0351] To a stirred mixture of tert-butyl (4-((((1r,4r)-4-aminocyclohexyl)oxy)methyl)benzyl)carbamate (44 mg, 0.130 mmol, 1.00 equiv) in DCE (2.0 mL) was added carbonyldiimidazole (23 mg, 0.140 mmol, 1.08 equiv). The mixture was stirred at 60° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in 2.0 mL of MeCN, followed by the addition of 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetate (51 mg, 0.130 mmol, 1.00 equiv) and 1.0 mL of TEA in DMF. The mixture was stirred at room temperature for 2 h. The crude product was purified by reverse phase flash chromatography using the following conditions (Spherical C18, 48 g, 20-40 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 0% B to 100% B in 20 min, 210 nm; RT: 11.0 min) to give tert-butyl (4-((((1r,4r)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)cyclohexyl)oxy)methyl)benzyl)carbamate (21.0 mg, 0.033 mmol, 25% yield) as a light yellow solid. LCMS (ESI, m / z): 634 [M+H] +

[0352] Step 35-6: 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea [ka]

[0353] To a stirred mixture of tert-butyl (4-((((1r,4r)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)cyclohexyl)oxy)methyl)benzyl)carbamate (16 mg, 0.030 mmol, 1.00 equiv) in DCM (1.8 mL) was added TFA (0.6 mL). The resulting mixture was stirred at room temperature for 2 h. After the mixture was concentrated under reduced pressure, the crude product was dissolved in 1.0 mL of ACN, and then 1.0 mL of saturated aqueous NaHCO3 was added to adjust the pH value to 8. The crude product (30 mg) was purified by preparative HPLC under the following conditions (Column: X-select CSH C18 OBD Column 30*150 mm 5 μm, n; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 20% B in 10 min, hold 20% B; Wavelength: 254 nm; RT1 (min): 10.57; Number Of Runs: 0) to give 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea (7.6 mg, 0.014 mmol, 56% yield) as a white solid. LCMS (ESI, m / z): 534 [M+H] + ; 1 H NMR (400MHz, methanol-d4) δ 8.50(s,1H), 7.75(d,J=7.9Hz,1H), 7.49(s,1H), 7.47-7.37(m,1H), 7.42(s,4H), 5.14(dd,J=13.3 , 5.2Hz,1H), 4.57(s,2H), 4.55-4.39(m,4H), 4.09(s,2H), 3.44-3.35(m,1H), 2.91(ddd,J=17.6, 13 .5, 5.4Hz,1H), 2.78(ddd,J=17.5, 4.7, 2.4Hz,1H), 2.49(qd,J=13.2, 4.6Hz,1H), 2.21-2.08(m,1H) , 2.07(s,2H), 1.97(d,J=12.7Hz,2H), 1.47-1.39(m,1H), 1.37(d,J=10.6Hz,1H), 1.31-1.16(m,2H)

[0354] Assessment of compound activity Standard physiological, pharmacological, and biochemical procedures are available for testing compounds and identifying those having the desired antiproliferative activity. Such assays include, for example, biochemical assays such as binding assays, radioactive incorporation assays, as well as a variety of cellular assays.

[0355] biology Targeted protein degradation represents a new paradigm in drug discovery, where small molecules can be used to induce novel protein-protein interactions, enabling the destruction of targeted disease-causing proteins. Inducing protein degradation as a therapeutic strategy has been clinically validated by a series of immunomodulatory drugs developed by Celgene, including lenalidomide and pomalidomide. Removing disease-causing proteins leads to therapeutic benefits derived from immunomodulatory drug treatment. Specifically, CELMoD (including immunomodulatory drugs) has the ability to recruit substrate proteins to CRL4CRBN E3 ubiquitin ligase and subsequently induce their ubiquitination, after which the ubiquitin-tagged proteins are delivered to the 26S proteasome for subsequent degradation by the proteasome. GSPT1 (G1 to S phase transition protein 1) is a translation termination factor with intrinsic GTPase activity. GSPT1 in complex with eRF1 acts to terminate protein translation by recognizing mRNA stop codons, catalyzing the cleavage of the nascent protein from the terminal tRNA, and releasing ribosomal subunits from the termination site, allowing them to reform and begin translation at a new initiation site. Thus, GSPT1 plays an important role in protein synthesis and cell proliferation. Targeted degradation of GSPT1 by CELMoD elicits broad antitumor activity in AML and solid tumor cells (1, 2).

[0356] 1. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, Fang W, Wang NY, Nguyen D, Houston J, Carmel G, Tran T, Riley M, Nosaka L, Lander GC, Gaidarova S, Xu S、Ruchelman AL、Handa H、Carmichael J、Daniel TO、Cathers BE、Lopez-Girona A、Chamberlain PP、A novel brain modulator recruits GSPT1 to the CRL4(CRBN)ubiquitin ligase. Nature. 2016 Jul 14;535(7611):252-7. doi:10.1038 / nature18611. Epub 2016 Jun 22. PMID:27338790

[0357] 2. Surka C, Jin L, Mbong N, Lu CC, Jang IS, Rychak E, Mendy D, Clayton T, Tindall E, Hsu C, Fontanillo C, Tran E, Contreras A, Ng SWK, Matyskiela M, Wang K, Chamberlain P. Cathers B. Carmichael J. Hansen J. Wang JCY Minden MD. Fan J. Pierce DW. Pourdehnad M. Rolfe M. Lopez-Girona A. Dick JE. targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021 Feb 4;137(5):661-677. doi:10. 1182 / blood.2020008676. PMID:33197925;PMCID:PMC8215192

[0358] Empty slingshot GSPT1 Container X Interconnector DF15 multiple myeloma cells expressing ePL-tagged GSPT1 were dispensed into compound-prespotted 384-well plates (Corning #3712). Compounds were dispensed into 384-wells with an acoustic dispenser (ATS Acoustic Transfer System from EDC Biosystems) in a 10-point dose-response curve using 3-fold dilutions starting at 10 μM in DMSO down to 0.0005 μM. DMSO was added to the assay as a control. 25 μL of medium (RPMI-1640 + 10% heat-inactivated FBS + 25 mM Hepes + 1 mM Na Pyruvate + 1x NEAA + 0.1% Pluronic F-68 + 1x Pen Strep Glutamine) containing 5000 cells was dispensed into each well. The assay plate was incubated at 37°C with 5% CO2 for 24 hours. After incubation, 25 μl of InCELL Hunter™ Detection Reagent Working Solution (DiscoverX, Catalog No. 96-0002, Fremont, CA) was added to each well and incubated for 30 minutes at room temperature in the dark. Luminescence was read after 30 minutes on a PHERAstar luminometer (Cary, NC).

[0359] EC of GSPT1 degradation 50 To measure the values, a four-parameter logistic model (sigmoidal dose-response model) was used.

number

[0360] Table 2. GSPT1 decomposition data [Table 22] [Table 23]

[0361] The above embodiments are intended to be merely illustrative, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures, all of which are considered to be within the scope of the invention and the appended claims.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula: A is independently selected from unsubstituted or substituted 3- to 12-membered cycloalkyl groups, 4- to 12-membered heterocyclic groups, 5- to 12-membered aryl groups, or 5- to 12-membered heteroaryl rings; B is independently selected from unsubstituted or substituted 3- to 12-membered cycloalkyl groups, 4- to 12-membered heterocyclic groups, 5- to 12-membered aryl groups, or 5- to 12-membered heteroaryl groups; X is O or -NR １１ Selected more independently; R １ is hydrogen, halogen, -C １ -C ６ Independently selected from alkyl or 3- to 6-membered cycloalkyl groups; R ２ is independently selected from hydrogen, halogen, -C(O), -C １ -C ６ alkyl, and 3- to 6-membered cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with -R １１ , -N(R １１ R １１ ), -NHR １１ or -OR １１ ; R ３ is hydrogen, halogen, -OR １１ , -N(R １１ R １１ ), - NHR １１ , -C １ -C ６ A alkyl group is independently selected from an alkyl group, a 3-6 membered cycloalkyl group, a 4-12 membered heterocycle, a 5-12 membered aryl group, or a 5-12 membered heteroaryl ring, where the alkyl group, cycloalkyl group, heterocycle, and heteroaryl group are -R １１ , -N(R １１ R １１ ), - NHR １１ OR １１ It may be replaced with; R ４ is hydrogen, halogen, -C １ -C ６ A alkyl group is independently selected from an alkyl group, a 3-6 membered cycloalkyl group, a 4-12 membered heterocycle, a 5-12 membered aryl group, or a 5-12 membered heteroaryl ring, where the alkyl group, cycloalkyl group, heterocycle, and heteroaryl group are -R １１ , - NHR １１ OR １１ It may be replaced with; R ５ is hydrogen, -C １ -C ６ A alkyl group is independently selected from an alkyl group, a 3-6 membered cycloalkyl group, a 4-12 membered heterocycle, a 5-12 membered aryl group, or a 5-12 membered heteroaryl ring, where the alkyl group, cycloalkyl group, heterocycle, and heteroaryl group are -R １１ , -N(R １１ R １１ ), - NHR １１ OR １１ It may be replaced with; R ６ is hydrogen, -C １ -C ６ A alkyl group is independently selected from an alkyl group, a 3-6 membered cycloalkyl group, a 4-12 membered heterocycle, a 5-12 membered aryl group, or a 5-12 membered heteroaryl ring, where the alkyl group, cycloalkyl group, heterocycle, and heteroaryl group are -R １１ , -N(R １１ R １１ ), - NHR １１ OR １１ It may be replaced with; Here are two R ５ and R ６ The substituents may bond together with the carbon atoms to which they are bonded to form a 5- or 6-membered ring, which may be saturated or partially saturated; furthermore, 1 or 2 R １１ Substitution with substituents is also acceptable; R ７ is hydrogen, halogen, -OR １１ , -C １ -C ６ Alkyl, -(C １ -C ６ Haloalkyl), -(C １ -C ６ Alkyl)-O-(C １ -C ６ Alkyl), -NHR １１ , -N(R １１ R １１ ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C ２ -C ６ Alkenyl, -O-(C) １ -C ６ (Haloalkyl)-O-(C) １ -C ６ Alkyl), -C(=O)-(C １ -C ６ Alkyl), -C(=O)OH, -C(=O)-O-(C １ -C ６ Alkyl), -C(=O)NH ２ , -C(=O)NH(R １１ ), -C(=O)N(R １１ R １１ ), -S(O) ２ R １１ , -S(=O)R １１ ,-SR １１ , -S (=O) ２ NH ２ , -S (=O) ２ NH(C) １ -C ６ Alkyl), or -S (=O) ２ N(C) １ -C ６ Alkyl) ２ Selected more independently, Here, the alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl is -R １１ , -N(R １１ R １１ ), -NHR １１ or -OR １１ may be substituted; R ８ is independently selected from hydrogen, halogen or -C １ -C ６ alkyl (-R １１ , -N(R １１ R １１ ), -NHR １１ or -OR １１ which may be substituted); R ９ is hydrogen, halogen, -OR １１ , -C １ -C ６ Alkyl, -(C １ -C ６ Haloalkyl), -(C １ -C ６ Alkyl)-O-(C １ -C ６ Alkyl), -NHR １１ , -N(R １１ R １１ ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C ２ -C ６ Alkenyl, -O-(C) １ -C ６ (Haloalkyl)-O-(C) １ -C ６ Alkyl), -C(=O)-(C １ -C ６ Alkyl), -C(=O)OH, -C(=O)-O-(C １ -C ６ Alkyl), -C(=O)NH ２ , -C(=O)NH(R １１ ), -C(=O)N(R １１ R １１ ), -S(O) ２ R １１ , -S(=O)R １１ ,-SR １１ , -S (=O) ２ NH ２ , -S (=O) ２ NH(C) １ -C ６ Alkyl), or -S (=O) ２ N(C) １ -C ６ Alkyl) ２ Selected more independently, Here, the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is -R １１ , -N(R １１ R １１ ), - NHR １１ OR １１ It may be replaced with; R １０ is hydrogen, halogen, -OR １１ , -C １ -C ６ Alkyl, -(C １ -C ６ Haloalkyl), -(C １ -C ６ Alkyl)-O-(C １ -C ６ Alkyl), -NHR １１ , -N(R １１ R １１ ), -CN, 3-12 membered cycloalkyl, 4-12 membered heterocycle, 5-12 membered aryl or 5-12 membered heteroaryl ring, -C ２ -C ６ Alkenyl, -O-(C) １ -C ６ (Haloalkyl)-O-(C) １ -C ６ Alkyl), -C(=O)-(C １ -C ６ Alkyl), -C(=O)OH, -C(=O)-O-(C １ -C ６ Alkyl), -C(=O)NH ２ , -C(=O)NH(R １１ ), -C(=O)N(R １１ R １１ ), -S(O) ２ R １１ , -S(=O)R １１ ,-SR １１ , -S (=O) ２ NH ２ , -S (=O) ２ NH(C) １ -C ６ Alkyl), or -S (=O) ２ N(C) １ -C ６ Alkyl) ２ Selected more independently, Here, the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is -R １１ , -N(R １１ R １１ ), - NHR １１ OR １１ It may be replaced with; R １１ is hydrogen, halogen, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C １ -C ６ Independently selected from haloalkyls, 3- to 12-membered cycloalkyls, 4- to 12-membered heterocycles, 5- to 12-membered aryls, or 5- to 12-membered heteroaryl rings; Here R １１ The alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl rings in the compound are each independently unsubstituted or have 1, 2, or 3 R groups. １２ Substituting with a substituent; R １２ In each case, hydrogen and -C １ -C ６ Alkyl, halogen, -OH, -O-(C １ -C ６ Alkyl)-,-NH ２ , independently selected from 3- to 12-membered alkyl groups, 5- to 12-membered heterocycles, 5- to 12-membered aryl groups, or 5- to 12-membered heteroaryl rings; where R １２ The alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl rings in each are independently unsubstituted or R １３ It has been replaced with; R １３ These are independently hydrogen, halo, and -C. １ -C ６ Alkyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Alkoxyalkyl, oxo, hydroxyl, or -C １ -C ６ It is an alkoxy; and furthermore Here, two R atoms are located on adjacent carbon atoms of the A or B group. ９ and R １０ They may bond to form a saturated, partially saturated, or aromatic, five or six-membered ring; furthermore, one or two R １３ The ring may be substituted with substituents, and if the ring is not an aromatic ring, it may contain oxo substituents; Here, A, B, R ３ , R ４ , R ５ , R ６ , R ７ , R ９ , R １０ , R １１ , R １２ and R １３ The heterocyclic ring and heteroaryl cyclic ring in the above may contain one, two, or three heteroatoms independently selected from O, N, or S. Compounds represented by, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, polymorphs or tautomers thereof, pharmaceutically acceptable salts of polymorphs or tautomers thereof, stereoisomers of any of the above forms, or mixtures thereof.

2. A compound according to claim 1 of formula I, wherein X is O, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

3. X is -NR １１ The compound according to claim 1 of formula I, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

4. A has 1 or 2 R ７ A compound according to claim 1 of formula I, substituted with a substituent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

5. R ７ is hydrogen, halogen or -C １ -C ６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

6. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, pharmaceutically acceptable salt of a polymorph or tautomer, stereoisomer of any of the above forms, or a mixture thereof, independently selected from hydrogen, F, Cl, or methyl.

7. A is phenyl, 【Chemistry 2】 The compound described in claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

8. B is a substituted or unsubstituted phenyl 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof, selected more independently.

9. B is one or more R ９ A compound according to claim 1 of formula I, substituted with a substituent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

10. R ９ However, hydrogen, halogen, -OR １１ , -C １ -C ６ Alkyl, -(C １ -C ６ Haloalkyl), -(C １ -C ６ Alkyl)-NH ２ , - (C １ -C ６ A compound according to claim 1, selected from alkyl)-OH, -CN, or a 3- to 12-membered cycloalkyl group, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

11. R ９ が、H、-OH、C-、F、-CH ３ 、-CH ２ CH ３ ,-(EH ２ ) ２ CH ３ ,-EH(EH ３ ) ２ ,-(EH ２ )OH、-H ２ NH ２ ,-CN,-OCH ３ ,-OCH(CH ３ ) ２ 、-OCHF ２ 、 【Chemistry 4】 A more selected compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

12. B is one or more R １０ A compound according to claim 1 of formula I, substituted with a substituent, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

13. R １０ is hydrogen, halogen, -CN, -OR １１ , - (C １ -C ６ Alkyl), -NH ２ ien-CH ２ NH ２ ien-CH ２ A compound according to claim 1, selected from OH, -OH, a 3- to 12-membered cycloalkyl, or a 4- to 12-membered heterocycle, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

14. B 【Transformation 5】 A more selected compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

15. R １ However, hydrogen or -C １ -C ６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

16. R ２ , R ３ and R ４ The compound according to claim 1, wherein is hydrogen, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

17. R ６ is hydrogen or -C １ -C ６ A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

18. R ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, pharmaceutically acceptable salt of a polymorph or tautomer, stereoisomer of any of the above forms, or a mixture thereof, wherein the compound is selected from hydrogen or methyl.

19. Formula II: 【Transformation 6】 [In the formula: R １ is independently selected from hydrogen or methyl; R １４ teeth Table 1 Table 2 Table 3 [More independently selected] Compounds represented by, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, polymorphs or tautomers thereof, pharmaceutically acceptable salts of polymorphs or tautomers thereof, stereoisomers of any of the above forms, or mixtures thereof.

20. 1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea, 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]methyl]urea, 1-(4-((2-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)urea, 1-(4-((3-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)urea, 1-(4-((3-aminobenzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)urea, 1-[4-(benzyloxy)phenyl]-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-(4-((3-(hydroxymethyl)benzyl)oxy)phenyl)urea, 1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-(4-((2-(hydroxymethyl)benzyl)oxy)phenyl)urea, 1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-(4-((2-hydroxybenzyl)oxy)phenyl)urea, 1-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)-3-(4-((2-hydroxybenzyl)oxy)phenyl)urea, 1-(4-{[4-(aminomethyl)-2-fluorophenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-methylphenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[5-(aminomethyl)pyridine-2-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[6-(aminomethyl)pyridine-3-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[5-(aminomethyl)pyrimidine-2-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[6-(aminomethyl)pyridazin-3-yl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}-3-methylphenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}-3-fluorophenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(6-{[4-(aminomethyl)phenyl]methoxy}pyridazin-3-yl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(6-{[4-(aminomethyl)phenyl]methoxy}pyridine-3-yl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-ethylphenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-n-propylphenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-methoxyphenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-(propan-2-yloxy)phenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-chlorophenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-(oxetane-3-yloxy)phenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-cyclopropylphenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-((2-aminobenzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)urea, 1-(4-((4-(aminomethyl)benzyl)oxy)-3-chlorophenyl)-3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)methyl)urea, 1-(4-{[4-(aminomethyl)-2-i-propylphenyl]methoxy}phenyl)-3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)-2-difluoromethoxyphenyl]methoxy}phenyl)-3-{[2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3S)-3-methyl-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}methyl)urea, 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3R)-3-methyl-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}methyl)urea, 3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}-1-(4-{[(1r,4r)-4-(aminomethyl)cyclohexyl]methoxy}phenyl)urea, or 3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea A more selected compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer thereof, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

21. A drug comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer in any of the above forms, or a mixture thereof.

22. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion complex, polymorph or tautomer, a pharmaceutically acceptable salt of a polymorph or tautomer, a stereoisomer of any of the above forms, or a mixture thereof.

23. The pharmaceutical composition according to claim 22, wherein the cancer is leukemia, and the leukemia is chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, or acute myeloid leukemia.

24. The pharmaceutical composition according to claim 23, characterized by being administered in combination with another second activator or supportive agent, wherein the other second activator is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth factor, cytokine, anticancer agent, antibiotic, Cox-2 inhibitor, immunomodulator, immunosuppressant, corticosteroid, or a pharmacologically active variant or derivative thereof.

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