Treatment for tumors driven by metabolic dysfunction

Abstract

To provide compounds, pharmaceutical compositions, and methods for treating patients with a proliferation disorder, such as cancer, complicated by metabolic dysfunction.SOLUTION: The present disclosure relates to modified or polymer conjugated MetAP2 (methionine aminopeptidase) inhibitors. The present disclosure also relates to methods of treating metabolically-driven diseases and disorders, such as certain cancers.SELECTED DRAWING: None

Description

[Technical field]

[0001] Field of Disclosure The present disclosure provides compounds, pharmaceutical compositions, and methods for the treatment of patients with proliferative diseases accompanied by metabolic dysfunction, such as cancer.The present disclosure relates to the fields of biomedicine, pharmacology, and molecular biology. [Background technology]

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Patent Application No. 62 / 277,293, filed January 11, 2016, U.S. Patent Application No. 62 / 393,929, filed September 13, 2016, and U.S. Patent Application No. 62 / 395,446, filed September 16, 2016, the entire contents of each of which are incorporated herein by reference.

[0003] Background of the disclosure Obesity and metabolic dysfunction are well established risk factors for the development of cancer in humans. However, once cancer or a disease associated with the proliferation is diagnosed, there is no specific treatment plan for metabolically dysfunctional individuals. Recent discoveries in cancer research have revealed a complex interplay between the endocrine health of certain cancer patients and the progression of cancer centered on metabolic factors, adipose tissue-derived hormones, and chronic inflammation with excess visceral obesity. In certain cancers, adipose tissue-derived hormones stimulate certain carcinogenic processes, thereby increasing the proliferation and invasiveness of cancer cells, and ultimately causing the patient to die sooner than cancer patients with normal levels of these metabolic factors. Other visceral fat cell-derived hormones play a protective role in cancer, often suppressing excess visceral obesity. Despite the fact that this cancer / metabolism relationship is directly linked to more than 80,000 deaths per year in the United States alone, there is still no specific treatment plan for this disease relationship and the patients.

[0004] Thus, there is a need for new compounds, pharmaceutical compositions, and methods for the treatment of patients with proliferative diseases accompanied by metabolic dysfunction, such as cancer. The present disclosure addresses these needs. Summary of the Invention

[0005] Disclosure Summary The present disclosure provides a method of treating or ameliorating at least one symptom of a proliferative disease, such as cancer, in a subject in need thereof, wherein the subject has a metabolic dysfunction, comprising administering to the subject a therapeutically effective amount of at least one of the compounds of the present disclosure to treat the proliferative disease.

[0006] The present disclosure also provides a method of treating a metabolically sensitive tumor in a subject in need thereof, the subject having a metabolic dysfunction, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure to treat the metabolically sensitive tumor.

[0007] In certain aspects, the disclosure provides a method for treating or ameliorating at least one symptom of cancer or treating a metabolically sensitive tumor in a subject in need thereof, wherein the subject is metabolically dysfunctional and the cancer is being treated, comprising administering a therapeutically effective amount of at least one compound of the following formula, or a pharma- ceutically acceptable salt, prodrug, metabolite, or analog or derivative thereof:

[0008] [ka]

[0009] During the ceremony, 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, or H2N(CH) 2m CO2H, 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 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; AA5 is a bond or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, and m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 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 ((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

[0010] [ka]

[0011] and R 9 is alkyl, aryl, aralkyl or a bond, or R 9 is bonded to Y to form a heterocycle; R 10 is an amino or a bond, R 11 is H or alkyl, W is a MetAP2 inhibitor moiety or alkyl; x is in the range from 1 to approximately 450 y is in the range of 1 to approximately 30 n is in the range of 1 to about 100 p is from 0 to 20, q is 2 or 3 r is 1, 2, 3, 4, 5 or 6.

[0012] In certain embodiments, at least one compound of the present disclosure, a pharma- ceutically acceptable salt, prodrug, metabolite, or analog or derivative thereof, is represented by the formula:

[0013] [ka]

[0014] or

[0015] [ka]

[0016] [ka]

[0017] The disclosure also provides a method for treating or ameliorating at least one symptom of cancer or treating a metabolically sensitive tumor in a subject in need thereof, wherein the subject has a metabolic dysfunction and is to be treated for cancer, the method comprising administering a therapeutically effective amount of at least one compound represented by the following formula, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof: ZQXYC(O)-W, In the formula, 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; 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; AA5 is a bond or 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) m CO2H, and 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

[0018] [ka]

[0019] and R 9 is alkyl, aryl, aralkyl or a bond, or R 9 is bonded to Y to form a heterocycle; R 10 is an amino or a bond, R 11 is H or alkyl, W is a MetAP2 inhibitor moiety p is from 0 to 20, q is 0 or 3, and r is 1, 2, 3, 4, 5, or 6.

[0020] The cancer is 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof.

[0021] The metabolic dysfunction is excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof.

[0022] The methods of the present disclosure can further include treating or ameliorating at least one symptom of metabolic dysfunction in the subject.The methods of the present disclosure can further include increasing adiponectin, decreasing leptin, decreasing fasting insulin, or a combination thereof in the subject.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. 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. No priority is granted to the claimed disclosures cited herein. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are merely illustrative and are not intended to be limiting in any way.

[0024] Other features and advantages of the disclosure will become apparent from the following detailed description, and from the claims. [Brief description of the drawings]

[0025] [Figure 1A] FIG. 1A is a graph of baseline body weight of mice on a high-fat diet compared to a low-fat diet. [Figure 1B] FIG. 1B is a graph showing tumor growth in mice on a high-fat diet compared to a low-fat diet. [Figure 2A] FIG. 2A is a graph showing tumor inhibition in lean mice following dosing with a compound of the present disclosure. [Figure 2B] FIG. 2B is a graph showing tumor inhibition in obese mice following dosing with a compound of the present disclosure. [Figure 2C]FIG. 2C is a graph depicting the percentage of tumor inhibition compared to vehicle in obese versus lean mice following dosing with a compound of the present disclosure. [Figure 3A] FIG. 3A is a graph showing weight loss in lean mice following dosing with a compound of the present disclosure. [Figure 3B] FIG. 3B is a graph showing weight loss in lean mice following dosing with a compound of the present disclosure. [Figure 4] FIG. 4 is a graph showing the relationship between body weight and tumor size in lean and obese mice following dosing with a compound of the present disclosure. [Diagram 5] FIG. 5 is a graph showing the reduction in the number of lung metastases in lean and obese mice following dosing with a compound of the disclosure. [Figure 6A] FIG. 6A is a graph showing the reduction in white blood cells in obese, tumor-bearing mice following administration of a compound of the present disclosure. [Figure 6B] FIG. 6B is a graph showing the reduction in white blood cells in obese, tumor-bearing mice following administration of a compound of the present disclosure. [Figure 7] FIG. 7 is a graph showing tumor growth inhibition in lean and obese tumor-bearing mice following dosing with other MetAP2 inhibitors. [Figure 8] FIG. 8 is a graph showing weight loss in lean and obese tumor-bearing mice following dosing with compounds of the present disclosure compared to other MetAP2 inhibitors. [Figure 9A] FIG. 9A is a graph showing the reduction in serum leptin in obese, tumor-free mice following dosing with a compound of the present disclosure. [Figure 9B] FIG. 9B is a graph showing increases in serum adiponectin in obese, tumor-free mice following dosing with a compound of the disclosure. [Figure 9C] FIG. 9C is a graph showing leptin to adiponectin ratios in obese, tumor-free mice following dosing with a compound of the present disclosure. [Figure 9D]FIG. 9D is a graph showing serum adiponectin levels in obese, tumor-free mice following dosing with compounds of the present disclosure compared to other MetAP2 inhibitors. [Figure 9E] No applicable information. [Figure 10A] FIG. 10A is a graph showing reduced tumor growth in lean, mammary tumor-bearing mice following dosing with a compound of the present disclosure. [Figure 10B] FIG. 10B is a graph showing reduced tumor growth in obese, mammary tumor-bearing mice following dosing with a compound of the present disclosure. [Figure 11A] FIG. 11A is a graph showing weight loss in lean, mammary tumor-bearing mice following dosing with a compound of the disclosure. [Figure 11B] FIG. 11B is a graph showing the change in body weight relative to baseline body weight in lean, mammary tumor-bearing mice following dosing with a compound of the disclosure. [Figure 11C] FIG. 11C is a graph showing weight loss in obese, mammary tumor-bearing mice following dosing with a compound of the present disclosure. [Figure 11D] FIG. 11D is a graph showing the change in body weight relative to baseline body weight in obese, mammary tumor-bearing mice following dosing with a compound of the disclosure. [Figure 12A] FIG. 12A is a graph showing absolute values ​​of various metabolic biomarkers in the serum of patients with carcinoid tumors following dosing with a compound of the present disclosure. [Figure 12B] FIG. 12B is a graph showing the percentage change in various metabolic biomarkers in serum relative to baseline in patients with carcinoid tumors following dosing with a compound of the present disclosure. [Figure 13A] FIG. 13A is a graph showing absolute values ​​of various metabolic biomarkers in the serum of patients with colon cancer following dosing with a compound of the present disclosure. [Figure 13B] FIG. 13B is a graph showing the percentage change in various metabolic biomarkers in serum relative to baseline in patients with colon cancer following dosing with a compound of the present disclosure. [Figure 14A]FIG. 14A is a graph showing absolute values ​​of various metabolic biomarkers in the serum of patients with endometrial cancer following dosing with a compound of the present disclosure. [Figure 14B] FIG. 14B is a graph showing the percentage change in various metabolic biomarkers in serum relative to baseline in patients with endometrial cancer following dosing with a compound of the present disclosure. [Figure 15A] FIG. 15A is a graph showing absolute values ​​of various metabolic biomarkers in the serum of patients with cervical cancer following dosing with a compound of the present disclosure. [Figure 15B] FIG. 15B is a graph showing the percentage change in various metabolic biomarkers in serum relative to baseline in patients with cervical cancer following dosing with a compound of the present disclosure. [Figure 16A] FIG. 16A is a graph showing absolute serum leptin levels in patients with hormone receptor positive breast cancer following dosing with a compound of the present disclosure. [Figure 16B] FIG. 16B is a graph showing the percentage change in serum leptin relative to baseline in patients with hormone receptor positive breast cancer following dosing with a compound of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Detailed Description of the Disclosure Method of Application The present disclosure provides a method of treating or ameliorating at least one symptom of a proliferative disease, such as cancer, in a subject in need of treatment, the subject having a metabolic dysfunction, comprising administering to the subject a therapeutically effective amount of at least one MetAP2 inhibitor to treat the proliferative disease. In a preferred embodiment, the proliferative disease is cancer. The cancer is 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. In addition to treating or ameliorating at least one symptom of a proliferative disorder, the methods of the disclosure may also include treating or ameliorating at least one symptom of a metabolic dysfunction.

[0027] The present disclosure also provides a method of treating or ameliorating at least one symptom of a proliferative disease, such as cancer, in a subject in need thereof, the subject having a metabolic dysfunction, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or derivative to treat the proliferative disease. In a preferred embodiment, the proliferative disease is cancer. The cancer is 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. In addition to treating or ameliorating at least one symptom of a proliferative disorder, the methods of the present disclosure may also include treating or ameliorating at least one symptom of a metabolic dysfunction.

[0028] The present disclosure also provides a method of treating or ameliorating at least one symptom of a proliferative disease in a subject in need of treatment, the subject having a metabolic dysfunction, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure to treat the proliferative disease. In a preferred embodiment, the proliferative disease is cancer. The cancer is 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. In addition to treating or ameliorating at least one symptom of a proliferative disorder, the methods of the disclosure may also include treating or ameliorating at least one symptom of a metabolic dysfunction.

[0029] The present disclosure also provides a method of treating metabolically sensitive tumors in a subject in need of treatment, the subject being metabolically insufficient, comprising administering to the subject a therapeutically effective amount of at least one MetAP2 inhibitor to treat the metabolically sensitive tumor. The metabolically sensitive tumors are the result 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. In addition to treating a metabolically sensitive tumor, the methods of the disclosure may also include treating or ameliorating at least one symptom of metabolic dysfunction.

[0030] The present disclosure also provides a method of treating metabolically sensitive tumors in a subject in need thereof, the subject being metabolically insufficient, comprising administering to the subject a therapeutically effective amount of at least one fumagillin analog or derivative to treat the metabolically sensitive tumor. The metabolically sensitive tumors are the result 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. In addition to treating a metabolically sensitive tumor, the methods of the disclosure may also include treating or ameliorating at least one symptom of metabolic dysfunction.

[0031] The present disclosure also provides a method of treating metabolically sensitive tumors in a subject in need thereof, the subject being metabolically insufficient, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure to treat the metabolically sensitive tumor. The metabolically sensitive tumors are the result 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, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. In addition to treating a metabolically sensitive tumor, the methods of the disclosure may also include treating or ameliorating at least one symptom of metabolic dysfunction.

[0032] Obesity has been identified as a risk factor for menopausal breast cancer, and excess visceral adipose tissue is associated with poorer response to chemotherapy and reduced progression and / or longer disease-free survival (Schaffler A. et al. (2007) Nat Clin Pract Endocrinol Metab 3:345-54; Vona-Davis, L. Rose, DP. (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 association, with recent data focusing particular attention on the adipokines leptin and adiponectin (Cleary, M. P. et al., (2009) Front Biosci (School Ed) 1:329-57; Cleary, M. P. et al., (2010) Vet Pathol 47:202-13). Molecular-based roles for leptin, adiponectin, and other hormones, such as insulin and insulin-like growth factors, have recently been described. Circulating levels of adiponectin are inversely related to body mass index (BMI); in contrast, serum leptin is directly related to BMI (Ryan, A. S. et al. (2003) Diabetes Care 26:2383-8; Wauters, M. et al. (2000) Eur J Endocrinol 143:293-311). Adiponectin levels are suppressed in obese individuals, especially those with high visceral fat content (Brochu-Gaudreau K, et al. Endocrine 2010, 37(1):11-32). Adiponectin is found in human serum at concentrations of 2-20 μg / ml (Grossmann, M. E. et al. (2008) Br J Cancer 98:370-9). The underlying mechanism of adiponectin signaling and carcinogenesis prevention is thought to involve activation of the intracellular signal AMPK and growth inhibition and survival pathways (Brochu-Gaudreau K et al., Endocrine 2010, 37(1):11-32; Pfeiler G et al., Maturitas 2009, 63(3):253-256).Furthermore, adiponectin exerts its biological activity indirectly through the selective sequestration of different growth factors (e.g., basic fibroblast growth factor, platelet-derived growth factor BB, and heparin-binding epidermal growth factor) and inhibition of their normal receptor binding. These interactions involve specific oligomeric forms of adiponectin (Barb, D. Williams, CJ. Neuwirth, AK. Mantzoros, CS. (2007) Am J Clin Nutr 86:s858-66; Wang et al. (2005) J Biol Chem 280:18341-7).

[0033] Several epidemiological studies have found an inverse correlation between adiponectin levels and risk of breast cancer (Barb et al. (2007) Am J Clin Nutr 86:s858-66; Miyoshi et al. (2003) Clin Cancer Res 9:5699-704; Mantzoros et al. (2004) J Clin Endocrinol Metab 89:1102-7; Chen, DC. et al. (2006) Cancer Lett 237:109-14). In breast cancer patients, adiponectin levels and the adiponectin to leptin ratio tend to be decreased compared to those found in lean women (Cleary MP. et al. (2009) Front Biosci (Schol Ed) 1:329-57; Cleary MP. et al. (2006) Cancer Lett 237:109-14). It has been reported that breast cancer patients with low adiponectin levels have more invasive tumors and a higher frequency of lymph node metastasis (Schaffler, A. et al. (2007) Nat Clin Pract Endocrinol Metab 3:345-54; Hou, WK. et al. (2007) Chin Med J (Engl) 120:1592-6).

[0034] In some embodiments, the present disclosure provides a method of using at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, and / or at least one compound of the present disclosure to treat certain types of tumors that are exacerbated by metabolic dysfunction, including 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, clear cell renal cancer, melanoma, multiple myeloma, or combinations thereof. In a preferred embodiment, the present disclosure discloses subcutaneous administration of a MetAP2 inhibitor in a cancer patient with metabolic dysfunction. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or combinations thereof. The present disclosure can restore the patient to a more metabolically neutral and stable state, and slow or reverse the progression of the patient's cancer.

[0035] Described herein is a method of improving the underlying metabolic dysfunction in patients with metabolically sensitive tumors. The method of treating metabolically sensitive tumors is by increasing adiponectin levels, decreasing leptin levels, improving the ratio of leptin to adiponectin, or a combination thereof. Subcutaneous administration of the MetAP2 inhibitors described herein has demonstrated the ability to improve these levels and ratios in cancer patients, and can therefore be employed to treat metabolically sensitive tumors that would benefit from upregulation of adiponectin along with improved leptin sensitivity. Thus, in some embodiments, the MetAP2 inhibitors described herein can treat cancers including postmenopausal hormone receptor positive (HR+) breast cancer, castration-resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder, hepatocellular carcinoma, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The above cancers are associated, at least in part, with adiponectin deficiency and / or adiponectin resistance.

[0036] The present disclosure also provides a method of treating cancer in a subject in need of treatment, the method comprising: (i) identifying whether the patient has postmenopausal hormone receptor positive (HR+) breast cancer, castration-resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, hepatocellular carcinoma, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof; (ii) determining whether the cancer patient is metabolically dysfunctional; and (iii) administering a therapeutically effective amount of at least one MetAP2 inhibitor, 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 metabolically dysfunctional in step (ii). Preferably, the subject is administered a compound of the present disclosure. Preferably, the compound is administered subcutaneously. The metabolic dysfunction includes excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels with chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin levels, high leptin levels, high fasting insulin levels, or a combination thereof. The method of the present disclosure may also further include treating or ameliorating at least one symptom of the metabolic dysfunction in addition to treating cancer.

[0037] In another aspect, the disclosure provides a method of determining whether a tumor is metabolically sensitive, the method comprising: (1) measuring fasting insulin and glucose levels to determine a patient's HOMA number (insulin sensitivity number); (2) comparing the HOMA number to that of lean patients; and (3) determining that the HOMA number is higher than that of metabolically normal patients, that the cancer is sensitive to treatment with at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, or at least one compound of the disclosure.

[0038] As used herein, a "subject in need thereof" is a subject having a cell proliferative disorder, or a subject at high risk for developing a cell proliferative disorder relative to the majority. A subject in need of treatment may have a pre-cancerous condition. Preferably, the subject in need of treatment has cancer. Preferably, said subject having a cell proliferative disorder also has a metabolic dysfunction.

[0039] A "subject" includes a mammal. A mammal can be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, a poultry, 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.

[0040] As used herein, the term "cell proliferative disorder" refers to a condition in which uncontrolled or abnormal growth of cells, or both, leads to the development of an unwanted condition or disease that may or may not be cancerous. Exemplary cell proliferative disorders of the present disclosure encompass a variety of conditions in which cell division is unregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, blister tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell that divides excessively or more rapidly than adjacent or juxtaposed cells in the same tissue. Cell proliferative disorders include precancerous or precancerous conditions. Cell proliferative disorders include cancer. Cell proliferative disorders include noncancerous conditions or disease states. Preferably, the methods provided herein are employed to treat or alleviate symptoms of cancer. The term "cancer" includes solid cancers as well as hematological and / or malignant tumors. A "precancerous cell" or "precancerous cell" is a cell that manifests a cell proliferative disorder that is a precancer or a precancerous condition. A "cancer cell" or "cancerous cell" is a cell that manifests a cell proliferative disorder that is a cancer or a cancerous condition. Any reproducible means of measurement can be employed to identify cancer or precancerous cells. Cancer or precancerous cells can be identified by histological typing or classification of a tissue sample (e.g., a biopsy sample). Cancer or precancerous cells can be identified using appropriate molecular markers.

[0041] Non-cancerous conditions or conditions include, but are not limited to, rheumatoid arthritis, inflammation, autoimmune diseases, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, non-toxic shock, gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, inflammatory bowel disease, Crohn's disease, skin-related hyperproliferative diseases, psoriasis, eczema, atopic dermatitis, hyperpigmentation disorder diseases, eye-related hyperproliferative diseases, age-related macular degeneration, ulcerative colitis, pancreatic fibrosis, hepatic fibrosis, acute and chronic kidney disease, irritable bowel syndrome, fever, restenosis, cerebral malaria, stroke and ischemic injury, neurological trauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary syndrome, cachexia malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute periostitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, hernia, laceration, or bone resorption diseases such as prolapsed disc syndrome, osteopetrosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, osteoporosis, graft-versus-host reaction, fibrolipohypertrophy, spinocerebellar degeneration type 1, Clove syndrome, harlequin ichthyosis, macrodactyly syndrome, Proteus syndrome (Wiedemann syndrome), multiple lentigines syndrome, systemic sclerosis, multiple sclerosis, lupus, fibromyalgia, herpes zoster and herpes simplex I and II, and AIDS and other viral diseases such as influenza and cytomegalovirus, diabetes mellitus, hemihyperplasia multiple lipomatosis syndrome, megalencephaly, rare hypoglycemia, Klippel-Treney syndrome, hamartoma, Cowden syndrome, or hypertrophic hyperglycemia.

[0042] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, squamous cell carcinoma of the anus, angiosarcoma, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer. , brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ganglioglioma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic tract and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, digestive system, cancer of the nervous system, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disease, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, ocular melanoma, retinoblastoma, bladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, 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 (endocrine pancreas), Kaposi's sarcoma, kidney cancer, renal cancer, kidney cancer, pharyngeal cancer, acute lymphoblastic leukemia, T-cell lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cellLung cancer, small cell lung cancer, squamous cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, B-cell lymphoma, primary effusion lymphoma, Waldenström's macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous cell neck cancer, oral cavity 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 carcinoma, neuroblastoma, oral cavity cancer, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, intrapancreatic tumor, paranasal sinus and nasal cancer, parathyroid cancer, bile duct cancer, penile cancer, throat cancer Head cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pituitary adenoma, plasma cell neoplasm / multiple myeloma, pleuroembryoblastoma, prostate cancer, rectal cancer, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma family of tumors, 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 uterine cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0043] A "cell proliferative disorder of the blood system" is a cell proliferative disorder involving cells of the blood system. Cell proliferative disorders of the blood system include lymphoma, leukemia, myeloid neoplasm, mast cell neoplasm, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granuloma, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, idiopathic myelofibrosis, and essential thrombocythemia. Cell proliferative disorders of the blood system include hyperplasia, dysplasia, and pseudoplasia of blood cells. Preferably, the composition of the present disclosure is used to treat a cancer selected from the group consisting of a blood cancer of the present disclosure and a blood cell proliferative disorder of the present disclosure. Hematological cancers of the present disclosure include multiple myeloma, lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphomas of lymphocytic and cutaneous origin), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0044] According to the American Joint Committee on Cancer (AJCC) TNM classification system, the cancer to be treated is staged, in which the tumor (T) is staged as TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d, the regional lymph nodes (N) are staged as NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c, and the distant metastases (M) can be staged as MX, M0, or M1. According to the American Joint Committee on Cancer (AJCC) classification, the cancer to be treated is staged as stage I, stage IIA, stage IIB, stage IIIA, stage IIIB, stage IIIC, or stage IV. According to the AJCC classification, the cancer to be treated is graded as grade GX (e.g., ungraded), grade 1, grade 2, grade 3, or grade 4. According to the AJCC pathological classification (pN), the cancer to be treated is staged as pNX, pN0, PN0(I-), PN0(I+), PN0(mol-), PN0(mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0045] The cancers to be treated include tumors that measure from about 2 cm to about 5 cm in diameter. The cancers to be treated include tumors that measure from about 2 cm to about 5 cm in diameter. The cancers to be treated include tumors that measure from about 3 cm or more in diameter. The cancers to be treated include tumors that measure more than 5 cm in diameter. The cancers to be treated are classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. The cancers to be treated are classified by microscopic appearance for mitotic figure counts (e.g., amount of cell division) or nuclear pleomorphism (e.g., changes in cells). The cancers to be treated are classified by microscopic appearance for areas of necrosis (e.g., areas of dead or degenerating cells). The cancers to be treated are classified by having an abnormal karyotype, an abnormal number of chromosomes, or one or more chromosomes that appear abnormal. The cancers to be treated are classified by being aneuploid, triploid, tetraploid, or having an altered ploidy. The cancers to be treated are classified according to whether they have chromosomal translocations, whole chromosomal deletions or duplications, or regions of partial chromosomal deletions, duplications, or amplifications.

[0046] The cancer to be treated is assessed by DNA cytometry, flow cytometry, or image cytometry. The cancer to be treated is typed according to whether it has 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthetic stage of cell division (e.g., S phase of cell division). The cancer to be treated is typed as being in low S phase or high S phase.

[0047] As used herein, a "normal cell" is a cell that is not classified as being part of a "cell proliferative disorder." A normal cell is one that is free of uncontrolled and / or abnormal growth that leads to the development of an unwanted condition or disease. Preferably, a normal cell is one that is capable of normally functioning cell cycle checkpoint mechanisms.

[0048] As used herein, "contacting a cell" refers to a compound or other composition of the present disclosure directly contacting or sufficiently close to elicit a desired biological effect on a cell.

[0049] 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.

[0050] In particular, in addition to treating or alleviating at least one symptom of one or more proliferative diseases, the compounds of the present disclosure can also treat or alleviate at least one metabolic dysfunction selected from the group including excess visceral adiposity, high leptin levels, low adiponectin levels, high leptin to adiponectin ratio, high fasting insulin levels associated with chronic inflammation, or combinations thereof. The metabolic dysfunction treated or ameliorated is preferably low adiponectin, elevated leptin, elevated fasting insulin, or combinations thereof.

[0051] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may treat or alleviate at least one symptom of obesity.

[0052] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can reduce body weight. In some embodiments, the subject is overweight or obese. In some embodiments, the subject is in need of reducing excess adipose tissue.

[0053] Obesity and being overweight refer to an excess of fat in a subject relative to lean body mass. Excessive fat accumulation is associated with an increase in the number of adipose tissue cell hyperplasia as well as size (hypertrophy or adiposity). Obesity can be caused by either genetic (e.g. Prader-Willi syndrome) or environmental causes. Obesity is variously measured in terms of absolute weight, weight-to-height ratio, degree of excess body fat, distribution of visceral and subcutaneous fat, and social and aesthetic norms. A common measurement of body fat is the Body Mass Index (BMI). BMI refers to the ratio of weight (in kilograms) to height squared (in meters). Body Mass Index is calculated according to the formula SI units: BMI=weight (kg) / height 2 (m 2 ) or US units: BMI = weight (lb) x 703) / height 2 (in 2 ) can be used to calculate it accurately.

[0054] As stated here, "overweight" is defined as a BMI of 25 kg / m 2 from 29.9 kg / m 2 As used herein, "obese" or "obesity" refers to a BMI of 30 kg / m2 or less or a condition in which the body is otherwise healthy. 2 Obesity is defined as a state of being otherwise healthy. There are several subcategories of obesity. 2 Adults with a BMI of 40 kg / m or more are said to be "very obese" or "very obese". 2 From the above, 44.9kg / m 2 Adults with a BMI of 35 kg / m 2 Adults who have at least one of the above obesity-related health conditions are said to be "morbidly obese" or "morbidly obese." 2 Adults who are above this age are said to be “super obese” or “very obese.” For children, the definition of overweight and obesity takes into account the effects of age and sex on body fat.

[0055] In different countries, obesity and overweight can be defined by different BMIs. The meaning of the term "obesity" encompasses the definitions in all countries. For example, in Asia, the increased risks associated with obesity occur with lower body mass index (BMI). In Asian countries, including Japan, "obesity" is defined as a BMI of 25.0 kg / m2 or more in a subject with at least one obesity-induced or obesity-related comorbidity in which weight loss is required or would be improved by weight loss. 2 It refers to a BMI of 100 or above. Latin American peoples tend to be classified closer to Asia than to Europe or North America.

[0056] BMI does not account for the fact that excess adipose tissue can occur selectively in different parts of the body, and that the development of adipose tissue is more dangerous to health in some parts of the body than in others. For example, "central obesity", typically associated with an "apple-shaped" body type, results from excess adiposity, especially in the abdomen, including abdominal fat and visceral fat, whereas "peripheral obesity", associated with a "pear-shaped" body type, resulting from excess adiposity, especially in the buttocks, carries a higher risk of comorbidities. Measurement of waist-to-hip circumference (WHR) can be used as an index of central obesity. The minimum WHR index for central obesity has been established in various ways, with centrally obese adults typically having a WHR of approximately 0.85 or more for women and approximately 0.9 or more for men.

[0057] A method of determining whether a subject is overweight or obese, which represents the ratio of excess adipose tissue to lean body mass, includes obtaining the subject's body composition. Body composition is obtained by measuring the thickness of subcutaneous fat at several sites, such as the abdomen, shoulders, arms, buttocks, and thighs. These measurements are used to estimate total body fat with an error margin of approximately 4%. Another measurement method is bioimpedance analysis (BIA), which uses the resistance of electrical current passing through the body to estimate body fat. Another method uses a large tank of water to measure the buoyancy of the body. High body fat leads to greater buoyancy, and greater muscle mass leads to a tendency to sink. Yet another method is fan-beam dual x-ray absorptiometry (DEXA). DEXA allows for non-invasive measurement of body composition, particularly total body fat and / or regional body fat. MRI can also be used to measure composition non-invasively.

[0058] In addition to treating or alleviating at least one symptom of one or more proliferative diseases, the compounds of the present disclosure can also reduce adipocytes or adipose tissue. Reducing adipocytes means reducing the number or size (fat content) of adipocytes. In some embodiments, the compounds of the present disclosure cause the subject's adipocytes to shrink. The adipose tissue can be white adipose tissue or brown adipose tissue.

[0059] 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 food intake. A reduction in food intake refers to a reduction in daily food intake. A reduction in daily food intake is from about 5% to about 50% (e.g., about 5%, about 10%, about 20%, about 30%, about 40% or about 50%). Based on a daily 2000 kcal diet, the reduction is from about 100 kcal to about 1000 kcal (e.g., about 100 kcal, about 200 kcal, about 400 kcal, about 600 kcal, about 800 kcal or about 1000 kl) per day.

[0060] In addition to treating or alleviating at least one symptom of one or more proliferative diseases, the compounds of the present disclosure can also reduce hunger in a subject. The subject can reduce food intake. Hunger, which is often used in appetite surveys, is assessed using a 10-point visual analog scale (VAS). (See Flint et al., Int. J. Obes. Relat. Metab. Disord. 24(1):38-48, 2000.) Specifically, subjects are asked to rate their overall hunger over the previous two days on a scale of 1 to 10, with 10 being extremely hungry and 1 being not hungry at all.

[0061] 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, which is assessed by tape measurement around the abdomen 1 cm above the iliac crest. A subject of the present disclosure may reduce waist circumference by approximately 1 inch to approximately 20 inches (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 inches).

[0062] 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 body fat and substantially preserve muscle mass in said patients. In some embodiments, administration enhances fat oxidation in patients compared to patients on a strict diet alone. Such patients can preserve substantially more muscle mass compared to the body fat loss in patients on a calorie-restricted diet alone.

[0063] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also lower insulin levels, leptin levels, or both in a subject. In some embodiments, the subject is overweight or obese. In some embodiments, the subject is in need of reducing excess adipose tissue.

[0064] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also improve the outcome of surgery in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure prior to surgery to improve the outcome of the surgery. In some embodiments, the administration reduces liver and / or abdominal fat in the patient to improve the outcome of the surgery. In some embodiments, the surgery is a non-acute surgery. Such surgeries include bariatric surgery, cardiovascular surgery, abdominal surgery, or orthopedic surgery.

[0065] As used herein, "monotherapy" refers to the administration of a single active or therapeutic compound of the present disclosure to a subject in need of treatment. For example, a cancer monotherapy is administered to a subject in need of cancer treatment with one of the compounds of the present disclosure or a pharma- ceutically acceptable salt, prodrug, metabolite, analog or derivative thereof. Monotherapy can be contrasted with combination therapy, in which a combination of multiple active compounds is administered, as described below. In one embodiment, monotherapy with a compound of the present disclosure, a pharma- ceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof is more effective than combination therapy in eliciting a desired biological effect.

[0066] As used herein, "combination therapy" or "co-therapy" includes the administration of at least two compounds of the present disclosure, or pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, as part of a specific treatment regimen intended to provide a beneficial effect of the synergistic action of at least two of the compounds of the present disclosure. The synergistic beneficial effect includes, but is not limited to, the mutual pharmaceutical action or synergistic action resulting from the combination of at least two of the compounds of the present disclosure. The administration of at least two of the compounds of the present disclosure in combination therapy is carried out over a defined period of time (usually minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" may, but generally does not, include the administration of two or more compounds of the present disclosure as part of separate monotherapy regimens that incidentally and optionally result in the combination of the present disclosure.

[0067] "Combination therapy" also includes administration of the compounds of the present disclosure in combination with a second active agent and / or a non-drug treatment (e.g., surgery or radiation therapy). In combination therapy further including a non-drug treatment, the non-drug treatment can be performed at any suitable time when a beneficial effect due to the synergistic action of the combination of the therapeutic agent and the non-drug treatment is achieved. For example, where appropriate, the beneficial effect can still be achieved when the non-drug treatment is temporarily removed from the administration of the therapeutic agent, perhaps even for days or weeks. The second active agent may be conjugated to a polymer.

[0068] "Combination therapy" is intended to include sequential administration of therapeutic agents, where each therapeutic agent is administered at a different time, as well as substantially simultaneous administration of at least two of these therapeutic agents or therapeutic agents. As used herein, substantially simultaneous means administration of at least two therapeutic agents within one hour 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 separate capsules of each therapeutic agent. As used herein, sequential means administration of one of the at least two therapeutic agents at least one hour after another of the at least two therapeutic agents. Preferably, sequential administration means administration of one of the at least two therapeutic agents at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, at least one week after another of the at least two therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be accomplished by any suitable route, including, but not limited to, oral, intravenous, subcutaneous, intramuscular, or direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent of a selected combination may be administered orally, while other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by subcutaneous injection. The order of the therapeutic agents is not strictly important.

[0069] In a preferred embodiment, the second active agent is a chemotherapeutic agent. The additional chemotherapeutic agent (also referred to as antineoplastic or antiproliferative agent) is an alkylating agent, an antibiotic, antimetabolite, an antidote, an interferon, a polyclonal or monoclonal antibody, an EGFR inhibitor, an FGFR inhibitor, an HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitosis inhibitor, an MTOR inhibitor, a multi-kinase inhibitor, a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, a VEGF / VEGFR inhibitor, a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, a molecular target or enzyme inhibitor (e.g., a kinase inhibitor), a cytidine analog drug, or any chemotherapeutic, antitumor, or antiproliferative agent listed at www.cancer.org / docroot / cdg / cdg_0.asp.

[0070] Exemplary alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan, Neosar), chlorambucil (Leukeran), melphalan (Alkeran), carmustine (BiCNU), busulfan (Busulfex), lomustine (CeeNU), dacarbazine (DTIC-Dome), oxaliplatin (Eloxatin), carmustine (Gliadel), ifosfamide (Ifex), mechlorethamine (Mustargen), busulfan (Myleran), carboplatin (Paraplatin), cisplatin (CDDP, Platinol), temozolomide (Temodar), thiotipa (Thioplex), bendamustine (Treanda), or streptozocin (Zanosar).

[0071] Exemplary antibiotics include, but are not limited to, doxorubicin (Adriamycin), doxorubicin liposomal (Doxil), mitoxantrone (Novantrone), bleomycin (Bleonoxane), daunorubicin (Cerubidine), daunorubicin liposomal (DaunoXome), dactinomycin (Cosmegen), epirubicin (Ellence), idarubicin (Idamycin), plicamycin (Mithracin), mitomycin (Mutamycin), pentostatin (Nipent), or valrubicin (Valstar).

[0072] Exemplary antimetabolites include, but are not limited to, fluorouracil (Adrucil), capecitabine (Xeloda), hydroxyurea (Hydrea), mercaptopurine (Purinethol), pemetrexed (Alimta), fludarabine (Fludara), nelarabine (Arranon), cladribine (Cladribine), and the like. Novaplus), clofarabine (Clolar), cytarabine (Cytosar-U), decitabine (Dacogen), cytarabine liposomal (DepoCyt), hydroxyurea (Droxia), pralatrexate (Folotyn), floxuridine (FUDR), gemcitabine (Gemzar), cladribine (Leustatin), fludarabine (Oforta), methotrexate (MTX, Rheumatrex), methotrexate (Trexall), thioguanine (Tabloid), TS-1, or cytarabine (Tarabine PFS).

[0073] Exemplary antidotes include, but are not limited to, amifostine (Ethyol) or mesna (Mesnex).

[0074] Exemplary interferons include, but are not limited to, interferon alpha-2b (IntronA) or interferon alpha-2a (Roferon-A).

[0075] Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin), ofatumumab (Arzerra), bevacizumab (Avastin), rituximab (Rituxan), cetuximab (Erbitux), panitumumab (Vectibix), tosizumab / iodine 131 These include tosizumab (Bexxar), alemtumab (Campath), ibritumomab (Zevalin, In-111, Y-90Zevalin), gemtuzumab (Mylotarg), eculizumab (Soliris), ordenosumab, nivolumab (Opdivo), pembrolizumab (Keytruda), ipilimumab (Yeroy), pidilizumab, and atezolizumab.

[0076] Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa), lapatinib (Tykerb), cetuximab (Erbitux), erlotinib (Tarceva), panitumumab (Vectibix), PKI-166, canertinib (CI-1033, matuzumab (Emd7200) or EKB-569.

[0077] Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin), lapatinib (Tykerb) or AC-480.

[0078] Histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza).

[0079] Exemplary hormones include, but are not limited to, tamoxifen (Soltamox, Nolvadex), raloxifene (Evista), megestrol (Megace), leuprolide (Lupron, Lupron Depot, Eligard, Viadur), fulvestrant (Faslodex) letrozole (Femara), triptorelin (Trelstar LA, Trelstar Examples of drugs that may be used include fluoxymesterone (Androxy, Halotestin), medroxyprogesterone (Provera, Depo-Provera), estramustine (Emcyt), flutamide (Eulexin), toremifene (Fareston), degarelix (Firmagon), nilutamide (Nilandron), abarelix (Plenaxis), or testolactone (Teslac).

[0080] Exemplary mitotic inhibitors include, but are not limited to, paclitaxel (Taxol, Onxol, Abraxane), docetaxel (Taxotere), vincristine (Oncovin, VincasarPFS), vinblastine (Velban), etoposide (Toposar, Etopophos, VePesid), teniposide (Vumon), ixabepilone (Ixempra), nocodazole, epothilones, vinorelbine (Navelbine), camptothecin (CPT), irinotecan (Camptosar), topotecan (Hycamtin), amsacrine, or lamellarin D (LAM-D).

[0081] Exemplary MTOR inhibitors include, but are not limited to, everolimus (Afinitor), or temsirolimus (Torisel), rapamune, ridaforolimus, or AP23573.

[0082] Exemplary multikinase inhibitors include, but are not limited to, sorafenib (Nexavar), sunitinib (Sutent), BIBW2992, E7080, Zd6474, PKC-412, motesanib, or AP24534.

[0083] Exemplary serine / threonine kinase inhibitors include, but are not limited to, ruboxistaurin, eril / fasudil hydrochloride, flavopiridol, seliciclib (CYC202, Roscovitrine), SNS-032 (BMS-387032), Pkc412, bryostatin, KAI-9803, SF1126, VX-680, Azd1152, Arry-142886 (AZD-6244), SCIO-469, GW681323, CC-401, CEP-1347, or PD332991.

[0084] Exemplary tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva), gefitinib (Iressa), imatinib (Gleevec), sorafenib (Nexavar), sunitinib (Sutent), trastuzumab (Herceptin), bevacizumab (Avastin), rituximab (Rituxan), lapatinib (Tykerb), cetuximab (Erbitux), panitumumab (Vectibix), everolimus (Afinitor), alemtuzumab ( Campath), gemtuzumab (Mylotarg), temsirolimus (Torisel), pazopanib (Votrient), dasatinib (Sprycel), nilotinib (Tasigna), vatalanib (Ptk787, ZK222584), CEP-701, SU5614, MLN518, XL999, VX-322, Azd0530, BMS-354825, SKI-606CP-690, AG-490, WHI-P154, WHI-P131, AC-220, or AMG888.

[0085] Exemplary VEGF / VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), ranibizumab, pegaptanib, or vandetinib.

[0086] Exemplary microtubule-targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastine, nocodazole, epothilones, and navelbine.

[0087] Exemplary topoisomerase poison drugs include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin, and idarubicin.

[0088] Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxol.

[0089] Exemplary common chemotherapeutic, anti-neoplastic, and anti-proliferative agents include, but are not limited to, altretamine (Hexalen), isotretinoin (Accutane, Amnesteem, Claravis, Sotret), tretinoin (Vesanoid), azacytidine (Vidaza), bortezomib (Velcade), asparaginase (Elspar), levamisole (Ergamisol), mitotane (Lysodren), procarbazine (Matulan), and the like. e), pegaspargase (Oncaspar), denileukin diftitox (Ontak), porfimer (Photofrin), aldesleukin (Proleukin), lenalidomide (Revlimid), bexarotene (Targretin), thalidomide (Thalomid) temsirolimus (Torisel), arsenic trioxide (Trisenox), verteporfin (Visudyne), mimosine (Leucenol), (1M tegafur-0.4M 5-chloro-2,4-dihydroxypyrimidine-1M potassium oxonate) or lovastatin.

[0090] In another embodiment, the additional chemotherapeutic agent may be a cytokine, such as G-CSF (granulocyte colony stimulating factor). In another embodiment, the compounds of the present disclosure, or pharma- ceutically acceptable salts, prodrugs, metabolites, or analogs or derivatives thereof, may be administered in combination with radiation therapy. Radiation therapy may also be administered in combination with the compounds of the present disclosure and other chemotherapeutic agents described herein, as part of a multi-drug combination. In yet another embodiment, the compounds of the present disclosure, or pharma- ceutically acceptable salts, prodrugs, metabolites, or analogs or derivatives thereof, may be administered in combination with any of the following chemotherapeutic agents, including, but not limited to, CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), CAF (cyclophosphamide, adriamycin, and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), rituximab, xerostomycin, cyclophosphamide ... It may be administered in combination with standard chemotherapy combinations such as Xeloda (Capecitabine), Cisplatin (CDDP), Carboplatin, TS-1 (Tegafur, Gimestat, and Otastat potassium in a molar ratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinotecan or Camptosar™) or CMFP (Cyclophosphamide, Methotrexate, 5-Fluorouracil, and Prednisone).

[0091] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, may be administered with inhibitors of enzymes, such as receptor kinases or non-receptor kinases. Receptor kinases and non-receptor kinases of the present invention are, for example, tyrosine kinases or serine / threonine kinases. Kinase inhibitors of the present disclosure are small molecules, polynucleic acids, polypeptides, or antibodies.

[0092] Exemplary kinase inhibitors include, but are not limited to, BIBW2992 (targets EGFR and Erb2), Cetuximab / Erbitux (targets Erb1), Imatinib / Gleevic (targets Bcr-Abl), Trastuzumab (targets Erb2), Gefitinib / Iressa (targets EGFR), Ranibizumab (targets VEGF), Pegaptanib (targets VEGF), Erlotinib / Tarceva (targets Erb1), Nilotinib (targets Bcr-Abl), and EGFR kinase inhibitors. (targets EGFR), lapatinib (targets Erb1 and Erb2 / Her2), GW-572016 / lapatinib ditosylate (targets HER2 / Erb2), panitumumab / vectibix (targets EGFR), vandetinib (targets RET / VEGFR), E7080 (multiple targets including RET and VEGFR), Herceptin (targets HER2 / Erb2), PKI-166 (targets EGFR), canertinib / CI-1033 (targets EGFR), sunitinib / SU-11464 / stent (targets EGFR and FLT3), matuzumab / Emd7200 (EGFR), EKB-569 (EGFR), Zd6474 (EGFR and VEGFR), PKC-412 (VEGR and FLT3), vatalanib / Ptk787 / ZK222584 (VEGR), CEP-701 (FLT3), SU5614 (FLT3), MLN518 (FLT3), XL999 (FLT3), VX-322 (FLT3), Azd0530 ( SRC), BMS-354825 (SRC), SKI-606 (SRC), CP-690 (JAK), AG-490 (JAK), WHI-P154 (JAK), WHI-P131 (JAK), sorafenib / nexavar (RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT3, and RET), dasatinib / sprycel (BCR / ABL and Src), AC-220 (FLT3),These include AC-480 (targets all HER proteins, "panHER"), motesanib diphosphate (targets VEGF1-3, PDGFR and c-kit), denosumab (targets RANKL and inhibits SRC), AMG888 (targets HER3), and AP24534 (multiple targets including FLT3).

[0093] Exemplary serine / threonine kinase inhibitors include, but are not limited to, Rapamune (targets mTOR / FRAP1), Deforolimus (targets mTOR), Certican / Everolimus (targets mTOR / FRAP1), AP23573 (targets mTOR / FRAP1), Eril / Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK), Seliciclib / CYC202 / Roscovitrine (targets CDK), SNS-032 / BMS-387032 (targets CDK), Rubovizone / Cycloprostaglandin (targets CDK), and Benzylpyridin (targets CDK). These include xistaurin (targets PKC), Pkc412 (targets PKC), bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K), VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase), Arry-142886 / AZD-6244 (targets MAP / MEK), SCIO-469 (targets MAP / MEK), GW681323 (targets MAP / MEK), CC-401 (targets JNK), CEP-1347 (targets JNK), and PD 332991 (targets CDK).

[0094] Contemplated second active agents include sulfonylureas (e.g., chlorpropamide, glipicides, glyburide, glimepiride), meglitinides (e.g., repaglinide and nateglinide), biguanides (e.g., metformin), thiazolidinediones (rosiglitazone, troglitazone, and pioglitazone), glucagon-like peptide-1 mimetics (e.g., exenatide and liraglutide), sodium-glucose cotransporter inhibitors (e.g., dapagliflozin), dipeptidyl peptidase-4 inhibitors (e.g., gliptins ... Medications administered to treat type 2 diabetes, such as glucose-linked transporter inhibitors, and α-glucosidase inhibitors (e.g., acarbose and miglitol), and / or other agents, such as, for example, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, lasix, and torsemide), potassium sparing agents (e.g., amiloride hydrochloride, spironolactone, and triamterene), peripheral medications (e.g., reserpine), central alpha agonists (e.g., clonidine hydrochloride, guanabenzyl acetate, guanidine hydrochloride, and guanidine hydrochloride ...). amphasine hydrochloride, and methyldopa), alpha-blockers (e.g., doxazosin mesylate, prazosin hydrochloride, and terazosin hydrochloride), beta-blockers (e.g., acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, penbutolol sulfate, pindolol, propranolol hydrochloride, and timolol maleate), mixed alpha-beta blockers (e.g., carvedilol and labetalol hydrochloride), direct vasodilators (e.g., hydralazine hydrochloride and minoxidil), diltiazem hydrochloride and verapamil hydrochloride), dihydropyridines (e.g. amlodipine besylate, felodipine, isradipine, nicardipine, nifedipine and nisoldipine), ACE inhibitors (e.g. benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, quinapril hydrochloride, ramipril and trandolapril), angiotensin II receptor blockers (e.g. losartan potassium, valsartan and irbesartan),and combinations thereof, as well as agents administered to treat cardiac diseases and conditions, such as hypertension, dyslipidemia, ischemic disease, cardiomyopathy, myocardial infarction, stroke, venous thromboembolism, pulmonary hypertension, which are associated with overweight or obesity, such as statins, such as mevastatin, lovastatin, pravastatin, simvastatin, belostatin, dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, and glenvastatin, typically for the treatment of lipemia.

[0095] Other second active agents that may be administered with (e.g., sequentially or simultaneously) include agents administered to treat ischemic heart disease, including statins, nitrates (e.g., Isosorbide Dinitrate and Isosorbide Mononitrate), beta blockers, and calcium channel antagonists, inotropes (e.g., Digoxin), diuretics (e.g., Furosemide), ACE inhibitors, calcium antagonists, antiarrhythmics (e.g., Sotolol, Amiodarone, and Disopyramide), and beta blockers, agents administered to treat cardiomyopathies, including angiotensin II, vasopressin, vasorelaxanthine, vasorexin ... Medications administered to treat myocardial infarction include tensin-converting enzyme inhibitors, angiotensin II receptor blockers, direct vasodilators, beta-blockers, antiarrhythmics, and thrombolytics (e.g., Alteplase, Retaplase, Tenecteplase, Anistreplase, and Urokinase), antiplatelet agents (e.g., Aspirin, Clopidogrel, medications administered to treat heart attacks, including anticoagulants (e.g., heparin) and thrombolytics; medications administered to treat venous thromboembolism, including antiplatelet agents, anticoagulants, and thrombolytics; inotropes, anticoagulants, diuretics, potassium (e.g., K-dur), vasodilators (e.g., nifedipine and diltiazem); Medications administered to treat pulmonary hypertension, including bronchodilators, anti-inflammatory drugs, leukotriene inhibitors, and anti-IgE agents. Specific asthma medications include Zafirlukast, Flunisolide, Triamcinolone,Medications administered to treat sleep apnea include Beclomethasone, Terbutaline, Fluticasone, Formoterol, Beclomethasone, Salmeterol, Theophylline, and Xopenex; Medications administered to treat nonalcoholic fatty liver disease include Modafinil and amphetamines. Medications that may be administered include antioxidants (e.g., Vitamin E and Vitamin C), insulin sensitizers (e.g., Metformin, Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectants, and lipid-lowering drugs, and medications administered to treat osteoarthritis of weight-bearing joints include acetaminophen, nonsteroidal anti-inflammatory drugs (e.g., Ibuprofen, Etodolac, Oxaprozin, Medications administered to treat Prader-Willi syndrome include steroids, supplements (e.g., glucosamine and chondroitin sulfate), human growth hormone (HGH), somatropin, and weight loss medications (e.g., Orlistat, Sibutramine, Methamphetamine, etc.), COX-2 inhibitors (e.g., Celecoxib), steroids, and artificial joint fluids. Medications given to treat polycystic ovary syndrome include insulin sensitizers, synthetic estrogen and progesterone combinations, spironolactone, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, and Topamax; and medications given to treat polycystic ovary syndrome include insulin sensitizers, synthetic estrogen and progesterone combinations, spironolactone,Drugs administered to treat erectile dysfunction include phosphodiesterase inhibitors (e.g., Tadalafil, Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g., Alprostadil), alkaloids (e.g., Yohimbine), and testosterone; drugs administered to treat infertility include Clomiphene, Clomiphene citrate, Bromophene, and Clomiphene. Bromocriptine, Gonadotropin-Releasing Hormone (GnRH), GnRH Agonists, GnRH Antagonists, Tamoxifen / Nolvadex, Gonadotropins, Human Chorionic Gonadotropin (HCG), Human Menopausal Gonadotropin (HmG), Progesterone, Recombinant Follicle Stimulating Hormone (FSH), Urinary Follicle Stimulating Hormone, Heparin, Follitropin Alpha, and Follitropin Beta. Medications administered to treat obstetric complications include Bupivacaine, Dinoprostone. PGE2, Meperidine HCl, Ferro-folic-500 / Iberet-folic-500, Meperidine, Methylergonovine Maleate, Ropivacaine HCl, Nalbuphine HCl, Oxymorphone HCl, Oxytocin, Dinoprostone (D Inoprostone, Ritodrine, Scopolamine hydrobromide, Sufentanil citrate, and labor inducers are included, and drugs administered to treat depression include serotonin reuptake inhibitors (e.g., Fluoxetine, Escitalopram, Citalopram, Paroxetine, Sertraline,and Venlafaxine, tricyclic antidepressants (e.g., Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dosulepine Hydrochloride, Doxepin, Imipramine, Iprindole, Lofepramine, Nortriptyline) , Opipramol, Protriptyline, and Trimipramine), monoamine oxidase inhibitors (e.g., Isocarboxazid, Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline, Nialamide, Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolide psychostimulants (e.g., amphetamines, methamphetamines, methylphenidate, and arecoline), antipsychotics (e.g., butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, Symbyax, tetrabenazine, and cannabidiol), and mood stabilizers (e.g., lithium carbonate, valproic acid, divalproex sodium). Medication administered to treat anxiety includes serotonin reuptake inhibitors, mood stabilizers, benzodiazepines (e.g., alprazolam, clonazepam, diazepam, and lorazepam), tricyclic antidepressants,These include monoamine oxidase inhibitors and beta-blockers, as well as other weight loss drugs including serotonin and noradrenaline reuptake inhibitors, noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors, and intestinal lipase inhibitors. Specific weight loss drugs include orlistat, sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, and topamax.

[0096] As used herein, "treating" or "treatment" refers to the management or care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, a pharma- ceutical acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder.

[0097] The compounds of the present disclosure, or pharma- ceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, can also be used to prevent a disease, condition, or disorder. As used herein, "preventing" or "prevent" refers to reducing or eliminating the onset of a symptom or complication of a disease, condition, or disorder.

[0098] As used herein, the term "alleviate" or "alleviating" describes the process of reducing the severity of a sign or symptom of a disease. Importantly, a sign or symptom can be alleviated without elimination. In a preferred embodiment, administration of the pharmaceutical composition of the present disclosure leads to the elimination of a sign or symptom, but elimination is not required. An effective dose is expected to reduce the severity of a sign or symptom. For example, a sign or symptom of a disease, such as cancer, which occurs in multiple locations, is alleviated if the severity of the cancer is reduced in at least one of multiple locations.

[0099] As used herein, "severity" refers to the likelihood of a cancer to progress from a pre-cancerous or benign state to a malignant state. Alternatively or additionally, it refers to the stage of a cancer, for example, according to the TNM system (accepted by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC)) or other field-recognized methods. The stage of a cancer refers to the extent or severity of a cancer, based on factors such as the location of the primary tumor, the size of the tumor, the number of tumors, and lymph node involvement (spread of the cancer to the lymph nodes). Alternatively or additionally, it refers to the aggressiveness of a tumor, according to field-recognized methods (see National Cancer Institute). Tumor grade is a system used to classify cancer cells with respect to how abnormal they appear under a microscope and how quickly the tumor grows and spreads. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to measure tumor grade vary with each type of cancer. Severity also describes the histologic grade, also called differentiation, which refers to how similar the tumor cells are to normal cells of the same tissue type (see National Cancer Institute). In addition, severity also describes the nuclear grade, which refers to the size and shape of the nuclei in the tumor cells and the percentage of tumor cells that are dividing (see National Cancer Institute).

[0100] In other aspects of the present disclosure, severity refers to the extent to which the tumor secretes growth factors, degrades extracellular matrix, is vascularized, loses adhesion to adjacent tissues, or metastasizes. Furthermore, severity refers to the number of locations to which the primary tumor has metastasized. Ultimately, severity includes the difficulty of treating tumors of various types and locations. For example, tumors that are inoperable, those cancers that are more intrusive to multiple body systems, and those that are most resistant to traditional treatments are considered to be the most severe. In such a situation, extending the life expectancy of the subject and / or reducing pain, reducing the ratio of cancerous cells or restricting the cells to one system, and improving the cancer stage / tumor grade / histological grade / nuclear grade are considered to alleviate the signs or symptoms of cancer.

[0101] As used herein, the term "symptom" may be defined as a disease, illness, disorder, or an indication that something is not right with the body. A symptom is something that is felt or noticed by the individual experiencing the symptom, but may not be easily noticed by others, which may be defined as non-medical professionals.

[0102] As used herein, the term "symptom" may be defined as an indication that something is not right in the body. However, a symptom may be defined as something that can be detected by a doctor, nurse, or other medical professional.

[0103] Cancer is a group of diseases that can cause almost any sign or symptom. The signs and symptoms depend on where the cancer is, how large it is, and how much it has affected nearby organs or structures. If the cancer has spread (metastasized), then symptoms will appear in different parts of the body.

[0104] As a cancer grows, it begins to push against nearby tissues, blood vessels, and nerves. This pressure creates some of the signs and symptoms of cancer. If the cancer is in a critical location, such as in some parts of the brain, even the smallest tumor can cause symptoms early on.

[0105] However, cancer can also start in places that don't cause any symptoms until the cancer gets quite large. Pancreatic cancer, for example, usually never grows large enough to be felt from outside the body. Some pancreatic cancers don't cause symptoms until they start to grow around nearby nerves, which can cause back pain. Other growths around the bile ducts, which block the flow of bile, can lead to a yellowing of the skin, known as jaundice. By the time pancreatic cancer causes these signs or symptoms, the cancer is usually at an advanced stage.

[0106] Cancer can also cause symptoms such as fever, weakness, or weight loss, possibly because cancer cells consume a lot of the body's energy supply and release substances that alter the body's metabolism, or the cancer may induce the immune system to produce these symptoms.

[0107] Sometimes cancer cells release substances into the bloodstream that cause symptoms not normally associated with cancer. For example, some pancreatic cancers can release substances that cause blood clots to develop in the veins of the legs. Some lung cancers make hormone-like substances that affect calcium levels in the blood and affect nerves and muscles, causing weakness and dizziness.

[0108] Cancer, when present with various subtypes of cancer cells, displays several common signs or symptoms. Many people with cancer experience weight loss at some point due to their disease. Unexplained (unintentional) weight loss of 10 pounds or more can be the first sign of cancer, especially pancreatic, stomach, esophageal, or lung cancer.

[0109] Fever is very common with cancer, but is more common in advanced disease. Almost all cancer patients will have a fever at some point, especially when the cancer or its treatment affects the immune system and the body works harder to fight infection. Less often, fever is an early sign of cancer, such as with leukemia or lymphoma.

[0110] Weakness can be an important symptom as cancer progresses, but it can occur earlier if the cancer causes ongoing blood loss, as is the case with cancers such as leukemia or colon or stomach cancer.

[0111] Pain can be an early symptom of some cancers, such as bone or testicular cancer, but in most cases pain is a symptom of advanced disease.

[0112] Along with skin cancers, some internal cancers cause visible skin symptoms. These changes may include the skin appearing darkened (hyperpigmentation), yellow (jaundice), or red (erythema), itching, or excessive hair growth.

[0113] Alternatively or additionally, cancer subtypes may display specific signs or symptoms. Changes in bowel habits or bladder function may indicate cancer. Long-term constipation, diarrhea, or changes in valve size may be signs of colon cancer. Painful urination, hematuria, or changes in bladder function (such as urinating more or less frequently) may be associated with bladder or prostate cancer.

[0114] Changes in skin condition or the appearance of new skin conditions may indicate cancer. Skin cancer appears as sores that ooze and do not heal. Long-lasting sores inside the mouth may be oral cancer, especially in patients who smoke, chew tobacco, or drink alcohol frequently. Sores on the penis or vagina are a sign of infection or early cancer.

[0115] Abnormal bleeding or discharge may indicate cancer. Abnormal bleeding occurs in early or advanced cancer. Blood in sputum (phlegm) is a sign of lung cancer. Blood in the stool (or dark or black stool) may be a sign of colon or rectal cancer. Cancer of the cervix or endometrium (the lining of the uterus) can cause uterine bleeding. Blood in the urine is a sign of bladder or kidney cancer. Blood oozing from the nipples is a sign of breast cancer.

[0116] A thickening or mass in the breast or other parts of the body can indicate the presence of cancer. Many cancers can be felt through the skin, mostly in the breasts, testicles, lymph nodes (glands), and soft tissues of the body. A lump or thickening can be an early or late sign of cancer. Any lump or thickening can be a sign of cancer, especially if the formation is new or growing in size.

[0117] Indigestion or Difficulty Swallowing May Indicate Cancer Although these symptoms usually have other causes, indigestion or swallowing problems may be a sign of cancer of the esophagus, stomach, or pharynx (throat).

[0118] Immediate changes in a wart or mole may indicate cancer. A change in the color, size, or shape of a wart, mole, or freckle, or loss of a clear border, may indicate the possible development of cancer. For example, a skin lesion may be melanoma.

[0119] A persistent cough or hoarseness may indicate cancer. A persistent cough may be a sign of lung cancer. A hoarseness may be a sign of cancer of the larynx (voice box) or thyroid gland.

[0120] The signs and symptoms listed above are those more commonly found with cancer, although there are many others that are less common and not listed above, however, all art-recognized signs and symptoms of cancer are contemplated and encompassed by this disclosure.

[0121] Treatment of cancer can result in a reduction in tumor size. A reduction in tumor size is also referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by 5% or more compared to the size before treatment, more preferably, the tumor size is reduced 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 means that allows for reproducible measurements. Tumor size may be measured as the diameter of the tumor.

[0122] Treatment of cancer can result in a reduction in tumor volume. Reduction in tumor volume is also referred to as "tumor regression". Preferably, after treatment, the tumor volume is reduced by 5% or more compared to the volume before treatment, more preferably, the tumor volume is reduced 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 means that allows for reproducible measurements.

[0123] Treatment of cancer can result in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more compared to the number before treatment, more preferably, the number of tumors is reduced 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 may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specific magnification. Preferably, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0124] Treatment of cancer can result in a reduction in the number of metastatic lesions in other tissues or organs far from the location of the primary tumor. Preferably, after treatment, the reduction in the number of metastatic lesions is 5% or more compared to the number before treatment, more preferably, the reduction in the number of metastatic lesions is 10% or more, more preferably, 20% or more, more preferably, 30% or more, more preferably, 40% or more, even more preferably, 50% or more, and most preferably, 75% or more. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting the number of metastatic lesions visible to the naked eye or at a specific magnification. Preferably, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0125] Treating cancer can result in an increase in the average survival time of the treated population compared to a population receiving only the vehicle. Preferably, the average survival time is increased by 30 days or more, more preferably by 60 days or more, more preferably by 90 days or more, and most preferably by 120 days or more. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average length of survival of a population following the initiation of treatment with the active compound. Furthermore, the increase in the average survival time of a population can be measured, for example, by calculating the average length of survival of a population following the completion of a first round of treatment with the active compound.

[0126] Treating cancer can result in an increase in the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time is increased by 30 days or more, more preferably by 60 days or more, more preferably by 90 days or more, and most preferably by 120 days or more. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival of a population following the start of treatment with an active compound. Furthermore, the increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival of a population following the completion of the first round of treatment with an active compound.

[0127] The treatment of cancer can result in an increase in the average survival time of a population of subjects receiving the treatment compared to a population receiving monotherapy with an agent that is not a compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the average survival time is increased by 30 days or more, more preferably by 60 days or more, more preferably by 90 days or more, and most preferably by 120 days or more. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival of a population following the initiation of treatment with an active compound. Furthermore, the increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival of a population following the completion of a first round of treatment with an active compound.

[0128] Treating cancer can result in a reduction in mortality in a population of treated subjects compared to a population receiving only the vehicle. Treating cancer can result in a reduction in mortality in a population of treated subjects compared to a population not receiving the vehicle. Treating cancer can result in a reduction in mortality in a population of treated subjects compared to a population receiving monotherapy with an agent that is not a compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mortality rate is reduced by 2% or more, more preferably, by 5% or more, more preferably, by 10% or more, and most preferably, by 25% or more. The reduction in mortality in a population can be measured by any reproducible means. The reduction in mortality in a population can be measured, for example, by calculating the average disease-related deaths per unit time following the start of treatment with the active compound for the population. The reduction in mortality in a population can also be measured, for example, by calculating the average disease-related deaths per unit time following the completion of the first round of treatment with the active compound for the population.

[0129] Treating cancer can result in a decrease in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% compared to before treatment, more preferably, the tumor growth rate is reduced by at least 10%, more preferably, by at least 20%, more preferably, by at least 30%, more preferably, by at least 40%, more preferably, by at least 50%, even more preferably, by at least 50%, and most preferably, by at least 75%. Tumor growth rate can be measured by any reproducible means. Tumor growth rate can be measured according to the change in tumor diameter per unit time.

[0130] Treating cancer can result in a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is 5% or less, more preferably, tumor regrowth is 10% or less, more preferably, 20% or less, more preferably, 30% or less, more preferably, 40% or less, more preferably, 50% or less, even more preferably, 50% or less, and most preferably, 75% or less. Tumor regrowth can be measured by any reproducible means. Tumor regrowth can be measured, for example, by measuring the increase in tumor diameter following tumor shrinkage following treatment. A reduction in tumor regrowth is indicated by failure of tumor to recur following cessation of treatment.

[0131] Treating or preventing a cell proliferation disorder can result in a decrease in the rate of cell proliferation. Preferably, after treatment, the rate of cell proliferation is reduced by at least 5%, more preferably at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 50%, and most preferably at least 75%. The rate of cell proliferation can be measured by any reproducible means. The rate of cell proliferation can be measured, for example, by measuring the number of cell divisions in a tissue sample per unit time.

[0132] Treatment or prevention of cell proliferation disorders can result in a reduction in the percentage of proliferating cells. The percentage of proliferating cells is reduced by at least 5%, more preferably at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 50%, and most preferably at least 75% after treatment. The percentage of proliferating cells can be measured by any reproducible means. Preferably, the percentage of proliferating cells can be measured, for example, by quantitatively measuring the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The percentage of proliferating cells is equivalent to the dividing index.

[0133] Treatment or prevention of a cell proliferation disorder can result in a reduction in the size of the locus or area of ​​cell proliferation. Preferably, the size of the locus or area of ​​cell proliferation is reduced by at least 5% after treatment, more preferably by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, even more preferably by at least 50%, and most preferably by 75% compared to the size before treatment. The size of the locus or area of ​​cell proliferation can be measured by any reproducible means. The size of the locus or area of ​​cell proliferation can be measured as the diameter or width of the locus or area of ​​cell proliferation.

[0134] Treatment or prevention of a cell proliferative disorder can result in a reduction in the number or percentage of cells with abnormal appearance or shape. Preferably, the number of cells with abnormal appearance or shape is reduced by at least 5% after treatment, more preferably at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 50%, and most preferably at least 75% compared to the size before treatment. Abnormal cell appearance or shape can be measured by any reproducible means. Abnormal cell shape can be measured by microscopic observation, for example, using an inverted tissue culture microscope. Abnormal cell shape can be captured as a multinucleated shape.

[0135] Treating cancer or a cell proliferative disorder can result in cell death, and 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, and light microscopy. Methods for measuring cell death are provided in Li et al., Proc Natl Acad Sci USA. 100(5): 2674-8, 2003. In some embodiments, cell death occurs by apoptosis.

[0136] Preferably, an effective amount of the compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is not significantly cytotoxic to normal cells. A therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of a therapeutically effective amount of the compound does not cause cell death of more than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of a therapeutically effective amount of the compound does not cause cell death of more than 10% of normal cells. In some embodiments, cell death occurs by apoptosis.

[0137] Contacting a cell with a compound of the present disclosure, its pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate can selectively cause or activate cell death in cancer cells. Administering a compound of the present disclosure, its pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate to a subject in need of treatment can selectively cause or activate cell death in cancer cells. Contacting a cell with a compound of the present disclosure, its pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate can selectively cause cell death in one or more cells affected by a cell proliferative disorder. Preferably, administering a compound of the present disclosure, its pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate to a subject in need of treatment can selectively cause cell death in one or more cells affected by a cell proliferative disorder.

[0138] The present disclosure relates to a method of treating or preventing cancer by administering to a subject in need of treatment a compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, wherein administration of the compound of the present disclosure, or a pharma- ceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, results in one or more of the following: accumulation of cells in the G1 and / or S phase of the cell cycle, cytotoxicity via cell death in cancer cells without significant cell death in normal cells, antitumor activity with a therapeutic index of at least 2 in animals, and activation of cell cycle checkpoints. As used herein, "therapeutic index" is the maximum tolerated dose divided by the effective dose.

[0139] A "therapeutically effective amount" of a compound, in terms of therapeutic applications, means an amount of the compound in a formulation that, when administered as part of a desired dosage regimen (to a mammal, preferably a human), relieves the symptoms, alleviates the condition, or delays or prevents the onset of a disease state, in accordance with clinically accepted criteria for the disease or condition to be treated, or for cosmetic purposes, for example, with a reasonable benefit / risk ratio applicable to any medical treatment. "Therapeutically effective amount" is synonymous with "effective dose."

[0140] As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to cause a beneficial or desired result. For example, for prophylactic use, beneficial or desired results include results such as reducing or decreasing the risk, reducing the severity, or delaying the onset of a disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and pathological endophenotypes manifested during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing the intensity, duration, frequency of onset of the disease, reducing one or more symptoms (biochemical, histological, and / or behavioral) resulting from the disease, including complications and pathological endophenotypes manifested during the development of the disease, improving the quality of life of those afflicted with the disease, reducing the dose of other medications required to treat the disease, enhancing the effectiveness of other medications, and / or delaying the progression of the disease in a patient. An effective dose can be administered by one or more administrations. For purposes of this disclosure, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to accomplish a direct or indirect prophylactic or therapeutic treatment. As understood from clinical findings, an effective dose of a drug, compound, or pharmaceutical composition may or may not be in combination with other drugs, compounds, or pharmaceutical compositions. Thus, an "effective dose" may be considered to be one or more therapeutic agents in the context of administration, or a single drug may be considered to be given in an effective amount if, in combination with one or more other agents, a desired result is obtained or achieved. For example, an effective amount of a compound of the present disclosure for treating a proliferative disease is an amount sufficient to treat or alleviate one or more symptoms associated with the proliferative disease. An "effective amount" is an amount sufficient to produce one or more of the following results (corresponding to various aspects of the present disclosure): a reduction in tumor size, a reduction in tumor volume, a reduction in the number of tumors, a reduction in metastatic lesions, an increase in survival time, a reduction in mortality, a reduction in tumor growth rate, a reduction in tumor regrowth, a reduction in the proportion of proliferative cells, or an improvement in the quality of life of a person suffering from a proliferative disease.

[0141] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., tumor cell cultures, or in animal models, usually rats, mice, rabbits, dogs, or pigs. 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 assessed, e.g., by measuring the ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic efficacy is the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions that exhibit high therapeutic indices are preferred. Dosages vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0142] Dosage and administration are adjusted to provide sufficient levels of the active agent or to sustain the desired effect. When providing one or more compounds described herein to a subject, administration of the compound will vary depending on factors such as the subject's age, weight, height, sex, general health condition, medical history, disease progression, route of administration, formulation, etc.

[0143] Dosage of the disclosed compounds is empirically determined herein by administering one or more doses. Dosage of the disclosed compounds is given individually and incrementally. Markers of disease state are observed to assess the effectiveness of the disclosed compounds. It will be apparent to one of skill in the art that dosage will vary depending on the individual, stage of disease (e.g., tumor size, number of tumors), and previous and ongoing treatments being used.

[0144] Toxicity and therapeutic efficacy of the compounds of the present disclosure can be measured in experimental animals by standard pharmaceutical procedures. Toxic doses are determined as the maximum tolerated dose (MTD) or LD50 (the dose lethal to 50% of the population). Effective doses are determined as the ED50 (therapeutically effective in 50% of the population) or the dose required to produce a mean amount of change in animals (e.g., the dose required to produce a mean reduction in systolic blood pressure of 10 mmHg in a group of subjects).

[0145] Ideally, the effective and toxic doses are determined in the same species. However, when they are determined in different species, allometric coefficients can be used to translate the effective and toxic doses to the other species. The dose ratio between the toxic and therapeutic effects is the therapeutic index, which can be expressed as the LD50 / ED50 ratio. When comparing mice to rats, a commonly accepted scaling factor is 2, and the rat dose can be estimated as half the dose in mice. Thus, if the toxic dose in rats is 100 mg / kg and the effective dose in mice is 1 mg / kg, the therapeutic index in rats can be calculated as the effective dose in rats is equal to 1 mg / kg / 2 or 0.5 mg / kg, and the therapeutic index is 200. The FDA defines a drug as having a narrow therapeutic range if (a) there is a 2-fold or less difference between the median lethal dose and the median effective dose, or (b) there is a 2-fold or less difference between the minimally toxic and minimally effective concentrations in the blood.

[0146] Compounds of the present disclosure that exhibit high therapeutic indices are preferred. While compounds of the present disclosure that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds of the present disclosure to the location of affected tissues in order to minimize the potential for harming uninfected cells, thereby reducing side effects.

[0147] Data obtained from animal studies can be used in formulating a dosage range for humans. Dosing of such compounds of the present disclosure is desirably within a range of circulating concentrations that includes the effective dose range with little or no toxicity. Dosing may vary within this range depending on the dosage form employed and the route of administration used. While for compounds of the present disclosure with a molecular weight (MW) of 1000 or less, the therapeutically effective dose can be initially estimated by cell culture analysis, animal models provide a better estimate of the dose of the conjugate whose linker requires cleavage to release the active moiety. Such information can be used to more accurately determine useful doses in humans. It is well known in the art that polymer conjugates dilute the activity of the active moiety (the polymer is the diluent). The above is exemplified in the following table for the dosage model of anticancer drugs in mice:

[0148] [Table 1]

[0149] The polymer conjugates and modified compounds of the present disclosure surprisingly provide superior efficacy and reduced toxicity compared to the unconjugated and / or unmodified parent drugs / active moieties.

[0150] For example, the fumagilliol complex and modified fumagilliol compounds of the present disclosure are surprisingly superior to fumagilliol small molecules, and increase tumor reduction in DIO mice at equivalent molar doses.Compounds of the present disclosure can be used at lower molar doses and less frequent administration to produce equivalent tumor reduction.Lower molar doses and reduced administration frequency reduce systemic drug exposure and systemic drug toxicity.

[0151] Traditional polymer conjugates dilute activity and increase dose by 5-20 fold with little change in therapeutic index (<2 fold). In contrast, the polymer conjugate compounds of the present disclosure surprisingly and unexpectedly enhance the therapeutic index (fold order of magnitude improvement) and demonstrate increased activity at lower doses.

[0152] In the methods of the present disclosure, the polymer conjugate compounds of the present disclosure demonstrate surprising efficacy in non-target compartments with less frequent administration of doses (e.g., q4d, a dose every 4th day; q7d, a dose every 7th day; q8d, a dose every 8th day), reduced doses of at least 84 mol% fumagilliol equivalents, reduced AUC, while increasing the therapeutic index (>10-fold).

[0153] In other embodiments, the present disclosure provides an effective dosage of the compound.For example, the present disclosure provides a method comprising administering a dosage of the compound that is effective for tumor reduction.For example, in the methods described herein, the proposed dosage of the compound of the present disclosure may include administration of a body weight-dependent dose of about 200mg / day, about 80mg / day, about 40mg / day, about 20mg / day, about 10mg / day, about 5mg / day, about 3mg / day, about 2mg / day, about 1mg / day, about 0.5mg / day, about 0.2mg / day, about 0.05mg / day, about 0.01mg / day, or about 0.001mg / day.

[0154] The effective amount of the agent for tumor reduction in a patient can also be administered based on body weight or body surface area, and is about 0.0001 mg / kg to about 5 mg / kg body weight per day. For example, contemplated dosages are about 0.001 to 5 mg / kg body weight per day, about 0.001 mg / kg to 1 mg / kg body weight per day, about 0.001 mg / kg to 0.1 mg / kg body weight per day, about 0.001 to 0.010 mg / kg body weight per day, or about 0.007 mg / kg body weight per day, in single, divided, or continuous doses. These doses are based on the patient's kg body weight, m 2 This may be adjusted for body surface area and age. For example, contemplated dosages are approximately 1 mg / m 2 to approximately 50 mg / m 2 , approximately 5 mg / m 2 to approximately 25 mg / m 2 , approximately 5 mg / m 2 to approximately 50 mg / m 2 , approximately 5 mg / m 2to approximately 15 mg / m 2 , or approximately 5 mg / m 2 to approximately 10 mg / m 2 It is.

[0155] An effective amount of a drug is an amount that provides an objectively identifiable improvement that can be noticed by a clinician or other qualified observer. For example, regression of a patient's tumor can be measured in relation to the diameter of the tumor. A decrease in tumor diameter indicates regression. Regression is also indicated by failure of the tumor to recur after treatment has been stopped. As used herein, the term "effective method of administration" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0156] Dosage regimens using the compounds can be selected depending on a variety of factors, including the type, species, age, weight, sex, and health 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, etc. A physician or veterinarian of ordinary skill in the art can determine or prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0157] Administration of the compounds of the present disclosure according to the methods of the present disclosure may be continuous or intermittent, depending, for example, on the physiological condition of the recipient, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to the skilled practitioner. Administration of the compounds of the present disclosure may be essentially continuous for a preselected period of time or in a series of spaced doses.

[0158] In the case of repeated administration over several days or longer, depending on the condition, treatment continues until the desired suppression of disease symptoms occurs or sufficient therapeutic levels are achieved. For example, administration from 1 to 5 times per week is contemplated. Other dosing schedules include 1 to 5 times per week, every 3 or 4 days, or less frequently. In some embodiments, 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 embodiments, the compounds of the present disclosure are administered about once a week, once every week, or about 1 to 4 times per month, based on the duration of response to drug administration. Intermittent dosing schedules with alternating gaps of 2 to 7 or even 14 days may be employed. In some embodiments, the treatment may begin with daily dosing and then change to weekly or monthly dosing. The progress of this treatment can be easily monitored by conventional techniques and assays, or by measuring MetAP2 as described in U.S. Pat. No. 6,548,477.

[0159] The frequency of administration may be determined and adjusted over the course of treatment. For example, the frequency of administration may be determined or adjusted based on the type and severity of the disease being treated, whether the drug is administered for preventative or therapeutic purposes, previous treatments, the patient's medical history and response to the drug, and the judgment of the attending physician. Typically, a clinician will administer a compound of the present disclosure until the dosage achieves the desired result.

[0160] Treatment can be continued for as long or as short a period as desired. Suitable treatment periods are, for example, at least about 1 week, at least about 4 weeks, at least about 1 month, at least about 6 months, at least about 1 year, at least about 2 years, or indefinitely. The treatment period can be terminated when a desired outcome, such as a tumor reduction goal, is achieved. For example, when a reduction of about 5% tumor size, about 10% tumor size, about 20% tumor size, about 30% tumor size, or more is achieved. The treatment regimen includes a correction phase in which the compound of the present disclosure is administered at a dose or administration frequency sufficient to provide a reduction in tumor size, followed by a maintenance phase in which the compound is administered at a lower dose or reduced administration frequency sufficient to prevent tumor regrowth.

[0161] Compounds and Pharmaceutical Compositions of the Disclosure The present disclosure provides compositions and drug conjugate compositions comprising a modified active moiety, a conjugate moiety, and a cleavable linker, where cleavage of the linker occurs substantially within the target tissue to produce a modified active moiety that exhibits reduced shed from the target tissue compared to the unmodified active moiety. The present disclosure also provides compositions comprising the modified active moiety.

[0162] The conjugate moiety used is based on the physicochemical properties of both the conjugate moiety and the active moiety, as well as knowledge of the biological requirements and disease state, e.g., the pharmacokinetic and pharmacodynamic properties of the active moiety. A person skilled in the art will be able to select an appropriate conjugate moiety based on the above considerations. The conjugate moiety is used to deliver small molecule active moieties or larger molecule active moieties, such as proteins, peptides, or oligonucleotides.

[0163] The conjugation moiety improves the delivery of the active moiety to the target. The conjugation moiety is selected to maximize the bioavailability of the active moiety, optimize the onset, duration, and delivery rate of the active moiety's effect, and keep the concentration of the active moiety in the target tissue within the therapeutic range as long as required for effective treatment. The conjugation moiety also helps to minimize adverse side effects of the active moiety. Thus, the conjugation moiety extends the pharmaceutical activity of the active moiety, stabilizes labile active moieties from chemical and proteolytic degradation, minimizes side effects, increases solubility, and targets the active moiety to specific cells or tissues.

[0164] Other properties of the conjugate moiety that are considered are that the conjugate moiety is minimally or non-immunogenic and non-toxic. The molecular weight of the conjugate moiety should be high enough to avoid premature elimination through renal ultrafiltration and low enough to prevent undesirable deposition in the body. In some embodiments, the conjugate moiety is hydrophilic and biodegradable. Non-biodegradable conjugate moieties are also suitable for the compositions and methods of the present disclosure. The conjugate moiety should be capable of carrying the required amount of the active moiety and should be protected against premature metabolism of the active moiety during transport to the target tissue.

[0165] Exemplary conjugates include all forms of polymers, synthetic polymers as well as natural product related polymers including peptides, polysaccharides, polynucleic acids, antibodies, and aptamers. Examples of polymers of the present disclosure are described in U.S. Patent No. 4,997,878 to Bock et al., U.S. Patent No. 5,037,883 to Kopecek et al., U.S. Patent No. 5,258,453 to Kopecek et al., U.S. Patent No. 6,464,850 to Zhang et al., and U.S. Patent No. 6,803,438 to Brocchini et al., the entire contents of each of which are incorporated herein by reference. Additional examples of polymers are described in Subr et al., J Controlled Release 18, 123-132 (1992). In some embodiments, the synthesis method of the polymer leads to the combination of two or more polymer chains, increasing the weight average molecular weight of the polymer conjugate. It is further recognized that if this combination occurs, the linkage is biodegradable.

[0166] The active moiety may be any compound or molecule that produces a therapeutic effect in a subject. In some embodiments, the compound or molecule has a molecular weight of 2000 daltons or less, 1500 daltons or less, 1000 daltons or less, 500 daltons or less, 250 daltons or less, 100 daltons or less, 75 daltons or less, 50 daltons or less, or 25 daltons or less. In some embodiments, the compound or molecule is a methionine aminopeptidase-2 (MetAP2) inhibitor. In some embodiments, the compound or molecule is fumagillin, fumagilliol, or an analog, derivative, salt, or ester thereof. The compound or molecule selected depends on the condition or disease to be treated. In some embodiments, more than one active moiety is employed. In some embodiments, an active moiety and a non-active "capping" moiety are used. In the compositions of the present disclosure, the conjugate moiety is attached to the active moiety through a linker. Any linker structure known in the art may be used to attach the modified active moiety to the conjugate moiety. The linker used depends on the physiological state of the target tissue, the properties of the active moiety being optimized, and the cleavage mechanism. D'Souza et al. have reviewed different types of linkers, including linkers that act through proteolytic cleavage ("Release from Polymeric Prodrugs: Linkages and Their Degradation" J. Pharm. Sci, 93, 1962-1979 (2004)). Blencoe et al. have described different self-immolative linkers (Self-immolative linkers in polymeric delivery systems" Polym. Chem. 2, 773-790 (2011). Ducry et al. have reviewed linkers in Bioconj. Chem. 21, 5-13 (2010) "Antibody-Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies".Peptide linkers suitable for cleavage by matrix metalloproteases (MMPs) are described in Chau et al., “Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models,” Int. J. Cancer 118, 1519-1526 (2006) and Chau et al., U.S. Patent Application Publication No. 2004 / 0116348. Other linker chemistries suitable for the compositions of the present disclosure are set forth in Shiose et al., Biol. Pharm. Bull. 30(12) 2365-2370 (2007); Shiose et al., Bioconjugate Chem. 20(1) 60-70 (2009); Senter, U.S. Pat. No. 7,553,816; De Groot, U.S. Pat. No. 7,223,837; King, U.S. Pat. No. 6,759,509; Susaki, U.S. Pat. No. 6,835,807; Susaki, U.S. Pat. No. 6,436,912; and Gemeihhart, U.S. Pat. No. 7,943,569.

[0167] In some embodiments, the linker is a peptide linker. Exemplary peptide linkers are described in U.S. Patent No. 6,835,807 to Susaki et al., U.S. Patent No. 6,291,671 to Inoue et al., U.S. Patent No. 6,811,996 to Inoue et al., U.S. Patent No. 7,041,818 to Susaki et al., U.S. Patent No. 7,091,186 to Senter et al., and U.S. Patent No. 7,553,816 to Senter et al., the entire contents of each of which are incorporated herein by reference. Further exemplary peptides and their truncations are described in Shiose et al., Biol. Pharm. Bull. 30(12) 2365-2370 (2007) and Shiose et al., Bioconjugate Chem. 20(1) 60-70 (2009). Peptide linkers suitable for cleavage by matrix metalloproteases (MMPs) are described in Chau et al., “Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models,” Int. J. Cancer 118, 1519-1526 (2006) and Chau et al., U.S. Patent Application Publication No. 2004 / 0116348.

[0168] The linker may be cleaved by any mechanism known in the art, for example, designed for proteolytic cleavage or for intracellular proteolytic cleavage. In some embodiments, the linker is designed such that no cleavage of the linker occurs in plasma, or that cleavage occurs at a very low rate in plasma. Exemplary linker structures are described in more detail below.

[0169] In some embodiments, the linker is structured to be preferentially cleaved in diseased tissue. Since most hydrolases are present in both normal and diseased tissues, the linker should be cleaved by hydrolases that are more active and / or more prevalent in diseased tissues. For example, tumors generally have an increased basal metabolic rate and overexpress proteolytic enzymes, especially cathepsins. The increase and the role of proteolytic enzymes in cancer are discussed in Mason et al., Trends in Cell Biology 21, 228-237 (2011).

[0170] In some embodiments, a class of modified active moieties are those that irreversibly bind to targets, i.e., after release from the complex, the active moiety is one that covalently binds to the biochemical target. Once bound, the active moiety cannot diffuse or be transported out of the cell. In the case of irreversible binding, the rate at which a small molecule binds to a target, K, must be greater than or equal to 100 kb for targeting to occur. rev1 , is the efflux rate of small molecules, K sm-1 If the efflux rate is high relative to the binding of the small molecule, equilibrium of the small molecule will exist between the plasma and intracellular compartments, and there will be no advantage to intracellular delivery over extracellular delivery.

[0171] In another embodiment, a class of modified active moieties are those that reversibly bind to targets. In the case of reversible binding, for targeting to occur, the equilibrium multiplier for small molecules to bind to a target, K=K rev1 / K rev-1 must be high. Also, the "on rate", K rev1 , is the efflux rate of small molecules, K sm-1, should be large compared to the binding of the small molecule. If the efflux rate is high compared to the binding of the small molecule, then an equilibrium of the small molecule exists between the plasma and intracellular compartments, and there is no advantage to intracellular delivery over extracellular delivery. Such a relationship is depicted diagrammatically below, where [PC] = concentration of polymer conjugate; [SM] = concentration of released small molecule; plasma = plasma concentration; icell = intracellular concentration; icell-target = small molecule reversibly bound to intracellular target; and inactive = inactive metabolite of the small molecule. In one embodiment, K rev-1 =0, the active moiety binds irreversibly to its target.

[0172] [ka]

[0173] In another embodiment, a class of modified active moieties are those that have very high equilibrium multipliers and high "on rates" relative to efflux. In another embodiment, a class of modified active moieties are those that undergo a high rate of intracellular metabolism relative to efflux.

[0174] In some embodiments, modifications to the active moiety are made using a linker that is structured such that upon cleavage, the linker fragment remains attached to the active moiety. The fragment alters either the molecular weight, hydrophobicity, polar surface, or charge of the active moiety, thereby producing a modified active moiety that has reduced efflux from target cells compared to the unmodified active moiety. For example, coupling MetAP2 inhibitor active moieties through a linker described herein provides a conjugate that, upon cleavage of the linker, produces an active moiety with a linker fragment attached (to the modified active moiety). The modified active moieties described herein have reduced efflux from cells compared to the unmodified active moiety, thereby resulting in a modified active moiety with superior potency relative to the parent small molecule, superior efficacy relative to the parent small molecule, and superior pharmacokinetic profile.

[0175] The present disclosure provides conjugates having a linker with the following structure:

[0176] [ka]

[0177] wherein each independently 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, or H2N(CH)2mCO2H, 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 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; AA5 is a bond or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) mCO2H; m is 2, 3, 4 or 5, -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 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 ((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

[0178] [ka]

[0179] R 9 is alkyl, aryl, aralkyl or a bond, or R 9 forms a heterocycle with Y; R 10 is an amino acid or a bond, R 11 is H or alkyl, W is a MetAP2 inhibitor moiety or an alkyl moiety or alkyl; x is in the range of 1 to about 450; y is in the range of 1 to about 30; n is in the range of 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 embodiments, n is in the range of 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.

[0180] In some embodiments, R4 is C1-C6 alkyl. In some embodiments, R4 is methyl. In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl. In some embodiments, R6 is 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some embodiments, R6 is 2-hydroxypropyl.

[0181] In some embodiments, the compound has a molecular weight of about 100 kDa or more. In some embodiments, the compound has a molecular weight of about 100 kDa or less. In other embodiments, the molecular weight is 95 kDa or less. The molecular weight is 90 kDa or less. In other embodiments, the molecular weight is 80 kDa or less. In other embodiments, the molecular weight is 70 kDa or less. In other embodiments, the molecular weight is 65 kDa or less. In other embodiments, the molecular weight is 60 kDa or less. In other embodiments, the molecular weight is 45 kDa or less. In other embodiments, the molecular weight is 35 kDa or less.

[0182] In some embodiments, the ratio of x to y is in the range of about 100:1 to about 1:1. In some embodiments, the ratio of x to y is in the range of about 30:1 to about 3:1. In other embodiments, the ratio of x to y is in the range of about 19:2 to about 7:2. In some embodiments, the ratio of x to y is in the range of about 9:1 to about 4:1. In some embodiments, the ratio of x to y is 11:1. In some embodiments, the ratio of x to y is 9:1. In some embodiments, the ratio of x to y is 4:1. In some embodiments, the ratio of x to y is about 12:1. For example, in certain embodiments, the x:y ratio is about 3:1, the x:y ratio is about 4:1, the x:y ratio is about 5:1, the x:y ratio is about 6:1, the x:y ratio is about 7:1, the x:y ratio is about 8:1, the x:y ratio is about 9:1, the x:y ratio is about 10:1, the x:y ratio is about 11:1, the x:y ratio is about 12:1, the x:y ratio is about 13:1, the x:y ratio is about 14:1, the x:y ratio is about 15:1, the x:y ratio is about 16:1. and the x:y ratio is approximately 17:1, the x:y ratio is approximately 18:1, the x:y ratio is approximately 19:1, the x:y ratio is approximately 20:1, the x:y ratio is approximately 21:1, the x:y ratio is approximately 22:1, the x:y ratio is approximately 23:1, the x:y ratio is approximately 24:1, the x:y ratio is approximately 25:1, the x:y ratio is approximately 26:1, the x:y ratio is approximately 27:1, the x:y ratio is approximately 28:1, the x:y ratio is approximately 29:1, or the x:y ratio is approximately 30:1.

[0183] In some embodiments, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L. In some embodiments, L is methoxy, ethoxy, pentafluorophenyloxy, phenyloxy, acetoxy, fluoride, chloride, methoxycarbonyloxy, ethoxycarbonyloxy, phenyloxycarbonyloxy, 4-nitrophenyloxy, trifluoromethoxy, pentafluoroethoxy, or trifluoroethoxy. In some embodiments, L is 4-nitrophenyloxy.

[0184] In some embodiments, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In some embodiments, AA1 is glycine. In some embodiments, AA2 is glycine. In some embodiments, AA3 is glycine. In some embodiments, AA4 is glycine or phenylalanine. In some embodiments, AA5 is leucine, phenylalanine, valine, or tyrosine. In some embodiments, AA6 is asparagine, citrulline, glutamine, glycine, leucine, methionine, threonine, or tyrosine. In some embodiments, 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, Try-Cit, Try-Leu, or Try-Met. In some embodiments, AA1, AA3, and AA5 are glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine. In some embodiments, AA2, AA4, and AA6 are glycine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, threonine, or tyrosine. In some embodiments, AA2 is a bond; and AA3 is a bond. In certain embodiments, AA1 is glycine; AA4 is phenylalanine; AA5 is leucine; and AA6 is glycine.

[0185] In some embodiments, W is

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] and

[0193] wherein R2 is -OH or methoxy; and R3 is H, -OH or methoxy.

[0194] In some embodiments, W is

[0195] [ka]

[0196] It is.

[0197] In some embodiments, W is

[0198] [ka]

[0199] It is.

[0200] In some embodiments, Q is NR. In other embodiments, Q is S.

[0201] In some embodiments, J is NR. In other embodiments, J is ((CH) q Q) rIn other embodiments, J is C5-C8 cycloalkyl. In some embodiments, J is aryl.

[0202] In some embodiments, Y is NR. In other embodiments, Y is S.

[0203] In some embodiments, -QXY- is

[0204] [ka]

[0205] [ka]

[0206] V is

[0207] [ka]

[0208] or bond; R 12 is H or Me; or R 12 is R 14 Together with R, it forms a piperidine ring; 11 is H or Me; and R 13 is R 12 Together, it forms a piperidine ring.

[0209] In some embodiments, -QXY- is

[0210] [ka]

[0211] It is.

[0212] In some embodiments, -QXY- is

[0213] [ka]

[0214] It is.

[0215] In some embodiments, -QXY- is

[0216] [ka]

[0217] It is.

[0218] In one embodiment, -QXY- is

[0219] [ka]

[0220] It is.

[0221] In some embodiments, -QXY- is

[0222] [ka]

[0223] and in some embodiments, -QXY- is

[0224] [ka]

[0225] It is.

[0226] In some embodiments, 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

[0227] [ka]

[0228] and W is

[0229] [ka]

[0230] It is.

[0231] In some embodiments, 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

[0232] [ka]

[0233] and W is

[0234] [ka]

[0235] It is.

[0236] In some embodiments, 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

[0237] [ka]

[0238] and W is

[0239] [ka]

[0240] It is.

[0241] In some embodiments, 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

[0242] [ka]

[0243] and W is

[0244] [ka]

[0245] It is.

[0246] In some embodiments, -QXY- is a self-immolative linker that releases the MetAP2 inhibitor in the form of a carbamate derivative as illustrated below.

[0247] [ka]

[0248] Another embodiment of the disclosure provides conjugates with a linker having the structure ZQXYC(O)-W, where, each individually, Z is H2N-AA2-AA3-AA4-AA5-AA6-C(O)- or H; 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 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; AA5 is a bond, alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, m is 2, 3, 4 or 5, Q is NR, O or S, X is M-(C(R)2)pMJM-(C(R)2)pMV, M is a bond or C(O), J is a bond or ((CH2) q Q) R is a 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

[0249] [ka]

[0250] R 9 is alkyl, aryl, aralkyl or a bond, or R 9forms a heterocycle with Y; R 10 is an amino acid or a bond, R 11 is H or alkyl, W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6.

[0251] In some embodiments, Z is H2N-AA5-AA6-C(O)-. In some embodiments, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine and AA6 is glycine. In some embodiments, AA5 is leucine and AA6 is glycine. In some embodiments, AA5 is valine and AA6 is glycine. In some embodiments, AA5 is phenylalanine and AA6 is glycine. In some embodiments, AA5 is glycine and AA6 is glycine. In some embodiments, AA5 is not valine.

[0252] In other embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-. In some embodiments, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA5 is leucine and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA5 is valine and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine. In some embodiments, AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine. In some embodiments, each of AA3, AA4, AA5, and AA6 is glycine. In some embodiments, AA5 is not valine.

[0253] In some embodiments, Z is H. In other embodiments, Z is H2N-AA6-C(O)-. In some embodiments, AA6 is glycine.

[0254] In some embodiments, Q is NR. In some embodiments, M is a bond. In some embodiments, J is a bond. In some embodiments, Y is NR.

[0255] In some embodiments, W is

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] [ka]

[0262] and

[0263] where R2 is -OH or methoxy; and R3 is H, -OH, or methoxy.

[0264] In some embodiments, W is

[0265] [ka]

[0266] It is.

[0267] In some embodiments, W is

[0268] [ka]

[0269] It is.

[0270] In one embodiment -QXY- is

[0271] [ka]

[0272] [ka]

[0273] and;

[0274] V is

[0275] [ka]

[0276] or bond; R 12 is H or Me; or R 12 is R 14 Together with R, it forms a piperidine ring; 11 is H or Me; and R 13 is R 12 Together, it forms a piperidine ring.

[0277] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY- is

[0278] [ka]

[0279] and W is

[0280] [ka]

[0281] It is.

[0282] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine, QXY- is

[0283] [ka]

[0284] and W is

[0285] [ka]

[0286] It is.

[0287] In some embodiments, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; -QXY- is

[0288] [ka]

[0289] and W is

[0290] [ka]

[0291] It is.

[0292] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine, QXY- is

[0293] [ka]

[0294] and W is

[0295] [ka]

[0296] It is.

[0297] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0298] [ka]

[0299] and W is

[0300] [ka]

[0301] It is.

[0302] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; -QXY- is

[0303] [ka]

[0304] and W is

[0305] [ka]

[0306] It is.

[0307] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0308] [ka]

[0309] and W is

[0310] [ka]

[0311] It is.

[0312] In one embodiment, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY- is

[0313] [ka]

[0314] and W is

[0315] [ka]

[0316] It is.

[0317] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5 and AA6 is glycine; -QXY- is

[0318] [ka]

[0319] and W is [ka]

[0320] It is.

[0321] In some embodiments, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY- is

[0322] [ka]

[0323] and W is

[0324] [ka]

[0325] It is.

[0326] In some embodiments, Z is H;

[0327] [ka]

[0328] and W is

[0329] [ka]

[0330] It is.

[0331] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; -QXY- is

[0332] [ka]

[0333] and W is

[0334] [ka]

[0335] It is.

[0336] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY- is

[0337] [ka]

[0338] and W is

[0339] [ka]

[0340] It is.

[0341] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY- is

[0342] [ka]

[0343] and W is

[0344] [ka]

[0345] It is.

[0346] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY- is

[0347] [ka]

[0348] and W is

[0349] [ka]

[0350] It is.

[0351] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0352] [ka]

[0353] and W is

[0354] [ka]

[0355] It is.

[0356] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0357] [ka]

[0358] and W is

[0359] [ka]

[0360] It is.

[0361] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0362] [ka]

[0363] and W is [ka]

[0364] It is.

[0365] In one embodiment, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY- is

[0366] [ka]

[0367] and W is

[0368] [ka]

[0369] It is.

[0370] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5 and AA6 is glycine; QXY- is

[0371] [ka]

[0372] and W is

[0373] [ka]

[0374] It is.

[0375] In some embodiments, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY- is

[0376] [ka]

[0377] and W is

[0378] [ka]

[0379] It is.

[0380] In some embodiments, Z is H; QXY- is

[0381] [ka]

[0382] and W is

[0383] [ka]

[0384] It is.

[0385] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY- is

[0386] [ka]

[0387] and W is

[0388] [ka]

[0389] It is.

[0390] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY- is

[0391] [ka]

[0392] and W is

[0393] [ka]

[0394] It is.

[0395] In some embodiments, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; -QXY- is

[0396] [ka]

[0397] and W is

[0398] [ka]

[0399] It is.

[0400] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY- is

[0401] [ka]

[0402] and W is

[0403] [ka]

[0404] It is.

[0405] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0406] [ka]

[0407] and W is

[0408] [ka]

[0409] It is.

[0410] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0411] [ka]

[0412] and W is

[0413] [ka]

[0414] It is.

[0415] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0416] [ka]

[0417] and W is

[0418] [ka]

[0419] It is.

[0420] In one embodiment, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY- is

[0421] [ka]

[0422] and W is

[0423] [ka]

[0424] be.

[0425] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5 and AA6 is glycine; QXY- is

[0426] [ka]

[0427] and W is

[0428] [ka]

[0429] It is.

[0430] In some embodiments, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY- is

[0431] [ka]

[0432] and W is

[0433] [ka]

[0434] It is.

[0435] In some embodiments, Z is H; QXY- is

[0436] [ka]

[0437] and W is

[0438] [ka]

[0439] It is.

[0440] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY- is

[0441] [ka]

[0442] and W is

[0443] [ka]

[0444] It is.

[0445] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; -QXY- is

[0446] [ka]

[0447] and W is

[0448] [ka]

[0449] It is.

[0450] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY- is

[0451] [ka]

[0452] and W is

[0453] [ka]

[0454] It is.

[0455] In one embodiment, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY- is

[0456] [ka]

[0457] and W is

[0458] [ka]

[0459] It is.

[0460] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0461] [ka]

[0462] and W is

[0463] [ka]

[0464] It is.

[0465] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0466] [ka]

[0467] and W is

[0468] [ka]

[0469] It is.

[0470] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine; QXY- is

[0471] [ka]

[0472] and W is

[0473] [ka]

[0474] It is.

[0475] In one embodiment, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY- is

[0476] [ka]

[0477] and W is

[0478] [ka]

[0479] It is.

[0480] In some embodiments, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5 and AA6 is glycine; QXY- is

[0481] [ka]

[0482] and W is

[0483] [ka]

[0484] It is.

[0485] In some embodiments, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY- is

[0486] [ka]

[0487] and W is

[0488] [ka]

[0489] It is.

[0490] In some embodiments, Z is H; QXY- is

[0491] [ka]

[0492] and W is

[0493] [ka]

[0494] It is.

[0495] Other active moieties that may be modified for use in the conjugates of the present disclosure include the following structures:

[0496] [ka]

[0497] It is.

[0498] In some embodiments, the active moiety is an antitumor compound. In other embodiments, the active moiety is a molecule that inhibits methionine aminopeptidase-2 (MetAP2), such as fumagillin, fumagiliol, or analogs, derivatives, salts, or esters thereof. MetAP2 is a cotranslational enzyme responsible for cleaving the inhibitor methionine from nascent polypeptides. MetAP2 has exclusive substrates that tend to increase activity when cells are dividing under conditions of cellular stress, hypoxia, etc. Fumagillin is a natural product derived from the biomass of the fungus Aspergillus Fumigatus Fresenius. Fumagillin and its derivatives are known to inhibit the aminopeptidase of MetAP2. Further exemplary 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., and U.S. Pat. No. 7,491,718 to Comess et al., the entire contents of which are incorporated herein by reference.Further examples of MetAP2 inhibitors are described in Wang et al., “Correlation of tumor growth suppression and methionine aminopeptidase-2-activity blockade using an orally active inhibitor”, PNAS105(6) 1838-1843(2008); Lee et al., “Design, Synthesis, and Antiangiogenic Effects of a Series of Potent Novel 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 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, 8047-8056 (2009); and Heinrich et al., International Publication WO 2010 / 003475.

[0499] Fumagillin is a small molecule that has been used as an antibacterial and antiprotozoal agent. Its physicochemical characteristics and preparation are well known (see U.S. Pat. No. 2,803,586 and Tumer, JR et al., The Stereochemistry of Fumagillin, Proc. Natl. Acad. Sci. 48, 733-735 (1962)). The fermentation product, fumagillin, is hydrolyzed to yield fumagillol, an alcohol that is converted to various derivatives, including carbamoyl fumagillol, MW 325. The synthesis and preparation of carbamoyl fumagillol and small molecule derivatives are described in U.S. Pat. No. 5,166,172.

[0500] 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 Causes Cell Transformation and Stimulates Proliferation", Oncogene 27, 3967 (2008)).

[0501] Carbamoyl fumagillol and derivatives, as well as other inhibitors of MetAP2, have shown therapeutic benefit in preclinical and clinical studies. These compounds inhibit cell proliferation and angiogenesis, as described in U.S. Pat. No. 5,166,172. Fumagillin analogs or derivatives, such as CKD-732 and PI-2458, have been studied in various systems, as described in detail in Bernier et al., "Fumagillin class inhibitors of methionine aminopeptidase-2," Drugs of the Future 30(5):497-508, 2005.

[0502] The anti-obesity effects of fumagillin and its analogs are well known. Rupnick et al., "Adipose tissue mass can be regulated through the vasculature" PNAS 99, 10730-10735, 2002, describe weight loss in ob / ob mice with daily doses of TNP-470 ranging from 2.5 mg / kg to 10 mg / kg. Brakenhielm, "Angiogenesis Inhibitor, TNP-470, Prevents Diet-Induced and Genetic Obesity in Mice" Circulation Research 94:1579-1588, 2004, describes the prevention of obesity with doses of TNP-470 of 15 or 20 mg / kg every other day. Kim et al., “Assessment of the anti-obesity effects of the TNP-470- analog, CKD-732,” JMolecular Endocrinology 38, 455-465, 2007, describes 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 murine models of nutritionally induced obesity,” Obesity 12, 2241-2246, 2010, describes that oral administration of fumagillin at a daily dose of 1 mg / kg resulted in weight loss in C57BL / 6 mice.

[0503] One of these derivatives, chloroacetylcarbamoyl fumagiriol (TNP-470), has been studied extensively (see H. Mann-Steinberg et al., "TNP-470: The Resurrection of the First Synthetic Angiogenesis Inhibitor," Chapter 35, Folkman and Figg, Angiogenesis; An Integrative Approach From Science to Medicine, Springer NY (2008)). TNP-470 has shown activity against a number of cancers, including lung, cervical, ovarian, breast, and colon cancers. Due to dose-limiting neurotoxicity, TNP-470 has been tested using a number of dosing regimens, but attempts to limit these toxicities have failed. Thus, TNP-470 has proven too toxic for human use. TNP-470 has a short half-life, requiring long-term intravenous administration for therapeutic applications. The metabolite of TNP-470, carbamoyl fumagillinol, has a half-life of 12 minutes in humans (see Herbst et al., "Safety and Pharmacokinetic Effects of TNP-470, an Angiogenesis Inhibitor, Combined 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)). In addition, fumagillin and its derivatives are hydrophobic and difficult to formulate.

[0504] Despite the known utility of fumagillin derivatives, the poor water solubility, short half-life, and neurotoxic side effects of these compounds have not been overcome and have failed to be used therapeutically. TNP-470 in combination with paclitaxel is being administered at a dose of 60 mg / m 3 times a week, based on the dose previously observed to limit neurotoxicity. 2Herbst et al., "Safety and pharmacokinetic effects on TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer," Journal of Clinical Oncology 20, 4440-4447, 2002. Similarly, Shin et al., "A Phase 1 pharmacokinetic and pharmacodynamics study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer," Investigational New Drugs 28, 650-658, 2010, determined that the MTD of CKD-732 was 15 mg / m2 on a 4-day schedule due to confusion and insomnia. 2 / day. Thus, the compounds of the present disclosure have greater potency, reduced toxicity (lower neurotoxicity), improved water solubility, better stability, and / or longer half-life (serum half-life) than currently known fumagillin derivatives.

[0505] As used herein, the term "reduced toxicity" has its ordinary meaning as understood by one of ordinary skill in the art. By way of example only and not intended to be limiting in any way, administration of the fumagillin analog conjugate causes fewer side effects in field tests in mice compared to the fumagillin analog alone.

[0506] The term "improved water solubility" has its ordinary meaning as understood by one of ordinary skill in the art. For illustrative purposes only and not intended to limit its meaning in any way, the following delineation of the term is informative: an increased amount of the fumagillin analog is soluble in water as a result of being covalently incorporated into a complex, compared to the amount of the uncomplexed fumagillin analog that is soluble in water alone.

[0507] The term "longer half-life" has its ordinary meaning as understood by one of ordinary skill in the art. For illustrative purposes only and not intended to limit its meaning in any way, the following delineation of the term is informative: a discernible increase in the time required for deactivation of the fumagillin conjugate, either in vivo or in vitro, as compared to the half-life of the fumagillin analog alone.

[0508] Without being bound by any theory, the nonenzymatic action of MetAP2 to suppress the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 / 2) is as important as the binding of eukaryotic translation initiation factors, eIFs, by MetAP2. Reflecting a potential ERK-related process, cellular MetAP2 inhibition involves suppression of sterol regulatory element-binding protein (SREBP) activity, thereby leading to reduced lipid and cholesterol biosynthesis. Interestingly, changes in the expression patterns of genes in liver and adipocytes after longer fumagillin exposure (approximately 9 months) indicate that MetAP2 inhibition also alters the relative abundance of factors associated with inflammation, consistent with ERK-dependent cellular processes. The putative mechanism of MetAP2 inhibition leading to mobilization of stored fat and catabolism of free fatty acids as a source of body energy is supported by the changes in plasma β-hydroxybutyrate, adiponectin, leptin, and FGF21 observed in previous studies. Increased levels of key catabolic hormones adiponectin and FGF21 combined with the appearance of ketone bodies (β-hydroxybutyrate) suggest that MetAP2 inhibition by the conjugated or modified fumagillin, fumagillol, or analogs, derivatives, salts, or esters of the present disclosure stimulates 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 total adipose tissue and negative energy balance. The conjugated or modified fumagillin, fumagillol, or analogs, derivatives, salts, or esters of the present disclosure can form covalent bonds with MetAP2, thereby irreversibly inhibiting and suppressing the existing enzyme until new pools of MetAP2 are generated in target cells (e.g., liver and adipose tissue).

[0509] In certain embodiments, the conjugated or modified fumagillin, fumagillol, or analog, derivative, salt, or ester compounds of the present disclosure have the formulas shown, for example, in Table 1 below.

[0510] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0511] *In the structural formula, Polymer has the structure:

[0512] [ka]

[0513] or Preferably, the structure:

[0514] [ka]

[0515] It is.

[0516] In some embodiments, the compound is

[0517] [ka]

[0518] It is.

[0519] In some embodiments, the compound is

[0520] [ka]

[0521] It is.

[0522] In some embodiments, the compound is [ka]

[0523] It is.

[0524] In some embodiments, the compound is

[0525] [ka]

[0526] It is.

[0527] In some embodiments, the compound is

[0528] [ka]

[0529] It is.

[0530] In some embodiments, the compound is

[0531] [ka]

[0532] It is.

[0533] In one or more embodiments, the compounds used in the present disclosure are selected from the following: 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-(pyrrolidine-1 cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylamiprop-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-diethylamiprop-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-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;7-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate;7-(benzenesulfonyl a cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;( cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;(1aRS,7bSR)-5-[2-((E)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid;(1 aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1 aS,7bR)-5-[2-((Z)-3-diethylamiprop-1-enyl)-4-fluorobenzene-sulfonylamino]-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;(1aS,7bR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino] 5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1 aS,7bR)-5-{2 [(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1 aR,7bS)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-(3-dimethylaminopropylamino)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)benzene- sulfonylamino]-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-hydroxypyrrolidine-1 (1aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[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-tetrahydro-cyclopropa[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;(1 aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[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-(azepidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azepidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR) -5-{2[(Z)-3-(azepidin-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]-benzenesulfonylamino} (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-ethylazepidin-3-yl)-4-fluorobenzenesulfonylamino] ... 4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[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-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1 aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(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-ethylpyrrolidin-3-yl)carbonylaminomethyl]-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (1aRS,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzene-sulfonylamino]-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-fluoro-benzenesulfonyl Amino)-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-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1 a,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-diethylaminopropylamino)benzenesulfonylamino]-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-ethylazepidin-3-ylmethyl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1 aS,7bR)-5-[2-((Z)-3-diethylamiprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1 aR,7bS)-5-[2-((Z)-3-diethylamiprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-(N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methylaminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methylaminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid 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]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(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;(1aRS,7bSR)-5-[2-(1-ethylpiperazin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(1-ethylazepidi 5-{2-[((S)-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-[((R)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid Sulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-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-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[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)ethyla (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;( ... (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(1-ethylpiperazin-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- ceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

[0534] In one or more embodiments, the compound is selected from:

[0535] [ka]

[0536] [ka]

[0537] [ka]

[0538] and pharma- ceutically acceptable salts or stereoisomers thereof.

[0539] For purposes of this disclosure, the chemical elements are identified according to the Periodic Table, CAS edition, Handbook of Chemistry and Physics, 67th Edition, 1986-87, inside cover.

[0540] The term "alkyl" refers to a fully saturated branched or unbranched carbon chain having a specified number of carbon atoms, or up to 30 carbon atoms unless otherwise specified. For example, a "lower alkyl" is an alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as positional isomers of these alkyls. An alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C for straight chain). 30 , C3-C for branched chains 30 ), or more preferably, 20 or fewer. Likewise, certain cyclic alkyls have from 3-10 carbon atoms in their ring structure, and can also have 5, 6 or 7 carbons in the ring structure.

[0541] Unless a particular number of carbon atoms is specified, "lower alkyl" herein refers to an alkyl group having 1 to 10 carbons, alternatively 1 to 6 carbons, in the backbone, as defined above, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, certain alkyl groups are lower alkyl. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0542] As used herein, the term "carbocycle" refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0543] As used herein, the term "aryl" includes 5-, 6-, and 7-membered monoaromatic groups that may contain 0-4 heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups that contain heteroatoms in their ring structure are also referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with the substituents described above, such as halogen, azido, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, and the like. The term "aryl" also includes polycyclic rings having two or more rings that share two or more carbon atoms between two adjacent rings (the rings are fused), at least one of which is an aromatic ring, and the remaining rings are cyclic alkyl, cyclic alkenyl, cyclic alkynyl, aryl, and / or heterocyclylalkynyl.

[0544] "Alkenyl" refers to either branched or unbranched unsaturated carbon chain radicals having the specified number of carbon atoms, or up to 26 carbon atoms if no specific carbon number is limited, and having one or more double bonds in the radical. Examples of alkenyls having from 6 to 26 carbon atoms include hexenyl, heptanyl, octanyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and the various variant forms of tetracosenyl, where the unsaturated bond may be anywhere in the radical and may be in either the (Z) or (E) configuration about the double bond.

[0545] The term "alkynyl" refers to a hydrocarbyl radical within the scope of alkenyl, but having one or more triple bonds within the radical.

[0546] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group, as defined below, 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 substituents of an alkyl that make it an ether are -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m -R1, where R1 is described below, is or resembles an alkoxyl, such as exemplified by -R1, ...

[0547] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, that include one or more heteroatoms. Heterocycles can also be polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthrene, 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, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocycle may be optionally substituted at one or more ring positions with the substituents described above, e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphonate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, and the like.

[0548] The term "alkylthio" refers to an alkyl group, as described above, with a sulfur radical attached. In certain embodiments, the "alkylthio" moiety includes -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2). m -R1, where m and R1 are defined below, is represented by one of the following: Representative alkylthio groups include thio groups such as methylthio, ethylthio, and the like.

[0549] As used herein, the term "nitro" means -NO2; the term "halogen" refers to F, Cl, Br, or I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is -SO2-.

[0550] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, such as moieties represented by the general formula:

[0551] [ka]

[0552] In the formula, R3, R5 and R6 are each independently a halogen, an alkyl, an alkenyl, -(CH2) m or R3 and R5 together with the N to which they are attached complete a heterocycle having from 4 to 8 ring elements; R1 represents an alkenyl, aryl, cyclic alkyl, cyclic alkenyl, heterocyclyl, or polycyclic group; and m is 0 or an integer ranging from 1 to 8. In certain embodiments, only one of R3 or R5 is a carbonyl, e.g., R3, R5, and the nitrogen do not together form an imide. In certain embodiments, R3 and R5 (and optionally R6) are each independently a halogen, an alkyl, an alkenyl, or -(CH2) m Thus, as used herein, the term "alkylamine" refers to an amine group having a substituted or unsubstituted alkyl group, as defined above, attached thereto, i.e., at least one of R3 and R5 is an alkyl group. In some embodiments, the amino group or alkylamine is a base, i.e., has a pK a > 7.00. In their protonated form, these functional groups have a pK of 7.00 or greater with respect to water. a Have.

[0553] The term "carbonyl" (C(O)) is art-recognized and includes those moieties that can be represented by the general formula:

[0554] [ka]

[0555] In the formula, X represents a bond, oxygen, or sulfur, and R7 represents a halogen, an alkyl, an alkenyl, -(CH2) m -R1 or a pharma- ceutical acceptable salt, and R8 is halogen, alkyl, alkenyl, or (CH2) m -R1, where m and R1 are as defined above. Wherein X is oxygen and R7 or R8 is not hydrogen, the formula is an "ester". Wherein X is oxygen and R7 is as defined above, the moiety is a carboxyl group as referred to herein, and further, particularly when R7 is a halogen, the formula represents a "carboxylic acid". Wherein X is oxygen and R8 is hydrogen, the formula represents a "formate". In general, the oxygen atom in the above formula is replaced with sulfur, and the formula represents a "thiocarbonyl" group. Wherein X is sulfur and R7 or R8 is not hydrogen, the formula represents a "thioester" group. Wherein X is sulfur and R7 is hydrogen, the formula represents a "thiocarboxylic acid" group. Wherein X is sulfur and R8 is hydrogen, the formula represents a "thioformate" group. Alternatively, when X is a bond and R7 is not hydrogen, the above formula represents a "ketone" group. Wherein, when X is a bond and R7 is not hydrogen, the above formula represents an "aldehyde" group.

[0556] As used herein, the term "substituted" is intended to include all permissible organic compounds. In a broad aspect, the permissible substituents are acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents are, for example, those described above. The permissible substituents can be one or more and the same or different for suitable organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen atom substituents and / or permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. This disclosure is not intended to be limiting in any manner on the permissible substituents of organic compounds. "Substituted" or "substituted with" also includes implicit provisos that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution does not undergo spontaneous transformation to produce a stable compound, e.g., spontaneous rearrangement, cyclization, deletion, and the like.

[0557] The term "sulfamoyl" is art-recognized and includes a moiety that may be represented by the general formula:

[0558] [ka]

[0559] wherein R3 and R5 are as defined above.

[0560] The term "sulfate" is art recognized and includes a moiety that can be represented by the general formula:

[0561] [ka]

[0562] wherein R7 is as defined above.

[0563] The term "sulfamide" is art recognized and includes a moiety that may be represented by the general formula:

[0564] [ka]

[0565] wherein R2 and R4 are as defined above.

[0566] The term "sulfonate" is art recognized and includes a moiety that can be represented by the general formula:

[0567] [ka]

[0568] wherein R7 is an electron pair, hydrogen, alkyl, cyclic alkyl, or aryl.

[0569] As used herein, the terms "sulfoxide" or "sulfonyl" refer to a moiety that can be represented by the general formula:

[0570] [ka]

[0571] In the formula, R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cyclic alkyl, heterocyclyl, alkyl, or aryl.

[0572] Analogous substituents are also added to alkenyl and alkynyl groups to form, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

[0573] As used herein, the definition of each designation, e.g., alkyl, m, n, etc., when it occurs more than one time in any one structural formula, is intended to be independently defined anywhere in the same structural formula.

[0574] The term "amino acid" is intended to include both amino-sensitive and acid-sensitive amino acids, whether natural or synthetic, including amino acid analogs and derivatives. In certain embodiments, the amino acids contemplated in this disclosure are naturally occurring amino acids in proteins or naturally occurring anabolic or catabolic amino acids containing amino and carboxyl. Naturally occurring amino acids are identified by conventional three-letter and / or one-letter abbreviations that correspond to the common names of the amino acids according to the following list. The abbreviations are accepted in the peptide art and are recommended by the IUPAC-IUB Commission on Biochemical Nomenclature.

[0575] 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) 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 radical derived from the corresponding α-amino acid by removing the OH moiety of the carboxyl group and the H moiety from the α-amino group.

[0576] The term "amino acid side chain" is that portion of an amino acid residue other than the backbone, as defined by KD Kopple, "Peptides and Amino Acids", WA Benjamin Inc., New York and Amsterdam, 1966, pp. 2 and 33, and examples of such common amino acid residues are -CH2CH2SCH3 (the side chain of methionine), -CH2(CH3)-CH2CH3 (the side chain of isoleucine), -CH2CH(CH3)2 (the side chain of leucine) or H- (the side chain of glycine). These side chains are pendant groups from the backbone Cα carbon.

[0577] As used herein, the term "peptide" refers to a sequence of amino acid residues joined or modified into peptide bonds. The term "peptide" is intended to include peptide analogs, peptide derivatives, peptidomimetics, and peptide variants. The term "peptide" should be understood to include peptides of all lengths. Peptide sequences described 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).

[0578] Certain compounds of the present disclosure exist in particular geometric or stereoisomeric forms. The present disclosure contemplates cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures within the scope of the present disclosure. Additionally, asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers as well as mixtures thereof are intended to be included in the present disclosure. Any representative examples of specific isomers are merely illustrative (e.g., examples of trans-isomers, but also cis-isomers).

[0579] For example, if a particular enantiomer of a compound of the present disclosure is desired, it can be produced by asymmetric synthesis or derivatization with such a chiral auxiliary, where the resulting diastereomeric mixture can be separated and the auxiliary group cleaved to give the pure desired enantiomer. Alternatively, if the molecule possesses a basic functional group, such as an amino group, or an acid functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid group or base, and the diastereomers thus produced can then be resolved by fractional or chromatographic means well known in the art to recover the resulting pure enantiomer.

[0580] As used herein, the term "substituted" means replacing any one or more hydrogen atoms on the designated atom with a group selected from the indicated, provided that the valence of the designated atom is not exceeded, such that the substitution results in a stable compound. When the substituent is keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not found in aromatic moieties. Cyclic double bond, as used herein, refers to a double bond formed between adjacent cyclic atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are meant to refer to a compound that is sufficiently robust and immobile for isolation and formulation into an effective therapeutic agent.

[0581] 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 shown to be bonded to any other atom of the compound shown in a formula without showing the atom to which it is bonded, then the substituent may be bonded through any atom of the formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0582] 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 two R1 moieties, and each occurrence of R1 is independently selected from the definitions of R1. Additionally, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0583] In the present disclosure, the structural formula of the compound shows a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc. In addition, there are crystalline polymorphs of the compound represented by the formula. It is noted that any crystalline form, crystalline mixture, or anhydride or hydrate thereof is within the scope of the present disclosure. Furthermore, the so-called metabolites generated by the decomposition of the present compound in vivo are also included within the scope of the present disclosure.

[0584] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonds of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers, and stereoisomers that are not superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of each enantiomeric form of opposite chirality is termed a "racemic mixture".

[0585] A carbon atom to which four nonidentical substituents are attached is termed a "chiral center."

[0586] A "chiral isomer" is a compound that has at least one chiral center. Compounds with one or more chiral centers exist as individual diastereomers or as a mixture of diastereomers. When there is one chiral center, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. With this in mind, the substituents on the chiral centers are arranged according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0587] Geometric isomers refer to the existence of constrained rotation around a double bond. These configurations, which follow the Cahn-Ingold-Pregold rules and indicate groups on the same or opposite sides of a double bond in a molecule, are distinguished by the prefixes cis and trans, or Z and E.

[0588] Additionally, the structures and other compounds discussed in this disclosure include all atropic isomers. An "atropic isomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to rotational constraints caused by the hindrance of rotation of a bulky group at the central bond. Such atropic isomers typically exist as mixtures, but their existence has been a result of recent developments in chromatography techniques, and it is possible to separate mixtures of two atropic isomers when selected.

[0589] A "tautomer" is one of two or more structural isomers that exist in equilibrium and can be transformed from one isomer to another. This transformation results in the formal transfer of a halogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solid form, one tautomer usually predominates. In solution, tautomerism is possible and 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 can be converted into each other by tautomerization is called tautomerism.

[0590] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which the simultaneous transfer of an electron and a halogen atom occurs; ring-chain tautomerism results when an aldehyde group (-CHO) on a sugar molecule reacts with a hydroxyl group (-OH) on the same molecule to give the cyclic (ring-like) form that appears as glucose.

[0591] Common tautomeric combinations are keto-enol, amide-nitrile, lactam-lactim, amide-imidic acid isomers in heterocycles (eg, in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine.

[0592] It is to be understood that the compounds of the present disclosure may be expressed as different tautomers, and where a compound has tautomeric forms, it should be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric forms.

[0593] The terms "polymorphism", "polymorphism" or "crystal form" mean that a compound (or a salt or solvate thereof) crystallizes in different crystal packing arrangements having the same elemental composition. Different crystal forms usually have different x-ray diffraction patterns, infrared spectra, melting temperatures, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to predominate. Polymorphs of a compound can be produced by crystallization under different conditions.

[0594] In addition, compounds of the present disclosure, e.g., salts of compounds, can exist in hydrated or non-hydrated (anhydrous) forms, or as hydrates with other solvent moieties. Non-limiting examples of solvates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0595] A "solvate" is a solvent addition form that contains a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap solvent molecules in a fixed molar ratio in the crystalline solid state, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance that retains the water in the molecular form H2O.

[0596] As used herein, the term "analog" refers to a chemical compound that is structurally the same but has a slightly different composition (such as the replacement of an atom with an atom of a different element, or the replacement of one functional group with another functional group in the presence of a particular functional group). Thus, an analog refers to a compound that is similar or comparable in function or appearance, but is not similar in structure or origin to the reference compound.

[0597] As defined herein, the term "derivative" refers to compounds that share a common core structure and are substituted with various groups as described herein.

[0598] The term "bioisostere" refers to a compound obtained by exchanging an atom or group of atoms with another, broadly similar, atom or group of atoms. The purpose of bioisostere replacement is to create a new compound with biological properties similar to the parent compound. Bioisostere replacement can be physicochemical or topological based. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0599] The present disclosure is intended to include all isotopes of atoms present in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0600] The synthetic processes of the present disclosure can tolerate a wide range of functional groups and therefore can employ a variety of substituted starting materials, and the processes generally provide the desired final compound at or near the end of the overall process, although in certain instances it may be desirable to further convert the compound to a pharma- ceutically acceptable salt, ester, or prodrug thereof.

[0601] The compounds of the present disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature, or intermediates made readily available, using standard synthetic methods and procedures known to those skilled in the art or that will become apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Classical sources, without being limited to one or several sources, such as Smith.MB, March,J.,March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 5th edition, John Wiley&Sons,New York,2001; and Greene,TW,Wuts,PGM,Protective Groups in Organic Synthesis, 3rd edition, John Wiley&Sons,New York,1999, which are incorporated herein by reference, are useful and recognized reference books on organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not limit, the general procedures for the production of the compounds of the present disclosure.

[0602] 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 herein by reference in its entirety.

[0603] The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt, solvate, diastereomer, polymorph, or form thereof, and a pharma- ceutically acceptable carrier or excipient.

[0604] A "pharmaceutical composition" is a preparation containing a compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in the form of a loose or dosage unit. The dosage unit form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single aerosol inhalation pump, or a bottle. The amount of active ingredient (e.g., a preparation of the disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is an effective amount and varies according to the particular treatment involved. Those skilled in the art will understand that it may sometimes be necessary to vary the dosage from day to day depending on the age and condition of the patient. The dosage also depends on the route of administration. Various 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 compounds of the present disclosure are sprays, ointments, pastes, creams, emulsions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharma- ceutical acceptable carrier and with any preservatives, buffers, or propellants that are required.

[0605] As used herein, "pharmaceutical acceptable excipient" or "pharmaceutical acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic absorption delaying agents, and the like, suitable for pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrin solution, and 5% human serum albumin.

[0606] Pharmaceutically acceptable carriers include solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water, and the like. Similarly, the carrier or diluent is a delay material known in the art, such as glyceryl monostearate or glyceryl distearate, ethyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate, alone or with wax. Other fillers, excipients, flavorings, and other additives known in the art are also included in the pharmaceutical composition according to the present disclosure. Liposomes and non-water-miscible vehicles such as fixed oils may also be used. The use of such media and agents for pharma-ceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the composition is contemplated. Supplementary active compounds may also be incorporated into the composition. In some embodiments, the pharmaceutical composition includes DMSO.

[0607] The term "pharmaceutical acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of the compounds. These salts can be formed in situ during the final isolation and purification of the compounds, or by separately reacting the purified compounds in free base form with a suitable organic or inorganic acid and isolating the salt formed. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, eg, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0608] The phrase "pharmacologically acceptable" as used herein refers to those ligands, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals, within the scope of sound medical judgment, are substantially non-pyrogenic, and are free of excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio.

[0609] As used herein, the term "metabolite" refers to metabolic products of the disclosed compounds, or pharma- ceutically acceptable salts, solvates, diastereomers, and polymorphs that exhibit the same activity in vivo as the disclosed compounds.

[0610] As used herein, the term "prodrug" refers to a compound of the present disclosure, or a pharma- ceutically acceptable salt, solvate, diastereomer, or polymorph, covalently bound to one or more promoieties, such as an amino acid moiety or other water-soluble moiety. The compound of the present disclosure, or a pharma- ceutical acceptable salt, solvate, diastereomer, or polymorph, is released from the promoiety through hydrolysis, oxidation, and / or enzymatic release mechanisms. In some embodiments, the prodrug compositions of the present disclosure exhibit the added benefits of increased water solubility, improved stability, and improved pharmacokinetic profiles. The promoiety is selected to obtain the desired properties of the prodrug. For example, the promoiety, e.g., an amino acid moiety or other water-soluble moiety, such as a phosphate at R4, is selected based on solubility, stability, bioavailability, and / or in vivo delivery or uptake. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters (e.g., ethyl ester, morpholinoethanol ester) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl), N-Mannich bases of amino functional groups, Schiff bases, and enaminone, oxime, acetal, ketal, and enol esters of ketone and aldehyde functional groups of the compounds of the present disclosure. See Bundegaard, H., Design of Prodrug, p1-92. Elesevier, New York-Oxford (1985).

[0611] The compounds of the present disclosure, or pharma- ceutically acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs thereof (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, inhalation, buccal, sublingually, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. Administration can be systemic, e.g., intravenous, or local. In some embodiments, the route of administration is intravenous, intramuscular, subcutaneous, transdermal, intraperitoneally, intrathecal, intrathoracic, intrauterine, intrarectal, intravaginal, topical, etc. In some embodiments, the compounds are administered subcutaneously.

[0612] The pharmaceutical compositions of the present disclosure are formulated to suit 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 may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetate; buffers such as acetates, citrates, or phosphates; and agents for adjusting isotonicity such as sodium chloride or dextrin. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be sealed in ampoules, disposable syringes, or other dosage vials made of glass or plastic.

[0613] The compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by well-known methods currently used for chemotherapy treatment. For example, for cancer treatment, the compounds of the present disclosure can be injected directly into a tumor, into the bloodstream, or into a body cavity, injected subcutaneously or orally, or applied through the skin using a patch. The dose selected should be sufficient to effect effective treatment, but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, pre-cancer, etc.) and the health of the patient should and should be closely monitored during and for a reasonable period after treatment.

[0614] In certain embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs thereof, are administered in suitable dosage forms or formulations prepared by combining a therapeutically effective amount (e.g., an effective amount sufficient to achieve a desired therapeutic effect) of a compound of the present disclosure, or a pharma- ceutically acceptable salt, ester, solvate, diastereomer, polymorph, or prodrug thereof, with standard pharmaceutical carriers or diluents according to conventional procedures (i.e., to produce a pharmaceutical composition of the present disclosure). These procedures may include, as appropriate, for obtaining the desired preparation by mixing, granulating, compressing, or dissolving the ingredients.

[0615] 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 techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0616] Oral dosage forms such as capsules, tablets, pills, powders, granules, etc. can be prepared by any means known in the art. The compounds of the present disclosure may be mixed with enteric materials and compressed into tablets. Alternatively, the preparations of the present disclosure can be incorporated into chewable tablets, crushable tablets, tablets that dissolve quickly in the mouth, or mouthwashes.

[0617] For administration to the lungs (e.g., intrabronchial), the compounds of the present disclosure can be formulated with conventional excipients to produce inhalation compositions in the form of fine powders or sprayable liquids. For administration to the eye, the compounds of the present disclosure can be formulated with conventional excipients, for example, in the form of eye drops or intraocular implants. Among the excipients useful for eye drops are thickening or gelling agents, which minimize tearing loss and improve retention in the eye.

[0618] Liquid dosage forms for oral or other administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, compositions for ophthalmic, oral, or other systemic administration may also contain auxiliary agents, such as wetting agents and emulsifying and suspending agents.

[0619] Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers, are useful for administration. Liquid formulations can be directly nebulized, and lipophilized powders can be nebulized after reconstitution. Compounds of the present disclosure can be aerosolized by using fluorocarbon formulations and metered-dose inhalers, or can be inhaled as lipophilized, micronized powders.

[0620] The dosage form for topical or transdermal administration of the novel pharmaceutical composition is an ointment, paste, cream, emulsion, gel, powder, solution, spray, inhaler, or patch. The active agent is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with any preservatives or buffers. For example, administration via the dermal route can be achieved by aqueous drops, mist, emulsion, or cream.

[0621] Transdermal patches have the added advantage of allowing controlled delivery of active ingredients to the body. Such dosage forms are made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0622] Compositions for rectal or vaginal administration are suppositories made by mixing the compounds of the present disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, etc., or suppositories that are solid at ambient temperature and liquid at body temperature, thereby melting in the rectal or vaginal cavity and releasing the active agent. Alternatively, contemplated formulations can be administered by insertion of an endoscope into the rectum of a subject followed by release from the lumen of the endoscope.

[0623] Those skilled in the art are referred to general reference texts that provide detailed descriptions of the known techniques discussed herein or equivalent techniques, such as 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, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley and Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). These references may, of course, be consulted in making or using the embodiments of the present disclosure.

[0624] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure are apparent from the different examples. The examples set forth are intended to illustrate different components and methodologies useful in practicing the present disclosure. The examples are not intended to limit the disclosed claims. Based on the present disclosure, one skilled in the art will be able to recognize and employ other components and methodologies useful in practicing the present disclosure. EXAMPLES

[0625] The following examples are provided to further illustrate different features of the present disclosure. The examples also illustrate methodologies useful in practicing the present disclosure. These examples are not intended to limit the present disclosure.

[0626] Example 1 - In vivo study in B16F10 Melanoma / DIO mice - Body weight, tumor growth, adipose tissue mass, and white blood cell count

[0627] In vivo experiments were conducted to establish a syngeneic mouse model to demonstrate that feeding-induced obesity accelerates tumor growth. The experiments were to demonstrate efficacy of compounds of the present disclosure in this obese and metabolic tumor model. Specifically, efficacy was demonstrated against tumors in obese animals and in corresponding lean animals. The experiments were to compare the weight change in both obese and lean animal groups, measure biological changes in hematological parameters, and compare the conjugate molecules of the present disclosure with related small molecules for efficacy.

[0628] C57BL / 6 male mice were fed ad libitum for 12–14 weeks with a high-fat diet (HFD), consisting of 60% kcal from fat (DIO), until the average body weight of the obese mice was >40 g. Age-matched C57Bl / 6 male mice were maintained on a normal rodent diet (10% fat, low-fat diet, LFD) for 12–14 weeks. The experiment consisted of 2 × 10 5 B16F10 melanoma cells were initiated by injection into the flank of lean and obese animals.

[0629] The tumor is 100 mm 3 At older ages, mice were treated with 5% mannitol / water (vehicle control), Compound 1, or Compound 4. Treatment was by subcutaneous intracapsular injection of 5 ml / kg every 4th day (Compound 1) or every 2nd day (Compound 4) for 17 days at the doses and schedules shown in Table 2.

[0630] [Table 3]

[0631] Compound 4 was CKD-732 (also known as beloranib and ZGN-433). Compound 4 has previously been shown to be effective in inducing weight loss in DIO mice at a dose of 1 mg / kg (Hughes TE et al., "ZGN-201 (ZGN), a methionine aminopepeptidase 2 (MetAP2) inhibitor, durably eliminatesexsess body fat in obese mice through regulation of fat metabolism and food intake" European Association for the Study of Diabetes; September 20-24, 2010; Stockholm, Sweden. Presentation 244). Compound 4 here is the hemitartrate salt of the following structure:

[0632] [ka]

[0633] Figure 1A shows the baseline body weight of obese and lean mice bearing B16F10 melanoma. Figure 1B shows the B16F10 melanoma tumor growth in obese and lean mice over time. Data were analyzed using multiple comparisons and two-way ANOVA, ***p<0.005 and ****p<0.0001. The results in Figure 1A show that there was no significant difference in body weight within the obese or lean populations before the start of the experiment, but the mean body weight of the obese population was significantly different from the mean body weight of the lean population. The results in Figure 1B show that tumors grew significantly faster and were significantly larger in animals made obese by consuming a high-fat diet (DIO mice) compared to animals consuming an age-matched low-fat diet (lean mice).

[0634] Figure 2A shows B16F10 melanoma tumor growth in lean mice after treatment with vehicle or a compound of the present disclosure at 8 mg / kg or 24 mg / kg. Figure 2B shows B16F10 melanoma tumor growth in obese mice after treatment with vehicle or a compound of the present disclosure at 8 mg / kg or 24 mg / kg. Data was analyzed using two-way ANOVA with multiple comparisons *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. The results in Figures 2A and 2B show that compound 1 inhibits tumor growth in both lean and obese animals in a dose-dependent manner. However, in FIG. 2C, the potency of inhibition was greater in obese mice (tumor size reductions of 58% and 76% after 8 and 24 mg / kg of compound 1, respectively) compared to lean mice (tumor size reductions of 43% and 55% after 8 and 24 mg / kg of compound 1, respectively).

[0635] Figure 3A shows the body weight of B16F10 melanoma-bearing lean mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of a compound of the present disclosure. Figure 3B shows the body weight of B16F10 melanoma-bearing lean mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of a compound of the present disclosure. Data was analyzed using two-way ANOVA with multiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results in Figures 3A and 3B show that Compound 1 causes weight loss in both lean and obese mice. However, weight loss was more inhibited in obese mice (-19% and -27% (relative to baseline) in response to 8 and 24 mg / kg of Compound 1) compared to lean mice (-11% and -7% (relative to baseline) in response to 8 and 24 mg / kg of Compound 1).

[0636] Figure 4 shows the relationship between body weight and tumor size in DIO and lean mice treated with vehicle and Compound 1. The results in Figure 4 show that the effect of Compound 1 in reducing tumor size is associated with its ability to reduce body weight. This effect is more robust in obese mice (based on the magnitude of change in both parameters, as well as the larger slope of the linear regression) and is more strongly correlated with obesity compared to lean mice (based on the p-value from the linear regression analysis).

[0637] Figure 5 shows the mean number (+ / -SEM) of metastatic lung foci in obese and lean B16F10 melanoma / DIO mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of a compound of the present disclosure or 2 mg / kg of another MetAP2 inhibitor (compound 4). The results in Figure 5 show that obese mice have a higher number of lung metastases than lean mice (lean 3.6+ / -1.4 foci / mouse vs. obese 0.4+ / -0.24 foci / mouse, respectively; no statistical difference). The results also show that compound 1 dose-dependently reduces the number of lung metastases in obese mice, although the difference is not statistically significant (1.38+ / -0.73 foci / mouse and 0.5+ / -0.22 foci / mouse after 8 and 24 mg / kg, respectively). Another MetAP2 inhibitor (compound 4) was less effective in reducing the number of lung metastases in obese mice (2.4 + / - 0.8 foci / mouse).No differences in lung metastases were observed between lean mouse groups (data not shown).

[0638] Table 3 shows the adipose tissue mass in obese mice bearing B16F10 melanoma after treatment with vehicle or 8 mg / kg or 24 mg / kg of a compound of the present disclosure or 2 mg / kg of another MetAP2 inhibitor (compound 4). Data were analyzed using one-way ANOVA with multiple comparisons *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results in Table 3 show that obese tumor-bearing mice have significantly higher adipose tissue mass than lean tumor-bearing ones. The results also show that compound 1 reduced body fat in obese animals (results were statistically significant only in the epididymis). Adipose tissue mass in control, vehicle-treated animals was 2-5 times lower than tumor-free DIO mice (not shown). Table 3 also shows the adipose tissue mass in B16F10 melanoma-bearing lean mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of a compound of the present disclosure or 2 mg / kg of another MetAP2 inhibitor (compound 4). Data was analyzed using multiple comparisons and one-way ANOVA *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results in Table 3 show that none of the adipose tissue attached to the lean mice is affected by treatment with compound 1.

[0639] [Table 4]

[0640] Figure 6 shows the white blood cell counts in obese and lean B16F10 melanoma / DIO mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of a compound of the present disclosure or other MetAP2 inhibitors (compound 4). Data were analyzed using one-way ANOVA with multiple comparisons *p< 0.05, **p< 0.01, ***p< 0.005 and ****p< 0.0001. The results in Figure 6 show that obese mice exhibit leukocytosis (elevated circulating white blood cell (WBC) levels) and compound 1 reduces WBC. Figure 6 also shows that obese mice responded significantly to 8 mg / kg compound 1, but not lean mice, demonstrating that obese mice are more sensitive to the effect on WBC.

[0641] Figure 7 shows B16F10 melanoma tumor growth in obese and lean mice after treatment with vehicle or 2 mg / kg of an unconjugated small molecule MetAP2 inhibitor (compound 4). The results in Figure 7 show that compound 4 significantly inhibits tumor growth in obese mice (by 28%), albeit to a lesser extent than that observed with compound 1 (57% reduction at 8 mg / kg). In contrast to what is seen with compound 1, compound 4 has no effect on tumor growth in lean mice.

[0642] To directly compare the amount of active MetAP2 inhibitor delivered by 8 mg / kg of compound 1 versus 2 mg / kg of compound 4, one must account for the amount of activity in compound 1, which is approximately 20% by weight or 1.6 mg / kg of activity delivered by the 8 mg / kg dose. In addition, the administration frequency of compound 1 was every 4 days, half the frequency of compound 4. Therefore, the dose of active MetAP2 inhibitor delivered to mice from compound 1 was approximately 2.5 times less than that delivered by compound 4 (based on mg / kg for each dose). However, to compare the total amount of active MetAP2 inhibitor delivered over the duration of the experiment (17 days), the difference in administration frequency must also be taken into account (compound 4 was administered every 2 days versus compound 1 every 4 days). In total, compound 4 was administered 9 times versus compound 1 5 times, which means that 2.25 times more active MetAP2 inhibitor was delivered by compound 4 versus compound 1. Despite the higher amount of active MetAP2 delivered with compound 4, its efficacy was lower than that of compound 1, highlighting the superior and unexpected benefits of the compounds of the present disclosure.

[0643] Figure 8 shows the body weight of tumor-bearing obese and lean mice after treatment with vehicle or 2 mg / kg of another small molecule MetAP2 inhibitor (compound 4). The results in Figure 8 show that compound 4 significantly reduces body weight in obese mice (-7.9% after 2 mg / kg), albeit to a lesser extent than that observed with compound 1 (-18.9% after 8 mg / kg), despite the higher doses of compound 4 administered over the course of the experiment (as described above). In contrast to that observed with compound 1, compound 4 had no effect on body weight in lean mice.

[0644] Example 2 - In vivo study in DIO mice - leptin and adiponectin

[0645] Leptin is an adipocyte-derived hormone discovered based on its ability to inhibit caloric intake by signaling through receptors located on neurons in the hypothalamus of the central nervous system (CNS). Genetic deletion of leptin in mice and humans results in severe obesity, which is reversed following exogenous delivery of recombinant leptin. Circulating levels of leptin are positively correlated with adipocyte mass in the host, and increased leptin levels are observed in obese animals and humans. Unlike normal-weight animals and humans, obese animals and humans do not sense endogenously elevated leptin levels and are resistant to the appetite suppressing, anti-obesity effects. In the case of long-term and persistent time-course development of obesity, peripheral tissues and organs are exposed to elevated leptin levels for many years. It is now recognized that leptin controls several biological processes outside the CNS (e.g., immune function, angiogenesis, endothelial homeostasis, hepatocyte regeneration), and the reverse conclusion of exposure to abnormally high leptin levels is now being recognized. Specifically, leptin has been shown to activate survival pathways in cancer stem cells (e.g., Oct4) and thus appears to be involved in cancer recurrence (Feldman et al., PNAS, 2012, 109(3), 829-834). In addition, preclinical models of tumor progression have shown that leptin derived from human adipose stromal cells directly increases cancer cell proliferation as well as contributing to metastatic disease. Importantly, the effect of ASC-derived leptin is significantly greater when ASCs are isolated from obese, as opposed to lean, human donors (Strong et al., Breast Can. Res., 2015, 17:112). Therefore, leptin has been suggested to be a component of the mechanistic link between obesity and cancer. (Park et al., Nat Rev Endocrinol. 2014, 10(8): 455-465).

[0646] Another endpoint of interest in both metabolic disease and now cancer (mechanistically as well as from a prognostic point of view) is the adipocyte-derived hormone, adiponectin. This protein is released from adipocytes into the circulation where it acts on liver and muscle tissue to elicit beneficial responses by enhancing the action of insulin. More recently, adiponectin has been shown to be protective in colon cancer by directly regulating pathways that control malignant potential (cell proliferation, adhesion, invasion, and colony formation), regulating metabolism (AMPK / S6), inflammation (STAT3 / VEGF), and cell cycle (P21 / p27 / p53 / cyclin) in both murine MCA38 and human HT29, and regulating HCT116 and LoVo colon cancer cell lines in an LKB-1-dependent manner (Moon et al., Gut, 2013, 2(4):561-70). Clinical studies in breast cancer have shown that adiponectin is protective against cancer recurrence, as increased levels are positively correlated with disease-free survival (Duggan et al., J Clin Oncol, 2011, 29(1):32-9). Considering the possible role of the two hormones, leptin and adiponectin, in metabolic disease and cancer, we measured (using ELISA) plasma leptin and adiponectin levels in samples obtained from in vivo experiments in obese and lean mice harboring syngeneic B16F10 melanoma or tumor-free obese mice.

[0647] C57BL / 6 male mice were fed ad libitum a high-fat diet (HFD), TD.06414, consisting of 60% Kcal from fat (DIO), for 16 weeks until the mean body weight of the obese mice was >40 g.

[0648] Mice were treated with 5% mannitol in water (vehicle control) and Compound 1 or Compound 4. Treatment was by subcutaneous injection of 5 ml / kg every 4 days (q4d) and Compound 1 at 2.0 mg / kg or 6.0 mg / kg.

[0649] FIG. 9A shows serum leptin levels in obese DIO mice after treatment with vehicle or 2 mg / kg or 6 mg / kg of compound 1 of the present disclosure. FIG. 9B shows serum adiponectin levels in obese DIO mice after treatment with vehicle or 2 mg / kg or 6 mg / kg of compound 1 of the present disclosure. Data was analyzed using one-way ANOVA with multiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results of FIG. 9A and FIG. 9B show that compound 1 lowers serum leptin levels and raises serum adiponectin at each dose tested. In particular, compound 1 has a significant effect on lowering serum leptin levels.

[0650] Figure 9C shows serum leptin:adiponectin ratio in obese DIO mice after treatment with vehicle or 2 mg / kg or 6 mg / kg of compound 1 of the present disclosure. Data was analyzed using one-way ANOVA with multiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results in Figure 9C show a decrease in leptin:adiponectin ratio at each dose tested. In particular, compound 1 has a significant effect on lowering leptin:adiponectin serum levels at a dose of 6 mg / kg.

[0651] Figure 9D shows serum adiponectin levels in lean mice bearing B16F10 melanoma after treatment with vehicle, 8 mg / kg or 24 mg / kg of compound 1 of the present disclosure, or 2 mg / kg of compound 4. Figure 9E shows serum adiponectin levels in obese DIO mice bearing B16F10 melanoma after treatment with vehicle, 8 mg / kg or 24 mg / kg of compound 1 of the present disclosure, or 2 mg / kg of compound 4. Data were analyzed using one-way ANOVA with multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. The results in Figures 9D and 9E show that compound 1 significantly increases serum adiponectin in both lean and obese tumor-bearing mice. In contrast, compound 2 had no effect on serum adiponectin levels in either lean or obese tumor-bearing mice.

[0652] Example 3 - In vivo EO771 mammary tumor / DIO mouse study - tumor growth, body weight

[0653] Female mice were surgically ovariectomized and then fed a high-fat diet (60% fat) for 14 weeks to induce obesity and metabolic dysfunction, or a low-fat diet (10% fat). Mammary tumors were then induced by injecting syngeneic EO771 cells (50,000 / mouse) into the fourth mammary gland. When tumors were evident, Compound 1 (at 24 mg / kg) or vehicle (5% mannitol / water) was administered subcutaneously every fourth day for a total of four times.

[0654] FIG. 10A shows tumor growth in lean EO771 mammary tumor / DIO mice after treatment with vehicle or 24 mg / kg of compound 1 of the present disclosure. FIG. 10B shows tumor growth in obese EO771 mammary tumor / DIO mice after treatment with vehicle or 24 mg / kg of compound 1 of the present disclosure. Data were analyzed using two-way ANOVA with multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. The results in FIG. 10A and FIG. 10B show that EO771 tumors are 71% larger in obese female mice than in lean female mice on day 15. The results also show that compound 1 reduces tumor growth in both lean and obese female mice with a similar degree of efficacy in tumor size (53% reduction in lean mice vs. 52% reduction in obese mice).

[0655] FIG. 11A shows body weight in lean EO771 mammary tumor / DIO mice after treatment with vehicle or 24 mg / kg of compound 1 of the present disclosure. FIG. 16B shows body weight change relative to baseline in lean EO771 mammary tumor / DIO mice after treatment with vehicle or 24 mg / kg of compound 1 of the present disclosure. FIG. 11C shows body weight in obese EO771 mammary tumor / DIO mice after treatment with vehicle or 24 mg / kg of compound 1 of the present disclosure. FIG. 1D shows body weight change in obese EO771 mammary tumor / DIO mice after treatment with vehicle or 24 mg / kg of compound 1 of the present disclosure. Data were analyzed by two-way ANOVA with multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. The results in Figures 11A-11D show that administration of 24 mg / kg of compound 1 every 4 days reduced body weight in both lean and obese female mice bearing mammary tumors with similar magnitude of effect (18% reduction in lean mice and 21% reduction in obese mice, respectively).

[0656] Table 4 shows that Compound 1 significantly reduced adipose tissue mass (at autopsy in three depots, parametrium, retroperitoneum, and inguinal) in obese mice after two-day treatment for two weeks. A similar effect of Compound 1 was seen in lean mice, although it was less significant.

[0657] [Table 5]

[0658] Example 4 - Phase 1 Dose Escalation Study of Compound 1 to Evaluate Safety and Tolerability in Patients with Highly Refractory or Advanced Solid Tumors - Experimental Design

[0659] The Phase 1 clinical trial of Compound 1 has several objectives.

[0660] The primary objective is: Determine the safety and tolerability of Compound 1 in patients with highly refractory or advanced solid tumors. Determining the maximally tolerated dose of Compound 1 in patients with highly refractory or advanced solid tumors Determining the recommended phase 2 dose (RP2D) of compound 1 in patients with highly refractory or advanced solid tumors

[0661] The secondary objective is: Evaluation of the pharmacokinetics (PK) of Compound 5, the active moiety and metabolite of Compound 1, in patients with highly refractory or advanced solid tumors. Document the evidence of antitumor activity of Compound 1 in patients with highly refractory or advanced stage solid tumors.

[0662] The objectives of the examination include: Evaluate the effect of Compound 1 in patients with highly refractory or advanced solid tumors by biomarker analysis and PET scan imaging (clinically relevant and approved by investigators and medical observers). · Evaluate the pharmacokinetic (PD) effect of Compound 1 by MetAP2 analysis and DCEMRI imaging (clinically valid and approved by investigators and medical observers) in patients with highly refractory or advanced stage solid tumors. Document the effects of Compound 1 on metabolic factors in patients with highly refractory or advanced solid tumors. - To assess muscle and fat mass in selected patients using MRI or CT imaging.

[0663] Study description

[0664] This is a Phase 1 dose escalation study of Compound 1 administered subcutaneously to evaluate the safety and tolerability in patients with highly refractory or advanced solid tumors. An accelerated titration dose escalation schedule is applied to one patient per dose level during the first cycle of treatment until the patient has a grade 2 toxicity deemed by the investigator to be possibly, probably, or definitely related to the study drug. A cycle is 28 days in total consisting of 4 weeks of treatment and includes a pre-dose safety test prior to beginning the next treatment cycle. Once a grade 2 toxicity deemed to be at least possibly related to the study drug is observed during the patient's first cycle of treatment, the accelerated phase of the study ends and the non-accelerated phase (3+3 dose escalation schedule) begins. A minimum of three evaluable patients accrue at the dose that triggers the switch to the non-accelerated schedule and at subsequent dose levels before a dose-limiting toxicity (DLT) is found.

[0665] During the Accelerated Dose Escalation Plan Phase, the Sponsor, Medical Monitor, and Safety Review Committee (SRC) will decide to switch to the 3+3 Non-Accelerated Phase before any Grade 2 toxicity deemed at least possibly related to the study drug is observed in the patient's first cycle of treatment.

[0666] In the 3+3 non-accelerated phase, if one of three patients has a DLT (defined below), the group is expanded to a maximum of six patients. If only one of six patients has a DLT, dose escalation continues. If two patients have a DLT, dose escalation is stopped regardless of the number of patients being treated in this group (e.g., if patients 1 and 4 have a DLT, patients 5 and 6 will not be treated). The dose at which two of six patients have a DLT is considered to be at least one dose level above the MTD. It is fully evaluated by treating all six patients at the next lower dose. If more than one patient has a DLT at this lower dose level, de-escalation continues until a dose level is identified at which one or zero of six patients have a DLT. This dose is identified as the MTD.

[0667] Once the MTD is determined, up to six more patients, up to a total of 12 patients, will be treated at this dose level for further characterization of treatment-emergent adverse events (TEAEs).

[0668] Patients who experience Grade 3 or greater toxicity deemed by the investigator to be possibly, probably, or definitely due to administration of Compound 1 may withhold their next dose for up to 14 days (the designated day of administration will be considered Day 1 of the dose delay) and treatment will be resumed at the same dose level when the patient's toxicity returns to Grade 1 or the patient's prestudy baseline. Patients who are withheld for more than 14 days will not continue in the study. Dose delays extending from Day 1 of scheduled treatment initiation up to 2 weeks will be considered a clinical concern for the patient and will be considered unrelated to study drug based on agreement between the investigator, medical observer, and patient.

[0669] During the study, the SRC will decide whether to open additional dose groups. New dose groups higher or lower than the highest dose being employed may be added with the approval of the investigators, medical observers, and the SRC.

[0670] Intra-patient dose escalation to the next higher dose group will be considered for patients who do not show at least Grade 2 adverse events considered possibly related to the study drug in the first cycle and successfully complete the Tumor Burden Assessment after Cycle 2. This type of dose escalation will only be allowed once patients in the next higher dose group have successfully completed the safety assessments of Cycle 1 without showing at least Grade 2 adverse events considered possibly related to the study drug. The decision to escalate the dose will be made by discussion between the investigator, medical observer, and sponsor, taking into account the patient's permission. If a patient is elevated to the next higher dose level in Cycles 4, 5, or 7 and beyond, additional plasma PK samples will be collected on a scheduled basis.

[0671] A patient will be allowed to continue treatment if: There is a clinical response, or There is stable disease as assessed by imaging studies at C2, C4, C6, and every 3 cycles thereafter, or · Researchers and medical observers agree that you would benefit from the treatment.

[0672] Each patient will receive a dose once weekly for 4 weeks (days 1, 8, 15, and 22), including a safety follow-up before the start of the next treatment cycle. Patients will complete 2 cycles prior to disease assessment by RECIST 1.1 criteria. The following are the dose values ​​that will be employed:

[0673] [Table 6]

[0674] The Common Terminology Criteria for Adverse Events (CTCAE) v4.02 will be used to measure toxicity. A DLT was defined as any of the following adverse events that are clinically significant and that the investigator considers to be possibly, probably, or definitely related to continued administration of Compound 1 despite maximal medical support: Any non-hematologic toxicity of grade 3 or higher lasting 7 days; or nausea, diarrhea and / or vomiting of grade 3 or higher lasting 3 days, if the patient has received maximal medical intervention and / or prophylactic antiemetic therapy, or Any grade 3 or higher hematological toxicity lasting 3 days; or Any grade 3 or higher febrile neutropenia.

[0675] Study population: Approximately 30 patients

[0676] Study Drug Administration: Compound 1 administered by subcutaneous infusion on days 1, 8, 15, and 22 of each cycle, including safety follow-up prior to the beginning of the next treatment cycle.

[0677] Selection criteria:

[0678] Patients must provide written informed consent, understand the requirements of the study, and agree to comply with the requirements of the study.

[0679] Male or female, aged 21 to 85 years old.

[0680] Patients have histologically or cytologically advanced, refractory, late-stage solid tumors that have progressed on standard treatment and for which there is no effective anti-cancer treatment.

[0681] Patients were to have at least one radiographically measurable lesion of 1 cm or greater in greatest dimension by conventional computed tomography scanning (CT) techniques (based on RECIST criteria) or, in the opinion of the investigator, to have reliably and consistently tracked disease and the patient was identified as eligible by a medical observer.

[0682] Eastern Cooperative Oncology Group (ECOG) status ≤1.

[0683] Life expectancy 3 months or more

[0684] Women of childbearing potential must not be breastfeeding and must have a negative serum pregnancy test 72 hours before the start of the study. If the female partner is not menopausal or surgically sterile, then female and male study subjects must be willing to use a dual method of birth control, such as condoms or an occlusive cap (e.g., diaphragm or cervical / internal cap), plus a spermicide (e.g., foam, gel, film, cream, suppository), throughout the period of study participation, including 90 days after the last treatment.

[0685] The laboratory data is as follows: · Hematology: ANC >1500 cells / mm 3 , platelet count>100000 cells / mm 3 and hemoglobin >9 g / dL. · Urinalysis: No clinically significant abnormalities. Coagulation: INR and PTT within normal limits. HIV-positive patients were eligible if they met the following criteria: CD4 count ≥ 100 / mm 3 , undetectable viral load within the past 3 months, and receiving antiretroviral treatment for at least 4 weeks prior to study entry.

[0686] Patients eligible for imaging scans must be able to lie flat for 45 minutes.

[0687] Exclusion criteria Patients undergoing organ transplant surgery.

[0688] Patients with primary brain malignancies, brain metastases, or active CNS pathology.

[0689] Patients with a history of hepatitis A, B, or C receiving active antiviral treatment.

[0690] Patients on anticoagulant therapy: However, standard ASA, antiplatelet agents, and doses, pre-approved by a medical observer, are permitted.

[0691] Patients with a history of gastric bypass surgery or banding procedures.

[0692] Patients who require insulin to control diabetes mellitus. Those taking non-glucose-dependent acting insulin secretagogues, sulfonamides, such as glyburide and any agent in this class.

[0693] For example, patients taking more than 5 mg prednisone, 0.75 mg dexamethasone, 20 mg hydrocortisone, 0.6 mg betamethasone, 4 mg methylprednisone, 25 mg cortisone, etc. Nasal, inhaled, or topical corticosteroids are permitted.

[0694] Patients with uncontrolled or refractory hypertension: systolic > 180 or diastolic > 110 despite medical therapy, or a decrease in blood pressure: systolic < 90 or diastolic < 50.

[0695] Patients with a 12-lead ECG obtained during screening showing a QTc (Bazett's correction, corrected QT interval) ≥ 470 ms or patients with congenital long QT syndrome. Isolated right bundle branch block (RBBB) and incomplete right bundle branch block (IRBBB) and left anterior fascicle block (LAH) are permitted. Any uncontrolled arrhythmias (patients with rate-controlled atrial fibrillation are not excluded unless they are taking chronic anticoagulants based on exclusion criterion #4).

[0696] Renal function: Serum creatine, >1.5X upper limit of normal (ULN) for patients with higher than normal creatine levels, or calculated creatine clearance <50mL / min / 1.73 2 That which is.

[0697] Liver function: Total bilirubin ≥ 1.5X upper limit of normal (ULN); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5X ULN. Patients with liver metastases or liver tumors with ALT or AST ≤ 5.0X ULN are permitted.

[0698] Participant in another investigational drug trial within 30 days prior to first dose of study drug.

[0699] Pretreatment:

[0700] Treatment with any of the following drugs for 4 weeks or less or 5 half-lives prior to the first dose of the study drug, whichever is shorter: All cytotoxic or cytostatic chemotherapy, monoclonal antibody therapy, radiation therapy, targeted therapy, hormonal agents, TKIs (tyrosine kinase inhibitors), angiogenesis and VEGF inhibitors. Major surgery within 4 weeks before the first dose of study drug. Any treatment with radioimmunotherapy within 12 weeks prior to the first dose of study drug.

[0701] Any other current condition or social situation which, in the opinion of the investigator, would preclude participation in the study or would prevent the patient from complying with the study.

[0702] A significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from complying with the procedures of the study, or that would place the patient at unacceptable risk if he or she were to participate in the study, or that would compromise his or her ability to interpret the data from the study.

[0703] Patients with a history of hypersensitivity to any of the test materials or related compounds

[0704] Assuming that the biologically active small molecule portion of compound 1, compound 5, is a CYP3A4&5 inhibitor, patients requiring chronic, concomitant treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4 / 5) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort).

[0705] Patients who have received radiotherapy within 4 weeks prior to the first dose of study drug, or in the case of focal radiotherapy (e.g., for pain relief or for lytic lesions at risk of fracture) within 2 weeks prior to the first dose of study drug, or who have not recovered from the toxicity of radiotherapy.

[0706] Use of prescription or non-prescription appetite stimulants (i.e., megestrol acetate, mirtazapine, dononabinol, anabolic steroids) within 2 months prior to the first dose of study medication.

[0707] Research evaluation

[0708] Below is a summary of the prerequisites and testing required prior to enrollment and will be conducted during patient enrollment in this Phase 1 study.

[0709] Screening period (before day 1, up to day 14) A signed consent form · Medical history Physical examination (total); rectal and genital examination may be delayed if not clinically indicated. Height and weight ECOG performance status Vital signs (temperature, blood pressure, pulse, and respiratory rate) Evaluation of concomitant medications 12-lead ECG (triplets) Serum pregnancy test (for women of childbearing potential who are not infertile) · Hematology Clinical chemistry, coagulation, lipid, and urinalysis (microscopy if dipstick positive) Tumor burden assessment by radiological assessment using RECIST 1.1 criteria (CT scan may be used if detected within no more than 30 days of treatment day 1) PET and DCE MRI scans when approved by investigators and medical observers and clinically indicated For body composition analysis, MRI or CT scans of selected patients approved by the investigator and medical observer, with reference image manual Available clinically accepted assays resulting in protein biomarkers associated with the patient's specific tumor type (e.g., PSA, CA-125, AFP, CEA, beta-hCG, Ca19-9, etc.)

[0710] Pre-dose studies, excluding treatment period (PK, PD, biomarkers, and retention), may be performed within 72 hours prior to treatment. · Medical history · Body weight (administered each treatment day prior to study medication calculations - body weight from previous visit may be used for study medication dosing calculations). Questionnaire regarding dietary habits, eating habits, and physical activity ECOG performance status (pre-injection day 1 of each cycle) Vital signs (temperature, blood pressure, pulse, and respiratory rate) Evaluation of concomitant medications 12-lead ECG (triplets) Local tolerance at the subcutaneous therapeutic injection site Serum pregnancy test (for non-infertile women of childbearing potential) (day 1 prior to dosing) · Hematology Clinical chemistry, coagulation, lipid, and urinalysis (microscopy if dipstick positive) Collection of blood samples for PK and PD analysis Collection of blood samples for diagnostic biomarkers and retention PET and DCE MRI scans when approved by investigators and medical observers and clinically indicated For body composition analysis, MRI or CT scans of selected patients approved by the investigator and medical observer, with reference image manual Tumor burden assessment will be performed every other cycle (i.e. Cycles 2, 4, 6) using RECIST 1.1. After completion of Cycle 6, tumor burden assessment will be performed every 3 cycles. If stable or positive response is evident, a follow-up (4 weeks) confirmatory radiological evaluation will be performed. Available clinically accepted assays resulting in protein biomarkers associated with the patient's specific tumor type (e.g., PSA, CA-125, AFP, CEA, beta-hCG, Ca19-9, etc.) Adverse event review (including symptom review)

[0711] End of Treatment (EOT) Evaluation (The EOT visit will be scheduled as soon as possible after the investigator determines that study treatment is no longer an option or after the patient is withdrawn from the study.) Weight Questions about eating habits and physical activity ECOG performance status (pre-injection day 1 of each cycle) Vital signs (temperature, blood pressure, pulse, and respiratory rate) Evaluation of concomitant medications 12-lead ECG (triplets) Local tolerance at the subcutaneous therapeutic injection site · Hematology Clinical chemistry, coagulation, lipid, and urinalysis (microscopy) Collection of blood samples for PK and PD analysis Collection of blood samples for biomarkers and retention Tumor burden assessment by radiological assessment using RECIST 1.1 criteria Available clinically accepted assays resulting in protein biomarkers associated with the patient's specific tumor type (e.g., PSA, CA-125, AFP, CEA, beta-hCG, Ca19-9, etc.) Adverse event review (including symptom review)

[0712] End-of-study (EOS) assessment (EOS is 30 days after the EOT (± 3 days) visit) Physical Examination Height and weight Questions about eating habits and physical activity ECOG performance status Vital signs (temperature, blood pressure, pulse, and respiratory rate) Evaluation of concomitant medications 12-lead ECG (triplets) Local tolerance at the subcutaneous therapeutic injection site Serum pregnancy test (for women of childbearing potential who are not infertile) · Hematology Clinical chemistry, coagulation, lipid, and urinalysis (microscopy) Collection of blood samples for PK and PD analysis Collection of blood samples for biomarkers and retention Tumor burden assessment will be performed using RECIST 1.1 Available clinically accepted assays resulting in protein biomarkers associated with the patient's specific tumor type (e.g., PSA, CA-125, AFP, CEA, beta-hCG, Ca19-9, etc.) Adverse event review (including symptom review)

[0713] Study endpoint

[0714] Safety end point Incidence, grade, and duration of AEs · Global and limited area acceptability assessment Laboratory evaluation Physical examination, vital signs, and ECG parameters

[0715] Pharmacokinetics and Tumor Burden Endpoints PK profile from Dose 1 until the patient is no longer taking study drug Change in disease status, overall response rate (CR+PR), and disease control rate (CR+PR+SD)

[0716] Examination end point PET and DCE MRI evaluation PD(MetAP2) profile from Dose 1 until the patient is no longer taking study drug MRI or CT assessment of changes in body composition Biomarker assessments (TNF-α, IL-6, MCP-1, IGF-1, hsCRP, leptin, insulin, SHBG (for select patients), VEGF, bFGF, and adiponectin) from Dose 1 until the patient is no longer taking study drug Metabolic assessments (glucose, total cholesterol, LDL, HDL, free fatty acids, lipids, triglycerides, and VLDL), and dietary and nutritional assessments from Dose 1 until the patient is no longer taking study medication.

[0717] statistical analysis

[0718] Given the small patient sampling size in this Phase 1 study, descriptive statistics will be used for all safety, efficacy, and pharmacokinetic parameters. Categorical variables will be summarized with frequency distributions (number of patients and percentages), continuous variables will be summarized with mean, standard deviation, median, minimum, and maximum, and time-to-event variables will be summarized using estimated median time values ​​using the Kaplan-Meier method.

[0719] The frequency of patients experiencing at least one AE is expressed by tissue and preferred term according to the MedDRA Medical Terminology. Detailed information for each AE includes a description of the event, duration, whether the AE was serious, seriousness, relationship to study drug, actions taken, clinical outcome, and whether it is a DLT. The severity of the AE is graded according to CTCAE v4.02. AEs classified as dose limiting are listed.

[0720] Summary tables present the number of patients (by dose group) observed with an AE and the corresponding percentage. The denominator used to calculate the incidence rate consists of patients who received at least one dose of Compound 1 in each dose group. Within each table, AEs are classified by MedDRA system and preferred term. Additional subcategories are based on the severity of the event and its relationship to study drug.

[0721] Adverse events resulting in discontinuation of treatment or withdrawal from the study, serious adverse events, and deaths during the study will be tallied. All DLTs will be reported and the MTD will be identified.

[0722] Vital signs and ECGs are summarized using descriptive statistics. Summary tables are prepared to examine the distribution of laboratory measurements over time. Shift tables are provided to examine the distribution of laboratory toxicities. In addition, patient profiles are displayed with adverse events, vital signs, clinical laboratory tests, physical examinations, and ECGs (pre-treatment, post-treatment).

[0723] Example 5 - Phase 1 Study - Metabolic Dysfunction

[0724] Metabolic dysfunction, defined as elevated levels of hormones such as insulin, leptin, IGF-1, or low levels of hormones such as adiponectin, or elevated leptin:adiponectin ratios, is typically associated with obesity (defined as having a body mass index >30 kg / m2). Obesity is most often the result of excess nutrition and physical immobility over time, which leads to the accumulation of nutrients as triglycerides in adipose tissue. In this scenario, as more triglycerides are deposited, fat cells in the adipose tissue become enlarged, leading to increased obesity, until these cells reach a critical size beyond which they can no longer expand. Enlarged fat cells exhibit increased leptin secretion (leading to increased circulating leptin levels in proportion to the mass of adipose tissue) and decreased adiponectin secretion (leading to decreased circulating adiponectin levels, an indicator of metabolic dysfunction).

[0725] In addition, the enlarged adipocytes induce localized hypoxia, which leads to cellular stress, cell death, and simultaneous infiltration of immune cells (macrophages and lymphocytes) to ingest excess triglycerides and cellular debris. Subsequent events include persistent inflammation within the adipose tissue, proliferation of adipose stem cells contributing to adipocyte hyperplasia, and increased angiogenesis, all of which contribute to metabolic dysfunction.

[0726] These events occur primarily in visceral (abdominal) adipose tissue, as opposed to subcutaneous adipose tissue, and the relationship between visceral adipose tissue mass and metabolic dysfunction (albeit to a lesser extent than subcutaneous adipose tissue) is well known. However, since the measurement of BMI does not capture the distribution of adipose tissue in the body or take into account muscle mass, super-obesity and pathological disorders in adipose tissue that lead to metabolic dysfunction as described above can occur in all patients with a BMI in the normal (e.g., 20-25 kg / m2) or overweight (e.g., 25-30 kg / m2) range. To determine whether a patient is metabolically dysfunctional, BMI is not accurate for the reasons mentioned above, and more accurate tests include measuring circulating hormone levels such as insulin, leptin, adiponectin, and IGF-1.

[0727] In this study, circulating hormone levels, including insulin, leptin, adiponectin, and IGF-1, were measured in cancer patients (fasting state) and in response to weekly subcutaneous administration of Compound 1 using a range of doses. It is noted that patients with carcinoid, colon, cervical, endometrial, and breast cancer exhibited baseline values ​​of these hormones while exhibiting various degrees of metabolic dysfunction. Furthermore, the direction of change in these hormone levels following weekly administration of Compound 1 indicates an improvement in metabolic dysfunction.

[0728] FIG. 12 shows circulating levels of metabolic biomarkers insulin, adiponectin, leptin, IGF-1, and leptin:adiponectin ratio (LAR) both at baseline and after weekly administration of Compound 1 in a male patient with carcinoid tumor weighing 24.5 kg / m2 (e.g., normal). FIG. 12A shows the absolute values ​​of the metabolic biomarkers, and FIG. 12B shows the % change relative to baseline over time. Results in FIGS. 12A and 12B show that fasting insulin at baseline is abnormally high, but is reduced by 89% (relative to baseline) after 4 weeks of weekly administration of Compound 1. In addition, leptin as well as leptin:adiponectin ratio (LAR) were all reduced, indicating improved metabolic function after administration of Compound 1.

[0729] In another example shown in FIG. 13, a female patient with colon cancer (BMI=23.5 or normal) was administered 6 mg / m once a week. 2 at 8.5 mg / m 2 The dose was increased to 100 mg / kg / day. Figure 13A shows the absolute values ​​of the metabolic biomarkers, and Figure 18B shows the % change over time. Figures 13A and 13B show that after administration of Compound 1, metabolic dysfunction improved, with leptin decreasing from baseline, while adiponectin increased over the same period, resulting in a 62% decrease in LAR from an increase of 4.7 from baseline.

[0730] In another example shown in FIG. 14, a female patient with endometrial cancer (BMI=25.1 or overweight) received 8.5 mg / m once a week. 2 at 11.9 mg / m 2The dose was increased to 1.5 mg / kg / day. Figure 14A shows the absolute values ​​of the metabolic biomarkers, and Figure 14B shows the % change over time. Figures 14A and 14B show that after Compound 1 administration, metabolic dysfunction improved, with leptin decreasing from baseline, while adiponectin increased over the same period, resulting in an 85% decrease in LAR from an increase of 4.5 from baseline. Because insulin data was not available at baseline, % change from baseline was not calculated, but insulin decreased by 80% from the initial 4 week period after initiation of treatment (when insulin data was first available) to the 8 week period after initiation of treatment.

[0731] In another example shown in FIG. 15, a female patient with cervical cancer (BMI=22.5 or normal) was administered 11.9 mg / m once a week. 2 100 mg of Compound 1 for 8 weeks. Figure 15A shows the absolute values ​​of the metabolic biomarkers, and Figure 15B shows the % change over time. Figures 15A and 15B show that leptin was reduced by 88% from baseline and LAR was reduced by 78% from baseline, indicating improvement in metabolic dysfunction after 8 weeks of Compound 1. Insulin was reduced by 50% from baseline by 8 weeks post-treatment, also indicating improvement in metabolic dysfunction after Compound 1 treatment.

[0732] In another example shown in FIG. 16, a female patient with hormone receptor positive breast cancer (BMI=27.5 or overweight) received 15.3 mg / m once a week. 2 10 mg of Compound 1 for 8 weeks. Figure 16A shows the absolute values ​​of metabolic biomarkers, and Figure 16B shows the % change over time. Figures 16A and 16B show that leptin was reduced by 70% from baseline, indicating an improvement in metabolic dysfunction after 8 weeks of Compound 1 administration.

Claims

1. 1. A method for assisting in identifying a cancer in a subject that is sensitive to a treatment regimen comprising administration of a MetAP2 inhibitor, comprising: a) determining a subject's fasting insulin and glucose levels to measure said subject's HOMA number; b) comparing said HOMA number to the HOMA number of lean patients with metabolically normal levels; and c) determining that the cancer is responsive to a treatment regimen comprising administration of the MetAP2 inhibitor if the HOMA number is higher than the HOMA number of the lean patient with metabolically normal levels, the MetAP2 inhibitor being capable of: 【Chemistry 1】 [In the formula, x is an integer from 1 to 450; y is an integer from 1 to 30; n is an integer from 1 to 100 It is.] or a pharma- ceutically acceptable salt thereof. A method comprising:

2. The method of claim 1 , wherein the treatment regimen further comprises administration of at least one second active agent.

3. The method of claim 2 , wherein the second active agent comprises at least one kinase inhibitor.

4. 4. The method of claim 3, wherein the at least one kinase inhibitor is a multi-kinase inhibitor, a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, an MTOR inhibitor, or a combination thereof.

5. 3. The method of claim 2, wherein the second active agent comprises fulvestrant.

6. The method of claim 2 , wherein the second active agent comprises a chemotherapeutic agent.

7. 7. The method of claim 6, wherein the chemotherapeutic agent comprises an alkylating agent, an antibiotic, an antidote, an interferon, a polyclonal or monoclonal antibody, an EGFR inhibitor, an FGFR inhibitor, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitosis inhibitor, an MTOR inhibitor, a multi-kinase inhibitor, a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, a VEGF / VEGFR inhibitor, a taxane or a taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, a cytidine analog drug, an anti-neoplastic or anti-proliferative agent, or any combination thereof.

8. 3. The method of claim 2, wherein the MetAP2 inhibitor and the second active agent are administered sequentially or substantially simultaneously.

9. 2. The method of claim 1, wherein the subject exhibits at least one metabolic dysfunction, the metabolic dysfunction being high fasting insulin levels, excess visceral adiposity, high leptin levels, low adiponectin levels, a high leptin to adiponectin ratio, high fasting insulin levels associated with chronic inflammation, or a combination thereof.

10. 10. The method of claim 9, wherein the metabolic dysfunction is high fasting insulin levels.

11. 2. The method of claim 1, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, clear cell renal carcinoma, melanoma, multiple myeloma, thyroid cancer, or a combination thereof.

12. The method of claim 11, wherein the breast cancer is postmenopausal HR+ / Her2- breast cancer.

13. The method of claim 11 , wherein the prostate cancer is castration-resistant prostate cancer.

14. 2. The method of claim 1, wherein the MetAP2 inhibitor is administered once a week, 1 to 5 times a week, every 3 to 4 days, once every two weeks, or 1 to 4 times a month.

15. The MetAP2 inhibitor is administered at a concentration of 1 mg / m ２ to 50 mg / m ２ , 5 mg / m ２ to 25 mg / m ２ , 5 mg / m ２ to 50 mg / m ２ , 5 mg / m ２ to 15 mg / m ２ , or 5 mg / m ２ to 10 mg / m ２ The method of claim 1 , wherein the amount of

16. The method of claim 1 , wherein the MetAP2 inhibitor is administered parenterally or subcutaneously.

17. The method of claim 1 , wherein the MetAP2 inhibitor is provided as a pharmaceutical composition comprising the MetAP2 inhibitor and a pharma- ceutically acceptable carrier.

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