Biomarkers of metap2 inhibitors and applications thereof

Abstract

To provide biomarkers of METAP2 inhibitors and applications thereof.SOLUTION: The present disclosure relates to small molecule or polymer conjugated MetAP2 inhibitors. The present disclosure also relates to methods of treating, or ameliorating at least one symptom of metabolic dysfunction associated with treatment in a subject having a disease, such as cancer. The present disclosure also relates to methods of treating, or ameliorating at least one symptom of cancer comprising administering a combination of a polymer conjugated MetAP2 inhibitor and at least one second agent that may induce metabolic dysfunction.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 751,335, filed October 26, 2018, and U.S. Provisional Application No. 62 / 844,271, filed May 7, 2019, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Obesity and metabolic disorders are common disease states in people worldwide. This chronic condition leads to systemic inflammation, promotes angiogenesis and fibrosis, and renders many patients immunosuppressed, making other coexisting diseases (such as cancer) difficult to treat. While obesity is a growing problem, the aging population further complicates treatment, as patient populations with multiple coexisting diseases require both ways to identify which obesity-related factors negatively impact other diseases and to provide treatments that can slow or reverse the progression of these factors.

[0003] Traditional chemotherapy and targeted therapy have been shown to be less effective in obese cancer patients (Incio et al., Cancer Discov; (2016) 6(8); 852-869; Kruger et al., British Journal of Cancer (2018) 119:832-839). Recently, a new class of cancer treatment has emerged: immunotherapy, which has shown clinical success in a significant proportion of cancer patients. Quite unexpectedly, however, most cancer patients still resist immunotherapy treatment (Yu and Cui, 2018, Oncol. Lett. 16:4105-4130). What is becoming clear is that cancer patients with obesity and / or metabolic disorders do not respond to treatments (including traditional chemotherapy and emerging therapies such as immunotherapy) in the same way as their non-obese counterparts (Murphy et al., J Immunol 2018; 201:1837-1841). One major challenge will be to identify which obesity-related factor or factors are the primary contributors to this unexpected treatment resistance and to reverse them.

[0004] Some targeted therapies for cancer and other diseases lose their effectiveness after a relatively short period of time. Currently, one mechanism that explains this loss of activity is "induced metabolic disturbances" (including hyperglycemia leading to hyperinsulinemia) by the treatment itself or by co-administered drugs. Here, we show that treatment with the disclosed compounds improves the induced metabolic disturbances, allowing for continued treatment with the therapeutic agent.

[0005] Metabolic disturbances can be induced by cancer therapy and thus limit the efficacy of that therapy. Hyperglycemia during chemotherapy occurs in approximately 10%–30% of patients. It is well known that glucocorticoids and L-asparaginase can cause acute hyperglycemia during chemotherapy. Prolonged hyperglycemia is also frequently observed in patients with hematological malignancies treated with L-asparaginase-based regimens and total body irradiation, among others. Glucocorticoid-induced hyperglycemia often progresses due to increased insulin resistance, decreased insulin secretion, and excessive hepatic glucose output, depending on the type, dose, and delivery method of the glucocorticoid formulation. The incidence of hyperglycemia (defined as blood glucose levels >200 mg / dl) in hospitalized patients without a history of diabetes treated with glucocorticoids exceeds 50%. Mammalian-targeted rapamycin (mTOR) inhibitors are associated with a high incidence of hyperglycemia (13%–50%). Immunotherapy induces hyperglycemia in patients treated with pembrolizumab, with hyperglycemic events occurring in 45%-49% of patients, with 3%-6% experiencing grade 3 or 4 hyperglycemia (Hwangbo et al., Endocrinol Metab (Seoul) 2017 March; 32(1): 23-29).

[0006] Cancer cells derive much of their energy from glucose. To meet the increased glucose needs of cancer cells, the PI3K / AKT / mTOR pathway is often upregulated (amplified) or mutated. Collaborative research efforts are underway to develop therapies that inhibit or downregulate this pathway. However, inhibiting this pathway leads to on-target toxicity, creating a hyperglycemia / hyperinsulinemia feedback loop that thwarts its effectiveness and leads to treatment failure.

[0007] Obesity increases circulating estrogen, insulin, and IGFs, resulting in chronic low-grade inflammation, and these various effects combine directly or indirectly to induce well-known tumor pathways and contribute to the accumulation of myeloid-derived suppressor cells, while reprogramming macrophages to an alternative activated pro-inflammatory and immunosuppressive M2 phenotype. Many pathways affected by obesity include the angiogenic factors VEGF, bFGF, IGF, and PLGF (Silha et al., International Journal of Obesity (2005) 29:1308-1314), key transcription factors such as STAT3 (Wunderlich et al., (2013) Mechanisms of Chronic JAK-STAT3-SOCS3 Signaling in Obesity, JAK-STAT, 2:2:e23878), and numerous immune suppressive factors such as myeloid-derived suppressor cells (MDSCs) (Ostrand-Rosenberg, (2018) Myeloid-derived suppressor cells: their role in cancer and obesity, Current Opinion in Immunology 51:68-75). MDSCs and M2 macrophages are a major source of immunosuppression, allowing tumors to evade effective host immune surveillance and resist anticancer therapy (Weber et al., Front. Immunol. 9:1310. doi: 10.3389 / fimmu.2018.01310). Induction and selective shift of macrophages toward an immunosuppressive M2 phenotype may be a primary physiological and metabolic adaptive response to insulin insensitivity as well as a secondary consequence of immune processes in the setting of chronic low-grade inflammation. Tumor cell modification of these processes may promote angiogenesis, tumor cell migration and invasion, as well as metastasis, resulting in unfavorable treatment outcomes (Okwan-Duodu et al., 2013).

[0008] A number of proteins responsible for limiting the clinical benefit of immunotherapy have been identified, including the enzymes indoleamine-pyrrole 2,3-dioxygenase (IDO-1) and arginase-1 (Arg-1), the cytokine IL-10, and the adipokine leptin. Furthermore, tumor infiltration by regulatory T cells (Tregs), alternatively polarized ("M2") macrophages, and myeloid-derived suppressor cells (MDSCs) has been associated with tumor escape from immune surveillance and subsequent disease progression (Shimizu et al., International Immunology, 30(10): 445-455).

[0009] MetAP2 inhibitors have a long clinical history and have shown antitumor and antimetabolic effects in animal studies and human clinical trials (Tran et al., Cancer Chemother. Pharmacol. (2004) 54:308-314; Joharapurkar et al., Diabetes, Metabolic Syn. and Obesity: Targets and Therapy (2014) 7:73-84). Here, we show that administration of MetAP2 inhibitors can suppress or reverse the expression or abundance of several of these biomarkers, which may result in improved clinical benefit in cancer patients who are obese and potentially have metabolic disorders.

[0010] Recent studies also suggest that the adipokine leptin is a contributor to enhanced tumor growth in a mouse model of obesity-driven breast cancer (Strong et al., Breast Cancer Research (2015) 17:112-127) and a mediator of obesity-associated resistance in another mouse model of obesity-driven kidney cancer (Murphy et al., J. Immunol., 2018;201:1837-1841). One mechanism by which leptin promotes obesity-driven cancer is by increasing MDSC content (Clements et al., J Leukoc Biol. 2018;103:395-407). Summary of the Invention

[0011] The present disclosure provides methods for altering the expression of cells and / or tissues and / or proteins that otherwise block the clinical activity of various cancer therapeutics. In some aspects, the subject is overweight or obese or has a metabolic disorder.

[0012] The present disclosure provides a method of treating or ameliorating at least one symptom of cancer in a subject in need thereof, the method comprising administering to a subject a compound of formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, in combination with a therapeutically effective amount of at least one second active agent, wherein the at least one compound and the at least one second active agent are administered to the subject in amounts sufficient to treat or ameliorate at least one symptom of cancer.

[0013] The present disclosure provides a compound of the formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p ranges from 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second active agent, wherein the at least one compound and the at least one second active agent are administered to a subject in an amount sufficient to treat or ameliorate at least one symptom of cancer.

[0014] The present disclosure provides a method of decreasing the amount of at least one of IL-10, Arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in the plasma, or any combination thereof, of a subject, comprising administering to said subject an amount of at least one of IL-10, Arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof ... [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) m CO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) mCOH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, in combination with a therapeutically effective amount of at least one second active agent, wherein the at least one compound and the at least one second active agent are administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

[0015] The present disclosure provides a method for reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in the plasma, or any combination thereof, of a subject having cancer, comprising administering to said subject a compound of the formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, in combination with at least one second active agent, wherein the at least one compound and the at least one second active agent are administered to a subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

[0016] The present disclosure provides a method of treating or ameliorating at least one symptom of cancer in a subject in need thereof, the method comprising administering to a subject a compound represented by ZQXYC(O)-W, wherein, independently at each occurrence, Z is -H, -H2N-AA3-AA4- AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; and AA4 is a bond, or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA5 is a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a therapeutically effective amount of at least one second therapeutic agent, wherein the at least one compound and the at least one second active agent are administered in amounts sufficient to treat or ameliorate at least one symptom of cancer.

[0017] The present disclosure provides at least one compound represented by ZQXYC(O)-W, wherein, independently at each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; and AA4 is a bond, for use in a method of treating or ameliorating at least one symptom of cancer in a subject. AA5 is a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) mCOH (where m is 2, 3, 4, or 5); Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second active agent, wherein the at least one compound and the at least one second active agent are administered to a subject in an amount sufficient to treat or ameliorate at least one symptom of cancer.

[0018] The disclosure provides a method of decreasing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in the plasma, or any combination thereof, of a subject, the method comprising administering to the subject at least one compound represented by ZQXYC(O)-W, wherein, independently at each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, AA4 is either a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine; AA5 is either a bond or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, in combination with a therapeutically effective amount of at least one second therapeutic agent, wherein the at least one compound and the at least one second active agent are administered in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof.

[0019] The present disclosure provides at least one compound represented by ZQXYC(O)-W, (wherein, independently at each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)- or Z is H2N-AA5-AA6-C(O); AA3 is a bond, alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, stearate ... AA4 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine; AA5 is a bond or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second therapeutic agent, wherein the at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and the at least one second active agent are administered in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof.

[0020] The present disclosure provides a method of treating or ameliorating at least one symptom of cancer in a subject in need thereof, the method comprising administering to a subject a compound of formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, wherein the compound is administered in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

[0021] In accordance with the present disclosure, there is provided a compound of the formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or any pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is provided, wherein the at least one compound, or any pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is administered to a subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

[0022] The present disclosure provides a method of treating or ameliorating at least one symptom of a metabolic disorder associated with the treatment of a subject having cancer, the method comprising administering to a subject a compound of formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) m CO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) mCOH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p ranges from 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, wherein the compound is administered in an amount sufficient to treat or ameliorate at least one symptom of a metabolic disorder associated with the treatment of a subject having cancer.

[0023] In accordance with the present disclosure, there is provided a compound of formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) m CO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) mCOH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p ranges from 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is provided, wherein at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is administered to a subject in an amount sufficient to treat or ameliorate at least one symptom of the metabolic disorder implicated in the treatment.

[0024] The present disclosure provides a method of decreasing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in the plasma, or any combination thereof, of a subject having cancer, the method comprising: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, wherein the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, in the tumor microenvironment, or in plasma, or any combination thereof, is reduced.

[0025] The present disclosure provides a method for reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in the plasma, or any combination thereof, of a subject having cancer, comprising administering to said subject a compound of the formula: [ka] wherein, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) m CO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) mCOH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is provided, wherein the at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is administered to a subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in a tumor microenvironment, or in plasma, or any combination thereof.

[0026] The present disclosure provides a method for treating or ameliorating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one PI3K inhibitor.The present disclosure also provides a combination comprising at least one MetAP2 inhibitor and at least one PI3K inhibitor for use in treating or ameliorating at least one symptom of cancer in a subject.The present disclosure also provides a combination comprising at least one MetAP2 inhibitor and at least one PI3K inhibitor for use in the manufacture of a medicament for treating or ameliorating at least one symptom of cancer in a subject.

[0027] The present disclosure provides a method for treating or ameliorating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one AKT inhibitor.The present disclosure also provides a combination comprising at least one MetAP2 inhibitor and at least one AKT inhibitor for use in treating or ameliorating at least one symptom of cancer in a subject.The present disclosure also provides a combination comprising at least one MetAP2 inhibitor and at least one AKT inhibitor for use in the manufacture of a medicament for treating or ameliorating at least one symptom of cancer in a subject.

[0028] The present disclosure provides a method for treating or ameliorating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one mTOR inhibitor.The present disclosure also provides a combination comprising at least one MetAP2 inhibitor and at least one mTOR inhibitor for use in treating or ameliorating at least one symptom of cancer in a subject.The present disclosure also provides a combination comprising at least one MetAP2 inhibitor and at least one mTOR inhibitor for use in the manufacture of a medicament for treating or ameliorating at least one symptom of cancer in a subject.

[0029] The present disclosure provides a method for treating or ameliorating at least one symptom of metabolic disorder induced by cancer treatment in a subject, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor.The present disclosure provides at least one MetAP2 inhibitor for use in treating or ameliorating at least one symptom of metabolic disorder induced by cancer treatment in a subject.The cancer treatment can include administering a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, or any combination thereof.

[0030] In some aspects of the above methods, combinations, and uses, the at least one MetAP2 inhibitor can be any conjugate or compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative of any conjugate or compound of the present disclosure. In some aspects, the at least one MetAP2 inhibitor can be a compound of the formula: [ka] A complex or compound of the formula:

[0031] In some aspects of the above methods, combinations and uses, the at least one MetAP2 inhibitor can be ZGN-1061 or beloranib.

[0032] In some aspects of the above methods, combinations and uses, the at least one compound, or at least one MetAP2 inhibitor, has the formula: [ka] provided that, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p ranges from 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6. In some aspects, Z is [ka] [ka] [ka] It can be represented by an equation selected from the group consisting of:

[0033] In some aspects, R4 can be methyl. In some aspects, R5 can be methyl. In some aspects, R6 can be 2-hydroxypropyl. In some aspects, Z can be -NH-AA6-C(O)-QXYC(O)-W. In some aspects, AA6 can be glycine. In some aspects, Z can be -NH-AA5-AA6- C(O)-QXYC(O)-W. In some aspects, AA5 can be leucine and AA6 can be glycine. In some aspects, AA5 can be valine and AA6 can be glycine. In some aspects, AA5 can be phenylalanine and AA6 can be glycine. In some aspects, AA5 can be glycine and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In some aspects, AA5 can be leucine and each of AA3, AA4 and AA6 can be glycine. In some aspects, AA5 can be valine and each of AA3, AA4 and AA6 can be glycine. In some aspects, AA5 can be phenylalanine and each of AA3, AA4 and AA6 can be glycine. In some aspects, AA3 can be glycine, AA4 can be phenylalanine, AA5 can be leucine and AA6 can be glycine. In some aspects, AA3, AA4, AA5 and AA6 can be glycine.

[0034] In some aspects, as -QXY, [ka] Either one is possible.

[0035] In some respects, as W [ka] is possible.

[0036] In some aspects, the ratio of x to y can range from about 30:1 to about 3:1, in some aspects the ratio of x to y can be about 11:1.

[0037] In some aspects of the above methods, combinations and uses, at least one MetAP2 inhibitor has the formula: [ka] The present invention can have either

[0038] In some aspects of the above methods, combinations, and uses, the at least one MetAP2 inhibitor can be represented by ZQXYC(O)-W, where, independently at each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; and AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. alanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond or is glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) mCOH (where m is 2, 3, 4, or 5); Q is NR, O, or S; X is M-(C(R)2) p - MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0-20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6.

[0039] In some aspects, Z can be -NH-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be leucine and AA6 can be glycine. In some aspects, Z can be -NH-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be valine and AA6 can be glycine. In some aspects, Z can be -NH-AA5-AA6-C(O)- QXYC(O)-W, AA5 can be phenylalanine and AA6 can be glycine. In some aspects, Z can be -NH- AA5-AA6-C(O)-QXYC(O)-W, AA5 can be glycine and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be leucine, and each of AA3, AA4, and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be valine, and each of AA3, AA4, and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be phenylalanine, and each of AA3, AA4, and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be glycine, AA4 can be phenylalanine, AA5 can be leucine, and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, and each of AA3, AA4, AA5, and AA6 can be glycine. In some aspects, -QXY can be [ka] Either one is possible.

[0040] In some respects, as W [ka] is possible.

[0041] In some aspects, the selection of the at least one MetAP2 inhibitor comprises: [ka] [ka] [ka] [ka] [ka] [ka] The method may be made from the group consisting of:

[0042] In some aspects of the above methods, combinations, and uses, the at least one PI3K inhibitor can be seravelisib (TAK-117), or BYL-719, or any combination thereof. In some aspects of the above methods, combinations, and uses, the AKT inhibitor can be AZD5363 (capavasertib).

[0043] In some aspects of the above methods, combinations, and uses, the therapeutically effective amount or effective amount of the at least one MetAP2 inhibitor can be about 0.0001 mg to about 5 mg per kg of body weight per day, or about 0.001 mg to about 0.005 mg per kg of body weight per day, or about 0.001 mg to about 0.1 mg per kg of body weight per day. In some aspects, the at least one MetAP2 inhibitor is administered about once to about 5 times per week. In some aspects, the at least one MetAP2 inhibitor is administered on a once every 4 days dosing schedule. In some aspects, the at least one MetAP2 inhibitor is administered on a once every 7 days dosing schedule. In some aspects, the at least one MetAP2 inhibitor is administered on a once every 14 days dosing schedule. In some aspects, the at least one MetAP2 inhibitor is administered once every 3 weeks. In some aspects, the at least one MetAP2 inhibitor is administered once a month. In some aspects of the above methods, combinations, and uses, the subject is treated for at least 6 months, or for at least 1 year, or for at least 2 years, or for at least 3 years. In some aspects of the above methods, combinations, and uses, the at least one MetAP2 inhibitor can be administered parenterally or subcutaneously.

[0044] In some aspects of the above methods, combinations, and uses, the therapeutically effective amount or effective amount of at least one compound of the present disclosure can be from about 0.0001 mg to about 5 mg per kg of body weight per day, or from about 0.001 mg to about 0.005 mg per kg of body weight per day, or from about 0.001 mg to about 0.1 mg per kg of body weight per day. In some aspects, at least one compound of the present disclosure is administered about once to about 5 times per week. In some aspects, at least one compound of the present disclosure is administered on a once every 4 days dosing schedule. In some aspects, at least one compound of the present disclosure is administered on a once every 7 days dosing schedule. In some aspects, at least one compound of the present disclosure is administered on a once every 14 days dosing schedule. In some aspects, at least one compound of the present disclosure is administered once every 3 weeks. In some aspects, at least one compound of the present disclosure is administered once per month. In some aspects of the above methods, combinations, and uses, the subject is treated for at least 6 months, or for at least 1 year, or for at least 2 years, or for at least 3 years. In some aspects of the above methods, combinations, and uses, at least one compound of the present disclosure can be administered parenterally or subcutaneously.

[0045] In some aspects of the above methods, combinations, and uses, the cancer can be any one or combination of metabolic hormone sensitive cancers, postmenopausal HR+ / Her2- breast cancer, triple negative breast cancer, prostate cancer, esophageal cancer, esophageal adenocarcinoma, tongue cancer, colorectal adenocarcinoma, gastrointestinal stromal tumor (GIST), cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, thyroid cancer, and insulin-like growth factor sensitive lung cancer.

[0046] In some aspects of the above methods, combinations, and uses, treating and / or ameliorating at least one symptom of a metabolic disorder associated with the treatment can include reducing insulin levels, reducing hyperinsulinemia, reducing hyperglycemia, reducing C-peptide levels, increasing adiponectin, reducing leptin, reducing fasting insulin, improving insulin resistance, reducing leptin to adiponectin ratio, reducing glucose levels, reducing cholesterol, reducing triglycerides, or any combination thereof in a subject. In some aspects of the above methods, combinations, and uses, treating and / or ameliorating at least one symptom of a metabolic disorder associated with the treatment can include preventing hyperglycemia, and / or preventing hyperinsulinemia, and / or preventing elevated glucose levels induced by administration of the treatment.

[0047] In some aspects of the above methods, combinations, and uses, a "reduction in the level" or a "decrease in the amount" can mean a decrease or reduction of at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0048] In some aspects of the above methods, combinations, and uses, treatment (e.g., treatment related to a metabolic disorder) can include administration of a phosphoinositide-3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, or a combination thereof.

[0049] In some aspects of the above methods, combinations, and uses, the second agent or second active agent can include a phosphoinositide-3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, dexamethasone, or a combination thereof.

[0050] Non-limiting examples of PI3K inhibitors include ceravelisib (TAK-117), BYL-719, and any other PI3K inhibitors known in the art. Non-limiting examples of AKT inhibitors include AZD5363 (capavasertib), ipaselatib (GDC0068), and any other AKT inhibitors known in the art. Non-limiting examples of MetAP2 inhibitors include ZGN-1061, beloranib, and any other MetAP2 inhibitors known in the art. In some aspects, the MetAP2 inhibitor can be any complex or compound mentioned herein.

[0051] Non-limiting examples of PI3K / AKT / mTOR pathway inhibitors can include (paclitaxel + sirolimus + tanespimycin), A-443654, AB-610, ACP-2127, ADC-0008830, AE-116, AEZS-126, AEZS-127, afuresertib + trametinib, AL-58203, AL-58805, AL-58922, ALM-301, AP-185, AP-23675, AP-23841, apitolisib, ARQ-751, ASP-7486, AST-0669, AT-104, AT-13148 , AUM-302, AZD-3147, AZD-8055, AZD-8154, BAY-1001931, BAY-1125976, BAY-1125976, BGT-226, bimiralidib, BN-107, BN-108, borsertib, buformin, BVD-723, capivasertib, CC-115, CC-2141, CC-2142, Certican ODT, CL-27, COTI-2, CT-365, dactolisib tosylate, DC-120, DHM-25, dihydroartemisinin, DS-3078, DS-7423, duvelisib, EM-101 , everolimus, FP-208, FT-1518, FXY-1, galarmin, GDC-0349, gedatricisib, GM-6, GNE-317, GNE-555, GSK-690693, GT-0486, HD-148 series, HEC-68498, HM-032, HM-5016699, HMPL-518, ipatasertib, IPI-549, ISC-4, J-9, JRP-890, KIT-2014, KS-99, LD-101, lithium carbonate, LY-2503029, LY-2780301, M-2698, ME-344, milansertib mesylate , MK-2206, MKC-1, monetel, NISC-6, nPT-mTOR, NSC-765844, NV-128, onatasertib, ONC-201, ONC-222, ONC-235, OSU-53, OT-043, OT-043, P-7170, P-7170, PBD-1226, perifosine, PF-04691502, pimasertib hydrochloride + voxtalisib, PKI-179, PQR-311, PQR-316, PQR-401, PQR-4XX, PQR-514, PQR-530, PQR-620, PWT-33597, PX-316,Resilisib sodium, RES-529, Ridaforolimus, RMC-5552, RP-6503, RV-1729, RX-0183, RX-0201, RX-0201N, RX-0301, RX-1792, RX-8243, samotricisib, sapanisertib, SB-2602, SCC-31, SF-1126, SF-2523, SN-202, SPR-965, SR-13668, STP-503, SX-MTR1, TAFA-93, TAM-01, TAM-03, TAS-117, TASP-04159 14, TE-7105, temsirolimus, tenalisib, TOP-216, trametinib dimethylsulfoxide + uprosertib, triciribine phosphate, UB-1201, uprosertib, VCC-405567, VCC-668662, vistusertib, VLI-27, voxtalisib, VS-5584, WX-008, WXFL-10030390, X-387, X-414, X-480, XL-388, XL-418, XP-105, Y-31, Zortress, and any combination thereof.

[0052] Unless otherwise specified, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are for illustrative purposes only and are not intended to limit the invention. [Brief description of the drawings]

[0053] [Figure 1]FIG. 1 is a series of graphs showing the change in E0771 breast tumor volume over time in days in response to treatment of lean (FIGS. 1A and 1B) and obese (FIGS. 1A and 1C) mice with vehicle or compound 20 (denoted in the figures as compound A).

[0054] [Diagram 2] FIG. 2 is a series of graphs showing the change in body weight over time in lean (FIG. 2A) and obese (FIG. 2B) mice treated with vehicle or compound 20 (denoted as Compound A in the figures).

[0055] [Diagram 3] FIG. 3 is a series of graphs showing the weight changes in parametrial adipose tissue (FIG. 3A), inguinal adipose tissue (FIG. 3B), and retroperitoneal adipose tissue (FIG. 3C) in lean and obese mice treated with vehicle or compound 20 (denoted as Compound A in the figures).

[0056] [Figure 4] FIG. 4 is a series of graphs showing changes in leptin expression levels (FIG. 4A), adiponectin expression levels (FIG. 4B), and leptin / adiponectin ratio (LAR) (FIG. 4C) in lean and obese mice treated with vehicle or compound 20 (depicted as compound A in the figures).

[0057] [Diagram 5] FIG. 5 is a series of graphs showing changes in levels of immunosuppressive cytokines (such as IL10) in lean (FIG. 5A) and obese (FIG. 5B) mice treated with compound 20 (denoted as compound A in the figures).

[0058] [Figure 6-1] FIG. 6 is a plot and comparison graph showing changes in tumor suppressor myeloid-derived suppressor cells (MSDCs) in tumor cells of lean and obese mice treated with compound 20 (referred to as compound A in the drawings). [Figure 6-2]FIG. 6 is a plot and comparison graph showing changes in tumor suppressor myeloid-derived suppressor cells (MSDCs) in tumor cells of lean and obese mice treated with compound 20 (referred to as compound A in the drawings).

[0059] [Figure 7A] FIG. 7A shows images of immunohistochemical staining of EO771 mammary tumors from vehicle-treated obese mice for the Treg marker FoxP3.

[0060] [Figure 7B] FIG. 7B is an image of immunohistochemical staining for the Treg marker FoxP3 of EO771 mammary tumors from obese mice treated with compound 5 (denoted as compound A in the figures).

[0061] [Figure 8A] FIG. 8A is an image of immunohistochemical staining of EO771 mammary tumors from vehicle-treated obese mice for the tumor-associated macrophage enzyme Arg-1.

[0062] [Figure 8B] FIG. 8B is an image of immunohistochemical staining for the tumor-associated macrophage enzyme Arg-1 of EO771 mammary tumors from obese mice treated with compound 20 (denoted as compound A in the figures).

[0063] [Figure 9A] Figure 9A is a series of graphs showing serum leptin levels in cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 9A shows the change in leptin levels in ng / ml. [Figure 9B] Figure 9B is a series of graphs showing serum leptin levels in cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 9B shows the change in leptin levels as a % change compared to baseline.

[0064] [Figure 10A] Figure 10 is a series of graphs showing serum adiponectin levels in cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 10A shows the change in adiponectin levels in μg / ml. [Figure 10B] Figure 10 is a series of graphs showing serum adiponectin levels in cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 10B shows the change in adiponectin levels as a % change compared to baseline.

[0065] [Figure 11A] Figure 11 is a series of graphs showing leptin / adiponectin ratios in the serum of cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 11A shows the leptin / adiponectin ratio in ng / μg. [Figure 11B] Figure 11 is a series of graphs showing leptin / adiponectin ratios in the serum of cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 11B shows the leptin / adiponectin ratio as a percent change compared to baseline.

[0066] [Figure 12A] Figure 12 is a series of graphs showing levels of the pro-angiogenic marker VEGF-C in the serum of cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 12A shows the change in VEGF-C levels in pg / ml. [Figure 12B]Figure 12 is a series of graphs showing levels of the pro-angiogenic marker VEGF-C in the serum of cancer patients treated with Compound 20 (listed as Compound A in the drawings) as part of the SDX-101 clinical trial. Figure 12B shows the change in levels of VEGF-C as a % change compared to baseline.

[0067] [Figure 13A] Figure 13 is a series of graphs showing the levels of the pro-angiogenic and tumor-promoting marker IGF-1 in the serum of cancer patients treated with compound 20 (listed as compound A in the figures) as part of a clinical trial of SDX-101. Figure 13A shows the change in IGF-1 levels in ng / ml. [Figure 13B] Figure 13 is a series of graphs showing levels of the pro-angiogenic and pro-tumor marker IGF-1 in the serum of cancer patients treated with compound 20 (listed as compound A in the figures) as part of the SDX-101 clinical trial. Figure 13B shows the change in levels of IGF-1 as a % change compared to baseline.

[0068] [Figure 14A] Figure 14 is a series of graphs showing levels of the pro-angiogenic biomarker bFGF / FGF2 in the serum of cancer patients treated with compound 20 (listed as compound A in the drawings) as part of the SDX-101 clinical trial. Figure 14A shows the change in bFGF / FGF2 levels in pg / ml. [Figure 14B] Figure 14 is a series of graphs showing levels of the pro-angiogenic biomarker bFGF / FGF2 in the serum of cancer patients treated with Compound 20 (listed as Compound A in the drawings) as part of the SDX-101 clinical trial. Figure 14B shows the change in bFGF / FGF2 levels as a % change compared to baseline.

[0069] [Figure 15A]Figure 15 shows the effect of compound 20 (denoted as Compound A in the figures) on insulin levels in heavily treated cancer patients with baseline insulin >20 μU / ml. The graph shows absolute values ​​(Figure 15A). [Figure 15B] Figure 15 shows the effect of compound 20 (denoted as Compound A in the figures) on insulin levels given to cancer patients with multiple previous treatments and baseline insulin >20 μU / ml. The graph shows the % change (Figure 15B).

[0070] [Figure 16] Figure 16 shows the attenuation of glucose spikes in a mouse model of hyperglycemia with a PI3K inhibitor, where normal C57B1 / 6 mice were dosed with a PI3K inhibitor to induce hyperglycemia and pre-treated with compound 20 (depicted as compound A in the figures) for 10 days on a 4 day dosing schedule, or 24 hours prior to injection of the PI3K inhibitor, or 4 hours prior to injection of the PI3K inhibitor.

[0071] [Figure 17] FIG. 17 shows the time course of increasing apoptosis in the cultured human lymphoblastoid cell line TK6 seeded at 2×105 cells / ml and treated with the small molecule fumagillin derivatives of the present disclosure for 16 hours (top panel) or 24 hours (bottom panel).

[0072] [Figure 18] FIG. 18 shows that induction of caspase 3 / 7 markers of apoptosis increased over time (16 hours, top panel; 24 hours, bottom panel) in the cultured human lymphoblastoid cell line TK6 plated at 2×105 cells / ml and treated with the small molecule fumagillin derivatives of the present disclosure.

[0073] [Figure 19]Figure 19 shows that the insulin resistance calculated using the HOMA2-IR score method was improved overall in cancer patients treated with compound 20. Most of these late-stage cancer patients did not have obvious metabolic disorders, demonstrating the surprising effect of improving insulin resistance in cancer patients.

[0074] [Figure 20] FIG. 20 surprisingly shows that in metabolically normal mice that were suffering from hyperglycemia as a result of PI3K treatment, treatment with a combination of a drug from the PI3K class of therapeutics (BYL-719) and compound 20 (depicted in the drawing as compound A) reduced insulin over time.

[0075] [Figure 21] FIG. 21 surprisingly shows that treatment of metabolically normal mice that were suffering from hyperglycemia as a result of PI3K treatment with a combination of a drug from the PI3K class of therapeutics (BYL-719) and compound 20 (depicted in the figures as compound A) reduced C-peptide over time.

[0076] [Figure 22] FIG. 22 is a graph showing the volume change (% change from baseline) of MCF-7 tumors in mice treated with either vehicle control, 8 mg / kg of compound 20 (referred to as compound A), or 16 mg / kg of compound 20.

[0077] [Diagram 23] FIG. 23 is a graph showing the volume change (% change from baseline) of MCF-7 tumors in mice treated with vehicle control, 8 mg / kg of Compound 20 (referred to as Compound A), a combination of 8 mg / kg of Compound 20 and 25 mg / kg of BYL-719, or 25 mg / kg of BYL-719 alone.

[0078] [Figure 24]FIG. 24 is a graph showing the volume change (% change from baseline) of MCF-7 tumors in mice treated with vehicle control, 8 mg / kg of Compound 20 (referred to as Compound A), a combination of 8 mg / kg of Compound A and 45 mg / kg of BYL-719, or 45 mg / kg of BYL-719 alone.

[0079] [Diagram 25] FIG. 25 is a graph showing the change in tumor volume at day 37 in mice treated with either a vehicle control, compound 20 (referred to as compound A) alone, BYL-719 alone, or a combination of compound 20 and BYL-719.

[0080] [Figure 26] FIG. 26 is a graph showing glucose levels in mice treated with either compound 20 (referred to as compound A) alone, the AKT inhibitor AZD5363 alone, or a combination of compound 20 and AZD5363.

[0081] [Figure 27] FIG. 27 is a graph showing blood glucose levels in mice treated with vehicle control or the PI3K inhibitor BYL-719.

[0082] [Figure 28] FIG. 28 is a graph showing blood glucose levels in mice treated with either vehicle control, ZGN-1061 alone, BYL-719 alone, or a combination of ZGN-1061 and BYL-719. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] The present disclosure provides methods for inducing or causing favorable changes in cells and / or tissues and / or proteins that would otherwise block the clinical activity of various cancer therapeutics. In some aspects, the subject is overweight, obese, or metabolically impaired, either as a pre-existing condition or induced by some second agent.

[0084] The present disclosure provides a method for eliminating or preventing the negative systemic effects of some cancer therapies on the metabolic system of a patient. For example, some cancer therapies induce hyperglycemia and subsequently hyperinsulinemia, which may weaken the efficacy of the cancer therapy. The MetAP2 inhibitors of the present disclosure can eliminate or prevent the negative metabolic effects of these cancer therapies, thereby improving the outcome of cancer treatment in cancer patients in need of treatment. The method of the present disclosure includes administering at least one compound of the present disclosure, or a pharma- ceutical acceptable salt, prodrug, metabolite, analog, or derivative thereof, in a therapeutically effective amount according to a rational schedule to a subject to treat or improve these causative disease modifiers and improve the outcome of treatment.

[0085] The present disclosure also provides a method of altering the tumor microenvironment in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, in a therapeutically effective amount according to a rational schedule, thereby enhancing the efficacy of a concomitant therapy to treat or ameliorate such a disease or condition.

[0086] The present disclosure also provides methods for reducing several pro-angiogenic factors associated with obesity or cancer. Herein, we show for the first time that MetAP2 inhibitors can also suppress angiogenesis through systemic reduction of the pro-angiogenic factors VEGF-C, bFGF, and IGF-1.

[0087] How to use The present disclosure provides a method for treating or ameliorating at least one symptom of a proliferative disorder in a subject in need thereof, comprising administering to the subject at least one MetAP2 inhibitor in a therapeutically effective amount, and reducing the expression of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, VEGF-C, IGF-1, bFGF in the tumor, or in the tumor microenvironment, or in the plasma, or in any combination thereof, of the subject having cancer. In a preferred aspect, the proliferative disorder is cancer. The cancer can be any of HR+ / Her2- breast cancer, triple negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The subject may be an overweight or obese subject. The subject may have a metabolic disorder, including excess visceral fat, elevated leptin levels, decreased adiponectin levels, high leptin to adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin associated with chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. The metabolic disorder is preferably low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. The method of the present disclosure may include treating or ameliorating at least one symptom of a metabolic disorder in addition to treating or ameliorating at least one symptom of a proliferative disorder.

[0088] The present disclosure provides a method for treating or improving at least one symptom of a metabolic disorder related to a cancer therapy of a subject, comprising administering to the subject at least one therapeutically effective amount of a MetAP2 inhibitor.The cancer can be HR+ / Her2- breast cancer, triple negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, or multiple myeloma.The subject can also be an overweight or obese subject.The metabolic disorder can include excess visceral fat, elevated leptin levels, reduced adiponectin levels, high leptin to adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin associated with chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. Preferably, the metabolic disorder is low adiponectin, elevated leptin, elevated fasting insulin, hyperglycemia, or a combination thereof. In addition to treating or ameliorating at least one symptom of a proliferative disorder, the methods of the present disclosure can also include treating or ameliorating at least one symptom of a metabolic disorder.

[0089] The present disclosure provides a method for reducing expression of IL-10 in the systemic circulation (i.e., blood, plasma, or serum) or in a tumor in a subject having cancer, comprising administering to a subject having a metabolic disorder at least one MetAP2 inhibitor in a therapeutically effective amount, thereby reducing expression of IL-10 in the tumor or plasma in the subject having cancer.

[0090] The present disclosure provides a method for reducing expression of arginase-1 in a tumor, or in the tumor microenvironment, or in the systemic circulation (i.e., blood, plasma, or serum) of a subject having cancer, comprising administering to a subject having a metabolic disorder at least one MetAP2 inhibitor in a therapeutically effective amount, thereby reducing expression of arginase-1 in the tumor or plasma of the subject having cancer.

[0091] The present disclosure provides a method for reducing expression of myeloid-derived suppressor cells in a tumor or in the systemic circulation (i.e., blood) of a subject having cancer, comprising administering to a subject having a metabolic disorder a therapeutically effective amount of at least one MetAP2 inhibitor, thereby reducing expression of myeloid-derived suppressor cells in the tumor, or in the tumor microenvironment, or in the plasma of the subject having cancer.

[0092] The present disclosure provides a method for reducing expression of regulatory T cells in a tumor or in the systemic circulation (i.e., blood) of a subject having cancer, comprising administering to a subject having a metabolic disorder a therapeutically effective amount of at least one MetAP2 inhibitor, thereby reducing expression of regulatory T cells in the tumor, or in the tumor microenvironment, or in the plasma of the subject having cancer.

[0093] The present disclosure provides a method for reducing leptin expression in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one MetAP2 inhibitor, thereby reducing leptin expression in the tumor, or tumor microenvironment, or plasma of the subject having cancer.

[0094] The present disclosure provides a method for reducing expression of a growth factor in a tumor or in the systemic circulation (i.e., blood, plasma, or serum) of a subject with cancer, comprising administering to a subject with a metabolic disorder at least one MetAP2 inhibitor in a therapeutically effective amount to reduce expression of a growth factor in the tumor, or in the tumor microenvironment, or in the plasma of the subject with cancer. The growth factor can be VEGF-C, IGF-1, bFGF, or a combination thereof.

[0095] The present disclosure provides a method of treating or ameliorating at least one symptom of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or derivative, or a reversible MetAP2 inhibitor to reduce expression of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, insulin, VEGF-C, IGF-1, bFGF, and / or increase the level of the hormone adiponectin in the tumor, or in the tumor microenvironment, or in the plasma in the subject having cancer.

[0096] The present disclosure provides a method for treating or ameliorating at least one symptom of a metabolic disorder associated with cancer treatment in a subject having cancer, comprising administering to the subject at least one fumagillin analog, or fumagillin derivative, or fumagillin conjugate in a therapeutically effective amount, thereby treating or ameliorating at least one symptom of a metabolic disorder associated with cancer treatment in the subject.

[0097] The present disclosure provides a method for reducing expression of IL-10 in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or fumagillin derivative to reduce expression of IL-10 in the tumor, or in the tumor microenvironment, or in the plasma of the subject having cancer.

[0098] The present disclosure provides a method for reducing expression of arginase-1 in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or fumagillin derivative to reduce expression of arginase-1 in the tumor, or in the tumor microenvironment, or in the plasma of a subject having cancer.

[0099] The present disclosure provides a method for reducing expression of myeloid-derived suppressor cells in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or fumagillin derivative to reduce expression of myeloid-derived suppressor cells in the tumor, or tumor microenvironment, or plasma of the subject having cancer.

[0100] The present disclosure provides a method for reducing expression of regulatory T cells in a tumor or plasma of a subject having cancer, comprising administering to the subject at least one fumagillin analog or fumagillin derivative in a therapeutically effective amount to reduce expression of regulatory T cells in the tumor, or plasma, or tumor microenvironment of the subject having cancer.The present disclosure provides a method for reducing expression of leptin in a tumor or plasma of a subject having cancer, comprising administering to the subject at least one fumagillin analog or fumagillin derivative in a therapeutically effective amount to reduce expression of leptin in the tumor, or tumor microenvironment, or plasma of the subject having cancer.

[0101] The present disclosure provides a method for reducing expression of a growth factor in a tumor or in plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or derivative to reduce expression of a growth factor in the tumor, or in the tumor microenvironment, or in plasma of the subject having cancer, the growth factor being VEGF-C, IGF-1, bFGF, or a combination thereof.

[0102] The present disclosure provides a method of treating or ameliorating at least one symptom of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure to reduce expression of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSC), regulatory T cells, leptin, insulin, VEGF-C, IGF-1, bFGF in the tumor, or in the tumor microenvironment, or in the plasma in a subject having cancer.

[0103] The present disclosure provides a method for treating or ameliorating at least one symptom of a metabolic disorder associated with cancer treatment in a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, thereby treating or ameliorating at least one symptom of a metabolic disorder associated with cancer treatment in a subject having cancer.

[0104] The present disclosure provides a method for reducing expression of IL-10 in a tumor or in plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, thereby reducing expression of IL-10 in the tumor, or in the tumor microenvironment, or in plasma in a metabolically disturbed subject having cancer.

[0105] The present disclosure provides a method for reducing expression of Arginase-1 in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, thereby reducing expression of Arginase-1 in the tumor, or in the tumor microenvironment, or in the plasma of the subject having cancer.

[0106] The present disclosure provides a method for reducing expression of myeloid-derived suppressor cells in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, thereby reducing expression of myeloid-derived suppressor cells in the tumor, or tumor microenvironment, or plasma of the subject having cancer.

[0107] The present disclosure provides a method for reducing expression of regulatory T cells in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, thereby reducing expression of regulatory T cells in the tumor, or in the tumor microenvironment, or in the plasma of the subject having cancer.

[0108] The present disclosure provides a method for reducing expression of a growth factor in a tumor or plasma of a subject having cancer, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure to reduce expression of a growth factor in the tumor, or in the tumor microenvironment, or in the plasma of the subject having cancer. The growth factor can be VEGF-C, IGF-1, bFGF, or a combination thereof.

[0109] Obesity has been identified as a risk factor for breast cancer, and excess visceral adipose tissue is associated with a worse response to chemotherapy and delayed progression, and / or disease-free survival (Schaffler, A. et al. (2007) Nat Clin Pract Endocrinol Metab 3:345-354; Vona-Davis, L. Rose, D P. (2007) Endocr Relat Cancer 14:189-206). Adipose tissue-derived factors (e.g., leptin, adiponectin, aromatase, IL-6) have been proposed as possible mediators of the obesity-breast cancer link, with recent data highlighting the adipokines leptin and adiponectin (Cleary, M P. et al. (2009) Front Biosci (School Ed) 1:329-357; Cleary, M P. et al. (2010) Vet Pathol 47:202-213). The molecular basis supporting the role of leptin, adiponectin, and other hormones (e.g., insulin, insulin-like growth factor) has recently been reported. Circulating adiponectin levels are inversely correlated with body mass index (BMI) whereas serum leptin is positively correlated with BMI (Ryan, A S. et al. (2003) Diabetes Care 26:2383-2388; Wauters, M. et al. (2000) Eur J Endocrinol 143:293-311). Obese individuals, especially those with high visceral fat mass, have reduced levels of adiponectin (Brochu-Gaudreau K et al. Endocrine 2010;37(1):11-32). Adiponectin is found in human serum at concentrations between 2 and 20 μg / ml (Grossmann, M E. et al. (2008) Br J Cancer 98:370-379).The mechanisms underlying adiponectin signaling and cancer prevention are thought to involve activation of the intracellular signal AMPK and inhibition of proliferation and survival pathways (Brochu-Gaudreau K et al. Endocrine 2010;37(1):11-32; Pfeiler G et al. Maturitas 2009;63(3):253-256). In addition, adiponectin exerts its biological activities indirectly through selective sequestration of various growth factors (e.g. basic fibroblast growth factor, platelet-derived growth factor BB, heparin-binding epidermal growth factor) and inhibition of normal receptor binding. These interactions involve specific oligomeric forms of adiponectin (Barb, D., Williams, C J., Neuwirth, A K., Mantzoros, C S. (2007) Am J Clin Nutr 86:858-s866; Wang et al. (2005) J Biol Chem 280:18341-18347).

[0110] Several epidemiological studies have found an inverse association between adiponectin levels and breast cancer risk (Barb et al. (2007) Am J Clin Nutr 86:858-866; Miyoshi et al. (2003) Clin Cancer Res 9:5699-5704; Mantzoros et al. (2004) J Clin Endocrinol Metab 89:1102-1107; Chen, D C. et al. (2006) Cancer Lett 237:109-114). In breast cancer patients, adiponectin levels and adiponectin-to-leptin ratios tend to be lower than those found in lean women (Cleary M P. et al. (2009) Front Biosci (Schol Ed) 1:329-357; Cleary, M P. et al. (2006) Cancer Lett 237:109-114). Breast cancer patients with lower adiponectin levels have been reported to have more aggressive tumors and a higher frequency of lymph node metastasis (Schaffler, A. et al. (2007) Nat Clin Pract Endocrinol Metab 3:345-354; Hou, W K. et al. (2007) Chin Med J (Engl) 120:1592-1596).

[0111] In one aspect, the disclosure provides a method of treating certain types of tumors exacerbated by metabolic disorders, including HR+ / Her2- breast cancer, triple negative breast cancer, Her2+ breast cancer, invasive breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, acute myeloid leukemia, utilizing at least one MetAP2 inhibitor, and / or at least one fumagillin analog or derivative, and / or at least one compound of the disclosure. In a preferred aspect, the method of the present invention discloses the subcutaneous administration of a MetAP2 inhibitor to a cancer patient with a pre-existing metabolic disorder or a metabolic disorder induced by treatment. The metabolic disorders may include excess visceral fat, elevated leptin levels, decreased adiponectin levels, a large leptin to adiponectin ratio, elevated fasting insulin levels associated with chronic inflammation, hyperglycemia, elevated HbA1c, or any combination thereof. The methods of the present invention may restore the patient to a more metabolically neutral and stable state, slowing or reversing the progression of the patient's cancer.

[0112] Described herein is a method for improving underlying metabolic disorders in patients with metabolically sensitive tumors. The method for treating tumors includes increasing adiponectin levels, decreasing leptin levels, improving (reducing) leptin to adiponectin ratio, decreasing insulin levels, decreasing fasting glucose levels, or a combination thereof. Subcutaneous administration of MetAP2 inhibitors as described herein has been demonstrated to have the ability to improve these levels and ratios in cancer patients, and can be used to treat metabolically sensitive tumors to benefit from upregulation of adiponectin as well as improved leptin and insulin sensitivity. Thus, in some aspects, the MetAP2 inhibitors described herein can treat cancers including hormone receptor positive (HR+) breast cancer, triple negative breast cancer, Her2+ breast cancer, castration resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, acute myeloid leukemia, or a combination thereof, which may be related, at least in part, to adiponectin insufficiency and / or adiponectin resistance.

[0113] The present disclosure also provides a method of treating cancer in a subject in need of treatment, the method comprising the steps of: (i) identifying a patient with hormone receptor positive (HR+) breast cancer, triple negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, acute myeloid leukemia; (ii) determining whether the cancer patient has a metabolic disorder; and (iii) administering a therapeutically effective amount of at least one MetAP2 inhibitor, or at least one fumagillin analog or derivative, or at least one compound of the present disclosure, if the subject is identified as having one of the cancers in step (i) and the metabolic disorder in step (ii). The subject is preferably administered a compound of the present disclosure. The compound is preferably administered subcutaneously. The metabolic disorder may include excess visceral fat, elevated leptin levels, decreased adiponectin levels, large leptin to adiponectin ratio, elevated fasting insulin levels associated with chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. The metabolic disorder is preferably low adiponectin, elevated leptin, elevated fasting insulin, hyperglycemia, or a combination thereof. The method of the present disclosure may include treating or improving at least one symptom of a metabolic disorder in addition to treating cancer.

[0114] In another aspect, the disclosure provides a method for determining whether a tumor is metabolically sensitive, the method comprising: (1) identifying the tumor type as one from a list of known metabolically sensitive tumors (meningioma, thyroid cancer, esophageal adenocarcinoma, liver cancer, gallbladder cancer, GIST, pancreatic cancer, kidney cancer, CRC, prostate cancer, multiple myeloma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer); (2) measuring the patient's fasting insulin and glucose levels to determine a HOMA score (level of insulin sensitivity); (3) comparing the HOMA score to a HOMA score of a lean patient; and (4) determining that the HOMA score level is higher than a metabolically normal level, the cancer is sensitive to treatment with at least one MetAP2 inhibitor, or at least one fumagillin analog or derivative, or at least one compound of the disclosure.

[0115] In another aspect, the present disclosure provides a method of applying MetAP2 inhibitors simultaneously with the treatment of inducing metabolic disorder.The treatment can be cancer treatment.The therapeutic agent can be any of PI3K inhibitors, AKT inhibitors, mTOR inhibitors, PI3K / AKT / mTOR pathway inhibitors, or any combination thereof.

[0116] As used herein, a "subject in need thereof" is a subject having a cell proliferative disorder or at increased risk compared to the general population for developing a cell proliferative disorder. A subject in need thereof may have a pre-cancerous condition (such as hyperplasia). Preferably, a subject in need thereof has cancer or metastasis from a primary cancer mass, or a hematological cancer. Preferably, a subject having a cell proliferative disorder also has a pre-existing metabolic disorder, or a metabolic disorder induced by treatment.

[0117] A "subject" includes a mammal. The mammal can be, for example, any mammal, such as a human, a primate, a mouse, a rat, a dog, a cat, a cow, a horse, a goat, a rabbit, a camel, a sheep, or a pig. Preferably, the mammal is a human. The terms "subject" and "patient" are used interchangeably herein.

[0118] As used herein, the term "cell proliferative disorder" refers to a condition in which uncontrolled and / or abnormal cell proliferation leads to the development of an unwanted condition or disease, which may or may not be cancer. Representative cell proliferative disorders of the present disclosure include a variety of conditions in which cell division is disrupted. Non-limiting examples of representative cell proliferative disorders include neoplasms, benign tumors, malignant tumors, precancerous conditions, intraepithelial neoplasia, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancer, carcinoma, leukemia, lymphoma, B-cell lymphoma, sarcoma, and rapidly dividing cells. As used herein, the phrase "rapidly dividing cells" is defined as any cell that is dividing at a rate that exceeds or is greater than the rate expected or observed in nearby or adjacent cells in the same tissue. Cell proliferative disorders include precancers or precancerous conditions. Cell proliferative disorders include cancers or metastases from a primary cancer mass. Cell proliferative disorders include noncancerous conditions or disorders. The methods presented herein are preferably used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematological tumors, and / or malignant tumors or metastases from or derived from a primary cancer mass. A "precancerous cell" or "precancerous cell" is a cell that exhibits a cell proliferation disorder that is a precancer or precancerous condition. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferation disorder that is cancer. As used herein, the terms "metastasis," "metastatic cancer," and "metastatic lesion" refer to the development of a secondary malignant growth at a location distant from the primary site of cancer. Any reproducible means of measurement can be used to identify cancer or precancerous cells. Cancer or precancerous cells can be identified by histological typing or grading of tissue samples (e.g., biopsy samples) or by evidence of DNA mutations. Cancer or precancerous cells can be identified using appropriate molecular markers.

[0119] Representative cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, B-cell lymphoma, anal cancer, anorectal cancer, anal canal cancer, anal squamous cell carcinoma, angiosarcoma, appendix cancer, childhood cerebellar astrocytoma, childhood cerebellar astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, bladder cancer, bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebellar astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic tract and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal cancer, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system cancer, Central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasms, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastic tumor glioma, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (pancreatic endocrine tissue), Kaposi's sarcoma, kidney cancer, renal cancer, pharyngeal cancer, acute lymphoblastic leukemia, T-cell lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, cancer of the lip and oral cavity, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the lung, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia , medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the head and neck, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet tumor cancer, pancreatic endocrine tumor, paranasal sinus and nasal cavity cancer, parathyroid cancer, bile duct cancer, penile cancer, pharyngeal cancer,Pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pituitary adenoma, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family sarcoma tumor, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis, ureter and other urinary tracts, gestational trophoblastic tumor, urethral cancer, endometrial and uterine cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor.

[0120] A "cell proliferative disorder of the hematopoietic system" is a cell proliferative disorder involving cells of the hematopoietic system. Cell proliferative disorders of the hematopoietic system can include lymphoma, B-cell lymphoma, leukemia, myeloid neoplasm, mast cell neoplasm, myelodysplasia, benign monoclonal globulinemia, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, primary myelofibrosis, and essential thrombocythemia. Cell proliferative disorders of the hematopoietic system can include hematopoietic hyperplasia, dysplasia, and metaplasia. The compositions of the present disclosure are preferably used to treat a cancer selected from the group consisting of blood cancers of the present disclosure and hematopoietic cell proliferative disorders of the present disclosure. Hematological cancers of the present disclosure can include multiple myeloma, lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, lymphomas of lymphoid and cutaneous origin), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0121] The cancer to be treated may be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) is assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, T4d; the regional lymph nodes (N) are assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, N3c; and the distant metastases (M) are assigned a stage of MX, M0, M1. The cancer to be treated may be staged according to the American Joint Committee on Cancer (AJCC) classification as stage I, stage IIA, stage IIB, stage IIIA, stage IIIB, stage IIIC, stage IV. The cancer to be treated may be assigned a grade according to the AJCC classification as grade GX (e.g., grade cannot be assessed), grade 1, grade 2, grade 3, grade 4. Cancers to be treated can be staged according to the AJCC classification (pN): pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1 (mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, pN3c.

[0122] The cancers to be treated can include tumors determined to be about 2 centimeters or less in diameter. The cancers to be treated can include tumors determined to be about 2 centimeters to about 5 centimeters in diameter. The cancers to be treated can include tumors determined to be about 3 centimeters or more in diameter. The cancers to be treated can include tumors determined to be more than about 5 centimeters in diameter. The cancers to be treated can be classified as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated under a microscope. The cancers to be treated can be classified by microscopic mitotic count (e.g., amount of cell division) or nuclear pleomorphism (e.g., changes within cells). The cancers to be treated can be classified by microscopic correlation with area of ​​necrosis (e.g., area of ​​dying or degenerating cells). The cancers to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having an abnormally appearing single chromosome. The cancers to be treated can be classified as being aneuploid, triploid, tetraploid, or having an altered ploidy. Cancers to be treated can be classified as having a chromosomal rearrangement, having a deletion or duplication of an entire chromosome, or having a deletion, duplication, or amplification of part of a chromosome.

[0123] The cancer to be treated can be assessed by DNA cytometry, flow cytometry, or image cytometry. The cancer to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthetic phase of cell division (e.g., S phase of cell division). The cancer to be treated can be typed as having low S phase or high S phase.

[0124] As used herein, a "normal cell" is a cell that cannot be classified as part of a "cell proliferative disorder." A normal cell lacks uncontrolled and / or abnormal proliferation that leads to the development of an unwanted condition or disease. A normal cell preferably has normally functioning cell cycle checkpoint mechanisms.

[0125] As used herein, "contacting a cell" means that a compound or other composition of the disclosure is in direct contact with a cell or in sufficient proximity to induce a desired biological effect in the cell.

[0126] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also treat or alleviate a variety of related disorders.

[0127] In particular, the compounds of the present disclosure can treat or alleviate at least one symptom of one or more proliferative disorders, as well as treat or alleviate at least one metabolic disorder selected from the group consisting of excess visceral fat, elevated leptin levels, reduced adiponectin levels, high leptin to adiponectin ratio, elevated fasting insulin levels associated with chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof.Preferably, the metabolic disorder to be treated or alleviated is low adiponectin, elevated leptin, elevated fasting insulin, hyperglycemia, or a combination thereof.

[0128] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the disclosure may also treat or alleviate at least one symptom of obesity or a metabolic disorder induced by the treatment.

[0129] The compounds of the present disclosure can treat or alleviate at least one symptom of one or more proliferative disorders, and can also reduce body weight.In some aspects, the subject is overweight or obese.In some aspects, the subject needs to reduce excess adipose tissue.Preferably, the adipose tissue to be reduced is visceral adipose tissue, or the adipose tissue in the vicinity of tumor or metastasis.

[0130] Obesity and overweight refer to an excess of fat in a subject in proportion to lean body mass. Excessive fat accumulation is associated with an increase in the size (hypertrophy or adiposity) as well as the number (hyperplasia) of the cells of adipose tissue. Obesity can result from any number of genetic (e.g. Prader-Willi syndrome) or environmental causes. Obesity is variously measured in terms of absolute weight, weight:height ratio, degree of excess body fat, and distribution of visceral or subcutaneous fat. One common indicator of body fat is the body mass index (BMI). BMI refers to the ratio of weight in kilograms to height in meters squared. Body mass index is calculated using the formula in SI units: BMI = weight (kg) / height. 2 (m 2 ), or in US units: BMI = weight (lbs) x 703 / height 2 (inch 2 ) can be used to calculate it accurately.

[0131] As used herein, "overweight" is defined as a BMI of 25 kg / m 2 ~29.9 kg / m 2 As used herein, "obese" or "obesity" refers to a condition in an otherwise healthy adult with a BMI above 30 kg / m 2 It refers to the state of an otherwise healthy adult. There are several subcategories of obesity. A BMI of 35 kg / m 2 Adults with a BMI of 40–44.9 kg / m2 are said to be "severely obese" or "severely obese." 2 Adults with a BMI of 35 kg / m or greater 2Adults with a BMI over 45 kg / m2 and at least one obesity-related health condition are said to be "morbidly obese" or "morbidly obese." 2 Adults who are overweight are referred to as "super obese" or "very obese." For children, the definitions of overweight and obesity take into account the effects of age and sex on body fatness.

[0132] Different countries may define obesity and overweight using different BMIs. The term "obesity" encompasses all national definitions. For example, the increased risk associated with obesity occurs at lower body mass indexes (BMIs) in Asian countries. In Asian countries, including Japan, "obesity" is defined as a BMI of 25.0 kg / m2 or more in subjects who need to lose weight or who have at least one obesity-induced or obesity-related comorbidity that would be improved by weight loss. 2 South and Central Americans tend to be classified closer to Asian than to European or North American.

[0133] BMI does not take into account the fact that excess adipose tissue may occur selectively in different parts of the body, so that the development of adipose tissue in one part of the body than in another part of the body may be more dangerous to health. For example, "central obesity" is typically associated with an "apple-shaped" body, which is the result of excess fat, especially in the abdominal region (which includes abdominal fat and visceral fat), and is associated with a greater risk of comorbidities than "peripheral obesity" (which is typically associated with a "pear-shaped" body, which is the result of excess fat, especially in the buttocks). One indicator of central obesity is the measurement of waist-to-hip circumference (WHR). The minimum WHR that indicates central obesity has been set at various levels, with adults with central obesity typically having a WHR of approximately 0.85 or greater in women and 0.9 or greater in men.

[0134] A method that considers the ratio of excess adipose tissue to lean body mass to determine whether a subject is obese or overweight can include obtaining a subject's body composition. Body composition can be obtained by measuring the thickness of subcutaneous fat in multiple locations on the body (such as the abdominal region, subscapular region, arms, buttocks, and thighs). These measurements are then used to estimate total body fat with an error of about 4%. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of electrical current flowing through the body to estimate body fat. Another method is to measure the buoyancy of the body using a large tank of water. More body fat makes you more buoyant, but more muscle mass tends to sink. Another method is fan-beam dual-energy x-ray absorptiometry (DEXA). DEXA allows for non-invasive determination of body composition, particularly the weight of total body fat and / or regional fat. MRI can also be used to non-invasively determine composition.

[0135] In other cases, the present invention can alleviate the symptoms of a metabolic disorder induced by a second therapy or other agent. In a preferred embodiment, the other agent is a PI3K inhibitor, an AKT inhibitor, or an mTOR inhibitor.

[0136] In other cases, the subject may be pre-treated with a compound of the invention for 1 hour, 4 hours, 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or up to about 8 weeks.

[0137] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce adipocytes or adipose tissue.Reducing adipocytes means reducing the number or size (fat mass) of adipocytes.In some aspects, the compounds of the present disclosure shrink the adipocytes of a subject.The adipose tissue can be white adipose tissue or brown adipose tissue.

[0138] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also reduce waist circumference. Waist circumference is measured by wrapping a tape measure around the abdomen 1 cm above the iliac crest. A subject of the present disclosure may lose between about 1 inch and about 20 inches in waist circumference (e.g., any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 inches).

[0139] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also reduce body fat and substantially maintain the muscle mass of the patient.In some aspects, when administered, fat oxidation increases in the patient compared to the patient who is only restricted in dietary intake.Such patients can maintain substantially more muscle mass compared to the body fat reduction in the patient who is only utilizing an energy-restricted diet.

[0140] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also lower one or both of insulin and leptin levels in a subject.In some aspects, the subject is overweight or obese and has elevated fasting insulin and / or leptin.In some aspects, the subject needs to reduce excess adipose tissue.

[0141] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also improve surgical outcomes. It includes administering at least one compound of the present disclosure in a therapeutically effective amount to a subject before surgery to improve surgical outcomes. In some aspects, administration reduces liver fat and / or abdominal fat in the patient, improving surgical outcomes. In some aspects, the surgery is a non-emergency surgery. Such surgery can include weight loss surgery, cardiovascular surgery, abdominal surgery, and orthopedic surgery.

[0142] As used herein, "monotherapy" refers to administering a single active or therapeutic compound of the present disclosure to a subject in need thereof. For example, a cancer monotherapy using one of the compounds of the present disclosure, or any of its pharmacologic acceptable salts, prodrugs, metabolites, analogs, or derivatives, is administered to a subject in need of cancer treatment. Monotherapy can be contrasted with combination therapy, which is the administration of a combination of multiple active compounds, as described below. In one aspect, monotherapy using a compound of the present disclosure, or any of its pharmacologic acceptable salts, prodrugs, metabolites, polymorphs, or solvates, is more effective than combination therapy in inducing a desired biological effect.

[0143] As used herein, "combination therapy" or "co-therapy" includes administering at least two compounds of the present disclosure, or any of their pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, as part of a particular treatment regimen to provide beneficial effects from the synergy of the at least two compounds of the present disclosure. Non-limiting examples of beneficial effects of the combination include synergy resulting from the combination of the at least two compounds of the present disclosure in terms of pharmacokinetics or pharmacodynamics. The administration of the at least two compounds of the present disclosure in combination is typically performed over a period of time (usually minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" may include the administration of two or more compounds of the present disclosure as part of separate monotherapy regimens that coincidentally result in the combination of the present disclosure, but this is generally not the case.

[0144] "Combination therapy" also includes the application of the disclosed compound in combination with a second active agent and / or non-drug therapy (e.g., exercise, diet, surgery, radiation therapy).When combination therapy further includes a non-drug therapy, the non-drug therapy can be performed at any appropriate time, as long as the beneficial effect from the synergistic action of the combination of the therapeutic agent and the non-drug therapy is achieved.For example, in appropriate cases, when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, the beneficial effect is still achieved, perhaps for several days or even weeks.The second active agent can be conjugated with a polymer.

[0145] "Combination therapy" includes sequential administration of the therapeutic agents (each therapeutic agent is administered at a different time), as well as substantially simultaneous administration of the therapeutic agents or at least two of the therapeutic agents. A substantially simultaneous manner, as used herein, refers to administration of at least two therapeutic agents within 2 hours of each other. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single composition with a fixed ratio of each therapeutic agent, or by administering separate capsules containing each of the therapeutic agents. A sequential manner, as used herein, refers to administration of one of the at least two therapeutic agents more than 2 hours after administration of the other of the at least two therapeutic agents. In sequential administration, it is preferred that one of the at least two therapeutic agents is administered at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, at least 1 week, at least 2 weeks, at least 4 weeks, or at least 8 weeks after administration of the other therapeutic agent. The sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, subcutaneous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent of the selected combination can be administered by subcutaneous injection, while the other therapeutic agent of the combination can be administered orally or intravenously. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by subcutaneous injection. The order in which the therapeutic agents are administered is not critical for some agents.

[0146] In a preferred aspect, the second active agent is a chemotherapeutic or targeted agent. Additional chemotherapeutic or targeted agents (also called anti-neoplastic or anti-proliferative agents) can include, in a preferred embodiment, 5FU or an oral version thereof, or capecitabine, or an agent from the PI3K, AKT, mTOR class of drugs.

[0147] In some aspects, the second active agent is a compound that induces metabolic disorders. In some aspects, the second active agent is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / AKT / mTOR pathway inhibitor. In some aspects, the second active agent is alpelisib / BYL-719, AZD5363 (capavasertib), everolimus, or any combination thereof.

[0148] In some aspects, BYL-719 can be administered to a patient orally (by mouth, PO). In some aspects, BYL-719 can be administered once daily. In some aspects, BYL-719 can be administered in an amount of 150 mg per day. In some aspects, BYL-719 can be administered in an amount of 200 mg per day. In some aspects, BYL-719 can be administered in an amount of 250 mg per day. In some aspects, BYL-719 can be administered in an amount of 300 mg per day.

[0149] The present disclosure provides a method of treating or ameliorating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one PI3K inhibitor.

[0150] In some aspects of the methods of the present disclosure, the at least one MetAP2 inhibitor can be ZGN-1061. ZGN-1061 has the following structure: [ka] has.

[0151] In some aspects of the disclosed methods, the at least one MetAP2 inhibitor can be beloranib. Veroranib has the following structure: [ka] has.

[0152] In some aspects of the methods of the present disclosure, the at least one PI3K inhibitor can be seravelisib (TAK-117). Seravelisib (TAK-117) has the following structure: [ka] has.

[0153] In some aspects of the methods of the present disclosure, the at least one PI3K inhibitor can be BYL-719. BYL-719 has the following structure: [ka] has.

[0154] In some aspects of the methods of the present disclosure, non-limiting examples of MetAP2 inhibitors can include A832234, JNJ4929821, triazolopyrimidine, A357300, LAF389, indazole, triazole fumagarone, ZGN-1061, CKD-732, XMT-1191, TNP-470, PPI-2458, or any combination thereof.

[0155] In some aspects of the disclosure, the MetAP2 inhibitor has the following structure: [ka] [ka] [ka] The present invention can have either

[0156] In another aspect of the present disclosure, the severity describes the extent to which the tumor secretes growth factors, degrades the extracellular matrix, becomes vascularized, and is no longer attached to adjacent tissues. Additionally, the severity describes the number of locations to which the primary tumor has metastasized. Finally, the severity includes the difficulty of treating tumors of various types and locations. In this context, delaying cancer recurrence, slowing cancer progression, extending the subject's life expectancy, and / or reducing pain and / or improving quality of life, reducing the proportion of cancerous cells or restricting the cells to one system, cancer stage / tumor grade / histological grade / nuclear grade are considered to alleviate the signs or symptoms of cancer.

[0157] As used herein, the term "symptom" is defined as any sign of disease, illness, injury, chronic discomfort, acute discomfort, or that something is not going well within the body. Symptoms are felt or noticed by the individual experiencing them, but are not easily noticeable by a third party, which is defined as someone other than a health care professional.

[0158] The term "sign" is also defined herein as an indication that something is not going well in the body. A sign is defined as something that a doctor, nurse, or other health care professional can see.

[0159] Cancer is a group of diseases that can cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, the stage of the cancer, and how much the cancer affects nearby organs or structures. If the cancer spreads (metastasizes), signs or symptoms may appear in different parts of the body.

[0160] As cancer grows, it begins to put pressure on nearby organs, blood vessels, and nerves. This pressure causes some of the signs and symptoms of cancer. If the cancer is in a vital area (such as some parts of the brain), even the smallest tumors can cause early symptoms, which can be hard to detect.

[0161] Cancer may begin in one location and not cause any symptoms there until it grows to a significant size or progresses to an advanced stage. For example, pancreatic cancer usually never grows large enough to be detected from outside the body. Some pancreatic cancers do not cause symptoms until they begin to grow around nearby nerves. Other pancreatic cancers grow around the bile ducts and block the flow of bile, causing the skin to turn yellow (known as jaundice). By the time pancreatic cancer causes these signs and symptoms, it has usually reached an advanced stage.

[0162] Cancer can also cause symptoms such as fever, fatigue, and unwanted weight loss. This may be because cancer cells induce a systemic pro-inflammatory state, or use up much of the body's energy supply, or release substances that alter the body's metabolism (e.g., the hypermetabolic state known as cachexia), or they may result from an immune system response to the cancer.

[0163] Cancer cells release substances into the bloodstream that can sometimes cause symptoms not normally thought to result from cancer. For example, some cancers of the pancreas release substances that cause blood clots to develop in the veins of the legs. Some lung cancers produce hormone-like substances that affect the nerves and muscles, causing weakness and dizziness.

[0164] Cancer exhibits several common signs or symptoms that occur when various subtypes of cancer cells are present. Most people with cancer will lose weight at some time during their disease. Unexplained (unintentional) weight loss of 10 pounds or more may be the first sign of cancer, especially of the pancreas, stomach, esophagus, and lungs.

[0165] Fever is very common in cancer, but is more frequent as the disease progresses. Nearly all patients with cancer will have a fever at some point, especially when the cancer or its treatment affects the immune system and makes it harder for the body to fight infection. Less commonly, fever can be an early sign of cancer, such as leukemia or lymphoma.

[0166] Fatigue can be an important symptom as cancer progresses, but it can occur earlier in some cancers, such as leukemia, or when the cancer is causing blood loss, as in some colon and stomach cancers.

[0167] Pain can be an early symptom of some cancers (e.g. bone cancer, testicular cancer), but pain is most often a symptom of advanced disease.

[0168] In addition to skin cancer, some internal cancers can cause visible skin signs. These changes include darker looking skin (hyperpigmentation), yellow looking skin (jaundice), or red looking skin (erythema); itching; and excessive hair growth.

[0169] Alternatively, or in addition, different subtypes of cancer show special signs or symptoms. Changes in bowel habits or bladder function may tell you about cancer. Long-term constipation, diarrhea, or changes in stool size may be signs of colorectal cancer. Painful urination, blood in the urine, or changes in bladder function (such as urinating more or less frequently) may be related to bladder or prostate cancer.

[0170] Changes in the skin condition, or the appearance of a new skin condition, may indicate cancer. Skin cancer may bleed and appear as sores that do not heal. Long-lasting sores in the mouth may be oral cancer, especially in patients who smoke or chew tobacco or who frequently consume alcohol. Sores in the penis or vagina may be a sign of infection or early cancer.

[0171] Unusual bleeding or blood discharge may indicate cancer. Unusual bleeding can occur with early or advanced cancer. Blood in saliva (phlegm) can be a sign of lung cancer. Blood in the stool (or dark or black colored stool) can be a sign of colon or rectal cancer. Cancer of the cervix or endometrium (lining of the uterus) can cause vaginal bleeding. Blood in the urine can be a sign of bladder or kidney cancer. Bleeding from the nipples can be a sign of breast cancer.

[0172] A thickening or mass in the breast or other parts of the body may indicate the presence of cancer. Many cancers can be felt through the skin, mainly in the breast, testicles, lymph nodes (lymph glands), and soft tissues of the body. A lump or thickening can be an early or late sign of cancer. Any lump or thickening, especially if it is new or growing in size, may indicate cancer.

[0173] Indigestion or difficulty swallowing may indicate cancer. Although these symptoms commonly have other causes, indigestion or difficulty swallowing may be a sign of esophageal, stomach, or pharyngeal (throat) cancer.

[0174] Recent changes in a wart or mole may indicate cancer. Any wart, mole, or freckle that changes color, size, shape, or loses its distinct borders may indicate the development of cancer. For example, the skin lesion may be melanoma.

[0175] A persistent cough or hoarseness may indicate cancer. A cough that won't go away may be a sign of lung cancer. A hoarseness may be a sign of cancer of the pharynx (vocal cords) or thyroid gland.

[0176] While the signs and symptoms listed above are the most common signs and symptoms seen with cancer, there are many other signs and symptoms that are less frequent and are not presented herein, however, all signs and symptoms known to be associated with cancer are contemplated and encompassed by this disclosure.

[0177] Cancer treatment may result in tumor growth retardation or tumor size reduction. Tumor size reduction may also be referred to as "tumor regression." After treatment, the tumor size is preferably reduced by 5% or more compared to the size before treatment; more preferably by 10% or more; more preferably by 20% or more; more preferably by 30% or more; more preferably by 40% or more; even more preferably by 50% or more; and most preferably by 75% or more. Tumor size may be measured by any reproducible means of measurement. Tumor size may be measured as the diameter of the tumor.

[0178] Cancer treatment may result in a reduction in tumor volume. After treatment, tumor volume is preferably reduced by 5% or more compared to pre-treatment size; more preferably by 10% or more; more preferably by 20% or more; more preferably by 30% or more; more preferably by 40% or more; even more preferably by 50% or more; and most preferably by 75% or more. Tumor volume may be measured by any reproducible means of measurement.

[0179] Cancer treatment may result in a reduction in the number of tumors. After treatment, the number of tumors is preferably reduced by 5% or more compared to the number before treatment; more preferably by 10% or more; more preferably by 20% or more; more preferably by 30% or more; more preferably by 40% or more; even more preferably by 50% or more; and most preferably by 75% or more. The number of tumors can be measured by any reproducible measuring means. The number of tumors can be measured by counting the tumors visible with the naked eye or at a specified magnification. The specified magnification is preferably 2x, 3x, 4x, 5x, 10x, or 50x.

[0180] As a result of cancer treatment, the number of metastatic lesions in other tissues or organs distant from the primary tumor site may be reduced. After treatment, the number of metastatic lesions is preferably reduced by 5% or more compared to the number before treatment; more preferably reduced by 10% or more; more preferably reduced by 20% or more; more preferably reduced by 30% or more; more preferably reduced by 40% or more; even more preferably reduced by 50% or more; and most preferably reduced by 75% or more. The number of metastatic lesions can be measured by any reproducible measuring means. The number of metastatic lesions can be measured by counting the metastatic lesions visible with the naked eye or at a specified magnification. The specified magnification is preferably 2x, 3x, 4x, 5x, 10x, or 50x.

[0181] As a result of cancer treatment, the mean progression time or mean survival time of a population of treated subjects may be increased compared to a population that receives only the vehicle. Preferably, the mean progression time or mean survival time is increased by more than 30 days; more preferably, it is increased by more than 60 days; more preferably, it is increased by more than 90 days; and most preferably, it is increased by more than 120 days. The increase in the mean progression time or mean survival time of a population can be measured by any reproducible measurement means. The increase in the mean progression time or mean survival time of a population can be measured, for example, by calculating the mean length of progression or survival of the population after starting treatment with the active compound. The increase in the mean progression time or mean survival time of a population can also be measured, for example, by calculating the mean length of progression or survival of the population after completing the first treatment with the active compound.

[0182] As a result of cancer treatment, the average survival time of a population of treated subjects may be increased compared to an untreated population. Preferably, the average survival time is increased by more than 30 days; more preferably, the average survival time is increased by more than 60 days; more preferably, the average survival time is increased by more than 90 days; and most preferably, the average survival time is increased by more than 120 days. The increase in the average survival time of a population can be measured by any reproducible measurement means. The increase in the average survival time of a population can be measured, for example, by calculating the average length of survival for the population after starting treatment with an active compound. The increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival for the population after completing the first treatment with an active compound.

[0183] As a result of the cancer treatment, the mean progression time or mean survival time of the treated population may be increased compared to the population receiving monotherapy with a drug that is not a compound of the present disclosure or a pharma- ceutical acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mean progression time or mean survival time is increased by more than 30 days; more preferably, the mean progression time or mean survival time is increased by more than 60 days; more preferably, the mean progression time or mean survival time is increased by more than 90 days; and most preferably, the mean progression time or mean survival time is increased by more than 120 days. The increase in the mean progression time or mean survival time of the population can be measured by any reproducible measurement means. The increase in the mean progression time or mean survival time of the population can be measured, for example, by calculating the mean progression or survival length of the population after starting treatment with the active compound. The increase in the mean progression time or mean survival time of the population can also be measured, for example, by calculating the mean progression or survival length of the population after completing the first treatment with the active compound.

[0184] The cancer treatment may result in a reduced mortality rate in the treated population compared to a population receiving only the vehicle. The cancer treatment may result in a reduced mortality rate in the treated population compared to a population receiving a monotherapy with a drug that is not a compound of the present disclosure or a pharma- ceutical acceptable salt, prodrug, metabolite, analog, or derivative thereof. The mortality rate is preferably reduced by more than 2%; more preferably reduced by more than 5%; even more preferably reduced by more than 10%; and most preferably reduced by more than 25%. The reduced mortality rate in the treated population may be measured by any reproducible means of measurement. The reduced mortality rate in the treated population may be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after starting treatment with the active compound. The reduced mortality rate in the population may also be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after completing the initial treatment with the active compound.

[0185] As a result of cancer treatment, the tumor growth rate may decrease. After treatment, the tumor growth rate is preferably at least 5% slower than the rate before treatment; more preferably, the tumor growth rate is at least 10% slower; more preferably, at least 20% slower; more preferably, at least 30% slower; more preferably, at least 40% slower; more preferably, at least 50% slower; even more preferably, at least 50% slower; and most preferably, at least 75% slower. The tumor growth rate can be measured by any reproducible measurement means. The tumor growth rate can be measured by the change in tumor diameter per unit time.

[0186] Cancer treatment may result in a reduction in tumor regrowth (sometimes referred to as progression-free survival). After treatment, tumor regrowth is preferably less than 5%; more preferably less than 10%; more preferably less than 20%; more preferably less than 30%; more preferably less than 40%; more preferably less than 50%; even more preferably less than 60%; and most preferably less than 75%. Tumor regrowth can be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring the increase in tumor diameter after tumor shrinkage after a previous treatment. A reduction in tumor regrowth is indicated by the failure of tumors to recur after treatment is stopped.

[0187] As a result of treating or preventing cell proliferation disorder, the proliferation rate of cells may be decreased. After treatment, the proliferation rate of cells is preferably decreased by at least 5%; more preferably decreased by at least 10%; more preferably decreased by at least 20%; more preferably decreased by at least 30%; more preferably decreased by at least 40%; more preferably decreased by at least 50%; even more preferably decreased by at least 50%; most preferably decreased by at least 75%. The proliferation rate of cells can be measured by any reproducible measuring means. The proliferation rate of cells is measured, for example, by measuring the number of dividing cells per unit time in a tissue sample.

[0188] The percentage of proliferating cells may be reduced as a result of treating or preventing cell proliferation disorder. After treatment, the percentage of proliferating cells is preferably reduced by at least 5%; more preferably reduced by at least 10%; more preferably reduced by at least 20%; more preferably reduced by at least 30%; more preferably reduced by at least 40%; more preferably reduced by at least 50%; even more preferably reduced by at least 50%; most preferably reduced by at least 75%. The percentage of proliferating cells may be measured by any reproducible measuring means. The percentage of proliferating cells is preferably measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The percentage of proliferating cells may be equal to the mitotic index.

[0189] Treating or preventing a cell proliferation disorder may result in a reduction in the size of the area or zone of cell proliferation. After treatment, the size of the area or zone of cell proliferation is preferably at least 5% smaller; more preferably at least 10% smaller; more preferably at least 20% smaller; more preferably at least 30% smaller; more preferably at least 40% smaller; more preferably at least 50% smaller; even more preferably at least 50% smaller; most preferably at least 75% smaller. The size of the area or zone of cell proliferation can be measured by any reproducible measuring means. The size of the area or zone of cell proliferation can be measured as the diameter or width of the area or zone of cell proliferation.

[0190] Treating or preventing cell proliferation disorders may result in a decrease in the number or percentage of cells with abnormal appearance or shape. After treatment, the number or percentage of cells with abnormal appearance or shape is preferably reduced by at least 5% compared to the size before treatment; more preferably reduced by at least 10%; more preferably reduced by at least 20%; more preferably reduced by at least 30%; more preferably reduced by at least 40%; more preferably reduced by at least 50%; even more preferably reduced by at least 50%; and most preferably reduced by at least 75%. The abnormal appearance or shape of cells can be measured by any reproducible measuring means. The abnormal shape of cells can be measured by microscopy, for example using an inverted tissue culture microscope. The abnormal shape of cells may take the form of nuclear pleomorphism.

[0191] Treating or preventing a cell proliferation disorder may result in cell death. Preferably, cell death results in at least a 10% reduction in the number of cells in the population. More preferably, cell death means at least a 20% reduction; more preferably, at least a 30% reduction; more preferably, at least a 40% reduction; more preferably, at least a 50% reduction; and most preferably, at least a 75% reduction. The number of cells in the population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy, or light microscopy. Methods for measuring cell death are provided in Li et al., Proc Natl Acad Sci USA. 100(5):2674-2678, 2003. In one aspect, cell death occurs by apoptosis.

[0192] Preferably, an effective amount of the compound of the present disclosure, or any of its pharma- ceutical acceptable salts, prodrugs, metabolites, polymorphs, solvates, does not have significant cytotoxicity to normal cells.A therapeutically effective amount of a compound does not have significant cytotoxicity to normal cells if the compound does not induce cell death in more than 10% of normal cells when administered in a therapeutically effective amount.A therapeutically effective amount of a compound does not significantly affect the survival of normal cells if the compound does not induce cell death in more than 10% of normal cells when administered in a therapeutically effective amount.

[0193] Contacting a cell with a compound of the present disclosure, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, solvates, can selectively induce or activate cell death in cancer cells. Administering a compound of the present disclosure, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, solvates, to a subject in need thereof can selectively induce or activate cell death (apoptosis) in cancer cells. Contacting a cell with a compound of the present disclosure, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, solvates, can selectively induce cell death in one or more cells affected by a cell proliferative disorder. Preferably, administering a compound of the present disclosure, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, solvates, to a subject in need thereof can selectively induce cell death in one or more cells affected by a cell proliferative disorder.

[0194] The present disclosure relates to a method of treating or preventing cancer by administering to a subject in need thereof a compound of the present disclosure, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, solvates, which results in one or more of: accumulation of cells in the G1 and / or S phases of the cell cycle; cytotoxicity through cell death in cancer cells without significant cell death in normal cells; antitumor activity with a therapeutic index in animals of at least 2; and activation of cell cycle checkpoints. As used herein, "therapeutic index" is the maximum tolerated dose divided by the effective dose.

[0195] A "therapeutically effective amount" of a compound for therapeutic use means the amount of compound in a preparation which, when administered (to a mammal, preferably a human) as part of a desired dosing regimen, alleviates the symptoms, improves the condition, or delays or prevents the onset of a disease state in accordance with clinically acceptable criteria (e.g., a reasonable benefit / risk ratio applicable to any medical treatment) for the disorder or condition being treated, or for cosmetic purposes. "Therapeutically effective amount" is synonymous with "effective dose."

[0196] As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to produce a beneficial or desired clinical result. For prophylactic applications, beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, or delaying the onset of a disease, including the disease, its complications, and the biochemical, histological, and / or behavioral symptoms of intermediate pathological phenotypes observed during disease progression. For therapeutic applications, beneficial or desired results include clinical results such as reducing the severity, duration, or frequency of onset, and / or reducing one or more symptoms (biochemical, histological, and / or behavioral symptoms) resulting from a disease, including its complications, and the intermediate pathological phenotypes observed during disease progression, and / or improving the quality of life of a person suffering from a disease, and / or reducing the dose of another drug required to treat the disease, and / or enhancing the effect of another drug, and / or delaying the progression of the disease in a patient. An effective dose can be administered in a single dose or in multiple doses. For purposes of this disclosure, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective dose" can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if the desired result can or is achieved in combination with one or more other agents. For example, an effective amount of a compound of the present disclosure for treating a proliferative disorder is an amount sufficient to treat or ameliorate one or more symptoms associated with the proliferative disorder. An "effective amount" is an amount sufficient to result in one or more of the following results (which also correspond to various aspects of this disclosure): reduction in tumor size, reduction in tumor volume, reduction in number of tumors, reduction in metastatic lesions, increased survival time, reduced mortality, reduced tumor growth rate, reduced tumor regrowth, reduction in the proportion of proliferating cells, and improved quality of life for an individual suffering from a proliferative disorder.

[0197] The therapeutically effective amount of any compound can be initially evaluated in cell culture assays (e.g., of neoplastic cells) or in animal models (usually rats, mice, rabbits, dogs, or pigs). The animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard procedures in cell cultures or experimental animals (e.g., ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0198] Dosage and administration are adjusted to provide sufficient levels of active agent or maintain desired effect.When providing one or more of the compounds described herein to a subject, the dose of the compound administered will vary depending on factors such as the subject's age, weight, height, sex, overall medical condition, medical history, disease progression, administration route, and formulation method.

[0199] In another aspect, the effective dose of the compound of the present disclosure is provided herein.For example, the method includes administering the compound of the present disclosure at a dose effective for tumor shrinkage.For example, the assumed dose of the compound of the present disclosure in the method described herein can include administration at any dose of about 200 mg / day, about 80 mg / day, about 40 mg / day, about 20 mg / day, about 10 mg / day, about 5 mg / day, about 3 mg / day, about 2 mg / day, about 1 mg / day, about 0.5 mg / day, about 0.2 mg / day, about 0.05 mg / day, about 0.01 mg / day, about 0.001 mg / day, independent of body weight.

[0200] An effective amount of the drug for improving metabolic disorders and / or improving tumor biomarkers and / or shrinking tumors in a patient can be administered based on body weight or body surface area and can be about 0.0001 mg to about 5 mg per kg of body weight per day. For example, expected doses can be about 0.001 mg to about 5 mg per kg of body weight per day, about 0.001 mg to about 2 mg per kg of body weight per day, about 0.001 mg to about 0.1 mg per kg of body weight per day, about 0.001 mg to about 0.010 mg per kg of body weight per day, or about 0.007 mg per kg of body weight per day, either as a single dose, divided dose, or continuous dose. These doses are determined based on the patient's body weight (kg), body surface area (m 2 ), and can be adjusted according to age (years). For example, the expected dose is about 1 mg / m 2 ~about 100 mg / m 2 , about 5 mg / m 2 ~about 25 mg / m 2 , about 5 mg / m 2 ~about 100 mg / m 2 , about 5 mg / m 2 ~about 15 mg / m 2 , about 5 mg / m 2 ~about 10 mg / m 2 Either one is possible.

[0201] An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement in a biomarker or tumor as noted by a clinician or other qualified observer. For example, the delay in progression or regression of a patient's tumor can be measured by reference to the diameter of the tumor. A decrease in the diameter of the tumor indicates regression. Regression can also be indicated by failure of the tumor to recur after treatment has ceased. As used herein, the phrase "effective mode of administration" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0202] Dosage regimens using the compounds of the present disclosure are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof being used. A skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent or arrest the progression of the disease.

[0203] Administration of the disclosed compounds according to the disclosed methods can be continuous or intermittent, depending, for example, on the physiological condition of the recipient, whether the purpose of administration is therapeutic or prophylactic, and other factors known to those of skill in the art. The disclosed compounds can be administered substantially continuously over a preselected period of time, or in a series of spaced doses.

[0204] For repeated administration over a period of hours or longer, depending on the disease, treatment is maintained until the symptoms of the disease are suppressed as desired or sufficient therapeutic levels are achieved. For example, administration from once to five times per week is contemplated. Other dosing regimens include every 3-4 days, or less frequently. In some aspects, the compounds of the present disclosure are administered about every 4th day, about every 7th day, about every 10th day, or about every 14th day. In some aspects, the compounds of the present disclosure are administered about once per week, once every two weeks, or about 1-4 times per month, depending on the duration of response to drug administration. Intermittent dosing regimens can be utilized, with administration at different dosing intervals spaced from 2 to 7 days, or even 14 days apart. In some aspects, treatment begins with daily administration, which is later changed to weekly or even monthly administration. The progress of this therapy is easily monitored by conventional techniques and assays, or by measuring standard clinical chemistry values.

[0205] The frequency of administration can be determined or adjusted throughout the treatment period. For example, the frequency of administration can be determined or adjusted based on the type and severity of the disease being treated, whether the drug is administered for prophylactic or therapeutic purposes, previous treatments, the patient's medical history, response to the drug, and the discretion of the clinician involved. Typically, the clinician will administer the compound of the present disclosure until a dosage is reached that achieves the desired result.

[0206] Treatment can be continued for a long or short period of time as desired. Suitable treatment periods can be, for example, at least about one week, at least about four weeks, at least about one month, at least about six months, at least about one year, at least about two years, or indefinitely. Treatment periods, whether as monotherapy or in combination with another agent, can end when a desired result (e.g., tumor reduction target) is achieved. For example, when about a 5% reduction in tumor size, about a 10% reduction in tumor size, about a 20% reduction in tumor size, about a 30% reduction in tumor size, or more is achieved. Treatment regimes can include a correction phase, in which the compound of the present disclosure is administered at a dose or frequency sufficient to achieve either tumor size reduction, tumor growth retardation, or tumor growth rate reduction, followed by a maintenance phase, in which the compound is administered at a lower dose or at a reduced frequency sufficient to prevent or retard tumor regrowth.

[0207] Compounds and Pharmaceutical Compositions of the Disclosure In some aspects, modification of the active moiety is achieved by using a linker that has a structure such that when cleaved, the fragment remains attached to the active moiety. The fragment can change any of the molecular weight, hydrophobicity, polar surface area, and charge of the active moiety, thereby generating a modified active moiety that has reduced efflux from target cells compared to the unmodified active moiety. For example, a MetAP2 inhibitor can be coupled to an active moiety through a linker as described herein to obtain a conjugate in which the linker is cleaved to generate an active moiety (modified active moiety) with a fragment of the linker attached. The modified active moiety as described herein may have reduced efflux from cells compared to the unmodified active moiety, resulting in a modified active moiety that is more effective than the parent small molecule and has a better pharmacokinetic profile.

[0208] According to the present disclosure, there is provided a method for producing ... semiconductor device comprising the steps of: [ka] A linkered conjugate is provided having the following structure:

[0209] In this structure, independently at each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2- AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, H2N(CH2) mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. AA4 is either a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA5 is either a bond or one of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA6 is either a bond or one of alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH, -NH(C-C hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R)) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6. In some aspects, n ranges from about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 55, or about 1 to about 50.

[0210] In some aspects, R4 is C1-C6 alkyl. In some aspects, R4 is methyl. In some aspects, R5 is C1-C6 alkyl. In some aspects, R5 is methyl. In some aspects, R6 is 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some aspects, R6 is 2-hydroxypropyl.

[0211] In some aspects, the compounds have a molecular weight greater than about 100 kDa. In other aspects, the compounds have a molecular weight less than about 100 kDa. In other aspects, the molecular weight is less than about 95 kDa. In other aspects, the molecular weight is less than about 90 kDa. In other aspects, the molecular weight is less than about 80 kDa. In other aspects, the molecular weight is less than about 70 kDa. In other aspects, the molecular weight is less than about 65 kDa. In other aspects, the molecular weight is less than about 60 kDa. In other aspects, the molecular weight is less than about 45 kDa. In other aspects, the molecular weight is less than about 35 kDa.

[0212] In some aspects, the ratio of x to y ranges from about 100:1 to about 1:1. In other aspects, the ratio of x to y ranges from about 30:1 to about 3:1. In some aspects, the ratio of x to y ranges from about 19:2 to about 7:2. In some aspects, the ratio of x to y ranges from about 9:1 to about 4:1. In some aspects, the ratio of x to y is about 11:1. In some aspects, the ratio of x to y is about 9:1. In some aspects, the ratio of x to y is about 4:1. In some aspects, the ratio of x to y is about 12:1. For example, in some aspects, the ratio x:y is about 3:1; the ratio x:y is about 4:1; the ratio x:y is about 5:1; the ratio x:y is about 6:1; the ratio x:y is about 7:1; the ratio x:y is about 8:1; the ratio x:y is about 9:1; the ratio x:y is about 10:1; the ratio x:y is about 11:1; the ratio x:y is about 12:1; the ratio x:y is about 13:1; the ratio x:y is about 14:1; the ratio x:y is about 15:1; the ratio x:y is about 16:1; the ratio the ratio x:y is about 17:1; the ratio x:y is about 18:1; the ratio x:y is about 19:1; the ratio x:y is about 20:1; the ratio x:y is about 21:1; the ratio x:y is about 22:1; the ratio x:y is about 23:1; the ratio x:y is about 24:1; the ratio x:y is about 25:1; the ratio x:y is about 26:1; the ratio x:y is about 27:1; the ratio x:y is about 28:1; the ratio x:y is about 29:1; the ratio x:y is about 30:1.

[0213] In some aspects, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L. In some aspects, L is methoxy, ethoxy, pentafluorophenyloxy, phenyloxy, acetoxy, fluoride, chloride, methoxycarbonyloxy; ethoxycarbonyloxy, phenyloxycarbonyloxy, 4-nitrophenyloxy, trifluoromethoxy, pentafluoroethoxy, or trifluoroethoxy. In some aspects, L is 4-nitrophenyloxy.

[0214] In some aspects, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In some aspects, AA1 is glycine. In some aspects, AA2 is glycine. In some aspects, AA3 is glycine. In some aspects, AA4 is glycine or phenylalanine. In some aspects, AA5 is leucine, phenylalanine, valine, or tyrosine. In some aspects, AA6 is asparagine, citrulline, glutamine, glycine, leucine, methionine, threonine, or tyrosine. In some aspects, AA5-AA6 are Leu-Cit, Leu-Gln, Leu-Gly, Leu-Leu, Leu-Met, Leu-Thr, Phe-Cit, Phe-Gln, Phe-Leu, Phe-Met, Phe-Thr, Val-Asn, Val-Cit, Val-Gln, Val-Leu, Val-Met, Val-Thr, Tyr-Cit, Tyr-Leu, Tyr-Met. In some aspects, AA1, AA3, and AA5 are glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine. In some aspects, AA2, AA4, and AA6 are glycine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, threonine, and tyrosine. In some aspects, AA2 is a bond; AA3 is a bond. In some aspects, AA1 is glycine; AA4 is phenylalanine; AA5 is leucine; and AA6 is glycine.

[0215] In some aspects, W is [ka] [ka] [ka] [ka] Either:

[0216] In these formulas, R2 is -OH or methoxy; R3 is either H, -OH, or methoxy.

[0217] In some aspects, W is [ka] Either:

[0218] In some aspects, W is [ka] It is.

[0219] In some aspects Q is NR.

[0220] In some aspects, J is NR. In other aspects, J is ((CH2) q Q) r In another aspect, J is C5-C8 cycloalkyl. In some aspects, J is aryl.

[0221] In some aspects Y is NR.

[0222] In some aspects, -QXY is [ka] [ka] Either:

[0223] V is [ka] or a bond, and R 12is H or Me;R 12 is R 14 Combined with R to form a piperidine ring; 11 is H or Me; R 13 is R 12 Combined with this to form a piperidine ring.

[0224] In some aspects, -QXY [ka] It is.

[0225] In some aspects, -QXY [ka] It is.

[0226] In some aspects, -QXY [ka] It is.

[0227] In some aspects, -QXY [ka] It is.

[0228] In some aspects, -QXY [ka] In some aspects, -QXY is [ka] It is.

[0229] In some aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is [ka] and W is [ka] It is.

[0230] In some aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is [ka] and W is [ka] It is.

[0231] In some aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is [ka] and W is [ka] It is.

[0232] In some aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is [ka] and W is [ka] It is.

[0233] In some aspects, -QXY- is a self-immolative linker that releases a MetAP2 inhibitor in the form of a carbamate derivative, as shown in the scheme below. [ka]

[0234] Another aspect of the disclosure provides a conjugate having a linker having the structure: ZQXYC(O)-W, wherein in this structure, independently at each occurrence, Z is H2N-AA2-AA3-AA4-AA5- AA6-C(O)- or H; AA2 is a bond or any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine; AA3 is a bond or any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine; and AA4 is AA5 is a bond or one of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H2N(CH2) m COH (where m is 2, 3, 4, or 5); Q is NR, O, or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond or C(O); J is a bond or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or [ka] ;R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6.

[0235] In some aspects, Z is H2N-AA5-AA6-C(O)-. In some aspects, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and AA6 is glycine. In some aspects, AA5 is leucine and AA6 is glycine. In some aspects, AA5 is valine and AA6 is glycine. In some aspects, AA5 is phenylalanine and AA6 is glycine. In some aspects, AA5 is glycine and AA6 is glycine. In some aspects, AA5 is not valine.

[0236] In another aspect, Z is H2N-AA3-AA4-AA5-AA6-C(O)-. In some aspects, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and each of AA3, AA4, and AA6 is glycine. In some aspects, AA5 is leucine, and each of AA3, AA4, and AA6 is glycine. In some aspects, AA5 is valine, and each of AA3, AA4, and AA6 is glycine. In some aspects, AA5 is phenylalanine, and each of AA3, AA4, and AA6 is glycine. In some aspects, AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine. In some aspects, each of AA3, AA4, AA5, and AA6 is glycine. In some aspects, AA5 is not valine.

[0237] In some aspects, Z is H. In another aspect, Z is H2N-AA6-C(O)-. In some aspects, AA6 is glycine.

[0238] In some aspects Q is NR. In some aspects M is a bond. In some aspects J is a bond. In some aspects Y is NR.

[0239] In some respects, W [ka] [ka] [ka] [ka] Either:

[0240] In these formulas, R2 is -OH or methoxy; R3 is either H, -OH, or methoxy.

[0241] In some respects, W [ka] Either:

[0242] In some respects, W [ka] It is.

[0243] In some aspects, -QXY [ka] [ka] Either:

[0244] V is [ka] or a bond; R 12 is H or Me;R 12 is R 14 Combined with R to form a piperidine ring; 11 is H or Me; R 13 is R 12 Combined with this to form a piperidine ring.

[0245] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0246] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0247] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0248] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0249] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0250] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0251] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0252] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0253] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0254] In some aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0255] In some aspects, Z is H; QXY is [ka] and W is [ka] It is.

[0256] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0257] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0258] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0259] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0260] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0261] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0262] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0263] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0264] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0265] In some aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0266] In some aspects, Z is H; QXY is [ka] and W is [ka] It is.

[0267] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0268] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0269] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0270] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0271] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0272] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0273] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0274] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0275] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0276] In some aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0277] In some aspects, Z is H; QXY is [ka] and W is [ka] It is.

[0278] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0279] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0280] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0281] In some aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0282] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0283] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0284] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0285] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is [ka] and W is [ka] It is.

[0286] In some aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0287] In some aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; and QXY is [ka] and W is [ka] It is.

[0288] In some aspects, Z is H; QXY is [ka] and W is [ka] It is.

[0289] Other active moieties that can be modified for use in the conjugates of the present disclosure include the following structures: [ka]

[0290] In some aspects, the active moiety is an antitumor compound. In another aspect, the active moiety is a molecule (e.g., fumagillin, fumagillol, or any of its analogs, derivatives, salts, or esters) that inhibits methionine aminopeptidase-2 (MetAP2). MetAP2 is a cotranslational enzyme responsible for cleaving off the initiator methionine from nascent polypeptides. This enzyme has a limited number of substrates that tend to be upregulated under conditions of cellular stress, hypoxia, and when cells are dividing. Fumagillin is a natural product derived from the biomass of the fungus Aspergillus fumigatus fresenius. Fumagillin and its analogs and derivatives are known to inhibit the aminopeptidase activity of MetAP2. Further representative MetAP2 inhibitors are described in U.S. Pat. No. 6,242,494 to Craig et al., U.S. Pat. No. 6,063,812 to Hong et al., U.S. Pat. No. 6,887,863 to Craig et al., U.S. Pat. No. 7,030,262 to BaMaung et al., U.S. Pat. No. 7,491,718 to Comess et al., and patent application WO2017027684, each of which is incorporated by reference herein in its entirety.Additional representative MetAP2 inhibitors are described in Wang et al., "Correlation of Tumor Growth Inhibition and Blockade of Methionine Aminopeptidase-2 Activity with Orally Active Inhibitors," PNAS 105(6) 1838-1843 (2008); Lee et al., "Design, Synthesis, and Antiangiogenic Effects of a Series of Novel Potent Fumagillin Analogues," Chem. Pharm. Bull. 55(7) 1024-1029 (2007); Jeong et al., "Total Synthesis and Antiangiogenic Activity of Cyclopentane Analogues of Fumagillol," Bioorganic and Medicinal Chemistry Letters 15, 3580-3583 (2005); Arico-Muendel et al., "Carbamate Analogues of Fumagillin as Potent Targeted Inhibitors of Methionine Aminopeptidase-2," J. Med. Chem. 52, pp. 8047-8056 (2009); Heinrich et al., International Publication No. WO 2010 / 003475.

[0291] Fumagillin is a small molecule that has been used as an antibacterial and antiprotozoal agent. Its physicochemical properties and methods for preparation are well known (see U.S. Patent No. 2,803,586 and Turner, JR et al., "Stereochemistry of Fumagillin," Proc. Natl. Acad. Sci. 48:733-735 (1962)). The fermentation product, fumagillin, can be hydrolyzed to produce the alcohol fumagillol, which in turn is converted to a variety of derivatives, including carbamoyl fumagillol, MW325. The synthesis and preparation of carbamoyl fumagillol and several small molecule derivatives are described in U.S. Patent No. 5,166,172.

[0292] Fumagillin and related compounds are believed to exert their biological effects through inhibition of MetAP2, an enzyme that removes N-terminal methionine from nascent cellular proteins (see Tucker, LA et al., Ectopic Expression of Methionine Aminopeptidase-2 Induces Cellular Transformation and Promotes Proliferation, Oncogene 27:3967 (2008)).

[0293] Carbamoyl fumagillol and derivatives, as well as other inhibitors of MetAP2, have shown therapeutic efficacy in preclinical and clinical trials. These compounds inhibit cell proliferation and angiogenesis as described in U.S. Patent No. 5,166,172. Fumagillin analogs or derivatives (CKD-732, PPI-2458, etc.) have been well studied in various systems and are described in detail, for example, in Bernier et al., Fumagillin Class Inhibitors of Methionine Aminopeptidase-2, Drugs of the Future, vol. 30(5):497-508, 2005.

[0294] The anti-obesity activity of fumagillin and its analogs is well known. Rupnick et al. ("Adipose tissue mass can be regulated through angiogenesis," PNAS 99:10730-10735, 2002) described weight loss in ob / ob mice administered TNP-470 at doses ranging from 2.5 mg / kg to 10 mg / kg daily. Brakenhielm described the prevention of obesity using TNP-470 at doses of 15 mg / kg or 20 mg / kg every 2 days ("The angiogenesis inhibitor TNP-470 prevents diet-induced and genetic obesity in mice," Circulation Research 94:1579-1588, 2004). Kim et al., "Evaluation of the anti-obesity effects of the TNP-470 analog CKD-732," J Molecular Endocrinology 38:455-465, 2007, described weight loss in C57BL / 6J mice and SD rats at a dose of 5 mg / kg / day. Lijnen et al., "Fumagillin reduces adipose tissue formation in a mouse model of nutritionally induced obesity," Hughes et al., Obesity 12:2241-2246, 2010, described daily oral delivery of 1 mg / kg fumagillin reduced body weight in C57BL / 6 mice.

[0295] One of these derivatives, chloroacetylcarbamoyl fumagillol (TNP-470), has been studied extensively (see H. Mann-Steinberg et al., "TNP-470: Resurrection of the First Synthetic Angiogenesis Inhibitor," Chapter 35, Folkman and Figg, Angiogenesis: An Integrative Approach from Science to Medicine, Springer, New York (2008)). TNP-470 has shown activity against a number of cancers, including lung, cervical, ovarian, breast, and colorectal cancers. TNP-470 has been tested using multiple dosing schedules because of dose-limiting neurotoxicity, but these attempts to limit toxicity have been unsuccessful. TNP-470 has therefore been found to be too toxic for use in humans. The short half-life of TNP-470 requires prolonged intravenous administration for therapeutic use. Carbamoyl fumagillol, a metabolite of TNP-470, has a half-life of 12 minutes in humans (see Herbst et al., "Safety and Pharmacokinetic Effects of the Angiogenesis Inhibitor TNP-470 in Combination with Paclitaxel in Patients with Solid Tumors: Evidence of Activity in Non-Small Cell Lung Cancer," Journal of Clinical Oncology 20(22):4440-4447 (2002)). In addition, fumagillin and its derivatives are difficult to formulate because of their hydrophobic nature.

[0296] Despite the known usefulness of fumagillin derivatives, their use as therapeutic agents has been unsuccessful due to inability to overcome the problems of these compounds' poor water solubility, short half-life, and neurotoxic side effects. TNP-470 in combination with paclitaxel has an MTD of 60 mg / m2 administered three times weekly, based on previously observed dose-limiting neuropsychiatric toxicity. 2(Herbst et al., "Safety and Pharmacokinetic Effects of the Angiogenesis Inhibitor TNP-470 in Combination with Paclitaxel in Patients with Solid Tumors: Evidence for Activity in Non-Small Cell Lung Cancer," Journal of Clinical Oncology 20(22):4440-4447 (2002)). Similarly, Shin et al. ("A Phase I Study of the Pharmacokinetics and Pharmacodynamics of the Antiangiogenic Agent CKD-732 in Patients with Refractory Solid Tumors," Investigational New Drugs 28:650-658 (2010)) found that the MTD of CKD-732 was 15 mg / m2 when administered on a 4-day schedule due to impaired consciousness and insomnia. 2 / day. Thus, the compounds of the present disclosure are more potent and / or have reduced toxicity (less neurotoxicity) and / or improved water solubility and / or are more stable and / or have a longer half-life (serum half-life) than currently known fumagillin derivatives.

[0297] The term "reduced toxicity" as used herein has its ordinary meaning as understood by one of ordinary skill in the art. By way of example only, and without limiting the meaning of this term in any way, administration of a fumagillin analog conjugate causes fewer side effects in an open field test in mice than the fumagillin analog alone.

[0298] The phrase "improved water solubility" has its ordinary meaning as understood by those skilled in the art. By way of example only, and without limiting the meaning of this phrase in any way, the following explanation of this phrase is provided for information purposes only, that as a result of the fumagillin analog being covalently incorporated into a complex, a greater amount of the fumagillin analog becomes soluble in water compared to the amount of the uncomplexed fumagillin analog that is soluble in water alone.

[0299] The phrase "longer half-life" has its ordinary meaning as understood by those skilled in the art. By way of example only, and without limiting the meaning of this phrase in any way, the following explanation of this phrase is provided for information purposes only, that the time required to deactivate a fumagillin conjugate in vivo or in vitro is increased to a slightly appreciable extent when compared to the half-life of the fumagillin analog alone in vivo or in vitro.

[0300] Without wishing to be bound by any theory, the nonenzymatic action of MetAP2 in suppressing extracellular signal-regulated kinases 1 and 2 (ERK1 / 2) may be important as well as the binding of eukaryotic initiation factors eIFs by MetAP2. Cellular responses to MetAP2 inhibition reflecting potential ERK-related processes could include the suppression of sterol regulatory element-binding protein (SREBP) activity, which leads to reduced lipid and cholesterol biosynthesis. Interestingly, changes in the expression patterns of genes in hepatic and adipose tissues after chronic (~9 months) exposure to fumagillin suggest that MetAP2 inhibition may also alter the relative amounts of factors involved in inflammation, consistent with a reduction in ERK-dependent cellular processes. The putative mechanism by which inhibition of MetAP2 leads to the mobilization of fat stores as an energy source by the body and the catabolism of free fatty acids is supported by changes in plasma β-hydroxybutyrate, adiponectin, leptin, and FGF21 (Hughes et al., Obesity (2013) vol. 21, no. 9, pp. 1782-1788). Increased levels of the key catabolic hormones adiponectin and FGF21, combined with the appearance of ketone bodies (β-hydroxybutyrate), suggest that inhibition of MetAP2 with either fumagillin, fumagillol, or their analogs, derivatives, salts, or esters complexed or modified with the compounds of the present disclosure, promotes energy expenditure, fat utilization, and lipid excretion. The reduction in leptin observed in previous studies and in the studies presented herein is also consistent with a reduction in total adipose tissue and negative energy balance. Fumagillin, fumagillol, or any of their analogs, derivatives, salts, or esters, complexed or modified with the compounds of the present disclosure, can form covalent bonds with MetAP2, thereby irreversibly inhibiting and silencing the existing enzyme until newly generated pools of MetAP2 are generated in target tissues (e.g., liver and adipose tissue).

[0301] In some aspects, fumagillin, fumagillol, or any of its analogs, derivatives, salts, or esters conjugated or modified with a compound of the present disclosure has the following formula, for example as shown in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] *In these formulas, "polymer" means [ka] Although it has the structure [ka] It is preferable that the structure is as follows:

[0302] In some aspects, the compound [ka] It is.

[0303] In some aspects, the compound [ka] It is.

[0304] In some aspects, the compound [ka] It is.

[0305] In some aspects, the compound [ka] It is.

[0306] In some aspects, the compound [ka] It is.

[0307] In some aspects, the compound [ka] It is.

[0308] In one or more aspects, the selection of compounds for use in the present disclosure includes cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; RS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;cis-(3aR,9bR)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;cis-(3aS,9bS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate;7-(benzenesulfonylamino))-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate;cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; ... o]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;(1aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[ c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5- {2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-{2 [(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino] (1aS,7bR)-5-[2-(3-dimethylaminopropyl-amino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(4-dimethylamino-butylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-(4-dimethylamino-butylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(5-dimethylamino-pentylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;( 1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)- 3-((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid sulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)- 5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzene Sulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid Hydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(pyrrolidin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS ... (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1, 1a,2,7b-Tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((S)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS ,7bSR)-5-(2-{[N-((S)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[N-((R)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(3-N,N,-di 1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidin-2-yl)carbonyl-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzenesulfonylamino] 5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid R)-5-(2-{N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfo; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid Carboxylic acid;(1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]o (1aRS,7bSR)-5-{2-[((R)-1-azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluorobenzenesulfonylamino)- 1,1a,2,7b-Tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)amino]ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl)}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylamino- 2-Methylprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1, 1a,2,7b-Tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; and pharma- ceutical acceptable salts, stereoisomers, esters, and prodrugs thereof.

[0309] In one or more aspects, the selection of the compound comprises: [ka]

[0310] [ka] and a pharma- ceutical acceptable salt or stereoisomer thereof.

[0311] For purposes of this disclosure, chemical elements are identified according to the "Periodic Table of the Elements", CAS version, Handbook of Chemistry and Physics, 67th Edition, 1986-1987, inside cover.

[0312] The term "alkyl" refers to a fully saturated branched or unbranched carbon chain group having the specified number of carbon atoms, or up to 30 carbon atoms if not specified. For example, "lower alkyl" refers to an alkyl having 1 to 10 carbon atoms, examples of which are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and positional isomers of these alkyls. Included in alkyls having 10 to 30 carbon atoms are decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In some aspects, a straight or branched chain alkyl has 30 or fewer carbon atoms in its backbone (C1-C for straight chain). 30 , C3-C for branched chains 30 ), and more preferably have 20 or fewer carbon atoms. Likewise, some cycloalkyls have from 3-10 carbon atoms in their ring structure, and can have 5, or 6, or 7 carbons in the ring structure.

[0313] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, having 1 to 10 carbon atoms, or 1 to 6 carbon atoms in the backbone structure, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have chains of similar length. Throughout this application, some alkyl groups are lower alkyl. In some aspects, a substituent designated herein as alkyl is a lower alkyl.

[0314] The term "carbocycle" as used herein means an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0315] As used herein, the term "aryl" includes 5-, 6-, and 7-membered monocyclic aromatic groups that may contain 0-4 heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Aryl groups that have heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." Aromatic rings may be substituted at one or more ring positions with substituents such as those described above (e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic moiety, heteroaromatic moiety, -CF3, -CN, and the like). The term "aryl" also includes polycyclic ring systems having two or more rings in which one or more carbons are common to two adjacent rings (the rings are "fused rings"), where at least one of the rings is aromatic and the other rings can be, for example, cycloalkyl, and / or cycloalkenyl, and / or cycloalkynyl, and / or aryl, and / or heterocyclyl.

[0316] "Alkenyl" means any fully saturated branched or unbranched carbon chain group having the specified number of carbon atoms, or up to 26 carbon atoms if not specified, and having one or more double bonds in the group. Representative examples of alkenyls having 6 to 26 carbon atoms are the various isomeric forms of hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in which the unsaturated bond can be located anywhere in the group and can have either the (Z) or (E) configuration about the double bond.

[0317] The term "alkynyl" refers to hydrocarbyl groups within the scope of alkenyl that have one or more triple bonds within the group.

[0318] The term "alkoxyl" or "alkoxy", as used herein, refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, the substituent of an alkyl that makes it an ether is or resembles an alkoxy, and includes -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m -R1 (where m and R1 are described below).

[0319] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, that include one to four heteroatoms in the ring structure. The heterocycle can be polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam (such as azetidinone, pyrrolidinone), sultam, sultone, and the like. The heterocycle can be substituted at one or more positions as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic moiety, heteroaromatic moiety, -CF3, -CN, and the like.

[0320] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In some aspects, the "alkylthio" moiety is an -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, -(S)-(CH2) m -R1, where m and R1 are defined below. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0321] The term "nitro" means -NO2; "halogen" refers to F, Cl, Br, or I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2-.

[0322] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, such as those represented by the general formula: [ka] It can be expressed as:

[0323] In these general formulas, R3, R5, and R6 are each independently a hydrogen atom, an alkyl group, an alkenyl group, or -(CH2) m R1 represents either -R1 or R3 and R5, together with the N to which they are attached, complete a heterocycle having 4-8 atoms in the ring structure; R1 represents either alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl; m is zero or an integer ranging from 1 to 8. In some aspects, only one of R3 and R5 can be a carbonyl, e.g., R3, R5, and the nitrogen do not combine to form an imide. In some aspects, each of R3 and R5 (and optionally R6) is independently selected from hydrogen, alkyl, alkenyl, -(CH2) m -R1. Thus, the term "alkylamine" refers herein to an amine group, as defined above, having a substituted or unsubstituted alkyl group attached thereto, i.e., at least one of R3 and R5 is an alkyl group. In some aspects, the amino group or alkylamine is basic, i.e., the pK a This means that the protonated forms of these functional groups have a pK greater than 7.00, which is greater than that of water. a has.

[0324] The term "carbonyl" (C(O)) is art-recognized and has the general formula: [ka] This includes a portion that can be represented by:

[0325] In these general formulas, X is a bond, oxygen or sulfur, and R7 is hydrogen, alkyl, alkenyl, -(CH2) m -R1, or a pharma- ceutically acceptable salt thereof, and R8 is hydrogen, alkyl, alkenyl, -(CH2), m -R1, where m and R1 are as defined above. When X is an oxygen and R7 or R8 is not hydrogen, the formula represents an "ester". When X is an oxygen and R7 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R7 is hydrogen, the formula represents a "carboxylic acid". When X is an oxygen and R8 is hydrogen, the formula represents a "formate". In general, when the oxygen atom of the above formula is replaced with a sulfur, the formula represents a "thiocarbonyl" group. When X is a sulfur and R7 or R8 is not hydrogen, the formula represents a "thioester" group. When X is a sulfur and R7 is hydrogen, the formula represents a "thiocarboxylic acid" group. When X is a sulfur and R8 is hydrogen, the formula represents a "thioformate" group. Conversely, when X is a bond, and R7 is not hydrogen, the above formula represents a "ketone" group. When X is a bond, and R7 is hydrogen, the above formula represents an "aldehyde" group.

[0326] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In one broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Representative substituents include, for example, those described herein above. Permissible substituents can be one or more substituents for suitable organic compounds and can be the same or different. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any of the permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. It is not intended that this disclosure be limited in any manner by the permissible substituents of organic compounds. It is understood that "substituted" or "substituted with" includes an implicit assumption that such substitution is consistent with the permissible valences of the atom and substituent being substituted and that the substitution results in a stable compound (e.g., not spontaneously transformed by rearrangement, cyclization, elimination, etc.).

[0327] The term "sulfamoyl" is art-recognized and refers to a group having the general formula: [ka] This includes a portion that can be represented by:

[0328] In this general formula, R3 and R5 are as defined above.

[0329] The term "sulfate" is known in the art and has the general formula: [ka] This includes a portion that can be represented by:

[0330] In this general formula, R7 is as defined above.

[0331] The term "sulfamide" is known in the art and has the general formula: [ka] This includes a portion that can be represented by:

[0332] In this general formula, R2 and R4 are as defined above.

[0333] The term "sulfonate" is known in the art and has the general formula: [ka] This includes a portion that can be represented by:

[0334] R7 in this general formula is either an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0335] The term "sulfoxide" or "sulfinyl" as used herein refers to a group represented by the general formula: [ka] "(a)" means a part that can be represented by

[0336] In this general formula, R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, and aryl.

[0337] Analogous substitutions can be made on alkenyl and alkynyl groups to form, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

[0338] As used herein, the definition of each designation (e.g., alkyl, m, n, etc.), when it occurs more than one time in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0339] The term "amino acid" is intended to encompass any compound, whether natural or synthetic, that contains both amino and acid functional groups, including analogs and derivatives of amino acids. In some aspects, the amino acids contemplated in this disclosure are the naturally occurring amino acids found in proteins, or the naturally occurring anabolic or catabolic products of such amino acids, which contain amino and carboxyl groups. Naturally occurring amino acids are identified throughout this specification by their conventional three-letter and / or one-letter abbreviations that correspond to the common names of the amino acids according to the following list: These abbreviations are accepted in the peptide art and are recommended by the IUPAC-IUB Commission on Biochemical Nomenclature.

[0340] The term "amino acid residue" refers to an amino acid. In general, the abbreviations used herein to designate naturally occurring amino acids are based on the recommendations of the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochemistry (1972) Vol. 11:1726-1732). For example, Met, Ile, Leu, Ala, and Gly represent the "residues" of methionine, isoleucine, leucine, alanine, and glycine, respectively. Residue refers to the group obtained by removing the OH moiety of the carboxyl group and the H moiety of the α-amino group from the corresponding α-amino acid.

[0341] The term "amino acid side chain" is the portion of an amino acid residue excluding the backbone and is defined by KD Kopple, Peptides and Amino Acids, WA Benjamin Inc., New York and Amsterdam, 1966, pp. 2 and 33. Examples of such side chains of amino acids are -CH2CH2SCH3 (methionine side chain), -CH2(CH3)-CH2CH3 (isoleucine side chain), -CH2CH(CH3)2 (leucine side chain), and H- (glycine side chain). These side chains are pendant from the Cα carbon of the backbone.

[0342] The term "peptide" as used herein refers to a sequence of amino acid residues linked together by peptide bonds or modified peptide bonds. The term "peptide" is intended to encompass peptide analogs, peptide derivatives, peptidomimetics, and peptide variants. The term "peptide" is understood to include peptides of any length. The peptide sequences presented herein are written according to the generally accepted convention, with the N-terminal amino acid on the left and the C-terminal amino acid on the right (e.g., H2N-AA1-AA2-AA3-AA4-AA5-AA6-CO2H).

[0343] Some compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis-isomers, trans-isomers, R-enantiomers, S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, that fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in a substituent (e.g., an alkyl group). All such isomers, as well as mixtures thereof, are contemplated to be included in the present disclosure. Any representation of a particular isomer is merely exemplary (e.g., the representation of a trans-isomer also includes the cis-isomer).

[0344] For example, if a particular enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to give the desired pure enantiomer. Alternatively, if the molecule contains a basic (such as amino) or acidic (such as carboxyl) functional group, diastereomeric salts can be formed with an appropriate optically active acid or base, and the diastereomers thus formed can then be resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0345] The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom are replaced with a group selected from the indicated groups, provided that the normal valence of the designated atom is not exceeded and that the replacement results in a stable compound. When a substituent is keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not present in aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, N=N). "Stable compound" and "stable structure" refer to a compound that is strong enough to survive isolation of the reaction mixture to a useful degree of purity and to render the formulation an effective therapeutic agent.

[0346] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without showing the atom bonding such substituent to the remainder of the compound of a given formula, such substituent may be bonded to any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0347] When any variable (e.g., R1) occurs more than one time in a constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R1 moieties, the group may optionally be substituted with up to 2 R1 moieties, and R1 at each occurrence is selected independently of the definition of R1. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0348] In this specification, the structural formula of a compound may represent one isomer for convenience in some cases, but all isomers (geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc.) are included in the present disclosure. In addition, the compound represented by the formula may have crystalline polymorphism. Any crystalline form, crystalline mixture, anhydride or hydrate thereof are included in the scope of the present disclosure. Furthermore, the so-called metabolites generated by the decomposition of the compound of the present disclosure in vivo are included in the scope of the present disclosure.

[0349] "Isomeric" means compounds that have the same molecular formula but differ in the order of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers of opposite chirality is called a "racemic mixture".

[0350] A carbon atom that is bonded to four different substituents is called a "chiral center."

[0351] "Chiral isomer" means a compound having at least one chiral center. Compounds with two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers (called a "diastereomeric mixture"). When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral centre under consideration are ranked according to the "priority rules" of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, vol. 5, p. 385; corrigendum, p. 511; Cahn et al., Angew. Chem. 1966, vol. 78, p. 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), p. 612; Cahn et al., Experientia 1956, vol. 12, p. 81; Cahn, J. Chem. Educ. 1964, vol. 41, p. 116).

[0352] "Geometric isomer" refers to diastereomers that exist due to hindered rotation about a double bond. These configurations are distinguished in the names by the prefixes cis and trans, or Z and E. These prefixes indicate whether the groups are on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0353] Additionally, the structures and other compounds discussed in this disclosure include all atropic isomers. An "atropisomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by bulky groups that are prevented from rotating around a central bond. Such atropisomers typically exist as mixtures, although recent advances in chromatographic techniques have made it possible in limited cases to separate mixtures of two atropisomers.

[0354] A "tautomer" is one of two or more structural isomers that exist in equilibrium with each other and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers is reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are capable of interconversion by tautomerization is called tautomerism.

[0355] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of electrons and hydrogen atoms occurs; and ring-chain tautomerism, which occurs as a result of one of the hydroxyl groups (-OH) in a sugar molecule reacting with an aldehyde group (-CHO) in the same molecule, giving the molecule a ring shape like that exhibited by glucose.

[0356] Common tautomeric pairs are keto-enol tautomers, amide-nitrile tautomers, lactam-lactim tautomers, amide-imidic acid tautomers, amine-enamines, and enamine-enamines in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine).

[0357] It is understood that the compounds of the present disclosure can be represented as different tautomeric forms. When a compound has tautomeric forms, all tautomeric forms are contemplated as being within the scope of the present disclosure, and the name of the compound does not exclude any tautomeric form.

[0358] The terms "polymorph", "polymorphism" and "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. The different crystalline forms usually differ in X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical properties, electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors may favor one crystalline form over another. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0359] In addition, the compounds of the present disclosure (e.g., salts of the compounds) can exist in hydrated or non-hydrated (anhydrous) form, or as hydrates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0360] "Solvate" means a solvation form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate. When the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by combining one or more molecules of water with one or more molecules of a substance, in which the water is retained in the molecular state as H2O.

[0361] As used herein, the term "analog" refers to a compound that has a similar structure but a slightly different composition (such as the replacement of one atom by an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or identical in function and appearance to the reference compound, but differs in structure or origin.

[0362] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0363] The term "bioisostere" refers to a compound obtained by replacing one atom or group of atoms with another similar atom or group of atoms. The purpose of bioisosteric replacement is to create a new compound whose biological properties resemble those of the parent compound. Bioisosteric replacements can be based on physicochemical or topology. Non-limiting examples of carboxylic acid bioisosteres include acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0364] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include atoms having the same atomic number but different mass numbers. As non-limiting examples of common examples, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0365] The synthetic processes of the present disclosure can tolerate a wide variety of functional groups. Thus, a variety of substituted starting materials can be used. These processes generally provide the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound into a pharma-ceutically acceptable salt, ester, or prodrug.

[0366] The compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, or compounds known in the literature, or from readily prepared intermediates, or utilizing standard synthetic methods and procedures known to those skilled in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for organic molecules and functional group transformations can be obtained from the relevant academic literature or standard reference books in the field. Without being limited to any one or several sources, classic reference books such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, John Wiley & Sons, Inc.: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc.: New York, 1999 (incorporated herein by reference) are useful and recognized reference books for organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are intended to illustrate general procedures for preparing the compounds of the present disclosure and are not intended to be limiting.

[0367] In particular, the compounds of the present disclosure and their synthesis are further described in PCT Publication Nos. WO 2011 / 150022 and WO 2011 / 150088, and U.S. Patent Nos. 9,173,956, 9,320,805, and 9,433,600, each of which is incorporated by reference herein in its entirety for all purposes.

[0368] The disclosure also provides a pharmaceutical composition comprising a compound of the disclosure, or a pharma- ceutically acceptable salt, solvate, diastereomer, polymorph thereof, and a pharma- ceutically acceptable carrier or excipient.

[0369] A "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one aspect, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or a salt, hydrate, solvate, or isomer thereof) contained in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that routine modifications may sometimes be required to the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the disclosed compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, inhalants, etc. In one aspect, the active compound is mixed under sterile conditions with a pharma- ceutical acceptable carrier and any necessary preservatives, buffers, and propellants.

[0370] As used herein, a "pharmaceutical acceptable excipient" or "pharmaceutical acceptable carrier" is intended to include any solvent, dispersion medium, coating, antibacterial or antifungal agent, isotonic or absorption delaying agent, etc., compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in this field. Preferred, non-limiting examples of such carriers or diluents include water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.

[0371] Pharmaceutically acceptable carriers include solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Representative liquid carriers include syrup, peanut oil, olive oil, water, and the like. Similarly, the carrier or diluent can include a time-delay material known in the art, such as glyceryl monostearate, glyceryl distearate, alone or in combination with wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, and the like. Other fillers, excipients, flavoring agents, and other additives known in the art can also be included in the pharmaceutical compositions of the present disclosure. Liposomes and non-aqueous vehicles (fixed oils) can also be used. The use of such media and agents for active pharmaceutical substances is well known in the art. Any conventional media or agent may be used in the composition, unless it is incompatible with the active compound. Additional active compounds can also be incorporated into the composition. In some aspects, the pharmaceutical composition includes DMSO.

[0372] The term "pharmaceutical acceptable salts" refers to inorganic and organic acid addition salts of a compound that are relatively non-toxic. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfite, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and the like. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, e.g., Berge et al. (1977), Pharmaceutical Salts, J. Pharm. Sci. 66:1-19).

[0373] As used herein, the phrase "pharmaceutical acceptable" is used herein to refer to ligands, and / or materials, and / or compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, substantially non-pyrogenic and free of undue toxicity, itching, allergic response or other problems or complications, consistent with a reasonable benefit / risk ratio.

[0374] As used herein, the term "metabolite" refers to a metabolic product of a compound of the present disclosure, or a pharma- ceutically acceptable salt, solvate, diastereomer, or polymorph thereof, that exhibits activity in vivo similar to that of a compound of the present disclosure, or a pharma- ceutically acceptable salt, solvate, diastereomer, or polymorph thereof.

[0375] As used herein, the term "prodrug" refers to a compound of the present disclosure, or any of its pharma- ceutical acceptable salts, solvates, diastereomers, or polymorphs, linked to one or more promoieties (such as an amino acid moiety, other water-soluble moiety, etc.). The compound of the present disclosure, or any of its pharma- ceutical acceptable salts, solvates, diastereomers, or polymorphs, can be released from the promoiety through hydrolytic and / or oxidative and / or enzymatic release mechanisms. In one aspect, the prodrug compositions of the present disclosure exhibit the additional advantages of increased water solubility, improved stability, and improved pharmacokinetic profiles. The promoiety can be selected to provide the desired characteristics of the prodrug. For example, the promoiety (e.g., an amino acid moiety or other water-soluble moiety (such as a phosphate in R4)) can be selected based on solubility, and / or stability, and / or bioavailability, and / or in vivo delivery or uptake. Non-limiting examples of prodrugs include esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups contained in the compounds of the present disclosure; esters (e.g., ethyl ester, morpholinoethanol ester) of carboxyl functional groups; N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases, enaminones; oxime, acetal, ketal, enol esters of ketone and aldehyde functional groups, and the like. See Bundegaard, H., Design of Prodrugs, pp. 1-92, Elesevier, New York-Oxford (1985).

[0376] The compounds of the present disclosure, or any of their pharma- ceutically acceptable salts, esters, solvates, diastereomers, polymorphs, prodrugs (or pharmaceutical compositions thereof), can be administered by any means known in the art. For example, the compounds or compositions of the present disclosure can be administered orally, nasally, transdermally, topically, pulmonary, by inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. Administration can be systemic (e.g., intravenous) or local. In some aspects, routes of administration can be intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vaginal, topical, and the like. In some aspects, the compounds are administered subcutaneously.

[0377] The pharmaceutical compositions of the present disclosure are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, subcutaneous), oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: sterile diluents (such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, other synthetic solvents, etc.); antimicrobial agents (such as benzyl alcohol, methylparaben, etc.); antioxidants (such as ascorbic acid, sodium bisulfite, etc.); chelating agents (such as ethylenediamine tetraacetate, etc.); buffers (such as acetates, citrates, phosphates, etc.); and agents for adjusting isotonicity (such as sodium chloride, dextrose, etc.). The pH can be adjusted using acids or bases (such as hydrochloric acid or sodium hydroxide). Parenteral preparations can be packaged in glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0378] The compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many of the well-known methods currently used in chemotherapy. For example, in the treatment of cancer, the compounds of the present disclosure can be injected directly into a tumor, or into the bloodstream or body cavity, or injected subcutaneously, or taken orally, or applied through the skin using a patch. The dose selected should be sufficient for effective treatment, but not so high as to cause unacceptable side effects. The state of the disease (e.g., cancer, precancer, etc.) and the health of the patient are preferably closely monitored during and for a reasonable period after treatment.

[0379] In one aspect, a compound of the present disclosure, or any of its pharma- ceutical acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs, is administered in a therapeutically effective amount (e.g., an effective level sufficient to achieve a desired therapeutic effect) of a compound of the present disclosure (as the active ingredient), or any of its pharma- ceutical acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs, in a suitable dosage form or formulation (i.e., by producing a pharmaceutical composition of the present disclosure) in accordance with conventional procedures with standard carriers or diluents, which may include mixing, granulating, compressing, or dissolving the ingredients as necessary to produce the desired preparation.

[0380] Parenteral dosage forms can be prepared by any means known in the art, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

[0381] Oral dosage forms (capsules, tablets, pills, powders, granules, etc.) can be prepared using any suitable method known in the art. For example, the compounds of the present disclosure can be mixed with enteric materials and compressed into tablets. Alternatively, the formulations of the present disclosure can be incorporated into chewable tablets, crushable tablets, tablets that dissolve quickly in the mouth, or mouthwashes.

[0382] For pulmonary (e.g., intrabronchial) administration, the compounds of the present disclosure can be formulated with conventional excipients to prepare inhalable compositions in the form of fine powder or sprayable liquid.For ocular administration, the compounds of the present disclosure can be formulated with conventional excipients to, for example, form eye drops or eye implants.Excipients useful in eye drops include thickening or gelling agents that improve retention in the eye and minimize tear loss.

[0383] Non-limiting examples of liquid dosage forms for oral or other routes of administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, compositions for eyes, oral compositions, and other systemic delivery compositions can also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents.

[0384] Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers, are useful for administration.Liquid formulations can be directly nebulized, and lyophilized powders can be nebulized after reconstitution.Alternatively, the compounds of the present disclosure can be aerosolized using fluorocarbon formulations and metered dose inhalers, or inhaled as lyophilized and milled powders.

[0385] The dosage form for topical or transdermal administration of the pharmaceutical composition of the present invention can include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and patches.The active agent is mixed with a medicament acceptable base under sterile conditions, and also with any preservative or buffer required as necessary.For example, administration of the dermal route can be achieved by using any of aqueous droplets, mist, emulsion, and cream.

[0386] Transdermal patches can have the added advantage of controlled delivery of active ingredients to the body. Such dosage forms can be made by dissolving or suspending the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0387] Compositions for rectal or vaginal administration can be suppositories, which can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients or bases (such as cocoa butter, polyethylene glycol, suppository wax, etc.) that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vagina to release the active agent. Alternatively, contemplated formulations can be administered by being released from the lumen of an endoscope after the endoscope is inserted into the rectum of a subject.

[0388] Those skilled in the art can refer to general reference books for detailed descriptions of known techniques discussed herein or equivalent techniques, including Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, New York; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, New York; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). Of course, these references may also be consulted in order to configure or to utilize an aspect of the present disclosure.

[0389] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure are apparent from the various examples. The examples provided illustrate various elements and methods useful in practicing the present disclosure. The examples do not limit the claimed disclosure. One of ordinary skill in the art can identify and utilize other elements and methods useful in practicing the present disclosure based on the present disclosure. EXAMPLES

[0390] Example 1: Effects of Compound 20 (shown as Compound A in the figures) on lean and obese mice Female C57B1 / 6 mice (Jackson Lab) were surgically deprived of their ovaries at 6 weeks of age and then fed a high-fat diet (HFD) or low-fat diet (LFD) during the recovery period until the average body weight of the HFD mice exceeded 40 grams. EO771 cells (50,000 cells; obtained from CH3 Biosystems) were then injected into the fourth mammary gland, allowing tumors to grow to approximately 50 mm. 3 Treatment with SDX-7320 was initiated when the tumor reached 100% CI, subcutaneously every 4 days for a total of 4 doses. 15 days after treatment initiation, mice were euthanized and peripheral blood samples were obtained. Plasma leptin and total adiponectin were analyzed by MSD. Accumulated adipose tissue was excised and weighed. Tumors were excised, weighed, one portion placed in 10% buffered formalin for histological analysis and another portion placed in ice-cold tissue culture medium before processing and leukocyte analysis by flow cytometry.

[0391] EO771 tumors grew faster in obese mice compared to age-matched lean mice (Figure 1A). Compound A significantly attenuated tumor growth in both lean and obese mice (Figure 1B, 1C). Compound A significantly reduced body weight in both lean and obese mice (Figure 2). This was due in part to a significant reduction in adipose tissue weight (Figure 3).

[0392] Example 2: Effect of Compound 20 (shown as Compound A in the figures) on tumor biomarkers and serum markers in lean and obese mice Leptin levels were significantly decreased in obese mice by compound A (Figure 4A), whereas adiponectin levels were significantly increased in both lean and obese mice by compound A (Figure 4B). The leptin / adiponectin ratio was significantly decreased in both lean and obese mice by compound A (Figure 4C).

[0393] Compound A significantly reduced the levels of the immunosuppressive cytokine IL-10 in obese mice (Figure 5B). Therefore, the effect of Compound A in reducing circulating levels of IL-10 is expected to alter the tumor microenvironment and reduce the immunosuppressive state of the TME.

[0394] A subset of tumor samples from each group (n=3 / group, except for n=2 samples from Compound A-treated obese mice due to low cell viability in one of the samples) were processed to analyze leukocyte content by flow cytometry. In particular, the intratumoral content of a population of immature myeloid-derived suppressor cells (MDSCs) was assessed by their increased CD11b + / GR-1 + These cells are known to suppress T cell-mediated immunity and allow tumors to escape immune surveillance. Compound A did not affect intratumoral MDSC content in lean mice, but in obese mice, the intratumoral content of these cells was reduced by more than 90% after treatment with Compound A (Figure 6).

[0395] EO771 mammary tumors were analyzed by immunohistochemistry (IHC) for the nuclear antigen FoxP3, a marker for Tregs (Hori et al., 2003, Science 299(5609):1057-1061). Results of this analysis showed that tumors from vehicle-treated obese mice had numerous FoxP3-positive cells within the tumor and surrounding capillaries (identified by the arrowheads in Figure 7A). In contrast, tumors from mice treated with compound A had reduced numbers of FoxP3-positive cells (indicated by the arrowheads in Figure 7B). This indicates that the tumor microenvironment (TME) was altered by compound A, resulting in a less immunosuppressive TME due to reduced numbers of Tregs. Slides were counterstained with hematoxylin to visualize the nuclei of the cells.

[0396] EO771 tumors from obese mice were further analyzed by IHC for arginase-1 (Arg-1), an enzyme that metabolizes arginine. Increased activity of Arg-1 in tumors reduces levels of extracellular arginine, depriving cytotoxic T lymphocytes of one important energy source, resulting in reduced tumoricidal activity (Popovic et al., J. Nutr. 137:1681S-1686S, 2007). IHC results showed that tumors from obese mice showed strong staining for Arg-1 in some regions of the tumor (T) and tumor stroma (S), as well as in some regions of surrounding tumor-associated adipocytes (A) (Figure 8A). In contrast, Arg-1 staining in tumors from obese mice treated with compound A was reduced, particularly in the tumor (T), although staining sometimes remained evident in the tumor stroma (S) and surrounding tumor-associated adipocytes (A) (Figure 8B).

[0397] Example 3: Effect of Compound 20 (shown in the figures as Compound A) on biomarker expression in human cancer patients The biomarkers examined below were measured using standard immunological assays in serum from late-stage cancer patients treated with Compound A as part of an ongoing clinical trial (SDX-0101). Compound A was administered subcutaneously as a sterile solution in 5% mannitol / water once every 7 days or once every 14 days. The results showed that leptin levels were generally decreased in patients treated with Compound A (Figure 9A), and this was especially evident when the data was expressed as "% change from baseline" (Figure 9B). Note that leptin data are fractions above baseline leptin (above 10 ng / ml). Conversely, levels of adiponectin, another adipokine (e.g., a hormone derived from adipocytes), were generally increased after treatment with Compound A (Figures 10A, 10B). The leptin to adiponectin ratio (LAR) was also generally smaller after treatment with Compound A was initiated (Figures 11A, 11B). Insulin is another biomarker in cancer patients with or without metabolic disorders. Insulin was measured in heavily pretreated cancer patients after subcutaneous administration of compound A once every 7 days or once every 14 days. Results showed that insulin levels (Figure 15A) and % change from baseline (for patients with insulin levels >20μU / ml) (Figure 15B) were generally reduced in patients treated with compound A. Insulin alone is known to be a potent mitogen and stimulator of tumor cells, but does not necessarily influence the effects of insulin resistance. Insulin resistance is recognized as a negative prognostic factor for cancer patients (Duggan et al., J Clin Oncol (2010) 29:32-39). Here we show that insulin resistance scores (using the HOMA2 IR method) were significantly reduced in patients with baseline insulin >20μU / ml, regardless of obesity status (Figure 19).

[0398] Vascular endothelial growth factor-C (VEGF-C), an angiogenic protein, was measured in the serum of cancer patients before and after treatment with compound A. In patients with baseline VEGF-C levels above 200 pg / ml, VEGF-C levels generally decreased after treatment with compound A (Figure 11A, B). In addition, serum levels of insulin-like growth factor-1 (IGF-1), another important cancer growth factor, were analyzed, and IGF-1 levels were frequently decreased after treatment with compound A was initiated in patients with baseline IGF-1 levels above 100 ng / ml (Figure 13A, B). Serum levels of bFGF / FGF2, another pro-angiogenic and pro-growth hormone, were shown to decrease after treatment with compound A was initiated, especially in patients whose baseline levels were above 5.0 pg / ml (Figure 14A, B). Note that in serum samples where the bFGF / FGF2 levels were below the LLOQ for the assay (LLOQ=2.6), a value of 2.0 pg / ml was assigned to facilitate presentation of the data in FIG. 14B ("Change in bFGF").

[0399] Insulin is a potent mitogen for tumors. In cancer patients, elevated insulin levels have been reported to correlate with disease progression and mortality (Tsujimoto et al., Int. J. Cancer, 2017, vol. 141, pp. 102-111). Figure 15 shows that insulin levels are generally decreased in cancer patients with baseline levels above 20 μU / ml. In a range of doses (1.7-65 mg / m2) of insulin was administered to cancer patients with a variety of tumors. 2 ) Compound A and dosing schedules (once a week or once every two weeks) were applied. Figure 19 shows that using the HOMA2 IR method to calculate insulin sensitivity improves insulin sensitivity in these patients.

[0400] This has come to light more recently with the emerging class of drugs that target the enzyme phosphatidylinositol-3-kinase (PI3K), specifically its catalytic subunit p110. Mechanism-based side effects have been observed preclinically and clinically, including hyperglycemia and hyperinsulinemia (Busaidy et al., 2012, J. Clin. Oncol. 30:2919-2928; Hopkins et al., 2018, Nature 560(7719):499-503). In normal mice, compound A (administered subcutaneously, once every 4 days for 10 days, followed by the PI3K inhibitor alpelisib / BYL-719) attenuated acute hyperglycemia induced by alpelisib / BYL-719 (45 mg / kg, orally) (Figure 16). Figures 20 and 21 show that hyperinsulinemia (measured both through insulin itself and its surrogate, C-peptide) improved over time. While glucose levels generally decreased regardless of when mice were pre-treated with Compound A prior to alpelisib / BYL-719, insulin levels showed a surprising and significant time-dependent improvement in hyperinsulinemia, which was confirmed by C-peptide levels.

[0401] Annexins are a family of calcium-dependent phospholipid-binding proteins that selectively bind phosphatidylserine (PS). Under normal physiological conditions, PS is located predominantly in the inner monolayer of the plasma membrane (Figure 1). Upon the onset of apoptosis, PS loses its asymmetric distribution across the phospholipid bilayer and translocates to the extracellular monolayer, thereby making the cell a target for phagocytosis. Once at the outer membrane surface, PS can be detected by fluorescently labeled annexin V in a calcium-dependent manner.

[0402] In early apoptosis, the plasma membrane excludes viability dyes such as aminoactinomycin D (7-AAD). Cells at this stage are identified as early apoptotic because they are stained with Annexin V but not with viability dyes. However, in late apoptosis, the loss of plasma membrane integrity allows Annexin V to access the PS inside the cell. Viability dyes can be used to distinguish these late apoptotic and necrotic cells (Annexin V and viability dye positive) from early apoptotic cells (Annexin V positive, viability dye negative). In this study, Annexin V expression was assessed on a BD FACSCanto II flow cytometer using the Annexin V PE Apoptosis Detection Kit from BioLegend (Cat. No. 640934). Figure 17 shows that the small molecule fumagillin derivatives of the present invention cause a time-dependent decrease in cell viability through apoptosis.

[0403] The Caspase-Glo® 3 / 7 Assay from Promega Corp is a homogeneous fluorescent assay that measures the activity of caspase-3 and caspase-7. These members of the cysteine ​​aspartate-specific proteases (caspases) family play important effector functions in apoptosis in mammalian cells.

[0404] The assay provides a fluorogenic caspase-3 / 7 substrate containing the tetrapeptide sequence DEVD in a reagent optimized for caspase activity, luciferase activity, and cell lysis. Addition of a single Caspase-Glo® 3 / 7 reagent in an "add-mix-measure" format results in cell lysis, followed by cleavage of the substrate by the caspase and generation of a "discharge-type" fluorescent signal by the luciferase. Fluorescence is proportional to the amount of caspase activity present. Figure 18 shows the time-dependent induction of apoptosis transducing the caspase-3 / 7 signal with increasing concentrations of the small molecules of the invention.

[0405] Example 4: Cancer treatment using a combination of Compound 20 and a PI3K inhibitor (shown as Compound A in the figures) Below is one example showing that a MetAP2 inhibitor, specifically compound 20 (herein referred to as compound A), can be used in combination with a PI3K inhibitor, specifically alpelisib / BYL-719, to treat cancer. In this example, 8-10 week old female nu / nu mice were used in which an estrogen pellet was implanted in the intrascapular region. First, 2.5×10 estrogen pellets (suspended in Matrigel) were implanted into the fourth mammary gland of the mice (n=10 / treatment group). 6 MCF-7 cells were injected into each well. MCF-7 mammary tumors grew to approximately 50 mm 3 When the mice reached 10 days of age, they were divided into treatment groups of n=10 and administered Compound A at the doses shown in Table 2. Twenty-four hours after receiving Compound A, a subset of the treatment groups were administered BYL-719 at the doses shown in Table 2. The route and schedule for administration of Compound A was subcutaneous injection (SC) and Q4D (once every 4 days), respectively. The route and schedule for administration of BYL-719 was oral (PO) and QD (once daily), respectively. Vehicle control was administered once daily (QD) orally (PO). [Table 2]

[0406] Baseline blood glucose levels were assessed using blood drawn from the tails of mice, once a week (4 hours after BYL administration) and when the mice were euthanized using a glucometer. When live mice were euthanized, peripheral blood samples were obtained (cardiac puncture) and plasma was prepared from the remaining blood for biomarker analysis. Upon euthanasia, tumors were excised, weighed, and divided into two parts; one half was placed in buffered formalin and the other half was frozen at -70°C after homogenization in RIPA buffer containing phosphatase and protease inhibitors.

[0407] Figure 22 shows the volume change (% change from baseline) of AMCF-7 tumors in mice treated with vehicle control, 8 mg / kg Compound A, or 16 mg / kg Compound A. Figure 23 shows the volume change of MCF-7 tumors in mice treated with vehicle control, 8 mg / kg Compound A, 8 mg / kg Compound A in combination with 25 mg / kg BYL-719, or 25 mg / kg BYL-719 alone. Figure 24 shows the volume change of MCF-7 tumors in mice treated with vehicle control, 8 mg / kg Compound A, 8 mg / kg Compound A in combination with 45 mg / kg BYL-719, or 45 mg / kg BYL-719 alone. Comparison of Figures 22, 23, and 24 shows that the effect of treatment with Compound A alone was less than the effect seen when Compound A was used in combination with BYL-719. The effects of Compound A in combination with BYL-719 appeared to be synergistic (at 25 mg / kg BYL-719) or additive (at 45 mg / kg BYL-719).

[0408] Figure 25 shows the tumor volume change at day 37 in all treatment groups. Figure 25 shows that the combination of compound A and BYL-719 significantly attenuates tumor growth at low BYL-719 dose (25 mg / kg) or high BYL-719 dose (45 mg / kg) when compared with the single agent activity of compound A or BYL-719 alone. Therefore, the results of this example show that MetAP2 inhibitors can be used in combination with PI3K inhibitors to treat cancer.

[0409] Example 5: Cancer treatment using a combination of Compound 20 and an AKT inhibitor (shown in the figures as Compound A)

[0410] The following is one example showing that MetAP2 inhibitors, specifically compound 20 (herein referred to as compound A), can be used in combination with AKT inhibitors, specifically AZD5363 / capavasertib, to treat cancer. In this example, male C57BI / 6 mice aged 8-10 weeks were used. Mice (n=8 per treatment group) were administered doses of either vehicle control (5% mannitol), compound A alone, a combination of compound A and AZD5363, or AZD5363 alone, as shown in Table 3. The route and schedule for administration of compound A was subcutaneous injection (SC) and Q4D (once every 4 days), respectively, at a dose of 8 mg / kg. The route and schedule for administration of AZD5363 was oral (by mouth, PO) and QD (once daily), respectively, at a dose of 200 mg / kg. The vehicle control was administered once daily (QD) and orally (PO). Blood glucose was monitored using 10 μl of blood drawn from the tail of mice with a glucometer starting before AZD5363 administration (time 0) and then at various time points after AZD5363 administration (15, 30, 60, 90, 120, 180 min). As shown in Figure 26, a single dose of AZD5363 (200 mg / kg, PO) in adult male C57BI / 6 mice rapidly and significantly increased blood glucose levels compared to vehicle, whereas pre-treatment of mice with SDX-7320 (8 mg / kg, SC, Q4D, total of 4 doses) significantly attenuated the AZD5363-induced glucose rise. [Table 3]

[0411] Without wishing to be bound by any theory, inhibitors of the PI3K / AKT / mTOR pathway can provide therapeutic benefit by disrupting insulin signaling and inhibiting the growth of some tumors, especially those with activating mutations in this pathway. However, due to the concomitant effects on normal physiological control of whole body glucose homeostasis, such inhibitors can also cause hyperglycemia and subsequent hyperinsulinemia. Hyperglycemia / hyperinsulinemia side effects have been observed in both preclinical models and in patients participating in clinical trials of novel PI3K / AKT / mTOR inhibitors. Attenuating induced hyperglycemia / hyperinsulinemia may provide benefits in terms of greater tumor growth reduction and longer survival compared to PI3K inhibitors alone. Thus, this example demonstrates that the conjugates and compounds of the present disclosure, including compound A, attenuate hyperglycemia induced by AKT inhibitors such as AZD5363. The attenuation of such side effects by Compound A can provide the advantage of enhanced anti-tumor activity when administered in combination with AZD5363, making the combination of the disclosed conjugates / compounds with AKT inhibitors a powerful method of treating cancer in a subject.

[0412] Example 6: Treatment of cancer with a combination of MetAP2 and PI3K inhibitors

[0413] The following is an example showing that MetAP2 inhibitors, particularly ZGN-1061, can be used in combination with PI3K inhibitors, particularly BYL-719, to treat cancer and attenuate the metabolic disorders induced by the treatment. In this example, male C57BI / 6 mice aged 10-12 weeks were used. Mice (n=8 per treatment group) were administered doses of either vehicle control (5% mannitol with 10 mM phosphate, pH 7.2), ZGN-1061 alone, a combination of ZGN-1061 and BYL-719, or BYL-719 alone, as shown in Table 4. The route and schedule of administration for each compound / combination of compounds are shown in Table 4. In Table 4, the time points of administration are shown relative to the administration of BYL-719. Blood glucose was monitored using 10 μl of blood drawn from the tail of the mice with a glucometer starting before BYL-719 administration (time point 0) and then at various time points after BYL-719 administration (15 min, 30 min, 60 min, 90 min, 120 min, 180 min). [Table 4] As shown in Figure 27, BYL-719 induced significant hyperglycemia. However, as shown in Figure 28, pre-treating mice with a MetAP2 inhibitor (ZGN-1061) at various time points before administration of BYL-719 attenuated the hyperglycemia induced by BYL-719. These results indicate that MetAP2 inhibitors (such as ZGN-1061) can attenuate hyperglycemia induced by PI3K inhibitors. This indicates that the combination of MetAP2 inhibitors and PI3K inhibitors is useful for treating cancer patients, especially those with treatment-induced hyperglycemia.

Claims

1. 2. For use in a method of treating or ameliorating at least one symptom of cancer in a subject, a compound of the formula: 【Chemistry 1】 at least one compound of R 4 is H or C 1 -C 6 is alkyl; R 5 is H or C 1 -C 6 is alkyl; R 6 is C 2 -C 6 is hydroxyalkyl; Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 1 is glycine, alanine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; AA 2 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH 2 , -NH(C 2 -C 6 hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 2】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second active agent, A combination wherein said at least one compound and said at least one second active agent are administered to said subject in an amount sufficient to treat or ameliorate at least one symptom of said cancer.

2. 2. The method of claim 1, wherein the compound is a compound of the formula: 【Chemistry 3】 at least one compound of R 4 is H or C 1 -C 6 is alkyl; R 5 is H or C 1 -C 6 is alkyl; R 6 is C 2 -C 6 is hydroxyalkyl; Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 1 is glycine, alanine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; AA 2 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH 2 , -NH(C 2 -C 6 hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 4】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second active agent, The combination, wherein the at least one compound and the at least one second active agent are administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, within a tumor, or within the tumor microenvironment, or in plasma, or any combination thereof.

3. 3. The combination for use according to claim 1 or 2, wherein the metabolic disorder is induced by said at least one second active agent.

4. The combination for use according to any one of claims 1 to 3, wherein the at least one second active agent is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / AKT / mTOR pathway inhibitor.

5. The combination for use according to any one of claims 1 to 4, wherein said at least one second active agent is a PI3K inhibitor.

6. The combination for use according to any one of claims 1 to 5, wherein said PI3K inhibitor is BYL-719 or seravelisib (TAK-117).

7. The combination for use according to any one of claims 1 to 6, wherein said at least one second active agent is an AKT inhibitor.

8. The combination for use according to any one of claims 1 to 7, wherein said AKT inhibitor is AZD5363 (capavasertib) or ipatasertib (GDC0068).

9. Selecting the at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 A combination for use according to any one of claims 1 to 8, which is made from the group consisting of:

10. The at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, has the formula: 【Chemistry 6】 A combination for use according to any one of claims 1 to 9, comprising any one of:

11. R 4 The combination for use according to any one of claims 1 to 10, wherein is methyl.

12. R 5 The combination for use according to any one of claims 1 to 11, wherein is methyl.

13. R 6 A combination for use according to any one of claims 1 to 12, wherein is 2-hydroxypropyl.

14. Z is -NH-AA 6 14. The combination for use according to any one of claims 1 to 13, wherein the moiety is -C(O)-QXYC(O)-W.

15. AA 6 The combination for use according to any one of claims 1 to 14, wherein is glycine.

16. Z is -NH-AA 5 -AA 6 16. The combination for use according to any one of claims 1 to 15, wherein the moiety is -C(O)-QXYC(O)-W.

17. AA 5 is leucine and AA 6 The combination for use according to any one of claims 1 to 16, wherein is glycine.

18. AA 5 is valine, and AA 6 The combination for use according to any one of claims 1 to 17, wherein is glycine.

19. AA 5 is phenylalanine, and AA 6 The combination for use according to any one of claims 1 to 18, wherein is glycine.

20. AA 5 is glycine and AA 6 The combination for use according to any one of claims 1 to 19, wherein is glycine.

21. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 21. The combination for use according to any one of claims 1 to 20, wherein the moiety is -C(O)-QXYC(O)-W.

22. AA 5 is leucine and AA 3 , A.A. 4 , A.A. 6 22. The combination for use according to any one of claims 1 to 21, wherein each of is glycine.

23. AA 5 is valine, and AA 3 , A.A. 4 , A.A. 6 23. The combination for use according to any one of claims 1 to 22, wherein each of is glycine.

24. AA 5 is phenylalanine, and AA 3 , A.A. 4 , A.A. 6 24. The combination for use according to any one of claims 1 to 23, wherein each of is glycine.

25. AA 3 is glycine and AA 4 is phenylalanine, and AA 5 is leucine and AA 6 The combination for use according to any one of claims 1 to 24, wherein is glycine.

26. AA 3 , A.A. 4 , A.A. 5 , A.A. 6 26. The combination for use according to any one of claims 1 to 25, wherein each of is glycine.

27. -QXY, 【Chemistry 7】 The combination for use according to any one of claims 1 to 26,

28. W, 【Chemistry 8】 The combination for use according to any one of claims 1 to 27,

29. 29. The combination for use according to any one of claims 1 to 28, wherein the ratio of x to y is in the range of about 30:1 to about 3:

1.

30. 30. The combination for use according to any one of claims 1 to 29, wherein the ratio of x to y is about 11:

1.

31. The at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, has the formula: 【Chemistry 9】 A combination for use according to any one of claims 1 to 30, comprising:

32. At least one compound represented by the formula ZQXYC(O)-W, wherein each occurrence independently represents: Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 Alanine, Asparagine, Citrulline, Glutamine, Glycine, Leucine, Methionine, Phenylalanine, Serine, Threonine, Tryptophan, Tyrosine, Valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 10】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second active agent, The combination of the at least one compound, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, analogs or derivatives, and the at least one second active agent are administered to the subject in an amount sufficient to treat or ameliorate at least one symptom of the cancer.

33. At least one compound represented by ZQXYC(O)-W, wherein each occurrence independently represents: Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-Wであり; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 Alanine, Asparagine, Citrulline, Glutamine, Glycine, Leucine, Methionine, Phenylalanine, Serine, Threonine, Tryptophan, Tyrosine, Valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 11】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, and at least one second active agent, The at least one compound, or any of its pharma- ceutically acceptable salts, prodrugs, metabolites, analogs, or derivatives, and the at least one second active agent are administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

34. The combination for use according to any one of claims 1 to 33, wherein said at least one second active agent is a compound that induces a metabolic disorder.

35. The combination for use according to any one of claims 1 to 34, wherein the at least one second active agent is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / AKT / mTOR pathway inhibitor.

36. The combination for use according to any one of claims 1 to 35, wherein said at least one second active agent is a PI3K inhibitor.

37. The combination for use according to any one of claims 1 to 36, wherein said PI3K inhibitor is BYL-719 or seravelisib (TAK-117).

38. The combination for use according to any one of claims 1 to 37, wherein said at least one second active agent is an AKT inhibitor.

39. The combination for use according to any one of claims 1 to 38, wherein said AKT inhibitor is AZD5363 (capavasertib) or ipatasertib (GDC0068).

40. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is leucine and AA 6 A combination for use according to any one of claims 1 to 39, wherein is glycine.

41. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is valine, and AA 6 A combination for use according to any one of claims 1 to 40, wherein is glycine.

42. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is phenylalanine, and AA 6 A combination for use according to any one of claims 1 to 41, wherein is glycine.

43. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is glycine and AA 6 A combination for use according to any one of claims 1 to 42, wherein is glycine.

44. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is leucine and AA 3 , A.A. 4 , A.A. 6 44. The combination for use according to any one of claims 1 to 43, wherein each of is glycine.

45. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is valine, and AA 3 , A.A. 4 , A.A. 6 45. The combination for use according to any one of claims 1 to 44, wherein each of is glycine.

46. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is phenylalanine, and AA 3 , A.A. 4 , A.A. 6 46. ​​The combination for use according to any one of claims 1 to 45, wherein each of is glycine.

47. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 3 is glycine and AA 4 is phenylalanine, and AA 5 is leucine and AA 6 A combination for use according to any one of claims 1 to 46, wherein is glycine.

48. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 3 , A.A. 4 , A.A. 5 , A.A. 6 48. The combination for use according to any one of claims 1 to 47, wherein each of is glycine.

49. -QXY, 【Chemistry 12】 A combination for use according to any one of claims 1 to 48,

50. W 【Chemistry 13】 50. The combination for use according to any one of claims 1 to 49,

51. The selection of the compound comprises: 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 【Chemistry 14-7】 A combination for use according to any one of claims 1 to 50, from the group consisting of:

52. The combination for use according to any one of claims 1 to 51, wherein said therapeutically effective amount is from about 0.0001 mg to about 5 mg per kg of body weight per day.

53. The combination for use according to any one of claims 1 to 52, wherein said therapeutically effective amount is from about 0.001 mg to about 0.1 mg per kg of body weight per day.

54. The combination for use according to any one of claims 1 to 53, wherein said compound is administered from about 1 to about 5 times per week.

55. 55. The combination for use according to any one of claims 1 to 54, wherein the compound is administered on any of the following dosing schedules: once every 4 days, once every 7 days, once every 2 weeks, once every 3 weeks, or once a month.

56. The combination for use according to any one of claims 1 to 55, wherein said compounds are administered on a once every 7 days dosing schedule.

57. The combination for use according to any one of claims 1 to 56, wherein the subject is treated for at least about 6 months.

58. The combination for use according to any one of claims 1 to 57, wherein the subject is treated for at least about 1 year, or at least about 2 years, or at least about 3 years.

59. The combination for use according to any one of claims 1 to 58, wherein said compounds are administered parenterally.

60. The combination for use according to any one of claims 1 to 59, wherein said compound is administered subcutaneously.

61. 61. The combination for use according to any one of claims 1 to 60, wherein the cancer is any one of postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, or a combination thereof.

62. 2. For use in a method of treating or ameliorating at least one symptom of cancer in a subject, a compound of the formula: 【Chemistry 15】 at least one compound of R 4 is H or C 1 -C 6 is alkyl; R 5 is H or C 1 -C 6 is alkyl; R 6 is C 2 -C 6 is hydroxyalkyl; Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 1 is glycine, alanine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; AA 2 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH 2 , -NH(C 2 -C 6 hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 16】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof; The at least one compound, or any of its pharma- ceutical acceptable salts, prodrugs, metabolites, analogs, or derivatives, is administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

63. 2. For use in treating or ameliorating at least one symptom of a metabolic disorder associated with the treatment of a subject having cancer, comprising administering to said subject a compound of the formula: 【Chemistry 17】 at least one compound of R 4 is H or C 1 -C 6 is alkyl; R 5 is H or C 1 -C 6 is alkyl; R 6 is C 2 -C 6 is hydroxyalkyl; Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 1 is glycine, alanine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; AA 2 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH 2 , -NH(C 2 -C 6 hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 18】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof; At least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is administered to the subject in an amount sufficient to treat or ameliorate at least one symptom of the metabolic disorder implicated in the treatment.

64. 2. For use in a method of reducing the amount of at least one of IL-10, arginase-1, myeloid derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in the plasma, or any combination thereof, of a subject having cancer, comprising administering to said subject a therapeutically effective amount of at least one of the following: 【Chemistry 19】 at least one compound of R 4 is H or C 1 -C 6 is alkyl; R 5 is H or C 1 -C 6 is alkyl; R 6 is C 2 -C 6 is hydroxyalkyl; Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 1 is glycine, alanine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; AA 2 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH 2 , -NH(C 2 -C 6 hydroxyalkyl), halide, or perfluoroalkyloxy; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 20】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x ranges from 1 to about 450; y ranges from 1 to about 30; n ranges from 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof; The at least one compound, or any of its pharma- ceutical acceptable salts, prodrugs, metabolites, analogs, or derivatives, is administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in a tumor microenvironment, or in plasma, or any combination thereof.

65. At least one compound for use according to any one of claims 1 to 64, wherein said growth factor is VEGF-C, IGF-1, bFGF or any combination thereof.

66. 3. At least one compound for use according to claim 2, wherein said cancer treatment induces a metabolic disorder in said subject.

67. At least one compound for use according to any one of claims 1 to 66, wherein said metabolic disorder is at least one of hyperglycemia, hyperinsulinemia, excess visceral fat, high leptin levels, reduced adiponectin levels, increased leptin to adiponectin ratio, elevated fasting insulin levels associated with chronic inflammation, or any combination thereof.

68. 68. At least one compound for use according to any one of claims 1 to 67, wherein the cancer treatment inducing a metabolic disorder in the subject is treatment with a phosphoinositide-3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, the PI3K / AKT / mTOR pathway inhibitor dexamethasone, or any combination thereof.

69. At least one compound for use according to any one of claims 1 to 68, wherein said PI3K inhibitor is ceravelisib (TAK-117) or BYL-719.

70. At least one compound for use according to any one of claims 1 to 69, wherein said AKT inhibitor is AZD5363 (capavasertib) or ipatasertib (GDC0068).

71. At least one compound for use according to any one of claims 1 to 70, wherein said treatment, improvement, method further comprises the administration of an immunotherapeutic agent.

72. At least one compound for use according to any one of claims 1 to 71, wherein said immunotherapeutic agent is a monoclonal antibody, a T cell, a modified T cell, a chimeric antigen receptor T cell, a tumor infiltrating lymphocyte, an immune checkpoint inhibitor, an interleukin, an interferon, a colony stimulating factor, or a combination thereof.

73. Selection of Z from the at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 At least one compound for use according to any one of claims 1 to 72, which is from the group consisting of:

74. The at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, has the formula: 【Chemical 22】 At least one compound for use according to any one of claims 1 to 73, having any one of:

75. R 4 At least one compound for use according to any one of claims 1 to 74, wherein is methyl.

76. R 5 At least one compound for use according to any one of claims 1 to 75, wherein is methyl.

77. R 6 At least one compound for use according to any one of claims 1 to 76, wherein is 2-hydroxypropyl.

78. Z is -NH-AA 6 At least one compound for use according to any one of claims 1 to 77, which is -C(O)-QXYC(O)-W.

79. AA 6 At least one compound for use according to any one of claims 1 to 78, wherein is glycine.

80. Z is -NH-AA 5 -AA 6 At least one compound for use according to any one of claims 1 to 79, which is -C(O)-QXYC(O)-W.

81. AA 5 is leucine and AA 6 At least one compound for use according to any one of claims 1 to 80, wherein is glycine.

82. AA 5 is valine, and AA 6 At least one compound for use according to any one of claims 1 to 81, wherein is glycine.

83. AA 5 is phenylalanine, and AA 6 At least one compound for use according to any one of claims 1 to 82, wherein is glycine.

84. AA 5 is glycine and AA 6 At least one compound for use according to any one of claims 1 to 83, wherein is glycine.

85. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 At least one compound for use according to any one of claims 1 to 84, which is -C(O)-QXYC(O)-W.

86. AA 5 is leucine and AA 3 , A.A. 4 , A.A. 6 86. At least one compound for use according to any one of claims 1 to 85, wherein each of is glycine.

87. AA 5 is valine, and AA 3 , A.A. 4 , A.A. 6 87. At least one compound for use according to any one of claims 1 to 86, wherein each of is glycine.

88. AA 5 is phenylalanine, and AA 3 , A.A. 4 , A.A. 6 At least one compound for use according to any one of claims 1 to 87, wherein each of is glycine.

89. AA 3 is glycine and AA 4 is phenylalanine, and AA 5 is leucine and AA 6 At least one compound for use according to any one of claims 1 to 88, wherein is glycine.

90. AA 3 , A.A. 4 , A.A. 5 , A.A. 6 90. At least one compound for use according to any one of claims 1 to 89, wherein each of is glycine.

91. -QXY, 【Chemistry 23】 At least one compound for use according to any one of claims 1 to 90,

92. W, 【Chemistry 24】 At least one compound for use according to any one of claims 1 to 91, which is

93. At least one compound for use according to any one of claims 1 to 92, wherein the ratio of x to y ranges from about 30:1 to about 3:

1.

94. At least one compound for use according to any one of claims 1 to 93, wherein the ratio of x to y is about 11:

1.

95. The at least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, has the formula: 【Chemistry 25】 At least one compound for use according to any one of claims 1 to 94, having the formula:

96. At least one compound represented by the formula ZQXYC(O)-W, wherein each occurrence independently represents: Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-Wであり; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 Alanine, Asparagine, Citrulline, Glutamine, Glycine, Leucine, Methionine, Phenylalanine, Serine, Threonine, Tryptophan, Tyrosine, Valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 26】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof; The at least one compound, or any of its pharma- ceutical acceptable salts, prodrugs, metabolites, analogs, or derivatives, is administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof.

97. 1. At least one compound represented by the formula ZQXYC(O)-W, wherein each occurrence independently represents: Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 Alanine, Asparagine, Citrulline, Glutamine, Glycine, Leucine, Methionine, Phenylalanine, Serine, Threonine, Tryptophan, Tyrosine, Valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemical 27】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof; At least one compound, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, is administered to the subject in an amount sufficient to treat or ameliorate at least one symptom of the metabolic disorder implicated in the treatment.

98. At least one compound represented by ZQXYC(O)-W, wherein each occurrence independently represents: IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, for use in a method for reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in the tumor microenvironment, or in plasma, or any combination thereof. Zは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Lまたは-NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-QXYC(O)-Wであり; AA 3 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 4 is a bond or is any of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine; AA 5 is a bond or any of glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, and asparagine; AA 6 Alanine, Asparagine, Citrulline, Glutamine, Glycine, Leucine, Methionine, Phenylalanine, Serine, Threonine, Tryptophan, Tyrosine, Valine, H 2 N(CH 2 ) m CO 2 H, where m is 2, 3, 4, or 5; Q is NR, O, or S; X is M-(C(R) 2 ) p -MJM-(C(R) 2 ) p -MV; M is a bond or C(O); J is a bond or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S; Y is NR, O, or S; R is H or alkyl; V is a bond or 【Chemistry 28】 and R 9 is an alkyl, aryl, aralkyl, or a bond; R 9 combines with Y to form a heterocycle; R 10 is an amide or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6), or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof; The at least one compound, or any of its pharma- ceutical acceptable salts, prodrugs, metabolites, analogs, or derivatives, is administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, or in a tumor microenvironment, or in plasma, or any combination thereof.

99. At least one compound for use according to any one of claims 1 to 98, wherein said growth factor is either VEGF-C, IGF-1, bFGF or any combination thereof.

100. 100. At least one compound for use according to any one of claims 1 to 99, wherein said cancer treatment induces a metabolic disorder in said subject.

101. At least one compound for use according to any one of claims 1 to 100, wherein said metabolic disorder is at least one of hyperglycemia, hyperinsulinemia, excess visceral fat, high leptin levels, reduced adiponectin levels, increased leptin to adiponectin ratio, elevated fasting insulin levels associated with chronic inflammation, or any combination thereof.

102. At least one compound for use according to any one of claims 1 to 101, wherein the cancer treatment inducing a metabolic disorder in the subject is treatment with a phosphoinositide-3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, the PI3K / AKT / mTOR pathway inhibitor dexamethasone, or any combination thereof.

103. At least one compound for use according to any one of claims 1 to 102, wherein the cancer treatment inducing a metabolic disorder in the subject is treatment with a phosphoinositide-3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, dexamethasone, or any combination thereof.

104. At least one compound for use according to any one of claims 1 to 103, wherein said PI3K inhibitor is ceravelisib (TAK-117) or BYL-719.

105. At least one compound for use according to any one of claims 1 to 104, wherein said AKT inhibitor is AZD5363 (capavasertib) or ipatasertib (GDC0068).

106. At least one compound for use according to any one of claims 1 to 105, wherein said treatment, improvement, method further comprises the administration of an immunotherapeutic agent.

107. At least one compound for use according to any one of claims 1 to 106, wherein said immunotherapeutic agent is a monoclonal antibody, a T cell, a modified T cell, a chimeric antigen receptor T cell, a tumor infiltrating lymphocyte, an immune checkpoint inhibitor, an interleukin, an interferon, a colony stimulating factor, or a combination thereof.

108. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and A 5 is leucine and AA 6 At least one compound for use according to any one of claims 1 to 107, wherein is glycine.

109. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and A 5 is valine, and AA 6 At least one compound for use according to any one of claims 1 to 108, wherein is glycine.

110. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and A 5 is phenylalanine, and AA 6 At least one compound for use according to any one of claims 1 to 109, wherein is glycine.

111. Z is -NH-AA 5 -AA 6 -C(O)-QXYC(O)-W, and A 5 is glycine and AA 6 At least one compound for use according to any one of claims 1 to 110, wherein is glycine.

112. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is leucine and AA 3 , A.A. 4 , A.A. 6 At least one compound for use according to any one of claims 1 to 111, wherein each of is glycine.

113. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is valine, and AA 3 , A.A. 4 , A.A. 6 At least one compound for use according to any one of claims 1 to 112, wherein each of is glycine.

114. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 5 is phenylalanine, and AA 3 , A.A. 4 , A.A. 6 At least one compound for use according to any one of claims 1 to 113, wherein each of is glycine.

115. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 3 is glycine and AA 4 is phenylalanine, and AA 5 is leucine and AA 6 At least one compound for use according to any one of claims 1 to 114, wherein is glycine.

116. Z is -NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-QXYC(O)-W, and AA 3 , A.A. 4 , A.A. 5 , A.A. 6 At least one compound for use according to any one of claims 1 to 115, wherein each of is glycine.

117. -QXY, 【Chemical Formula 29】 At least one compound for use according to any one of claims 1 to 116,

118. W 【Chemistry 30】 At least one compound for use according to any one of claims 1 to 117, which is

119. The selection of the compound comprises: 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 【Chemistry 31-5】 【Chemistry 31-6】 【Chemistry 31-7】 【Chemistry 31-8】 At least one compound for use according to any one of claims 1 to 118, which is from the group consisting of:

120. At least one compound for use according to any one of claims 1 to 119, wherein said cancer is any one of postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, renal clear cell carcinoma, melanoma, multiple myeloma, or a combination thereof.

121. At least one compound for use according to any one of claims 1 to 120, wherein said therapeutically effective amount is from about 0.0001 mg to about 5 mg per kg of body weight per day.

122. At least one compound for use according to any one of claims 1 to 121, wherein said therapeutically effective amount is from about 0.001 mg to about 0.1 mg per kg of body weight per day.

123. 123. At least one compound for use according to any one of claims 1 to 122, wherein said compound is administered from about 1 time to about 5 times per week.

124. At least one compound for use according to any one of claims 1 to 123, wherein the compound is administered on any of the following dosing schedules: once every 4 days, once every 7 days, once every 2 weeks, once every 3 weeks, or once a month.

125. 125. At least one compound for use according to any one of claims 1 to 124, wherein said compound is administered on a dosing schedule of once every 7 days.

126. At least one compound for use according to any one of claims 1 to 125, wherein the subject is treated for at least about 6 months.

127. At least one compound for use according to any one of claims 1 to 126, wherein the subject is treated for at least about 1 year, or at least about 2 years, or at least about 3 years.

128. At least one compound for use according to any one of claims 1 to 127, wherein said compound is administered parenterally.

129. At least one compound for use according to any one of claims 1 to 128, wherein said compound is administered subcutaneously.

130. At least one compound for use according to any one of claims 1 to 129, wherein said treatment, improvement, method further comprises the administration of a second active agent.

131. At least one compound for use according to any one of claims 1 to 130, wherein said compound is provided as a pharmaceutical composition comprising said compound and a pharma- ceutically acceptable carrier.

132. At least one compound for use according to any one of claims 1 to 131, wherein said at least one second active agent is a compound that induces a metabolic disorder.

133. At least one compound for use according to any one of claims 1 to 132, wherein the at least one second active agent is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / AKT / mTOR pathway inhibitor.

134. At least one compound for use according to any one of claims 1 to 133, wherein said at least one second active agent is a PI3K inhibitor.

135. At least one compound for use according to any one of claims 1 to 134, wherein said PI3K inhibitor is BYL-719 or seravelisib (TAK-117).

136. At least one compound for use according to any one of claims 1 to 135, wherein said at least one second active agent is an AKT inhibitor.

137. At least one compound for use according to any one of claims 1 to 136, wherein said AKT inhibitor is AZD5363 (capavasertib) or ipatasertib (GDC0068).

138. A combination comprising at least one MetAP2 inhibitor and at least one PI3K inhibitor for use in treating or ameliorating at least one symptom of cancer in a subject.

139. A combination comprising at least one MetAP2 inhibitor and at least one AKT inhibitor for use in treating or ameliorating at least one symptom of cancer in a subject.

140. A combination comprising at least one MetAP2 inhibitor and at least one mTOR inhibitor for use in treating or ameliorating at least one symptom of cancer in a subject.

141. The at least one MetAP2 inhibitor is 【Chemistry 32】 A combination for use according to any one of claims 1 to 140,

142. The combination for use according to any one of claims 1 to 141, wherein said at least one MetAP2 inhibitor is ZGN-1061.

143. The combination for use according to any one of claims 1 to 142, wherein said at least one MetAP2 inhibitor is beloranib.

144. The combination for use according to any one of claims 1 to 143, wherein said at least one PI3K inhibitor is seravelisib (TAK-117).

145. The combination for use according to any one of claims 1 to 144, wherein said at least one PI3K inhibitor is BYL-719.

146. The combination for use according to any one of claims 138 to 145, wherein said at least one AKT inhibitor is AZD5363 (capavasertib).

147. 147. The combination for use according to any one of claims 1 to 146, wherein said therapeutically effective amount of said at least one MetAP2 inhibitor is from about 0.0001 mg to about 5 mg per kg of body weight per day.

148. 148. The combination for use according to any one of claims 1 to 147, wherein said therapeutically effective amount of said at least one MetAP2 inhibitor is from about 0.001 mg to about 0.1 mg per kg of body weight per day.

149. 149. The combination for use according to any one of claims 1 to 148, wherein said at least one MetAP2 inhibitor is administered from about 1 time to about 5 times per week.

150. 150. The combination for use according to any one of claims 1 to 149, wherein the at least one MetAP2 inhibitor is administered on any of the following dosing schedules: once every 4 days, once every 7 days, once every 2 weeks, once every 3 weeks, or once a month.

151. 151. The combination for use according to any one of claims 1 to 150, wherein said at least one MetAP2 inhibitor is administered on a dosing schedule of once every 7 days.

152. The combination for use according to any one of claims 1 to 151, wherein the subject is treated for at least about 6 months.

153. The combination for use according to any one of claims 1 to 152, wherein the subject is treated for at least about 1 year, or at least about 2 years, or at least about 3 years.

154. The combination for use according to any one of claims 1 to 153, wherein said at least one MetAP2 inhibitor is administered parenterally.

155. The combination for use according to any one of claims 1 to 154, wherein said at least one MetAP2 inhibitor is administered subcutaneously.

156. At least one MetAP2 inhibitor for use in treating or ameliorating at least one symptom of a metabolic disorder induced by cancer treatment in a subject, said treating or ameliorating comprising administering at least one therapeutically effective amount of said at least one MetAP2 inhibitor.

157. 157. At least one MetAP2 inhibitor for use according to any one of claims 1 to 156, wherein said cancer treatment comprises administering a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, or any combination thereof.

158. At least one MetAP2 inhibitor for use according to any one of claims 1 to 157, wherein said metabolic disorder is at least one of hyperglycemia, hyperinsulinemia, excess visceral fat, high leptin levels, decreased adiponectin levels, increased leptin to adiponectin ratio, elevated fasting insulin levels associated with chronic inflammation, or any combination thereof.

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