Treatment of tumors caused by metabolic dysfunction

Abstract

The present invention relates to the treatment of tumors caused by metabolic dysfunction. The present disclosure relates to modified or polymer-conjugated MetAP2 inhibitors. The present disclosure also relates to methods for treating metabolically-induced diseases and conditions, such as certain cancers.

Description

[0001] This application is a divisional application. The application date of the original application is January 11, 2017, the application number is 201780016316.1 (PCT / US2017 / 012968), and the name of the invention is “Treatment of tumors caused by metabolic dysfunction”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of USSN 62 / 277,293, filed January 11, 2016, USSN 62 / 393,929, filed September 13, 2016, and USSN 62 / 395,446, filed September 16, 2016. The contents of each application are incorporated herein by reference in their entirety. Field of the Invention

[0004] The present disclosure provides compounds, pharmaceutical compositions and methods for treating patients suffering from proliferative disorders (e.g., cancer) complicated by metabolic dysfunction.The present disclosure relates to the fields of biomedicine, pharmacology and molecular biology. Technical Background

[0005] It is well-known that obesity and metabolic dysfunction are risk factors for people to develop cancer. However, for people with metabolic dysfunction, once they are diagnosed with cancer or proliferation-related conditions, there is no specific treatment option. Recent discoveries in cancer research have revealed a complex interaction between the endocrine health of certain cancer patients and the progression of their cancer, with the interaction focusing on metabolic factors, hormones derived from adipose tissue, and the chronic inflammation associated with excessive visceral obesity. In selected cancers, these hormones derived from adipose tissue stimulate specific carcinogenic pathways, thereby increasing cancer cell proliferation, invasion, and ultimately killing the patient faster than cancer patients with normal physiological levels of these metabolic factors. Other hormones derived from visceral adipose tissue play a protective role in cancer and are often suppressed by excessive visceral obesity. Despite the fact that this cancer / metabolism relationship has been reported to directly lead to more than 80,000 deaths each year in the United States alone, there is currently no treatment specifically designed for this disease relationship and patient population.

[0006] Therefore, there is a need for new compounds, pharmaceutical compositions and methods for treating patients suffering from proliferative disorders concurrent with metabolic dysfunction, such as cancer. The present disclosure addresses these needs. Summary of the Invention

[0007] The present disclosure provides methods of treating a proliferative disorder (e.g., cancer), or ameliorating at least one symptom of a proliferative disorder (e.g., cancer), in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of the present disclosure to the subject to treat the proliferative disorder, wherein the subject has a metabolic dysfunction.

[0008] The present disclosure also provides methods of treating a metabolic-sensitive tumor in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of the present disclosure to the subject to treat the metabolic-sensitive tumor, wherein the subject suffers from a metabolic dysfunction.

[0009] In one aspect, the present disclosure provides a method of treating cancer, or ameliorating at least one symptom of cancer, or treating metabolically-sensitive tumors in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of the formula:

[0010]

[0011] where, for each occurrence independently,

[0012] R4 is H or C1-C6 alkyl;

[0013] R5 is H or C1-C6 alkyl;

[0014] R6 is a C2-C6 hydroxyalkyl group;

[0015] 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;

[0016] AA1 is glycine, alanine, or H2N(CH2) m CO2H, where m is 2, 3, 4 or 5;

[0017] 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;

[0018] 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;

[0019] 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;

[0020] AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;

[0021] AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, where m is 2, 3, 4 or 5;

[0022] L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), halide or perfluoroalkyloxy;

[0023] Q is NR, O, or S;

[0024] X is M-(C(R)2) p -MJM-(C(R)2) p -MV;

[0025] M is a bond, or C(O);

[0026] J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S;

[0027] Y is NR, O, or S;

[0028] R is H or alkyl;

[0029] V is a key or ;

[0030] R 9 is alkyl, aryl, aralkyl, or a bond; or R 9 Combined with Y to form a heterocyclic ring;

[0031] R 10 is an amido group or a bond;

[0032] R 11 is H or alkyl;

[0033] W is a MetAP2 inhibitor moiety or an alkyl group;

[0034] x is in the range of 1 to about 450;

[0035] y is in the range of 1 to about 30;

[0036] n is in the range of 1 to about 100;

[0037] p is 0-20;

[0038] q is 2 or 3;

[0039] r is 1, 2, 3, 4, 5, or 6;

[0040] or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, wherein the subject suffers from a metabolic dysfunction, and wherein cancer is treated.

[0041] In one aspect, the present disclosure relates to at least one compound having the formula:

[0042] , , or

[0043] .

[0044] The present disclosure also provides a method for treating cancer, or ameliorating at least one symptom of cancer, or treating a metabolic-sensitive tumor in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound represented by ZQXYC(O)-W, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof,

[0045] where, for each occurrence independently,

[0046] Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)- or Z is H2N-AA5-AA6-C(O);

[0047] 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;

[0048] 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;

[0049] AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;

[0050] AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)mCO2H, where m is 2, 3, 4, or 5;

[0051] Q is NR, O, or S;

[0052] X is M-(C(R)2) p -MJM-(C(R)2) p -MV;

[0053] M is a bond, or C(O);

[0054] J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S;

[0055] Y is NR, O, or S;

[0056] R is H or alkyl;

[0057] V is a key or ;

[0058] R 9 is alkyl, aryl, aralkyl, or a bond; or R 9 Combined with Y to form a heterocyclic ring;

[0059] R 10 is an amido group or a bond;

[0060] R 11 is H or alkyl;

[0061] W is the MetAP2 inhibitor moiety;

[0062] p is 0-20;

[0063] q is 2 or 3; and

[0064] r is 1, 2, 3, 4, 5, or 6,

[0065] wherein the subject suffers from a metabolic dysfunction, and wherein cancer is being treated.

[0066] The cancer can be postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof.

[0067] The metabolic dysfunction can be excessive visceral adiposity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof.

[0068] The methods of the present disclosure may further comprise treating a metabolic dysfunction in the subject, or ameliorating at least one symptom of a metabolic dysfunction in the subject. The methods of the present disclosure may further comprise increasing adiponectin, decreasing leptin, decreasing fasting insulin, or a combination thereof in the subject.

[0069] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. In this specification, the singular also includes the plural, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used to implement or test the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety for all purposes. The references cited herein are not admitted to be prior art of the present disclosure. In the event of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods and examples are merely illustrative and are not intended to be limiting.

[0070] Other features and advantages of the disclosure will become apparent from the following detailed description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1A is a graph showing baseline body weight of mice fed a high fat diet compared to a low fat diet.

[0072] Figure 1B is a graph showing tumor growth in mice fed a high-fat diet compared to a low-fat diet.

[0073] Figure 2A is a graph showing tumor inhibition in lean mice following administration of a compound of the disclosure.

[0074] Figure 2B is a graph showing tumor inhibition in obese mice after administration of a compound of the present disclosure.

[0075] Figure 2Cis a graph showing the percent tumor inhibition in lean versus obese mice following administration of a Compound of the Disclosure relative to vehicle.

[0076] Figure 3A is a graph showing weight loss in lean mice following administration of a compound of the disclosure.

[0077] Figure 3B is a graph showing weight loss in obese mice after administration of a compound of the present disclosure.

[0078] Figure 4 is a graph showing the correlation between body weight and tumor size in lean and obese mice after administration of a compound of the present disclosure.

[0079] Figure 5 is a graph showing that the number of lung metastases was reduced in lean and obese mice after administration of a compound of the present disclosure.

[0080] FIG6 is a graph showing leukopenia in tumor-bearing obese mice after administration of a compound of the present disclosure.

[0081] Figure 7 is a graph showing inhibition of tumor growth in tumor-bearing lean and obese mice after administration of another MetAP2 inhibitor.

[0082] Figure 8 is a graph showing weight loss in tumor-bearing lean and obese mice following administration of a compound of the disclosure when compared to another MetAP2 inhibitor.

[0083] Figure 9A is a graph showing the reduction of serum leptin in non-tumor bearing obese mice after administration of a compound of the present disclosure.

[0084] Figure 9B is a graph showing increase in serum adiponectin in non-tumor bearing obese mice after administration of a compound of the present disclosure.

[0085] Figure 9C is a graph showing the ratio of leptin to adiponectin levels in non-tumor bearing obese mice after administration of a compound of the present disclosure.

[0086] Figure 9D is a graph showing serum adiponectin levels in tumor-bearing obese mice after administration of a compound of the present disclosure when compared to another MetAP2 inhibitor.

[0087] Figure 10A is a graph showing reduction in tumor growth in lean mice bearing mammary tumors following administration of a compound of the present disclosure.

[0088] Figure 10B is a graph showing reduction in tumor growth in obese mice bearing mammary tumors following administration of a compound of the present disclosure.

[0089] Figure 11A is a graph showing weight loss in lean mice bearing breast tumors following administration of a compound of the present disclosure.

[0090] Figure 11B is a graph showing the change in body weight relative to baseline in lean mice bearing breast tumors following administration of a compound of the present disclosure.

[0091] Figure 11C is a graph showing weight loss in obese mice bearing breast tumors after administration of a compound of the present disclosure.

[0092] Figure 11D is a graph showing the change in body weight relative to baseline in obese mice bearing mammary tumors after administration of a compound of the present disclosure.

[0093] Figure 12A is a graph showing the absolute values ​​of various metabolic biomarkers in the serum of carcinoid tumor patients after administration of a compound of the present disclosure.

[0094] Figure 12B is a graph showing the percent change from baseline in various metabolic biomarkers in the serum of carcinoid tumor patients following administration of a compound of the disclosure.

[0095] Figure 13A is a graph showing the absolute values ​​of various metabolic biomarkers in the serum of colon cancer patients after administration of a compound of the present disclosure.

[0096] Figure 13B is a graph showing the percent change from baseline in various metabolic biomarkers in the serum of colon cancer patients following administration of a compound of the present disclosure.

[0097] Figure 14A is a graph showing the absolute values ​​of various metabolic biomarkers in the serum of endometrial cancer patients after administration of a compound of the present disclosure.

[0098] Figure 14B is a graph showing the percent change from baseline in various metabolic biomarkers in the serum of endometrial cancer patients following administration of a compound of the present disclosure.

[0099] Figure 15A is a graph showing the absolute values ​​of various metabolic biomarkers in the serum of cervical cancer patients after administration of a compound of the present disclosure.

[0100] Figure 15Bis a graph showing the percent change from baseline in various metabolic biomarkers in the serum of cervical cancer patients following administration of a compound of the present disclosure.

[0101] Figure 16A is a graph showing the absolute value of leptin in the serum of hormone receptor-positive breast cancer patients after administration of the compound of the present disclosure.

[0102] Figure 16B is a graph showing the percent change from baseline in serum leptin in hormone receptor-positive breast cancer patients following administration of a compound of the present disclosure. DETAILED DESCRIPTION

[0103] How to use

[0104] The present disclosure provides methods for treating a proliferative disorder, or ameliorating at least one symptom of a proliferative disorder, in a subject in need thereof, comprising administering a therapeutically effective amount of at least one MetAP2 inhibitor to the subject to treat the proliferative disorder, wherein the subject suffers from a metabolic dysfunction. In a preferred aspect, the proliferative disorder is cancer. The cancer can be postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. In addition to treating a proliferative disorder or ameliorating at least one symptom of a proliferative disorder, the methods of the present disclosure can also include treating a metabolic dysfunction or ameliorating at least one symptom of a metabolic dysfunction.

[0105] The present disclosure also provides a method for treating a proliferative disorder in a subject in need thereof, or improving at least one symptom of a proliferative disorder, comprising administering a therapeutically effective amount of at least one fumagillin analog or derivative to the subject to treat the proliferative disorder, wherein the subject suffers from a metabolic dysfunction. In a preferred aspect, the proliferative disorder is cancer. The cancer can be postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. The methods of the present disclosure may further comprise treating a metabolic dysfunction, or improving at least one symptom of a metabolic dysfunction, in addition to treating a proliferative disorder or improving at least one symptom of a proliferative disorder.

[0106] The present disclosure also provides a method for treating a proliferative disorder in a subject in need thereof, or ameliorating at least one symptom of a proliferative disorder, comprising administering a therapeutically effective amount of at least one compound of the present disclosure to the subject to treat the proliferative disorder, wherein the subject suffers from a metabolic dysfunction. In a preferred aspect, the proliferative disorder is cancer. The cancer can be postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. In addition to treating a proliferative disorder or ameliorating at least one symptom of a proliferative disorder, the methods of the present disclosure can also include treating a metabolic dysfunction, or ameliorating at least one symptom of a metabolic dysfunction.

[0107] The present disclosure also provides a method for treating a metabolically sensitive tumor in a subject in need thereof, comprising administering a therapeutically effective amount of at least one MetAP2 inhibitor to the subject to treat the metabolically sensitive tumor, wherein the subject suffers from metabolic dysfunction. The metabolically sensitive tumor can be the result of postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. In addition to treating metabolically sensitive tumors, the methods of the present disclosure can also include treating metabolic dysfunction or ameliorating at least one symptom of metabolic dysfunction.

[0108] The present disclosure also provides a method for treating a metabolically sensitive tumor in a subject in need thereof, comprising administering a therapeutically effective amount of at least one fumagillin analog or derivative to the subject to treat the metabolically sensitive tumor, wherein the subject suffers from metabolic dysfunction. The metabolically sensitive tumor can be the result of postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. In addition to treating metabolically sensitive tumors, the methods of the present disclosure can also include treating metabolic dysfunction, or ameliorating at least one symptom of metabolic dysfunction.

[0109] The present disclosure also provides a method for treating a metabolically sensitive tumor in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of the present disclosure to the subject to treat the metabolically sensitive tumor, wherein the subject suffers from metabolic dysfunction. The metabolically sensitive tumor can be the result of postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. The metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. In addition to treating metabolically sensitive tumors, the methods of the present disclosure can also include treating metabolic dysfunction or ameliorating at least one symptom of metabolic dysfunction.

[0110] Obesity has been implicated as a risk factor for postmenopausal breast cancer, and excess visceral adipose tissue has been associated with poor response to chemotherapy and reduced progression and / or disease-free survival (Schaffler, A., et al. (2007) Nat Clin Pract Endocrinol Metab 3:345-54; Vona-Davis, L. Rose, D P. (2007) Endocr Relat Cancer 14:189-206). Adipose tissue-derived factors (e.g., leptin, adiponectin, aromatase, IL-6) have been proposed as possible mediators of the obesity-breast cancer link, with recent data drawing particular attention to the adipokines leptin and adiponectin (Cleary, MP., et al. (2009) Front Biosci (School Ed) 1:329-57; Cleary, MP., et al. (2010) Vet Pathol 47:202-13). Recently, the molecular basis for the major effects of leptin, adiponectin, and other hormones, such as insulin and insulin-like growth factor, has been described. Circulating adiponectin levels are inversely correlated with body mass index (BMI); in contrast, serum leptin is positively correlated with BMI (Ryan, 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 subjects, particularly those with high visceral fat content (Brochu-Gaudreau K, et al. Endocrine 2010, 37(1):11-32). Adiponectin concentrations in human serum are found to be 2-20 μg / ml (Grossmann, ME, et al. (2008) Br J Cancer 98:370-9). The potential mechanism of adiponectin signaling and cancer prevention is believed to involve activation of the intracellular signaling AMPK and inhibition of growth and survival pathways (Brochu-Gaudreau K, et al. Endocrine 2010, 37(1):11-32, Pfeiler G et al., Maturitas 2009, 63(3):253-256). In addition, adiponectin can indirectly exert its biological activities by selectively sequestering different growth factors (e.g., basic fibroblast growth factor, platelet-derived growth factor BB, heparin-binding epidermal growth factor) and inhibiting their normal receptor binding.These interactions involve specific oligomeric forms of adiponectin. Barb, D., Williams, C J., Neuwirth, K., Mantzoros, CS. (2007) Am J Clin Nutr 86:s858-66. Wang et al. (2005) J Biol Chem 280:18341-7).

[0111] Several epidemiological studies have found an inverse relationship between adiponectin levels and breast cancer risk (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, D C., et al. (2006) Cancer Lett 237:109-14). In breast cancer patients, adiponectin levels and the adiponectin-to-leptin ratio tend to be reduced relative to the ratio 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). Breast cancer patients with low adiponectin levels are reported to have more aggressive tumors and a higher frequency of lymph node metastases (Schaffler, A., et al. (2007) Nat Clin Pract Endocrinol Metab 3:345-54; Hou, W K., et al. (2007) Chin Med J (Engl) 120:1592-6).

[0112] In one aspect, the present disclosure provides methods for treating specific tumor types exacerbated by metabolic dysfunction using at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, and / or at least one compound of the present disclosure, including postmenopausal HR+ / Her2- breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. In a preferred aspect, the present methods disclose subcutaneous administration of a MetAP2 inhibitor in cancer patients with metabolic dysfunction. Metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. The present methods can restore patients to a more metabolically neutral and stable state and slow or reverse the progression of their cancer.

[0113] Described herein are methods for improving underlying metabolic dysfunction in patients with metabolically sensitive tumors. Methods for treating metabolically sensitive tumors include increasing adiponectin levels, decreasing leptin levels, improving the leptin-to-adiponectin ratio, 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, therefore, can be used to treat metabolically sensitive tumors that benefit from upregulating adiponectin along with improved leptin sensitivity. Thus, in certain aspects, 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 cancer, gallbladder cancer, hepatocellular carcinoma, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The above cancers may be associated, at least in part, with adiponectin deficiency and / or adiponectin resistance.

[0114] The present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising the steps of: (i) identifying a patient with postmenopausal hormone-receptor-positive (HR+) breast cancer, castration-resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, hepatocellular carcinoma, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof; (ii) determining whether the cancer patient has a metabolic dysfunction, and (iii) if the subject is identified as having one of the cancers in step (i) and the metabolic dysfunction in step (ii), 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. Preferably, the subject is administered a compound of the present disclosure. Preferably, the compound is administered subcutaneously. Metabolic dysfunction can include excessive visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. The methods of the present disclosure may further comprise treating a metabolic dysfunction, or ameliorating at least one symptom of a metabolic dysfunction, in addition to treating cancer.

[0115] In another aspect, the present disclosure provides a method of determining whether a tumor is metabolically sensitive and comprises: (1) measuring fasting insulin and glucose levels to determine the patient's HOMA score (insulin sensitivity level), (2) comparing the HOMA score to the score of a lean patient, and (3) determining that the cancer is susceptible to treatment with at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, or at least one compound of the present disclosure if the level of the HOMA score is greater than a metabolically normal level.

[0116] As used herein, a "subject in need thereof" is a subject having a cell proliferative disorder, or a subject at increased risk of developing a cell proliferative disorder relative to the general population. A subject in need thereof may have a precancerous condition. Preferably, the subject in need thereof has cancer. Preferably, the subject having a cell proliferative disorder also has a metabolic dysfunction.

[0117] "Subject" includes mammals. The mammal can be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, 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.

[0118] As used herein, the term "cell proliferative disorder" refers to a disorder in which the unregulated or abnormal growth (or both) of cells can lead to the development of an unwanted disorder or disease (which may or may not be cancerous). Exemplary cell proliferative disorders of the present disclosure encompass a variety of disorders in which cell division is dysregulated. Exemplary cell proliferative disorders include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematologic tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cell" is defined as any cell that divides at a rate that exceeds or is greater than the rate expected or observed in adjacent or juxtaposed cells in the same tissue. Cell proliferative disorders include precancerous or precancerous lesions. Cell proliferative disorders include cancer. Cell proliferative disorders include non-cancerous disorders or diseases. Preferably, the methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematologic tumors and / or malignant tumors. A "precancerous cell" or "precancer cell" is a cell exhibiting a cell proliferative disorder that is a precancerous or precancerous lesion. A "cancer cell" or "cancerous cell" is a cell exhibiting a cell proliferative disorder that is a cancer. Any reproducible measurement method can be used to identify cancerous or precancer cells. Cancerous or precancer cells can be identified by histological classification or grading of a tissue sample (e.g., a biopsy sample). Cancerous or precancer cells can be identified by using appropriate molecular markers.

[0119] Exemplary non-cancer conditions or diseases include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative disorders; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; Gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic lung inflammation; inflammatory bowel disease; Crohn's disease; skin-related proliferative disorders, psoriasis; eczema; atopic dermatitis; hyperpigmentation disorders , eye-related hyperproliferative disorders, age-related macular degeneration, ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic kidney disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neurotrauma; 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 syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; herniated, ruptured, or prolapsed disc syndrome; osteosclerosis; thrombosis; restenosis; silicosis; pulmonary sarcoma; bone resorption disorders, such as osteoporosis; graft-versus-host disease; fibrofatty hyperplasia; spinocerebullar ataxia type 1; CLOVES syndrome; Harlequin ichthyosis; macrodactyly syndrome; Proteus syndrome (Wiedemann syndrome); LEOPARD syndrome; systemic sclerosis; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases, such as herpes zoster, herpes simplex I or II, influenza virus, and cytomegalovirus; diabetes mellitus; hemihyperplasia-multiplelipomatosis syndrome); megalencephaly; rarely, hypoglycemia, Klippel-Trenaunay syndrome; hamartoma; Cowden syndrome; or overgrowth-hyperglycemia.

[0120] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancer, anorectal cancer, anal canal cancer, anal squamous cell carcinoma, angiosarcoma, appendix cancer, childhood cerebellar astrocytoma, childhood brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, allantoic cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, brain astrocytoma / malignant glioma , ependymoma, medulloblastoma, supratentorial primary perineurial tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal tract, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloproliferative disease, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid tumor, fungal disease, mycosis fungoides, Seziary syndrome Syndrome), endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, stomach (gastric) 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 lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, kidney cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, T-cell carcinoma lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, B-cell lymphoma, primary effusion lymphoma, Waldenstrammacroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myeloproliferative syndrome,Myeloproliferative / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oral cavity cancer, pharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, pancreatic endocrine tumor, sinus and nasal cavity cancer, parathyroid cancer, bile duct cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and superior temporal primitive neuroepithelial tumor, pituitary tumor, pituitary adenoma, plasma cell tumor / multiple myeloma, thoracic pulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, metastasis Sex cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcomas, Kaposi's sarcoma, soft tissue sarcoma, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, primitive neuroectodermal tumor of the upper neck, testicular cancer, laryngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, metastatic cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilm's Tumor.

[0121] A "hematologic cell proliferative disorder" is a cell proliferative disorder involving cells of the hematologic system. Cell proliferative disorders of the hematologic system may include lymphomas, leukemias, myeloid neoplasms, mast cell tumors, myelohyperplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, induced myeloproliferation, and essential thrombocythemia. Cell proliferative disorders of the hematologic system may include hyperplasia, dysplasia, and metaplasia of hematologic cells. Preferably, the compositions of the present disclosure may be used to treat a cancer selected from the hematologic cancers of the present disclosure or the hematologic cell proliferative disorders of the present disclosure. Hematological cancers of the present disclosure may include multiple myeloma, lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphocytic and cutaneous lymphomas), leukemias (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell tumors.

[0122] A cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, wherein the tumor (T) has been assigned a grade of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and wherein regional lymph nodes (N) have been assigned a grade of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and wherein distant metastases (M) can be assigned a grade of MX, M0, or M1. A cancer that is to be treated can be classified as grade I, grade IIA, grade IIB, grade IIIA, grade IIIB, grade IIIC, or grade IV according to the American Joint Committee on Cancer (AJCC) classification. A cancer that is to be treated can be assigned a grade of grade GX (e.g., grade cannot be assessed), grade 1, grade 2, grade 3, or grade 4 according to the AJCC classification. Cancer to be treated can be graded according to the AJCC pathological classification (pN) 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.

[0123] Cancers to be treated may include tumors that have been determined to be less than or equal to about 2 centimeters in diameter. Cancers to be treated may include tumors that have been determined to be from about 2 to about 5 centimeters in diameter. Cancers to be treated may include tumors that have been determined to be greater than or equal to about 3 centimeters in diameter. Cancers to be treated may be classified as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated by microscopic appearance. Cancers to be treated may be classified by microscopic appearance based on mitotic number (e.g., number of cell divisions) or nuclear pleomorphism (e.g., cell changes). Cancers to be treated may be classified by microscopic appearance based on area associated with necrosis (e.g., area of ​​dying or degenerating cells). Cancers to be treated may be classified as having an abnormal karyotype, possessing an abnormal number of chromosomes, or having one or more chromosomes that have an abnormal appearance. Cancers to be treated may be classified as aneuploid, triploid, tetraploid, or altered ploidy. Cancers that are to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region in which a portion of a chromosome is deleted, duplicated, or amplified.

[0124] A cancer that is to be treated can be assessed by DNA cytometry, flow cytometry, or imaging cytometry. A cancer that is to be treated can be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis phase of cell division (e.g., in the S phase of cell division). A cancer that is to be treated can be classified as having a low S-phase fraction or a high S-phase fraction.

[0125] As used herein, a "normal cell" is a cell that cannot be classified as part of a "cell proliferative disorder." A normal cell lacks unregulated or abnormal growth, or both, that can lead to unwanted disorder or disease development. Preferably, a normal cell has normally functioning cell cycle checkpoint control mechanisms.

[0126] As used herein, "contacting a cell" refers to a situation in which a subject compound or other composition of the present disclosure is in direct contact with a cell, or is close enough to induce a desired biological effect in the cell.

[0127] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also treat or alleviate a variety of related disorders.

[0128] In particular, in addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also treat or alleviate at least one metabolic dysfunction selected from the group consisting of visceral obesity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or a combination thereof. Preferably, the metabolic dysfunction to be treated or ameliorated is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof.

[0129] 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 at least one symptom of obesity.

[0130] 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 weight. In some aspects, the subject is overweight or obese. In some aspects, the subject needs to reduce excess adipose tissue.

[0131] Obesity and overweight refer to an excess of fat relative to lean body mass in a subject. Excess fat accumulation is associated with an increase in the size (hypertrophy or steatosis) and number (proliferation) of adipose tissue cells. Obesity can be due to any cause, whether genetic (such as Prader-Willi Syndrome) or environmental. Obesity is measured in different ways based on absolute weight, weight:height ratio, degree of excess body fat, distribution of visceral or subcutaneous fat, and social and aesthetic norms. A common measure of body fat is the body mass index (BMI). BMI refers to the ratio of weight (expressed in kilograms) to height (expressed in meters) squared. Body mass index can be accurately calculated using the following formula: SI units: BMI = weight (kg) / (height) 2 (m 2 ), or US units: BMI=(weight (lb)*703) / (height 2 (in 2 ).

[0132] As described herein, "overweight" means having a 25 kg / m 2 -29.9 kg / m 2 As used herein, "obese" or "obesity" refers to a person who has a BMI of 30 kg / m 2 or greater. Obesity has several subcategories. 2 Adults with a BMI of ≥40-44.9 kg / m 2 Adults with a BMI of 35 kg / m 2 Adults with a BMI of 45 kg / m2 or greater and at least one obesity-related health condition are termed "morbidly obese" or "morbidly obese." 2 Adults with a BMI of 5.5 or greater are considered "super obese" or "super overweight." For children, the definitions of overweight and obesity take into account the effects of age and sex on body fat.

[0133] Different countries may define obesity and overweight with different BMIs. The term "obesity" is intended to encompass all national definitions. For example, the increased risk associated with obesity appears in Asia with lower body mass indexes (BMIs). In Asian countries, including Japan, "obesity" refers to having at least one obesity-induced or obesity-related co-morbidity that requires or would be improved by weight loss, with a body mass index greater than or equal to 25.0 kg / m 2South and Central American ethnicity tended to be closer to Asians than to Europeans or North Americans.

[0134] BMI does not account for the fact that excess fat tissue can selectively occur in different parts of the body, and the development of fat tissue in some parts of the body may be more dangerous to health than in other parts of the body. For example, "central obesity," which is often associated with an "apple-shaped" body, is caused by excessive obesity, particularly in the abdominal area, including abdominal fat and visceral fat, and carries a higher risk of comorbidities than "peripheral obesity," which is often associated with a "pear-shaped" body caused by excess obesity, particularly in the buttocks. Measurement of the waist / hip ratio (WHR) can be used as an indicator of central obesity. The minimum WHR indicating central obesity has been set differently, with centrally obese adults typically having a WHR of about 0.85 or greater if they are female and about 0.9 or greater if they are male.

[0135] Methods for determining whether a subject is overweight or obese due to excess adipose tissue to lean body mass ratio may include obtaining the subject's body composition. Body composition can be obtained by measuring the thickness of subcutaneous fat in multiple parts of the body, such as the abdominal area, subscapular area, arms, buttocks, and thighs. These measurements are then used to estimate total body fat (with an error margin of approximately 4 percentage points). Another method is bioelectrical impedance analysis (BIA), which uses the resistance of an electric current through the body to estimate body fat. Another method is to measure body buoyancy with a large tank of water. Increased body fat will result in greater buoyancy, while greater muscle mass will result in a tendency to sink. Another method is fan beam dual energy X-ray absorptiometry (DEXA). DEXA allows non-invasive measurement of body composition, particularly total body fat and / or regional fat mass. MRI can also be used to non-invasively determine composition.

[0136] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce adipocytes or adipose tissue. Reducing adipocytes means reducing the number of adipocytes or reducing size (fat content). In some aspects, the compounds of the present disclosure reduce the adipocytes of the subject. The adipose tissue can be white adipose tissue or brown adipose tissue.

[0137] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compound of the present disclosure can also reduce food intake. Reducing food intake means reducing daily food intake. The reduction of daily food intake can be about 5% reduction-about 50% reduction (for example, about 5%, about 10%, about 20%, about 30%, about 40% or about 50%). Based on 2000 kcal daily food, reducing is about 100 kcal-about 1000 kcal reduction every day (for example, about 100 kcal, about 200 kcal, about 400 kcal, about 600 kcal, about 800 kcal or about 1000 kcal).

[0138] 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 hunger in a subject. The subject can also reduce food intake. Hunger can be assessed in the fasting state using a 10-point visual analog scale (VAS), which is well-suited for appetite studies. See Flint et al. Int. J. Obes. Relat. Metab. Disord . 24(1): 38-48, 2000. Specifically, subjects were asked to rate their overall hunger over the previous two days on a scale of 1-10, with 10 being very hungry and 1 being not at all hungry.

[0139] 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 waist circumference. Waist circumference is measured around the abdomen with a rubber tape measure 1 cm above the iliac crest. A subject of the present disclosure may have a waist circumference reduced by about 1 inch to about 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).

[0140] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce body fat and provide the patient with a substantial maintenance amount of muscle. In certain aspects, after administration, fat oxidation in the patient is increased compared to patients on a restricted food intake diet alone. Compared to the reduction in body fat in patients on an energy-restricted diet alone, such patients can maintain significantly more muscle mass.

[0141] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce insulin levels, leptin levels, or both in a subject. In some aspects, the subject is overweight or obese. In some aspects, the subject is in need of reducing excess adipose tissue.

[0142] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also improve surgical prognosis, which includes administering a therapeutically effective amount of at least one compound of the present disclosure to the subject before surgery to improve surgical outcome. In some aspects, administration reduces the patient's liver and / or abdominal fat and improves surgical outcome. In some aspects, the surgery is non-acute surgery. Such surgery may include obesity treatment surgery, cardiovascular surgery, abdominal surgery, or plastic surgery.

[0143] As used herein, "monotherapy" refers to the administration of a single active or therapeutic compound of the present disclosure to a subject in need thereof. For example, a cancer monotherapy is administered to a subject in need of treatment for cancer using a compound of the present disclosure, or one of its pharmaceutically acceptable salts, prodrugs, metabolites, analogs, or derivatives. Monotherapy can be contrasted with combination therapy, in which a combination of multiple active compounds is administered as described below. In one aspect, monotherapy using a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is more effective than combination therapy in reducing a desired biological effect.

[0144] As used herein, "combination therapy" or "co-therapy" includes the administration of at least two compounds of the present disclosure, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs or solvates thereof, as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of such at least two compounds of the present disclosure. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic synergy resulting from the combination of such at least two compounds of the present disclosure. The combined administration of such at least two compounds of the present disclosure is typically performed over a specified time period (usually minutes, hours, days or weeks, depending on the combination selected). "Combination therapy" can, but is generally not intended to, encompass the administration of two or more such compounds of the present disclosure as part of separate, monotherapy regimens that incidentally and arbitrarily result in a combination of the present disclosure.

[0145] "Combination therapy" also encompasses administration of a compound of the present disclosure in combination with a second active agent and / or non-drug therapy (e.g., surgery or radiation therapy). Combination therapy also includes non-drug therapy, which can be performed at any appropriate time, as long as a beneficial effect is achieved from the synergistic effect of the combination of the therapeutic agent and the non-drug therapy. For example, in appropriate circumstances, when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, a beneficial effect may still be achieved over several days or even weeks. The second active agent can be conjugated to a polymer.

[0146] "Combination therapy" is intended to encompass the administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at different times, as well as the administration of these therapeutic agents, or at least two therapeutic agents, in a substantially simultaneous manner. As used herein, substantially simultaneous means administering at least two therapeutic agents within 1 hour of each other. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single composition having a fixed ratio of each therapeutic agent or in separate capsules for each therapeutic agent. As used herein, sequential means administering one of the at least two therapeutic agents more than 1 hour after the administration of the other at least two therapeutic agents. Preferably, for sequential administration, one of the at least two therapeutic agents is administered at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, or at least 1 week after the administration of the other therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any appropriate route, including, but not limited to, oral, intravenous, subcutaneous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered by subcutaneous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by subcutaneous injection. The order in which the therapeutic agents are administered is not critical.

[0147] In a preferred aspect, the second active agent is a chemotherapeutic agent. The additional chemotherapeutic agent (also referred to as an anti-tumor agent or anti-proliferative agent) can be an alkylating agent listed at www.cancer.org / docroot / cdg / cdg_0.asp; an antibiotic; an anti-metabolite; an antidote; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a FGFR inhibitor, a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic 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-targeted drug, a topoisomerase poison, an inhibitor of a molecular target or enzyme (e.g., a kinase inhibitor), a cytidine analog drug, or any chemotherapeutic agent, anti-tumor or anti-proliferative agent.

[0148] 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); nitrogen mustard (Mustargen); busulfan (Myleran); carboplatin (Paraplatin); cisplatin (CDDP; Platinol); temozolomide (Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin (Zanosar).

[0149] Exemplary antibiotics include, but are not limited to, doxorubicin (Adriamycin); liposomal doxorubicin (Doxil); mitoxantrone (Novantrone); bleomycin (Blenoxane); daunorubicin (Cerubidine); liposomal daunorubicin (DaunoXome); actinomycin D (Cosmegen); epirubicin (Ellence); idarubicin (Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin (Nipent); or valrubicin (Valstar).

[0150] Exemplary antimetabolites include, but are not limited to, fluorouracil (Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine (Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine (Arranon); cladribine (Cladribine Novaplus); clofacitabine (Clolar); cytarabine (Cytosar-U); decitabine (Dacogen); liposomal cytarabine (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).

[0151] Exemplary antidotes include, but are not limited to, amifostine (Ethyol) or mesna (Mesnex).

[0152] Exemplary interferons include, but are not limited to, interferon alpha-2b (Intron A) or interferon alpha-2a (Roferon-A).

[0153] Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab (Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab (Vectibix); tositumomab / iodine 131 Tositumomab (Bexxar); alemtuzumab (Campath); ibritumomab tiuxetan (Zevalin; In-111; Y-90 Zevalin); gemtuzumab (Mylotarg); eculizumab (Soliris) or denosumab; nivolumab (Opdivo); pembrolizumab (Keytruda); ipilimumab (Yervoy); pidilizumab; and atezolizumab.

[0154] Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tasai); panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matuzumab (Emd7200) or EKB-569.

[0155] Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Trastuzumab); lapatinib (Tykerb); or AC-480.

[0156] Histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza).

[0157] Exemplary hormones include, but are not limited to, tamoxifen (Soltamox; tamoxifen citrate); raloxifene (Evista); megestrol acetate (Megace); leuprolide (Lupron; Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole (Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane (Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole (Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone acetate (Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin); toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron); abarelix (Plenaxis); or testolactone (Teslac).

[0158] Exemplary mitotic inhibitors include, but are not limited to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin; Vincasar PFS); 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).

[0159] Exemplary MTOR inhibitors include, but are not limited to, everolimus (Afinitor) or temsirolimus (Torisel); sirolimus (rapamune), ridaforolimus; or AP23573.

[0160] Exemplary multi-kinase inhibitors include, but are not limited to, sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474; PKC-412; motesanib; or AP24534.

[0161] Exemplary serine / threonine kinase inhibitors include, but are not limited to, ruboxistaurin; eril / easudil hydrochloride; flavopiridol; cylicidin (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 PD 332991.

[0162] Exemplary tyrosine kinase inhibitors include, but are not limited to, erlotinib (Ertezomib); 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 (dasatinib oral); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518;

[0163] Exemplary VEGF / VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent); ranibizumab; pegaptanib; or vandetanib.

[0164] Exemplary microtubule-targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastine, nocodazole, epothilones, and navelbine.

[0165] Exemplary topoisomerase poisons include, but are not limited to, teniposide, etoposide, doxorubicin, camptothecin, daunorubicin, actinomycin D, mitoxantrone, amsacrine, epirubicin, and idarubicin.

[0166] Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxel.

[0167] Exemplary commonly used chemotherapeutic agents, anti-tumor agents, and anti-proliferative agents include, but are not limited to, hexamethylmelamine (Hexalen); isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin (Vesanoid); azacitidine (Vidaza); bortezomib (Velcade); asparaginase (Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine (Matulane); pegaspargase (Oncaspar); denileukin-toxin conjugate (Ontak); porfin (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid); bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel); arsenic trioxide (Trisenox); verteporfin (verteporfin) (Visudyne); mimosine (Leucenol); (1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 M potassium oxazolidinone) or lovastatin.

[0168] In another aspect, the additional chemotherapeutic agent can be a cytokine such as G-CSF (granulocyte colony stimulating factor). In another aspect, the compounds of the present disclosure, or pharmaceutically acceptable salts, prodrugs, metabolites, analogs or derivatives thereof, can be administered in conjunction with radiation therapy. Radiation therapy can also be administered as part of a multi-drug therapy in combination with a compound of the present disclosure and another chemotherapeutic agent described herein. In yet another aspect, a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, may be administered in combination with a standard chemotherapy combination, such as, but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), rituximab, Xeloda (capecitabine), cisplatin (CDDP), carboplatin, TS-1 (tegafur, gimestat and otastat potassium in a 1:0.4:1 molar ratio), camptothecin-11 (CPT-11, irinotecan or Camptosar™), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

[0169] In certain aspects, the compounds of the present disclosure, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs or solvates thereof, can be administered with inhibitors of enzymes (e.g., receptor or non-receptor kinases). Receptor and non-receptor kinases of the present disclosure are, for example, tyrosine kinases or serine / threonine kinases. Kinase inhibitors of the present disclosure are small molecules, polynucleic acids, polypeptides, or antibodies.

[0170] Exemplary kinase inhibitors include, but are not limited to, BIBW 2992 (targeting EGFR and Erb2), cetuximab / erbitux (targeting Erb1), imatinib / Gleevic (targeting Bcr-Abl), trastuzumab (targeting Erb2), gefitinib / Iressa (targeting EGFR), ranibizumab (targeting VEGF), pegaptanib (targeting VEGF), erlotinib / tasai (targeting Erb1), nilotinib (targeting Bcr-Abl), lapatinib (targeting Erb1 and Erb2 / Her2), GW-572016 / lapatinib ditosylate (targeting HER2 / Erb2), panitumumab / Vectibix (targeting EGFR), vandetanib (targeting RET / VEGFR), E7080 (multi-targeting including RET and VEGFR), trastuzumab (targeting HER2 / Erb2), PKI-166 (targeting EGFR), canertinib / CI-1033 (targeting EGFR), sunitinib / SU-11464 / sunitinib (Sutent) (targeting EGFR and FLT3), matuzumab / Emd7200 (targeting EGFR), EKB-569 (targeting EGFR), Zd6474 (targeting EGFR and VEGFR), PKC-412 (targeting VEGR and FLT3), vatalanib / Ptk787 / ZK222584 (targeting VEGR), CEP-701 (targeting FLT3), SU5614 (targeting FLT3), MLN518 (targeting FLT3), XL999 (targeting FLT3), VX-322 (targeting FLT3), Azd0530 (targeting SRC), BMS-354825 (targeting SRC), SKI-606 (targeting SRC), CP-690 (targeting JAK), AG-490 (targeting JAK), WHI-P154 (targeting JAK), WHI-P131 (targeting JAK), sorafenib / nexavar (targeting RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3, and RET), dasatinib / dasatinib oral (BCR / ABL and Src), AC-220 (targeting Flt3), AC-480 (targeting all HER proteins, "panHER"), motesanib diphosphate (targeting VEGF1-3, PDGFR, and c-kit), denosumab (targeting RANKL, inhibiting SRC), AMG888 (targeting HER3), and AP24534 (multiple targets including Flt3).

[0171] Exemplary serine / threonine kinase inhibitors include, but are not limited to, sirolimus (targeting mTOR / FRAP1), rapamycin (Deforolimus) (targeting mTOR), Certican / Everolimus (targeting mTOR / FRAP1), AP23573 (targeting mTOR / FRAP1), Eril / Fasudil hydrochloride (targeting RHO), flavonoid antineoplastic drugs (targeting CDK), Celicib / CYC202 / Roscovitrine (targeting CDK), SNS-032 / BMS-387032 (targeting CDK), Lubotolin (targeting PKC), Pkc412 (targeting PKC), Dioscorea (targeting PKC), KAI-9803 (targeting PKC), SF1126 (targeting PI3K), VX-680 (targeting Aurora kinase), Azd1152 (targeting Aurora kinase), Arry-142886 / AZD-6244 (targeting MAP / MEK), SCIO-469 (targeting MAP / MEK), GW681323 (targeting MAP / MEK), CC-401 (targeting JNK), CEP-1347 (targeting JNK), and PD 332991 (targeting CDK).

[0172] Contemplated second active agents also include those administered to treat type 2 diabetes, such as sulfonylureas (e.g., sulfonylurea, glipizide, glyburide, glimepiride); meglitinides (e.g., repaglinide and nateglinide); biguanides (e.g., metformin); thiazolidinediones (rosiglitazone, troglitazone, and pioglitazone); glucan-like peptidomimetics (such as exenatide and liraglutide); sodium-glucose cotransporter inhibitors. (e.g., dapagliflozin), dipeptidyl peptidase 4 inhibitors (such as gliptins), sodium-glucose linked transporter inhibitors, renin inhibitors, and alpha-glucosidase inhibitors (e.g., acarbose and meglitol), and / or those administered to treat cardiac disorders and conditions, such as hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, myocardial infarction, stroke, venous thromboembolic disease, and pulmonary hypertension (which are associated with excess weight or obesity), e.g., chlorthalidone; hydrochlorothiazide; indapamide, metolazone; loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, lasix, torsemide); potassium-sparing agents (e.g., amiloride hydrochloride, spironolactone, and triamterene); peripheral agents (e.g., reserpine); central alpha-agonists (e.g., clonidine hydrochloride, guanabenzyl acetate, guanfacine hydrochloride, and methyldopa); alpha-blockers (e.g., doxazosin mesylate, prazosin hydrochloride, and terazosin hydrochloride); beta-blockers (e.g., acebutolol, atenolol, betaxolol, nisoprololfumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, penbutolol sulfate); sulfate), pindolol, propranolol hydrochloride, and timolol maleate); combined alpha- and beta-blockers (e.g., carvedilol and labetalol hydrochloride); direct vasodilators (e.g., hydralazine hydrochloride and minoxidil); calcium antagonists (e.g., diltiazem hydrochloride and verapamil hydrochloride); dihydropyridines (e.g., amlodipine besylate, felodipine, isradipine, nicardipine, nilvadipine, and nisoldipine);ACE inhibitors (benazepril hydrochloride, captopril, isalapril maleate, fosinopril sodium, lisinopril, moexipril, quinapril hydrochloride, ramipril, trandolapril); angiotensin II receptor blockers (e.g., losartan potassium, valsartan, and irbesartan); and combinations thereof, as well as statins such as mevastatin, lovastatin, pravastatin, simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, and glenvastatin, which are commonly used to treat dyslipidemia.

[0173] Other second active agents that can be co-administered (e.g., sequentially or simultaneously) include drugs administered to treat ischemic heart disease, including statins, nitrates (e.g., isosorbide dinitrate and isosorbide mononitrate), beta-blockers, and calcium channel antagonists, drugs administered to treat cardiomyopathy, including inotropic agents (e.g., digoxin), diuretics (e.g., furosemide), ACE inhibitors, calcium antagonists, anti-arrhythmics (e.g., sotalol, amiodarone, and disopyramide), and beta-blockers, drugs administered to treat myocardial infarction, including ACE inhibitors, angiotensin II receptor blockers, direct vasodilators, beta-blockers, anti-arrhythmics, and thrombolytics (e.g., alteplase, reteplase, tenecteplase, anistreplase, and urokinase), drugs administered to treat stroke, including antiplatelet agents ( For example, aspirin, clopidogrel, dipyridamole, and ticlopidine), anticoagulants (e.g., heparin), and thrombolytics, drugs administered to treat venous thromboembolic diseases include antiplatelet agents, anticoagulants and thrombolytics, drugs administered to treat pulmonary hypertension include inotropic agents, anticoagulants, diuretics, potassium (e.g., K-dur), vasodilators (e.g., nifedipine and diltiazem), bosentan, epoprostenol, and sildenafil, drugs administered to treat asthma include bronchodilators, anti-inflammatory drugs, leukotriene blockers, and anti-IgE drugs. Specific asthma medications include zafirlukast, flunisolide, triamcinolone, beclomethasone, terbutaline, fluticasone, formoterol, beclomethasone, salmeterol, theophylline, and levalbuterol (Xopenex), medications administered to treat sleep apnea include modafinil and amphetamines, medications administered to treat nonalcoholic fatty liver disease include antioxidants (e.g., vitamins E and C), insulin sensitizers (metformin, pioglitazone, rosiglitazone, and betaine), hepatoprotectants, and lipid-lowering agents, medications administered to treat osteoarthritis of weight-bearing joints include acetaminophen, Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, etodolac, oxapram, naproxen, diclofenac, and nabumetone), COX-2 inhibitors (e.g., celecoxib), steroids, supplements (such as glucosamine and chondroitin sulfate), and artificial joint fluids, Medications administered to treat Prader-Willi syndrome including human growth hormone (HGH), somatropin, and weight loss agents (e.g., orlistat, sibutramine, methamphetamine, lonamine, phentermine, bupropion, phendimetrazine, benzphetermine, and topiramate),Drugs used to treat polycystic ovary syndrome include insulin-sensitizers, combinations of synthetic estrogen and progesterone, spironolactone, eflornithine, and clomiphene; drugs used 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 used to treat infertility include clomiphene, sildenafil citrate, and vardenafil. Clomiphene, bromocriptine, gonadotropin-releasing hormone (GnRH), GnRH agonists, GnRH antagonists, tamoxifen / tamoxifen citrate (nolvadex), gonadotropins, human chorionic gonadotropin (HCG), human menopausal gonadotropin (HmG), progesterone, recombinant follicle-stimulating hormone (FSH), urofollicle-stimulating hormone, heparin, follitropin alfa and follitropin beta, drugs used to treat obstetric complications include bupivacaine hydrochloride, dinoprostone PGE2, meperidine HCl (meperidine HCl), iron-folic acid-500 / iberet-folic-500, meperidine, methylergonovine maleate, ropivacaine HCl (Ropivacaine HCl), nalbuphine HCl, oxymorphone HCl, oxytocin, dinoprostone, ritodrine, scopolamine hydrobromide, sufentanil citrate, and oxytocics, 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, dosulpyrine hydrochloride, doxepin, imipramine, iprindole, rofepramin); e), nortriptyline, opipramol, protriptyline, and trimipramine); monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, niacinamide, iproniazid, iproclozide, toloxatone, linezolid, dienolide kavapyronedesmethoxyyangonin, and dextroamphetamine); psychostimulants (e.g.,amphetamines, methamphetamine, methylphenidate, and arecoline); antipsychotics (e.g., butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, olanzapine-fluoxetine combination (Symbyax), tetrabenazine, and cannabidiol); and mood stabilizers (e.g., lithium carbonate, propranolol, Valproic acid, divalproex sodium, divalproex, lamotrigine, carbamazepine, gabapentin, oxcarbazepine, and topiramate), drugs administered to treat anxiety disorders include serotonin reuptake inhibitors, mood stabilizers, benzodiazepines (e.g., alprazolam, clonazepam, diazepam, and lorazepam), tricyclic antidepressants, monoamine oxidase inhibitors, and beta-blockers, and other weight loss agents, including serotonin and noradrenergic reuptake inhibitors; noradrenergic reuptake inhibitors; selective serotonin reuptake inhibitors; and intestinal lipase inhibitors. Specific weight loss agents include orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, phendimetrazine, benzphetermine, and topiramate. ,

[0174] As used herein, "treatment" describes the management and care of a patient for the purpose of combating a disease, disorder or condition and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, to alleviate the symptoms or complications of the disease, disorder or condition, or to eliminate the disease, disorder or condition.

[0175] The compounds of the present disclosure, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs or solvates thereof, can also be used to prevent diseases, disorders or conditions. As used herein, "preventing" or "preventing" describes reducing or eliminating the occurrence of symptoms or complications of a disease, disorder or condition.

[0176] As used herein, the terms "improve" or "reduce" are intended to describe a process of reducing the severity of a sign or symptom of a disorder, which can be reduced rather than eliminated. In a preferred aspect, administration of the pharmaceutical composition of the present disclosure results in the elimination of a sign or symptom, however, elimination is not necessary. An effective dose is expected to reduce the severity of a sign or symptom. For example, a sign or symptom of a disorder, such as cancer (which can occur in multiple locations), is reduced if the severity of the cancer is reduced in at least one of the multiple locations.

[0177] As used herein, the term "severity" is intended to describe the likelihood that a cancer will transition from a precancerous, or benign, state to a malignant state. Alternatively, or in addition, severity is intended to describe the stage of 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 methods recognized in the art. Cancer stage refers to the extent or severity of the cancer based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (where the cancer has spread). Alternatively, or in addition, severity is intended to describe tumor grade using methods recognized in the art (see, National Cancer Institute). Tumor grade is a system used to rank cancer cells based on how abnormal they appear under a microscope and how quickly they are likely to grow and spread. Many factors must be considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes histological grade (also called differentiation), which refers to how closely the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute). Additionally, severity describes nuclear grade, which refers to the size and shape of the nuclei in the tumor cells and the percentage of tumor cells that are positively differentiated (see, National Cancer Institute).

[0178] In another aspect of the present disclosure, severity describes the extent to which a tumor secretes growth factors, breaks down the extracellular matrix, becomes vascularized, loses adhesion to adjacent tissues, or metastasizes. Additionally, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of various types and locations. For example, inoperable tumors, those with a greater chance of infecting multiple body systems (hematologic and immunological tumors), and those most resistant to traditional therapies are considered the most severe tumors. In these cases, extending the subject's life expectancy and / or alleviating suffering, reducing the proportion of cancer cells or confining cells to one system, and improving cancer stage / tumor stage / histologic stage / nuclear stage are considered alleviating signs or symptoms of cancer.

[0179] As used herein, the term "symptom" is defined as an indication of a disease, condition, injury, or something wrong in the body. Symptoms are felt or noticed by the subject experiencing the symptom but may not be readily apparent to others. Others are defined as non-health-care professionals.

[0180] The term "sign" as used herein is also defined as an indication that something is wrong in the body. But a sign is defined as something that can be observed by a doctor, nurse, or other health care professional.

[0181] Cancer is a group of diseases that can cause almost any sign or symptom. Signs and symptoms will depend on where the cancer is, how big it is, and how much it affects nearby organs or structures. If the cancer has spread (metastasized), symptoms may appear in different parts of the body.

[0182] As cancer grows, it begins to press on nearby organs, blood vessels, and nerves. This pressure causes some of the signs and symptoms of cancer. If the cancer is in a vital area, such as parts of the brain, even the smallest tumor can cause early symptoms.

[0183] But sometimes cancer starts in a location that doesn't cause any symptoms until it's grown quite large. Pancreatic cancer, for example, usually doesn't grow large enough to be felt from outside the body. Some pancreatic cancers don't cause symptoms until they start growing around nearby nerves (which can cause back pain). Others grow around the bile ducts, blocking the flow of bile and causing a yellowing of the skin called jaundice. By the time pancreatic cancer causes these signs or symptoms, it's usually in an advanced stage.

[0184] Cancer can also cause symptoms such as fever, fatigue, or weight loss. This may be because cancer cells consume a large amount of the body's energy supply or release substances that change the body's metabolism. Or cancer may cause the immune system to react in a way that produces these symptoms.

[0185] Sometimes, cancer cells release substances into the bloodstream that cause symptoms not usually thought to be caused by the cancer. For example, some pancreatic cancers can release substances that cause blood clots in leg veins. Some lung cancers produce hormone-like substances that affect blood calcium levels, affecting nerves and muscles and causing weakness and dizziness.

[0186] Cancer manifests as several general signs or symptoms that occur when multiple subtypes of cancer cells are present. Most cancer patients will lose weight over time as a result of their disease. An unexplained (unintentional) weight loss of 10 pounds or more may be the first sign of cancer, particularly cancer of the pancreas, stomach, esophagus, or lung.

[0187] Fever is common in cancer, but it's more common in advanced disease. Almost all people with cancer will have a fever at some time, especially if the cancer or its treatment affects the immune system and makes it harder for the body to fight infection. Less often, a fever can be an early sign of cancer, such as leukemia or lymphoma.

[0188] Fatigue can be a significant symptom as cancer progresses. It can occur in the early stages of cancers such as leukemia, or in colon or stomach cancer if the cancer causes ongoing blood loss.

[0189] Pain can be an early symptom of some cancers, such as bone or testicular cancer. But most often, pain is a symptom of advanced disease.

[0190] In addition to skin cancer, some internal cancers can cause visible signs on the skin. These changes include skin that appears darker (hyperpigmentation), yellow (jaundice), or red (erythema); itching; or excessive hair growth.

[0191] Alternatively, or in addition, specific signs or symptoms may be present with a subtype of cancer. Changes in bowel habits or bladder function may indicate cancer. Long-term constipation, diarrhea, or changes in stool size may be signs of colon cancer. Painful urination, blood in the urine, or changes in bladder function (e.g., urinating more or less frequently) may be associated with bladder or prostate cancer.

[0192] Changes in the appearance of skin conditions or new skin conditions can indicate cancer. Skin cancers may bleed and look like sores that won't heal. Long-lasting sores inside the mouth can be a sign of oral cancer, especially in patients who smoke, chew tobacco, or drink alcohol regularly. Sores on the penis or vagina can be a sign of infection or early-stage cancer.

[0193] Unusual bleeding or discharge may indicate cancer. Unusual bleeding may occur with early-stage or late-stage cancer. Blood in your sputum (phlegm) may be a sign of lung cancer. Blood in your stool (or dark black or melena) may be a sign of colon or rectal cancer. Cancer of the cervix or endometrium (lining of the uterus) can cause vaginal bleeding. Blood in your urine may be a sign of bladder or kidney cancer. Nipple bleeding may be a sign of breast cancer.

[0194] Thickening or lumps in the breast or other parts of the body may indicate the presence of cancer. Many cancers can be felt through the skin, most often in the breast, testicles, lymph nodes (glands), and soft tissues of the body. A lump or thickening may be an early or late sign of cancer. Any lump or thickening may be a sign of cancer, especially if the formation is new or growing in size.

[0195] Indigestion or difficulty swallowing may indicate cancer. Although these symptoms often have other causes, indigestion or swallowing problems may be a sign of cancer of the esophagus, stomach, or pharynx (throat).

[0196] Recent changes in warts or moles could be a sign of cancer. Any wart, mole, or freckle that changes color, size, or shape, or loses its defined borders, indicates the potential development of cancer. For example, a skin lesion could be melanoma.

[0197] A persistent cough or hoarseness could be a sign of cancer. A persistent cough could be a sign of lung cancer. Hoarseness could be a sign of cancer of the larynx (vocal cords) or thyroid gland.

[0198] Although the signs and symptoms listed above are the more common signs and symptoms associated with cancer, there are many other signs and symptoms that are less common and not listed here. However, all art-recognized signs and symptoms of cancer are contemplated and encompassed in this disclosure.

[0199] Treatment of cancer can result in a decrease in tumor size. A decrease in tumor size can also be referred to as "tumor regression." Preferably, after treatment, the size of a tumor is reduced by 5% or more relative to its size before treatment; more preferably, the size of the tumor 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 greater than 75% or more. The size of a tumor can be measured by any reproducible measurement method. The size of a tumor can be measured as the diameter of the tumor.

[0200] Treatment of cancer can result in a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its pre-treatment size; 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 greater than 75% or more. Tumor volume can be measured by any reproducible measurement method.

[0201] Treatment of cancer results in a decrease in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative 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 greater than 75%. The number of tumors can be measured by any reproducible measurement method. The number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0202] Treatment of cancer can result in a reduction in the number of metastatic lesions in other tissues or organs away from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment; more preferably, the number of metastatic lesions 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 greater than 75%. The number of metastatic lesions can be measured by any reproducible measurement method. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0203] Treating cancer can result in an increase in the average survival time of a population of treated subjects compared to a population receiving vehicle alone. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the average survival time of a population can be measured by any reproducible method. The increase in the average survival time of a population can be measured after the start of treatment with the active compound, for example, by calculating the average survival time of the population. The increase in the average survival time of a population can also be measured after the completion of the first round of treatment with the active compound, for example, by calculating the average survival time of the population.

[0204] Treating cancer can result in an increase in the average survival time of a group of treated subjects compared to a group of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the average survival time of a group can be measured by any reproducible method. The increase in the average survival time of a group can be measured after the start of treatment with the active compound, for example, by calculating the average survival time of the group. The increase in the average survival time of a group can also be measured after the completion of the first round of treatment with the active compound, for example, by calculating the average survival time of the group.

[0205] Treatment of cancer can result in an increase in the mean survival time of a group of treated subjects compared to a group receiving a monotherapy with a drug that is not a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof. Preferably, the mean survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the mean survival time of a group can be measured by any reproducible method. The increase in the mean survival time of a group can be measured after the start of treatment with the active compound, for example, by calculating the mean survival time of the group. The increase in the mean survival time of a group can also be measured after the completion of the first round of treatment with the active compound, for example, by calculating the mean survival time of the group.

[0206] Treating cancer can result in a reduced mortality rate in the treated population compared to a population receiving vehicle alone. Treating cancer can result in a reduced mortality rate in the treated population compared to an untreated population. Treating cancer can result in a reduced mortality rate in the treated population compared to a population receiving a monotherapy with a drug that is not a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mortality rate is reduced by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%. Reduction in mortality rate in the treated population can be measured by any reproducible method. Reduction in mortality rate in a population can be measured, for example, by calculating the average number of disease-related deaths per unit time in the population after initiation of treatment with the active compound. Reduction in mortality rate in a population can also be measured after completion of the first round of treatment with the active compound, for example, by calculating the average number of disease-related deaths per unit time in the population.

[0207] Treating cancer can result in a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% relative to the pre-treatment value; 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 measurement method. Tumor growth rate can be measured as the change in tumor diameter per unit time.

[0208] Treating cancer can result in a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%. Tumor regrowth can be measured by any reproducible measurement method. Tumor regrowth can be measured, for example, by measuring the increase in tumor diameter after treatment, following previous tumor shrinkage. A reduction in tumor regrowth is indicated by the absence of a tumor recurrence after treatment has ceased.

[0209] Treatment or prevention of a cell proliferative 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 measurement method. The rate of cell proliferation can be measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0210] Treatment or prevention of a cell proliferative disorder can result in a decrease in the ratio of proliferating cells. Preferably, after treatment, the ratio of proliferating cells is reduced by at least 5%; 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 at least 75%. The ratio of proliferating cells can be measured by any reproducible measurement method. Preferably, the ratio of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The ratio of proliferating cells can be equivalent to the mitotic index.

[0211] Treatment or prevention of a cell proliferative disorder can result in a reduction in the size of an area or zone of cell proliferation. Preferably, after treatment, the size of the area or zone of cell proliferation is reduced by at least 5% relative to its size before 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 at least 75%. The size of an area or zone of cell proliferation can be measured by any reproducible measurement method. The size of an area or zone of cell proliferation can be measured as the diameter or width of the area or zone of cell proliferation.

[0212] Treatment or prevention of a cell proliferative disorder can result in a reduction in the number or proportion of cells with an abnormal appearance or morphology. Preferably, after treatment, the number of cells with abnormal morphology is reduced by at least 5% relative to their size before 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 at least 75%. Abnormal cell appearance or morphology can be measured by any reproducible measurement method. Abnormal cell morphology can be measured microscopically, for example, using an inverted tissue culture microscope. Abnormal cell morphology can take the form of nuclear polymorphism.

[0213] Treatment of cancer or a cell proliferative disorder may result in cell death, and preferably, cell death results in a reduction of at least 10% in the number of cells in a population. More preferably, cell death refers to a reduction of at least 20%; more preferably, a reduction of at least 30%; more preferably, a reduction of at least 40%; more preferably, a reduction of at least 50%; and most preferably, a reduction of at least 75%. The number of cells in a population can be measured by any reproducible method. The number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy, and light microscopy. Methods for measuring cell death are described in Li et al. et al ., Proc Natl Acad Sci US A. 100(5): 2674-8, 2003. In one aspect, cell death occurs by apoptosis.

[0214] Preferably, an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, has no significant cytotoxicity to normal cells. A therapeutically effective amount of a compound has no significant cytotoxicity to normal cells if administration of a therapeutically effective amount of the compound does not induce cell death in greater than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the survival of normal cells if administration of a therapeutically effective amount of the compound does not induce cell death in greater than 10% of normal cells. In one aspect, cell death occurs by apoptosis.

[0215] Contacting cells with a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce or activate cell death in cancer cells. Administering a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to a subject in need thereof, can selectively induce or activate cell death in cancer cells. Contacting cells with a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce cell death in one or more cells affected by a cell proliferative disorder. Preferably, administering a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to a subject in need thereof, can selectively induce cell death in one or more cells affected by a cell proliferative disorder.

[0216] The present disclosure relates to a method for treating or preventing cancer by administering a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, to a subject in need thereof, wherein administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, results in one or more of the following events: accumulation of cells in the G1 and / or S phase of the cell cycle, cytotoxicity via cell death in cancer cells without substantial cell death in normal cells, anti-tumor activity in animals with a therapeutic index of at least 2, and initiation of a cell cycle checkpoint. As used herein, the "therapeutic index" is the maximum tolerated dose divided by the effective dose.

[0217] A "therapeutically effective amount," with respect to a compound used in treatment, means that amount of the compound in a formulation that, when administered as part of a desired dosage regimen to a mammal, preferably a human, alleviates symptoms, ameliorates symptoms, or delays or prevents the onset of the disease state for the disorder or condition being treated, based on clinically acceptable criteria, e.g., a reasonable benefit / risk ratio applicable to any medical treatment or for cosmetic purposes. "Therapeutically effective amount" is synonymous with "effective dose."

[0218] As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For preventive uses, beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, or delaying the onset of a disease, including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes that arise during the course of the disease. For therapeutic uses, beneficial or desired results include clinical results such as reducing the intensity, duration, or frequency of disease attacks, and reducing one or more symptoms (biochemical, histological and / or behavioral) caused by the disease, including its complications and intermediate pathological phenotypes that arise during the course of the disease, improving the quality of life of those patients suffering from the disease, reducing the dosage of other drugs required to treat the disease, enhancing the effect of another drug, and / or delaying the progression of the disease in the patient. The effective dose can be administered via one or more modes of administration. For the purposes of this disclosure, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly carry out a preventive or therapeutic treatment. As understood from a clinical perspective, an effective dose of a drug, compound, or pharmaceutical composition may or may not be combined with another drug, compound, or pharmaceutical composition. Therefore, an "effective dose" can be considered in the context of administering one or more therapeutic agents, and a single drug can be considered to be given in an effective amount, and if combined with one or more other drugs, a desirable result may be achieved. For example, an effective amount of a compound of the present disclosure for treating a proliferative disorder is an amount sufficient to treat or improve one or more symptoms associated with a proliferative disorder. An "effective amount" is an amount sufficient to cause one or more of the following events (which may also correspond to various aspects of the present disclosure): reduce tumor size, reduce tumor volume, reduce tumor number, reduce metastatic lesions, increase survival time, reduce mortality, reduce tumor growth rate, reduce tumor regrowth, reduce the ratio of proliferating cells, or increase the quality of life of those patients suffering from a proliferative disorder.

[0219] For any compound, the therapeutically effective amount can be estimated initially in cell culture assays, for example, of tumor cells, or in animal models, typically 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 determined in cell cultures or experimental animals by standard pharmaceutical procedures, for example, ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD 50 / ED 50Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0220] Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. In providing one or more compounds described herein to a subject, the dose of the compound administered will vary depending on factors such as the subject's age, weight, height, sex, general medical condition, previous medical history, disease progression, route of administration, formulation, and the like.

[0221] The dosage of the compounds of the present disclosure can be determined empirically in subjects who have received one or more administrations. Incremental doses of the compounds of the present disclosure are administered to the subject. Indicators of the disease state can be used to evaluate the effects of the compounds of the present disclosure. It will be apparent to those skilled in the art that the dosage will vary depending on the subject, the grade of the disease (e.g., tumor size, tumor grade, number of tumors), and the past and current treatments employed.

[0222] The toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined in experimental animals by standard pharmaceutical procedures. The toxic dose can be measured as the maximum tolerated dose (MTD) or LD50 (the dose that causes lethality in 50% of the population). The effective dose can be measured as the ED50 (the dose that is therapeutically effective in 50% of the population) or the dose required to provide some mean change in animals (e.g., the dose required to provide an average reduction of 10 mm Hg systolic blood pressure in the subject group).

[0223] Ideally, the effective and toxic doses would be determined in the same species. However, if they are determined in different species, allometric scaling can be used to convert the effective or toxic dose to the other species. The dose ratio between the toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50. In a comparison of mice and rats, a generally accepted scaling factor is 2; the rat dose is estimated to be half the mouse dose. 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, which 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 less than a 2-fold difference between the median lethal dose and the median effective dose, or (b) there is less than a 2-fold difference between the minimum toxic concentration and the minimum effective concentration in blood.

[0224] Compounds of the Disclosure that exhibit large therapeutic indices are preferred. Although compounds of the Disclosure that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds of the Disclosure to the site of affected tissue to minimize potential damage to uninfected cells, thereby reducing side effects.

[0225] The data obtained from animal studies can be used to formulate dosage ranges for use in humans. The dosage of such compounds of the present disclosure is preferably within a circulating concentration range that encompasses an effective dose range with minimal or no toxicity. The dosage can vary within this range, depending on the dosage form used and the route of administration used. For compounds of the present disclosure with a MW of less than 1000, a therapeutically effective dose can be initially estimated from cell culture assays, while animal models will provide better estimates of the dosage for conjugates, where the linker needs to be cleaved 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 conjugation dilutes the activity of the active moiety (the polymer is the diluent). This is illustrated in the mouse dosing model of anti-cancer drugs shown in the table below.

[0226] Parent drug Drug dosage (mg / kg) Conjugate Conjugate dose (mg / kg) TNP-470 30 (qod) XMT-1107 800 Docetaxel 12 (Q4d) Opaxio 480 CPT-11 20 (q2d) EZN-2208 145 (q2d) Doxorubicin 5 (q4d) PK1 62 (q7d) Carboplatin 60 (Qd) AP-5356 2200

[0227] The polymer conjugates and modified compounds of the present disclosure surprisingly provide superior efficacy and lower toxicity when compared to the unconjugated and / or unmodified parent drug / active moiety.

[0228] For example, the fumagillol conjugates and modified fumagillol compounds of the present disclosure are surprisingly superior to fumagillol small molecules because they provide increased tumor reduction at equimolar doses in DIO mice. The compounds of the present disclosure can be used at lower molar doses and less frequent dosing to provide equivalent tumor reduction. Lower molar doses and reduced dosing frequency reduce systemic drug exposure and systemic drug toxicity.

[0229] Conventional polymer conjugates dilute activity, increasing the dose 5-20x and providing little change in therapeutic index (<2x). In contrast, the polymer conjugate compounds of the present disclosure surprisingly and unexpectedly provide an increased therapeutic index (order of magnitude improvement) and demonstrate increased activity with reduced doses.

[0230] In the methods of the present disclosure, the polymer conjugate compounds of the present disclosure surprisingly demonstrate the effect of less frequent dosing (e.g., q4d, every 4 days dosing, q7d, every 7 days dosing, q8d, every 8 days dosing), reducing the dose by at least 84 mol% fumagillol equivalents, reducing the AUC in non-target compartments, and concomitantly increasing the therapeutic index (>10x).

[0231] In another aspect, provided herein are effective doses of compounds of the present disclosure. For example, provided herein are methods comprising administering a dose of a compound of the present disclosure effective to reduce tumors. For example, contemplated doses of a compound of the present disclosure in the methods described herein may include administering a dose of about 200 mg / day, about 80 mg / day, about 40 mg / day, about 20 mg / day, about 10 mg / day, about 5 mg / day, about 3 mg / day, about 2 mg / day, about 1 mg / day, about 0.5 mg / day, about 0.2 mg / day, about 0.05 mg / day, about 0.01 mg / day, or about 0.001 mg / day, independent of body weight.

[0232] The effective amount of the drug to reduce the patient's tumor 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 / day. For example, contemplated doses can be from about 0.001-5 mg / kg body weight / day, about 0.001 mg / kg-1 mg / kg body weight / day, about 0.001 mg / kg-0.1 mg / kg body weight / day, about 0.001 to about 0.010 mg / kg body weight day, or about 0.007 mg / kg body weight day, in single, divided, or continuous doses. These doses can be based on the patient's body weight (kg), body surface area (m 2 ), and age (years). For example, a contemplated dose may be about 1 mg / m 2 Up to 50 mg / m 2 , about 5 mg / m 2 Up to 25 mg / m 2 , about 5 mg / m 2 Up to 50 mg / m 2 , about 5 mg / m 2 Up to 15 mg / m 2 , or about 5 mg / m 2 Up to 10 mg / m 2 .

[0233] An effective amount of a drug is an amount that provides an objectively discernible improvement, as indicated by a clinician or other qualified observer. For example, regression of a patient's tumor can be measured by reference to the diameter of the tumor. A decrease in the diameter of the tumor indicates regression. Failure of the tumor to recur after cessation of treatment also indicates tumor regression. As used herein, the term "dosage effective manner" refers to the amount of active compound that produces the desired biological effect in a subject or cell.

[0234] The dosage regimen for the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof used. A skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0235] Administration of the compounds of the present disclosure according to the methods of the present disclosure may be continuous or intermittent, depending upon, for example, the physiological condition of the recipient, whether the purpose of administration is therapeutic or prophylactic, and other factors known to skilled practitioners. Administration of the compounds of the present disclosure may be substantially continuous over a preselected period of time, or may be a series of spaced doses.

[0236] For repeated administration over several days or longer, depending on the condition, treatment continues until the desired suppression of disease symptoms occurs, or until sufficient therapeutic levels are reached. For example, administration of 1-5 times per week is contemplated. Other dosing regimens include 1-5 times per week, every 3-4 days, or less frequent regimens. In some aspects, the compounds of the present disclosure are administered approximately every 4 days, approximately every 7 days, approximately every 10 days, or approximately every 14 days. In some aspects, the compounds of the present disclosure are administered approximately once a week, once every two weeks, or approximately 1-4 times per month, depending on the duration of response to the administered medication. An intermittent dosing regimen of staggered dosing with intervals of 2 days to a maximum of 7 days or even 14 days is employed. In some aspects, treatment can begin with daily administration and then be changed to weekly or even monthly administration. The progress of this therapy is easily monitored by conventional techniques and analysis, or by measuring MetAP2 as described in U.S. Patent No. 6,548,477.

[0237] The frequency of administration can be determined and adjusted during the course of treatment. For example, the frequency of administration can be determined and adjusted based on the type and severity of the disease to be treated, whether the drug is being administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the drug, and the discretion of the attending physician. Typically, the physician will administer a compound of the present disclosure until a dosage is achieved that achieves the desired effect.

[0238] Treatment can be continued for a long time or a short time as needed. A suitable treatment period can be, 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 the desired result, such as a tumor reduction goal, is achieved. For example, when a loss of about 5% tumor size, about 10% tumor size, about 20% tumor size, about 30% tumor size or greater has been achieved. The treatment regimen may include a correction period during which the compound of the present disclosure is administered at a dose, or at a dosing frequency, sufficient to provide a reduction in tumor size, followed by a maintenance period during which the compound is administered at a lower dose, or at a reduced dosing frequency, sufficient to prevent tumor regrowth.

[0239] Compounds and pharmaceutical compositions of the present disclosure

[0240] The present disclosure provides compositions and drug conjugate compositions comprising a modified active moiety, a conjugate moiety, and a cleavable linker, wherein cleavage of the linker occurs substantially in the target tissue to produce a modified active moiety that has reduced efflux from the target tissue (compared to the unmodified active moiety). The present disclosure also provides compositions comprising a modified active moiety.

[0241] In addition to biological requirements, such as the pharmacokinetic and pharmacodynamic properties of the active moiety and knowledge of the disease state, the conjugate moiety used will also depend on the physicochemical properties of both the conjugate moiety and the active moiety. One skilled in the art will be able to select an appropriate conjugate moiety based on the above considerations. The conjugate moiety can be used to deliver a small molecule active moiety or a larger molecule active moiety, such as a protein, peptide, or oligonucleotide.

[0242] The conjugate moiety improves the delivery of the active moiety to the target. The conjugate moiety is selected to maximize the bioavailability of the active moiety, optimize the onset, duration, and rate of delivery of the active moiety, and maintain the concentration of the active moiety in the target tissue within the therapeutic range when effective treatment is required. The conjugate moiety can also help minimize adverse side effects of the active moiety. Thus, the conjugate moiety prolongs the pharmacological activity of the active moiety, stabilizes unstable active moieties from chemical and proteolytic degradation, minimizes side effects, increases solubility, and targets the active moiety to specific cells or tissues.

[0243] Other properties of the conjugate portion to be considered are that the conjugate portion is minimal or non-immunogenic and non-toxic. The molecular weight of the conjugate portion should be large enough to avoid rapid elimination via renal ultrafiltration and low enough to prevent unwanted accumulation in the body. In certain aspects, the conjugate portion is hydrophilic and biodegradable. Conjugate portions that are non-biodegradable are also suitable for the compositions and methods of the present disclosure. The conjugate portion should be able to carry the required amount of the active portion and prevent premature metabolism of the active portion that is transferred to the target tissue.

[0244] Exemplary conjugates include all forms of polymers, synthetic polymers, and polymers related to natural products, including peptides, polysaccharides, polynucleic acids, antibodies, and aptamers. In preferred aspects, the conjugate is a synthetic polymer. Exemplary polymers of the present disclosure are described in U.S. Patent Nos. 4,997,878 to Bock et al, 5,037,883 to Kopecek et al, 5,258,453 to Kopecek et al, 6,464,850 to Zhang et al, and 6,803,438 to Brocchini et al, each of which is incorporated herein by reference. Additional exemplary polymers are described in Subret al., J Controlled Release, 18, 123-132 (1992). In some aspects, the synthesis method of the polymer can result in the coupling of two or more polymer chains and can increase the weight-average molecular weight of the polymer conjugate. It is further recognized that if this coupling occurs, the connection will be biodegradable.

[0245] The active moiety can be any compound or molecule that produces a therapeutic effect in a subject. In some aspects, 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 aspects, the compound or molecule is a methionine aminopeptidase-2 (MetAP2) inhibitor. In some aspects, the compound or molecule is fumagillin, fumagillol, or its analogs, derivatives, salts or esters. The compound or molecule selected will depend on the condition or disease to be treated. In some aspects, two or more active moieties can be used. In some aspects, an active moiety and an inactive "cap" portion can be used. In the compositions of the present disclosure, the conjugate portion is connected to the active moiety via a linker. Any linker structure known in the art can be used to connect the modified active moiety and the conjugate portion. The linker used will depend on the physiological conditions of the target tissue, the nature of the active moiety to be optimized, and the cleavage mechanism. D'Souza et al. review various types of linkers, including those that function via proteolytic cleavage, "Release from Polymeric Prodrugs: Linkages and Their Degradation." J. Pharm. Sci ., 93, 1962-1979 (2004). Blencoe et al. describe various self-immolative linkers, “Self-immolative linkers in polymeric delivery systems.” Polym. Chem. 2, 773-790 (2011). Ducry et al in Bioconj. Chem. Linkers are reviewed in “Antibody-Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies”, 21, 5-13 (2010). Peptide linkers suitable for cleavage by matrix metalloproteinases (MMPs) are described in Chau et al. “Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models”. Int. J. Cancer118, 1519-1526 (2006) and Chau et al. U.S. Patent Publication No. 2004 / 0116348. Other linker chemistries suitable for use in the compositions of the present disclosure are shown 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. Patent No. 7,553,816; De Groot, U.S. Patent No. 7,223,837; King, U.S. Patent No. 6,759,509; Susaki, U.S. Patent No. 6,835,807; Susaki U.S. Patent No. 6,436,912; and Gemeinhart U.S. Patent No. 7,943,569.

[0246] In certain aspects, the linker is a peptide linker. Exemplary peptide linkers are described in U.S. Patent Nos. 6,835,807 to Susaki et al., 6,291,671 to Inoue et al., 6,811,996 to Inoue et al., 7,041,818 to Susaki et al., 7,091,186 to Senter et al., 7,553,816 to Senter et al., each of which is incorporated herein by reference. Additional exemplary peptides and their cleavage 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 metalloproteinases (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 Publication No. 2004 / 0116348.

[0247] The joint can be cleaved by any mechanism known in the art. For example, the joint can be designed for proteolytic cleavage or intracellular proteolytic cleavage. In some aspects, the design of the joint makes the joint not cleavage in plasma or has an extremely low cleavage rate in plasma. Exemplary joint structures are described in further detail below.

[0248] In certain aspects, the linker has a structure such that it is preferentially cleaved in diseased tissue. Because 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 tissue. For example, tumors generally have an upregulated metabolic rate and particularly overexpress proteases, including cathepsins. The upregulation and role of proteases in cancer were described by Mason et al. Trends in Cell Biology 21, 228-237(2011) description.

[0249] In certain aspects, the type of active moiety that is modified is one that irreversibly binds to its target, i.e., after release from the conjugate, the active moiety is covalently bound to the biochemical target. Once bound, the active moiety cannot diffuse or be transported out of the cell. In order for targeting to occur in the case of irreversible binding, the rate of small molecule binding to the target, k rev1 , relative to the rate of small molecule efflux k sm-1 If the rate of efflux is high relative to small molecule binding, a small molecule equilibrium will be established between the plasma and intracellular compartments and intracellular delivery will have no advantage over extracellular delivery.

[0250] In other aspects, the type of active moiety that is modified is one that binds irreversibly to its target. For targeting to occur in the case of irreversible binding, the equilibrium constant for small molecule binding to the target, K = k rev1 / k rev-1 should be large and the "on-rate", k rev1 Relative to the rate of small molecule efflux k sm-1 should be large. If the rate of efflux is high relative to small molecule binding, equilibrium will be established between the plasma and intracellular compartments and intracellular delivery will have no advantage over extracellular delivery. Such a relationship is illustrated below, where: [PC] = concentration of polymer conjugate; [SM] = concentration of released small molecule; plasma = plasma concentration; icell = intracellular concentration; icell-target = small molecule irreversibly bound to the intracellular target; and inactive = inactive metabolite of the small molecule. In certain aspects, when k rev-1 = zero, the moiety is irreversibly bound to its target.

[0251]

[0252]

[0253] In other aspects, the type of active moiety that is modified is a moiety that has a very high equilibrium constant and a high "on rate" relative to effluent. In other aspects, the type of active moiety that is modified is a moiety that undergoes intracellular metabolism at a high rate relative to effluent.

[0254] In certain aspects, modification of the active moiety is achieved by using a linker having such a structure so that upon cleavage, a fragment of the linker remains attached to the active moiety. That fragment may change any one of the molecular weight, hydrophobicity, polar surface area, or charge of the active moiety, thereby generating a modified active moiety with reduced efflux from the target cell compared to the unmodified active moiety. For example, the MetAP2 inhibitory active moiety provides a conjugate via coupling of a linker as described herein, wherein upon cleavage of the linker, an active moiety with a linker fragment attached to it (the modified active moiety) is generated. The modified active moieties described herein can have reduced efflux from the cell compared to the unmodified active moiety, resulting in a modified active moiety with an effect superior to that of the parent small molecule and a superior pharmacokinetic profile.

[0255] The present disclosure provides conjugates having a linker with the following structure:

[0256]

[0257] wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2)mCO2H, where m is 2, 3, 4, or 5; AA2 is a bond , or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, Tryptophan, or tyrosine; AA4 is 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, wherein 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 ; R 9 is alkyl, aryl, aralkyl, or a bond; or R 9 Combined with Y to form a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor 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 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6. In some aspects, 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.

[0258] In some aspects, R4 is C1-C6 alkyl. In some aspects, R4 is methyl. In some aspects, R5 is C1-C6 alkyl. In some aspects, R5 is methyl. In some aspects, R6 is 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some aspects, R6 is 2-hydroxypropyl.

[0259] In some aspects, the compound has a molecular weight greater than about 100 kDa. In some aspects, the compound has a molecular weight less than about 100 kDa. In other aspects, the molecular weight is less than about 95 kDa. In other aspects, the molecular weight is less than about 90 kDa. In other aspects, the molecular weight is less than about 80 kDa. In other aspects, the molecular weight is less than about 70 kDa. In other aspects, the molecular weight is less than about 65 kDa. In other aspects, the molecular weight is less than about 60 kDa. In other aspects, the molecular weight is less than about 45 kDa. In other aspects, the molecular weight is less than about 35 kDa.

[0260] In some aspects, the ratio of x to y is in the range of about 100:1 to about 1:1. In some aspects, the ratio of x to y is in the range of about 30:1 to about 3:1. In other aspects, the ratio of x to y is in the range of about 19:2 to about 7:2. In some aspects, the ratio of x to y is in the range of about 9:1 to about 4:1. In some aspects, the ratio of x to y is about 11:1. In some aspects, the ratio of x to y is about 9:1. In some aspects, the ratio of x to y is about 4:1. In some aspects, the ratio of x to y is about 12:1. For example, in some aspects, the ratio of x:y is about 3:1; the ratio of x:y is about 4:1; the ratio of x:y is about 5:1; the ratio of x:y is about 6:1; the ratio of x:y is about 7:1; the ratio of x:y is about 8:1; the ratio of x:y is about 9:1; the ratio of x:y is about 10:1; the ratio of x:y is about 11:1; the ratio of x:y is about 12:1; the ratio of x:y is about 13:1; the ratio of x:y is about 14:1; the ratio of x:y is about 15:1; the ratio of x:y is about 16:1 ; an x:y ratio of about 17:1; an x:y ratio of about 18:1; an x:y ratio of about 19:1; an x:y ratio of about 20:1; an x:y ratio of about 21:1; an x:y ratio of about 22:1; an x:y ratio of about 23:1; an x:y ratio of about 24:1; an x:y ratio of about 25:1; an x:y ratio of about 26:1; an x:y ratio of about 27:1; an x:y ratio of about 28:1; an x:y ratio of about 29:1; or an x:y ratio of about 30:1.

[0261] In certain aspects, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L. In certain aspects, L is methoxy, ethoxy, pentafluorophenoxy, phenoxy, acetoxy, fluoride, chloride, methoxycarbonyloxy; ethoxycarbonyloxy, phenoxycarbonyloxy, 4-nitrophenoxy, trifluoromethoxy, pentafluoroethoxy, or trifluoroethoxy. In certain aspects, L is 4-nitrophenoxy.

[0262] In certain aspects, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In certain aspects, AA1 is glycine. In certain aspects, AA2 is glycine. In certain aspects, AA3 is glycine. In certain aspects, AA4 is glycine or phenylalanine. In certain aspects, AA5 is leucine, phenylalanine, valine, or tyrosine. In certain aspects, AA6 is asparagine, citrulline, glutamine, glycine, leucine, methionine, threonine, or tyrosine. In some aspects, AA5-AA6 are Leu-Cit, Leu-Gln, Leu-Gly, Leu-Leu, Leu-Met, Leu-Thr, Phe-Cit, Phe-Gln, Phe-Leu, Phe-Met, Phe-Thr, Val-Asn, Val-Cit, Val-Gln, Val-Leu, Val-Met, Val-Thr, Tyr-Cit, Tyr-Leu, or Tyr-Met. In some aspects, AA1, AA3, and AA5 are glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine. In some aspects, AA2, AA4, and AA6 are glycine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, threonine, or tyrosine. In some aspects, AA2 is a bond; and AA3 is a bond. In certain aspects, AA1 is glycine; AA4 is phenylalanine; AA5 is leucine; and AA6 is glycine.

[0263] In some ways, W is

[0264]

[0265] wherein R2 is -OH or methoxy; and R3 is H, -OH or methoxy.

[0266] In some ways, W is

[0267] .

[0268] In some ways, W is .

[0269] In some aspects, Q is NR. In other aspects, Q is S.

[0270] In certain aspects, J is NR. In other aspects, J is ((CH2) q Q) r In other aspects, J is C5-C8 cycloalkyl. In certain aspects, J is aryl.

[0271] In certain aspects, Y is NR. In other aspects, Y is S.

[0272] In some ways, -QXY- is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0273] V is

[0274] , , , , , , , ,

[0275] , or key; R 12 is H or Me; or R 12 With R 14 Combined together to form a piperidine ring; R 11 is H or Me; and R 13 With R 12 Combined together to form a piperidine ring.

[0276] In some ways, -QXY- is .

[0277] In some ways, –QXY- is .

[0278] In some ways, –QXY- is .

[0279] In some ways, -QXY is .

[0280] In some ways, –QXY- is In some ways, -QXY- is .

[0281] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0282] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0283] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0284] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0285] In certain aspects, -QXY- is a self-immolating linker that releases the MetAP2 inhibitor as a carbamate derivative as shown in the following scheme:

[0286]

[0287] Another aspect of the present disclosure provides conjugates having a linker of the structure: ZQXYC(O)-W; wherein, independently for each occurrence, 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 AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)mCO2H, wherein 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 ; R 9 is alkyl, aryl, aralkyl, or a bond; or R 9 Combined with Y to form a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0-20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6.

[0288] In some aspects, Z is H2N-AA5-AA6-C(O)-. In some aspects, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine and AA6 is glycine. In some aspects, AA5 is leucine and AA6 is glycine. In some aspects, AA5 is valine and AA6 is glycine. In some aspects, AA5 is phenylalanine and AA6 is glycine. In some aspects, AA5 is glycine and AA6 is glycine. In some aspects, AA5 is not valine.

[0289] In other aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-. In certain aspects, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA5 is leucine and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA5 is valine and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine. In certain aspects, each of AA3, AA4, AA5, and AA6 is glycine. In certain aspects, AA5 is not valine.

[0290] In certain aspects, Z is H. In other aspects, Z is H2N-AA6-C(O)-. In certain aspects, AA6 is glycine.

[0291] In certain aspects, Q is NR. In certain aspects, M is a bond. In certain aspects, J is a bond. In certain aspects, Y is NR.

[0292] In some ways, W is:

[0293] , , , ,

[0294] , , , , , ,

[0295] , , , ,

[0296] , ,

[0297] , , , , , , , ,

[0298] , , ,

[0299] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0300] wherein R2 is -OH or methoxy; and R3 is H, -OH or methoxy.

[0301] In some ways, W is

[0302] , , , , , , , , , or .

[0303] In some ways, W is .

[0304] In some ways, -QXY- is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0305] V is:

[0306] , , , , , , , , ,

[0307] or key; R 12 is H or Me; or R 12 With R 14 Combined together to form a piperidine ring; R 11 is H or Me; and R 13 With R 12 Combined together to form a piperidine ring.

[0308] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0309] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is ; and W is .

[0310] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is ; and W is .

[0311] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is ; and W is .

[0312] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0313] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0314] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0315] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0316] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0317] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0318] In some ways, Z is H; QXY is ; and W is .

[0319] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0320] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is ; and W is .

[0321] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is ; and W is .

[0322] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is ; and W is .

[0323] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0324] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0325] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0326] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0327] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0328] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0329] In some ways, Z is H; QXY is ; and W is .

[0330] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0331] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is ; and W is .

[0332] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is ; and W is .

[0333] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is ; and W is .

[0334] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0335] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0336] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0337] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0338] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0339] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0340] In some ways, Z is H; QXY is ; and W is .

[0341] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0342] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine and AA6 is glycine; QXY is ; and W is .

[0343] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine and AA6 is glycine; QXY is ; and W is .

[0344] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine and AA6 is glycine; QXY is ; and W is .

[0345] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0346] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0347] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine and each of AA3, AA4 or AA6 is glycine; QXY is ; and W is .

[0348] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine; QXY is ; and W is .

[0349] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0350] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0351] In some ways, Z is H; QXY is ; and W is .

[0352] Other active moieties that can be modified for use in the conjugates of the present disclosure include the following structures:

[0353] ;

[0354] ;

[0355] ;and

[0356] .

[0357] In some aspects, the active moiety is an anti-tumor compound. In other aspects, the active moiety is a molecule that inhibits methionine aminopeptidase-2 (MetAP2), such as fumagillin, fumagillol, or an analog, derivative, salt, or ester thereof. MetAP2 is a cotransferase responsible for cleaving the initiator methionine from nascent polypeptides. It has several unique substrates that tend to be upregulated under cellular stress, hypoxic conditions, and when cells divide. 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 activity of MetAP2. Additional exemplary MetAP2 inhibitors are described in U.S. Pat. Nos. 6,242,494 to Craig et al., 6,063,812 to Hong et al., 6,887,863 to Craig et al., 7,030,262 to BaMaung et al., and 7,491,718 to Comess et al., each of which is incorporated herein by reference. Additional exemplary MetAP2 inhibitors are described in Wang et al., “Correlation of tumor growth suppression and methionine aminopeptidase-2 activity blockade using an orally active inhibitor.” PNAS 105(6) 1838-1843 (2008); Lee at al. “Design, Synthesis, and Antiangiogenic Effectsof a Series of Potent Novel FumagillinAnalogues”, Chem. Pharm. Bull. 55(7)1024-1029 (2007); Jeong et al. “Total synthesis and antiangiogenic activity of cyclopentane analogues of fumagillol”, Bioorganic and Medicinal Chemistry Letters15, 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 in International Patent Publication No. WO 2010 / 003475 by Heinrich et al.

[0358] Fumagillin is a small molecule that has been used as an antibacterial and antiprotozoal agent. Its physicochemical properties and production methods are well known (see U.S. Pat. No. 2,803,586 and Turner, JR. et al. , The Stereochemistry of Fumagillin, Proc. Natl. Acad. Sci. 48 , 733-735 (1962). The fermentation product, fumagillin, can be hydrolyzed to produce the alcohol fumagillol, which in turn can be converted to various derivatives including carbamoylfumagillol, MW 325. The synthesis and preparation of carbamoylfumagillol and some small molecule derivatives are described in U.S. Patent No. 5,166,172.

[0359] Fumagillin and related compounds are thought to exert their biological effects by inhibiting 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)).

[0360] Carbamoyl fumagillin and derivatives and other inhibitors of MetAP2 have shown therapeutic benefits in preclinical and clinical studies. These compounds inhibit cell proliferation and angiogenesis as described in U.S. Patent No. 5,166,172. Fumagillin analogs or derivatives, such as CKD-732 and PI-2458, have been described in, for example, Bernier et al., "Fumagillin class inhibitors of methionine aminopeptidase-2." Drugs of the Future 30(5): 497-508, 2005, and has been extensively studied in various systems as described in detail.

[0361] 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 reduction in ob / ob mice using TNP-470 at daily doses ranging from 2.5 mg / kg to 10 mg / kg. Brakenhielm describes the prevention of obesity with TNP-470 doses of 15 or 20 mg / kg (every other day), "The Angiogenesis Inhibitor, TNP-470, Prevents Diet-Induced and Genetic Obesity in Mice" Circulation Research94: 1579-1588, 2004. Kim, et al., in "Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732," J Molecular Endocrinology 38, 455-465, 2007, describe that a dose of 5 mg / kg / day reduced body weight in C57BL / 6J mice and SD rats. Lijnen et al., "Fumagillin reduces adipose tissue formation in murine models of nutritionally induced obesity," Obesity 12, 2241-2246, 2010, describe that oral delivery of 1 mg / kg fumagillin daily resulted in weight loss in C57BL / 6 mice.

[0362] One of these derivatives, chloroacetylcarbamoylfumagillol (TNP-470), has been extensively studied (see H. Mann-Steinberg, et al., "TNP-470: The Resurrection of the First Synthetic Angiogenesis Inhibitor," Chapter 35 in 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 multiple dosing regimens, but these attempts to limit its toxicity have been unsuccessful. Consequently, TNP-470 has been found to be too toxic for human use. TNP-470 has a short half-life, and prolonged intravenous administration is required for therapeutic use. TNP-470, a metabolite of carbamoylfumagillol, has a half-life of 12 minutes in humans (see Herbst et al., 2006). 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.

[0363] Despite the known usefulness of fumagillin derivatives, they have not been successfully used as therapeutic agents due to the inability to overcome the low water solubility, short half-life values, and neurotoxic side effects of these compounds. Based on the dose limitation of previously observed neuropsychiatric toxicity, the combination of TNP-470 and paclitaxel administered three times a week has been determined to have an MTD of 60 mg / m2. 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 Oncology20, 4440-4447, 2002. Similarly, Shin et al., "A Phase 1 pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer," Investigational New Drugs 28, 650-658, 2010, reported that the MTD of CKD-732 was 15 mg / m2 / day based on a dosing schedule every 4 days due to confusion and insomnia. Therefore, the compounds of the present disclosure are more effective, exhibit reduced toxicity (lower neurotoxicity), improved water solubility, greater stability, and / or have a longer half-life (serum half-life) than currently known fumagillin derivatives.

[0364] As used herein, the phrase "reduced toxicity" has its ordinary meaning as understood by those skilled in the art. By way of example only, and not as a limitation of the meaning of this term, administration of the fumagillin analog conjugate caused fewer side effects in an open field test in mice, as compared to the fumagillin analog alone.

[0365] The phrase "improved water solubility" has its ordinary meaning as understood by those skilled in the art. By way of example only, and not as a limitation of the meaning of this term, the following description of this term is meaningful: an increased amount of the fumagillin analog will dissolve in water due to its covalent binding to the conjugate, as compared to the amount of the unconjugated fumagillin analog alone that dissolves in water.

[0366] The phrase "longer half-life" has its ordinary meaning as understood by those skilled in the art. By way of example only, and not as a limitation on the meaning of this term, the following description of this term is meaningful: any suitable increase in the length of time required to deactivate the fumagillin conjugate in vivo or in vitro, as compared to the half-life of the fumagillin analog alone in vivo or in vitro.

[0367] Without wishing to be bound by any theory, non-enzymatic effects of MetAP2 in inhibiting the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 / 2) may be important, such as the binding of eukaryotic initiation factors eIF to MetAP2. Cellular responses to MetAP2 inhibition reflecting potential ERK-related processes may include inhibition of sterol regulatory factor binding protein (SREBP) activity, leading to reduced lipid and cholesterol biosynthesis. Interestingly, changes in the expression patterns of liver and adipose tissue genes after prolonged (approximately 9 months) fumagillin exposure suggest that MetAP2 inhibition may also alter the relative abundance of factors involved in inflammation, consistent with reduced ERK-dependent cellular processes. The putative mechanism of MetAP2 inhibition, which leads to the mobilization of fat depots and the catabolism of free fatty acids as a body energy source, is supported by changes in plasma β-hydroxybutyrate, adiponectin, leptin, and FGF21 observed in previous studies. Elevated levels of the key catabolic hormones adiponectin and FGF21, along with the appearance of ketone bodies (β-hydroxybutyrate), suggest that MetAP2 inhibition with conjugated or modified fumagillin, fumagillol, or analogs, derivatives, salts, or esters thereof of the compounds of the present disclosure stimulates energy expenditure, fat utilization, and lipid excretion. The reduction in leptin observed in previous studies and the studies provided herein is also consistent with a reduction in total adipose tissue and a negative energy balance. It is also possible that conjugated or modified fumagillin, fumagillol, or analogs, derivatives, salts, or esters thereof of the compounds of the present disclosure form a covalent bond with MetAP2, thereby irreversibly inhibiting and silencing the existing enzyme until a newly generated MetAP2 pool is generated in target tissues (e.g., liver and adipose tissue).

[0368] In certain aspects, the conjugated or modified fumagillin, fumagillol, or an analog, derivative, salt, or ester thereof of the Compounds of the Disclosure, for example, has the following formula as shown in Table 1.

[0369] Table 1

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] * Wherein the polymer has the following structure:

[0379] ,

[0380] And preferably the following structure:

[0381] .

[0382] In some aspects, the compound is:

[0383]

[0384] (Compound 1).

[0385] In some aspects, the compound is:

[0386]

[0387] (Compound 2).

[0388] In some aspects, the compound is:

[0389]

[0390] (Compound 3).

[0391] In some aspects, the compound is:

[0392] .

[0393] In some aspects, the compound is:

[0394] .

[0395] In some aspects, the compound is:

[0396] .

[0397] In one or more aspects, the compounds for use in the present disclosure may be selected from cis-(3aRS,9bRS)-7-(phenylsulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-(phenylsulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid Tetrahydro-2H-furo[2,3-c]benzopyran-6-carboxylic acid; cis-(3aR,9bR)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]benzopyran-6-carboxylic acid; cis-(3aS,9bS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]benzopyran-6-carboxylic acid; 7-[2-((Z)-3-diethylaminoprop-1-enyl) -4-Fluorophenylsulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate; 7-(phenylsulfonylamino)-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorophenylsulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorophenylsulfonylamino]-1,1a,2,7b-tetrahydrofuro[2,3-c]quinoline-6-carboxylic acid Hydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid;(1aRS,7bSR)-5-[2-((E)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]benzopyran-6-carboxylic acid; (1aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c] Benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid [sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropane[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropane[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropane[c]benzopyran-4-carboxylic acid [(Z)-3-(Pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]benzopyran-4-carboxylic acid;(1aRS,7bSR)-5-[2-(3-Dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-(3-Dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2-(3-Dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid -carboxylic acid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-(4-dimethylamino-butylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2-(4-dimethylaminobutylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-[2-(5-dimethylamino-pentylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropan[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]benzopyran-4-carboxylic acid Pyran-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropane[c]benzopyran-4-carboxylic acid;(1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro- Prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1 (aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropyl-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropyl-[c]benzopyran-4-carboxylic acid Acid; (1aRS, 7bSR) -5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS, 7bSR) -5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-(Pyrrolidin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid; (1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid;(1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; ,7bSR)-5-[2-((S)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[N-((S)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-(2-{[N-((R)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; -sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidin-2-yl)carbonyl-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid;(1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-(2-{N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-(2-{N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methylamino-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; ,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[((S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[((R)-1-Azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidin-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl)}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropyl[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropyl[c]benzopyran-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aR,7bS )-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane-[c]benzopyran-4-carboxylic acid; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof. ;

[0398] In one or more aspects, the compound is selected from:

[0399] ; ;

[0400] ; ; ; ; ; ; ; ; ; ; ; ; ,

[0401] and pharmaceutically acceptable salts or stereoisomers thereof.

[0402] For purposes of this disclosure, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Edition, 1986-87, inside cover.

[0403] If not otherwise specified, the term "alkyl" refers to a fully saturated, branched or unbranched carbon chain group having a specified number of carbon atoms, or up to 30 carbon atoms. For example, "low alkyl" refers to an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, and those of positional isomers of these alkyl groups. Alkyl groups of 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain aspects, a straight or branched chain alkyl group having 30 or fewer carbon atoms in its backbone (e.g., C1-C1 for a straight chain) may be used. 30 , for the branched chain C3-C 30 ), and more preferably 20 or less. Likewise, certain cycloalkyl groups have 3-10 carbon atoms in their ring structure, and may have 5, 6, or 7 carbons in the ring structure.

[0404] Unless the number of carbon atoms is otherwise specified, "lower alkyl" as used herein means an alkyl group as defined above, but having from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms, in its backbone structure, 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 the specification, certain alkyl groups are lower alkyl groups. In certain aspects, substituents designated herein as alkyl groups are lower alkyl groups.

[0405] The term "carbocycle," as used herein, refers to an aromatic or non-aromatic ring in which every atom of the ring is carbon.

[0406] As used herein, the term "aryl" includes 5-, 6-, and 7-membered monocyclic aromatic groups that may contain 0-4 heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, among others. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaryls." The aromatic ring may be substituted at one or more ring positions with substituents as described above, for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aromatic or heteroaromatic moiety, -CF , -CN, and the like. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbon atoms are common to two adjacent rings (the rings are "fused"), and in which at least one ring is aromatic, e.g., the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl.

[0407] "Alkenyl" refers to any branched or unbranched unsaturated carbon chain radical having the specified number of carbon atoms, or up to 26 carbon atoms, if the number of carbon atoms is not particularly limited; and having one or more double bonds in the radical. Examples of alkenyl groups of 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, wherein the unsaturated bond may be located anywhere in the radical and may have either the (Z) or (E) configuration around the double bond.

[0408] The term "alkynyl" refers to a hydrocarbon group that is within the scope of an alkenyl group, but having one or more triple bonds within the group.

[0409] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined below having an oxy group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, the substituents of an alkyl group that make an alkyl group an ether are or resemble alkoxy groups, for example, can be -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m - one of R1 represents, wherein m and R1 are described below.

[0410] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 10-membered ring structure, more preferably a 3- to 7-membered ring, which ring structure contains 1 to 4 heteroatoms. The heterocycle can also be polycyclic. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, benzopyran, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, o-phenanthroline, phenazine, phenarsazine chloride, phenothiazine, furazan, phenoxazine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocycle can be substituted at one or more positions with substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, thiol, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, CN, and the like.

[0411] The term "alkylthio" refers to an alkyl group as defined above having a thio group attached thereto. In certain aspects, the "alkylthio" moiety consists of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2) m -R1 represents, wherein m and R1 are as defined below. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0412] As used herein, the term "nitro" means -NO2; the term "halogen" designates F, Cl, Br, or I; the term "mercapto" means -SH; the term "hydroxy" means -OH; and the term "sulfonyl" means -SO2-.

[0413] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines, for example, moieties that can be represented by the following general formula:

[0414]

[0415] wherein R3, R5 and R6 each independently represent hydrogen, alkyl, alkenyl, (CH2) m-R1, or R3 and R5 taken together with the nitrogen atom to which they are attached complete a heterocyclic ring having 4-8 atoms in the ring structure; R1 represents alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclyl; and m is zero or an integer in the range of 1-8. In certain aspects, only one of R3 or R5 can be a carbonyl group, for example, R3, R5 and nitrogen together do not form an imide. In certain aspects, R3 and R5 (and optionally R6) each independently represent hydrogen, alkyl, alkenyl, or -(CH2) m -R1. Thus, as used herein, the term "alkylamine" means an amine group as defined above, having a substituted or unsubstituted alkyl group attached thereto, i.e., at least one of R3 and R5 is an alkyl group. In certain aspects, the amino or alkylamine is basic, meaning that it has a pK a > 7.00. The protonated forms of these functional groups have pK values ​​relative to water of 7.00 or higher. a s.

[0416] The term "carbonyl" (C(O)) is art-recognized and encompasses moieties that can be represented by the following general formula:

[0417]

[0418] wherein X is a bond or represents oxygen or sulfur, and R7 represents hydrogen, alkyl, alkenyl, -(CH2) m -R1 or a pharmaceutically acceptable salt, R8 represents hydrogen, alkyl, alkenyl or -(CH2) m -R1, wherein m and R1 are as defined above. When X is oxygen and R7 or R8 are not hydrogen, the general formula represents an "ester". When X is oxygen, and R7 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R7 is hydrogen, the general formula represents a "carboxylic acid". When X is oxygen, and R8 is hydrogen, the general formula represents a "format" group. Generally speaking, when the oxygen atom of the above formula is replaced by sulfur, the general formula represents a "thiocarbonyl" group. When X is sulfur and R7 or R8 is not hydrogen, the general formula represents a "thioester" group. When X is sulfur and R7 is hydrogen, the general formula represents a "thiocarboxylic acid" group. When X is sulfur and R8 is hydrogen, the general formula represents a "thioformate" group. On the other hand, when X is a bond, and R7 is not hydrogen, the above formula represents a "ketone" group. When X is a bond, and R7 is hydrogen, the above formula represents an "aldehyde" group.

[0419] As used herein, the term "substituted" is contemplated to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described herein above. For appropriate organic compounds, the permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the heteroatom valences. This disclosure is not intended to be limited in any way by the permissible substituents of an organic compound. It should be understood that "substituted" or "substituted with..." includes absolute limitations, i.e., such substitutions are based on the permissible valences of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., the compound does not spontaneously undergo transformations such as those caused by rearrangement, cyclization, elimination, and the like.

[0420] The term "sulfamoyl" is art-recognized and includes moieties that can be represented by the following general formula:

[0421]

[0422] wherein R3 and R5 are as defined above.

[0423] The term "sulfate" is art-recognized and includes moieties that can be represented by the following general formula:

[0424]

[0425] wherein R7 is as defined above.

[0426] The term "sulfonylamino" is art-recognized and includes moieties that can be represented by the following general formula:

[0427]

[0428] wherein R2 and R4 are as defined above.

[0429] The term "sulfonate" is art-recognized and includes moieties that can be represented by the following general formula:

[0430]

[0431] wherein R7 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0432] As used herein, the term "sulfoxide" or "sulfinyl" refers to a moiety that can be represented by the following general formula:

[0433]

[0434] where R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

[0435] Similar substitutions on alkenyl and alkynyl groups can produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl.

[0436] As used herein, the definition of each expression, for example, alkyl, m, n, etc., when it occurs more than one time in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0437] The term "amino acid" is intended to encompass all compounds, whether natural or synthetic, that include both an amino acid functional group and an acid functional group, including amino acid analogs and derivatives. In certain aspects, the amino acids contemplated by the present disclosure are those naturally occurring amino acids found in proteins, or naturally occurring anabolic or catabolic products of such amino acids, that contain an amino group and a carboxyl group. Naturally occurring amino acids are identified by the traditional three-letter and / or one-letter abbreviations corresponding to the common names of the amino acids, according to the following list. The abbreviations are accepted in the peptide field and recommended by the IUPAC-IUB Committee on Biochemical Nomenclature.

[0438] The term "amino acid residue" means an amino acid. Generally, the abbreviations used herein to designate naturally occurring amino acids are based on the recommendations of the IUPAC-IUB Committee 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. By residue is meant a group derived from the corresponding α-amino acid by eliminating the OH portion of the carboxyl group and the H portion of the α-amino group.

[0439] The term "amino acid side chain" is the portion of an amino acid residue that is not bound to the main chain, as defined in KD Kopple, "Peptides and Amino Acids", WA Benjamin Inc., New York and Amsterdam, 1966, pp. 2 and 33; examples of such common amino acid side chains 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 attached to the main chain Cα carbon.

[0440] The term "peptide", as used herein, refers to a sequence of amino acid residues linked together by peptide bonds or by modified peptide bonds. The term "peptide" is intended to encompass peptide analogs, peptide derivatives, peptidomimetics, and peptide variants. The term "peptide" is understood to include peptides of any length. The peptide sequences listed herein are written according to the generally accepted convention in which the N-terminal amino acid is on the left and C -The terminal amino acid is on the right (e.g., H2N-AA1-AA2-AA3-AA4-AA5-AA6-CO2H).

[0441] Certain compounds of the present disclosure may exist in particular geometric isomeric or stereoisomeric forms. The present disclosure contemplates all such compounds falling within the scope of the present disclosure, including their cis- and trans-isomers, R -and S The present invention relates to a group comprising a plurality of isomers, including (a)-enantiomers, (b)-isomers, (c)-isomers, (d)-isomers, (d)-isomers, racemic mixtures, and other mixtures. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, and mixtures thereof, are intended to be included in the present disclosure. Any representation of a specific isomer is merely exemplary (e.g., a trans-isomer is also included in a cis-isomer).

[0442] For example, if a specific enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated. The auxiliary group is then cleaved to provide the desired pure enantiomer. Alternatively, when the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0443] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a selected indicator group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When the substituent is a keto group (i.e., =O), then two hydrogen atoms of the atom are replaced. The keto substituent is not present on the aromatic moiety. As used herein, a ring double bond is a double bond (e.g., C=C, C=N, or N=N) formed between two adjacent ring atoms. "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently stable to withstand separation from a reaction mixture to a useful purity and formulation as an effective therapeutic agent.

[0444] When a bond connecting a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be attached to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is attached to the rest of the compound of a given formula, then such substituent may be attached via any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0445] When any variable (e.g., R1) occurs more than once in any constituent or formula of 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, then the group may be optionally substituted with up to two R1 moieties, with R1 at each occurrence being independently selected from the definition of R1. Likewise, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0446] In this specification, in some cases, for convenience, the structural formula of a compound represents certain isomers, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, etc. In addition, the compound represented by the structural formula may exist in crystal polymorphism. It is noted that any crystal form, mixture of crystal forms, or anhydride or hydrate thereof is included within the scope of the present disclosure. In addition, so-called metabolites produced by the degradation of the present compound in vivo are included within the scope of the present disclosure.

[0447] "Isomeris" refers to compounds that have the same molecular formula but differ in the sequence in which their atoms are bonded or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of one another are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of each enantiomeric form of opposite chirality is called a "racemic mixture."

[0448] A carbon atom that is bonded to four non-identical substituents is called a "chiral center."

[0449] "Chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist as either individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center in question are ordered according to the rules of Cahn, Ingold and Prelog ( Sequence Rule of Cahn, Ingold andPrelog) arrangement (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).

[0450] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about double bonds. These conformations are distinguished by prefixing their names with cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond of the molecule according to the Cahn-Ingold-Prelog rules.

[0451] In addition, the structures and other compounds discussed in this disclosure include all of their atropisomers. An "atropisomer" is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by the hindrance of rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, however, due to recent advances in chromatographic techniques, it is possible to separate mixtures of two atropisomers under selected circumstances.

[0452] A "tautomer" is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the migration of hydrogen atoms along adjacent conjugated double bonds. In solution, tautomers exist as a mixture of sets of tautomers. In the solid state, one tautomer typically predominates. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of interconvertible tautomers through tautomerization is known as tautomerism.

[0453] Of the various types of tautomerism possible, two are common. In keto-enol tautomerism, a simultaneous transfer of electrons and hydrogen atoms occurs. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) of the same molecule to give it a cyclic (ring-shaped) form, as exhibited by glucose.

[0454] Common tautomeric pairs are: keto-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclyl rings (e.g., in nucleic acid bases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine.

[0455] It is to be understood that the compounds of the present disclosure may be described as different tautomers. It is also to be understood that when a compound has tautomeric forms, 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 form.

[0456] The terms "crystal polymorph," "polymorph," or "crystal form" refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize under different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to dominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0457] Additionally, the compounds of the present disclosure, for example, salts of the compounds, can exist in either hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0458] "Solvate" means a compound containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance, where the water remains in its molecular state, such as HO.

[0459] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but slightly different in composition (e.g., one atom is replaced by an atom of a different element or in the presence of a particular functional group, or one functional group is replaced by another). Thus, an analog is a compound that is similar or comparable in function and appearance, but differs from the reference compound in structure or origin.

[0460] As defined herein, the term "derivative" refers to compounds having a common core structure, substituted with various groups as described herein.

[0461] The term "bioequivalent" refers to a compound produced by exchanging one atom or group of atoms for another substantially similar atom or group of atoms. The purpose of bioequivalent substitution is to create a new compound with similar biological properties as the parent compound. Bioequivalent substitution can be based on physicochemical or topological isomerism. Examples of carboxylic acid bioequivalents include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphates. See, for example, Patani and LaVoie, Chem. Rev. 96,3147-3176, 1996.

[0462] The present disclosure is intended to include all isotopes of atoms present in existing 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.

[0463] The synthetic methods of the present disclosure tolerate a wide variety of functional groups; thus, various substituted starting materials can be used. The methods generally provide the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound into a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0464] The compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by using standard synthetic methods and procedures or those known to those skilled in the art or those that will be 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 for the transformation and manipulation of functional groups can be obtained from the relevant scientific literature or from standard textbooks in the field. Although any one or more sources are not required, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms and Structures ( March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure ), 5th ed., John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protecting Groups in Organic Synthesis ( Protective Groups in Organic Synthesis ), 3rd edition, John Wiley & Sons: New York, 1999, incorporated herein by reference, is a recognized reference textbook on organic synthesis that is useful and known to those skilled in the art. The synthetic methods described below are designed to illustrate (but not limit) the general procedures for preparing the compounds of the present disclosure.

[0465] In particular, compounds of the present disclosure, and their synthesis, are further described in PCT Publication Nos. WO 2011 / 150022 and WO 2011 / 150088 and US Pat. Nos. 9,173,956, 9,320,805, and 9,433,600. Each of these publications is incorporated herein by reference in its entirety for all purposes.

[0466] The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0467] A "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one aspect, the pharmaceutical composition is in bulk or in unit dosage form. A unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, an aerosol inhaler with a pump, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dose composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that it is sometimes necessary to make routine adjustments to the dosage, depending on the patient's age and condition. The dosage will also depend on the route of administration. A variety of routes have been contemplated, including oral, pulmonary artery, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, aerosols, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one aspect, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0468] As used herein, "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference textbook in this field. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.

[0469] Pharmaceutically acceptable carriers include solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers include syrups, peanut oil, olive oil, water, and the like. Similarly, carriers or diluents may include time-delay materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax, ethylcellulose, hydroxypropyl methylcellulose, methyl methacrylate, and the like. Other fillers, excipients, flavorings, and other additives known in the art may also be included in pharmaceutical compositions according to the present disclosure. Liposomes and non-aqueous media such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents to date are incompatible with the active compound, their use in the composition is contemplated. Supplementary active compounds may also be incorporated into the composition. In certain aspects, the pharmaceutical composition comprises DMSO.

[0470] The term "pharmaceutically acceptable salt" refers to relatively non-toxic, inorganic and organic acid addition salts of a compound. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free base form with a suitable organic or inorganic acid, respectively, and isolating the salt so formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, among others. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, enzymes, and aluminum salts, among others. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66:1-19).

[0471] The phrase "pharmaceutically acceptable" as used herein refers to those ligands, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without substantial pyrogen, excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0472] As used herein, the term "metabolite" means a metabolic product of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof, which exhibits similar in vivo activity as the compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof.

[0473] As used herein, the term "prodrug" means a compound of the present disclosure that is covalently linked to one or more pro-moieties, such as an amino acid moiety or other water-soluble moiety, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof. A compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof can be released from the pro-moiety via hydrolysis, oxidation, and / or enzymatic release mechanisms. On the one hand, the prodrug compositions of the present disclosure exhibit increased water solubility, improved stability, and the added benefit of improved pharmacokinetic properties. The pro-moiety can be selected to obtain desired prodrug characteristics. For example, a pro-moiety, such as an amino acid moiety or other water-soluble moiety, such as a phosphate in R4, can be selected based on solubility, stability, bioavailability, and / or in vivo delivery or absorption. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyl functional groups of the compounds of the present disclosure, esters (e.g., ethyl esters, morpholinoethanol esters), N-acyl derivatives (e.g., N-acetyl) N-Mannich bases of carboxyl functional groups, Schiff bases and enaminones of amino functional groups, acetals, ketals, and enol esters of oxime, ketone, and aldehyde functional groups, and the like, see Bundegaard, H., et al. Design of Prodrugs, p1-92, Elesevier, New York-Oxford (1985).

[0474] The compound of the present disclosure, or its pharmaceutically acceptable salt, ester, solvate, diastereomer, polymorph, or prodrug (or its pharmaceutical composition) can be used through any mode known in the art.For example, the compound of the present disclosure or composition can be administered orally, nasally, transdermally, topically, pulmonary artery, inhaled, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectum, intrapleurally, intrathecally and parenterally.Use can be systemic, for example, intravenously, or locally.In some aspects, route of administration can be intravenously, intramuscularly, subcutaneously, intracutaneously, intraperitoneally, intrathecally, intrapleurally, intrauterine, rectum, vaginal, locally or the like.In some aspects, compound is administered subcutaneously.

[0475] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their planned routes of administration. Examples of routes of administration include parenteral, for example, intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methyl paraben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid ethyl; a buffer such as acetate, citrate, or phosphate, and an agent for regulating tension such as sodium chloride or glucose. pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be packaged in ampoules, disposable syringes, or multiple-dose bottles made of glass or plastic.

[0476] The compounds or pharmaceutical compositions of the present disclosure can be administered to a subject using many well-known methods currently used for chemotherapeutic treatments. For example, to treat cancer, the compounds of the present disclosure can be injected into a tumor, injected into the bloodstream or body cavity, injected subcutaneously, or administered orally or applied through the skin in contact with a patch. The selected dosage should be sufficient to constitute an effective treatment, but should not be so high as to cause unacceptable side effects. The state of the disease (e.g., cancer, precancerous stage, etc.) and the patient's health should preferably be closely monitored within a reasonable period of time during and after treatment.

[0477] In one aspect, the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs thereof, are administered in a suitable dosage form or formulation prepared by combining a therapeutically effective amount (e.g., an effective level sufficient to achieve the desired therapeutic effect) of the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs thereof (as active ingredients) with standard pharmaceutical carriers or diluents according to conventional procedures (i.e., by producing pharmaceutical compositions of the present disclosure). These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to achieve the desired preparation.

[0478] Parenteral dosage forms can be prepared by any method known in the art. For example, sterile injectable aqueous or oily suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.

[0479] Oral dosage forms, such as capsules, tablets, pills, powders, and granules, can be prepared using any suitable method known in the art. For example, the compounds of the present disclosure can be mixed with an enteric coating material and compressed into tablets. Alternatively, the formulations of the present disclosure can be incorporated into chewable tablets, crushable tablets, tablets that dissolve rapidly in the oral cavity, or mouthwashes.

[0480] For pulmonary artery (e.g., intratracheal) administration, the compounds of the present disclosure can be formulated with conventional excipients to prepare inhalable compositions in the form of fine powders or atomizable liquids. For ocular administration, the compounds of the present disclosure can be formulated with conventional excipients, for example, in the form of eye drops or eye implants. Among the excipients that can be used in eye drops are binders or gelling agents to minimize losses due to tearing by improving retention in the eye.

[0481] Liquid dosage forms for oral or other administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, the liquid dosage form may also contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, ophthalmic, oral, or other systemic delivery compositions may also contain adjuvants such as wetting agents, and emulsifiers and suspending agents.

[0482] Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers, are very useful for administration. Liquid formulations can be directly atomized, while lyophilized powders can be atomized after reconstitution. Alternatively, the compounds of the present disclosure can be aerosolized using fluorocarbon formulations and metered dose inhalers, or inhaled as a lyophilized and ground powder.

[0483] The dosage form for topical or transdermal administration of the pharmaceutical composition of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Optionally, the activating agent is mixed with a pharmaceutically acceptable carrier and any required preservatives or buffers under aseptic conditions. For example, the skin route of administration is achieved using aqueous drops, sprays, emulsions or creams.

[0484] Transdermal patches can have the additional advantage of providing controlled delivery of active ingredients to health. Such dosage forms can be made by dissolving or being dispersed in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. Rate can be controlled by or providing a rate-controlling membrane or by making the compound be dispersed in a polymer matrix or a gel.

[0485] Compositions for rectal or vaginal administration may be suppositories, which may be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity and releases the active agent. Alternatively, the contemplated formulations may be administered by release from the lumen of an endoscope after insertion into the rectum of a subject.

[0486] Those skilled in the art are referred to general reference texts for detailed descriptions of known technologies or equivalent technologies discussed herein. These texts include Ausubel et al., General protocols for molecular biology ( Current Protocols in Molecular Biology ,), John Wiley and Sons, Inc. (2005); Sambrook et al. ,Molecular Cloning,A Laboratory Manual( Molecular Cloning, A Laboratory Manual ) (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al. , General Protocols in Immunology ( Current Protocols in Immunology ), John Wiley&Sons, NY; Enna et al. , a general approach to pharmacology ( Current Protocols in Pharmacology ), John Wiley&Sons, NY;Fingl et al. , the pharmacological basis of treatment ( The Pharmacological Basis of Therapeutics )(1975), Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, PA, 18th ed. (1990). These texts may of course also be consulted in making or using aspects of the present disclosure.

[0487] Unless otherwise indicated, all percentages and ratios used herein are expressed by weight. Other features and advantages of the present disclosure are apparent from the various examples. The examples provided illustrate different components and methods that can be used to implement the present disclosure. The examples do not limit the disclosure of the requirements. Based on the present disclosure, a skilled artisan can identify and use other components and methods that can be used to implement the present disclosure. Example

[0488] The following examples are provided to further illustrate the various features of the present disclosure. The examples also illustrate useful methods for implementing the present disclosure. These examples do not limit the claimed disclosure.

[0489] Example 1 - In vivo testing B16F10 melanoma / DIO mice - body weight, tumor growth, adipose tissue mass and white blood cell count.

[0490] In vivo studies were conducted to establish a syngeneic mouse model to demonstrate that diet-induced obesity accelerates tumor growth. This study confirmed the efficacy of the compounds of the present disclosure in this obesity-driven, metabolism-driven tumor model. Specifically, efficacy against tumors in obese animals was confirmed, as was efficacy in corresponding lean animals. The study will compare weight changes in obese and lean groups; measure biological changes in hematological parameters; and compare the efficacy of the conjugate molecules of the present disclosure to related small molecules.

[0491] C57BL / 6 male mice were fed ad libitum TD.06414, a high-fat diet (HFD) containing 60% Kcal from adipose tissue (DIO), for 12-14 weeks until the average weight of obese mice was >40 g. Age-matched C57BL / 6 male mice were maintained on a normal rodent chow (10% fat, low-fat diet, LFD) for 12-14 weeks. 2 x 10 5 The study was initiated by introducing B16F10 melanoma cells into the flanks of lean and obese animals.

[0492] Once the tumor reaches >100 mm 3 Mice were treated with 5% mannitol / water (vehicle control), Compound 1, or Compound 4. Treatment was performed at a dose of 5 ml / kg every 4 days (Compound 1) or every 2 days (Compound 4) and according to the schedule shown in Table 2, via subcutaneous, intrascapular injection for a period of 17 days.

[0493] Table 2

[0494]

[0495] Compound 4 is CKD-732 (also known as beloranib and ZGN-433). Compound 4 has previously been shown to be effective in causing weight loss in DIO mice when administered at 1 mg / kg (Hughes TE., et al. ZGN-201 (ZGN) , a methionine aminopeptidase 2 ( MetAP2 ) inhibitors, which permanently eliminate excess body fat in obese mice by regulating fat metabolism and food intake ( ZGN-201 (ZGN), a methionine aminopeptidase 2 (MetAP2) inhibitor, durably eliminatesexcess body fat in obese mice through regulation of fat metabolism and food intake ) ”European Association for the Study of Diabetes (2010, September 20-24; Stockholm, Sweden. Presentation 244). Compound 4 referred to herein is a hemi-tartrate salt of the following structure:

[0496] Figure 1A Baseline body weights of obese and lean mice bearing B16F10 melanoma are shown. Figure 1B Figure 2. Tumor growth of B16F10 melanoma cells in obese and lean mice over time. Data were analyzed by two-way ANOVA for multiple comparisons, ***p<0.005 and ****p<0.0001. Figure 1A The results confirmed that before the study began, the mean weight of the obese group was significantly different from the mean weight of the lean group, while there was no significant difference in weight within the obese or lean groups. Figure 1B The results demonstrated that tumors grew significantly faster and reached significantly larger sizes in animals made obese by consuming a high-fat diet (DIO mice) compared to age-matched animals consuming a low-fat diet (lean mice).

[0497] Figure 2A Shown is B16F10 melanoma tumor growth in lean mice following treatment with vehicle or 8 mg / kg or 24 mg / kg of Compound 1 of the present disclosure. Figure 2B Shown is the growth of B16F10 melanoma tumors in obese mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of Compound 1 of the present disclosure. Data were analyzed by two-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 2A and 2B The results confirmed that compound 1 inhibited tumor growth in a dose-dependent manner in both lean and obese animals. Figure 2C The magnitude of inhibition was greater in obese animals (tumor volume in obese mice was reduced by 58% and 76% after 8 and 24 mg / kg of compound 1, respectively) than in lean mice (tumor volume was reduced by 43% and 55% after 8 and 24 mg / kg of compound 1, respectively).

[0498] Figure 3A Shown are body weights of lean mice bearing B16F10 melanoma tumors after treatment with vehicle or 8 mg / kg or 24 mg / kg of Compound 1 of the present disclosure. Figure 3BShown are the body weights of obese mice bearing B16F10 melanoma tumors after treatment with vehicle or 8 mg / kg or 24 mg / kg of Compound 1 of the present disclosure. Data were analyzed by two-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 3A and 3B The results demonstrated that Compound 1 reduced body weight in both lean and obese mice. However, the magnitude of the weight loss was greater in obese animals (-19% and -27% body weight changes (relative to baseline) in obese mice in response to 8 and 24 mg / kg Compound 1, respectively) than in lean mice (-11% and -7% body weight changes (relative to baseline) in response to 8 and 24 mg / kg Compound 1, respectively).

[0499] Figure 4 Shown is the relationship between body weight and tumor size in vehicle- and Compound 1-treated DIO and lean mice. Figure 4 The results demonstrate that the effect of compound 1 in reducing tumor size correlates with its ability to reduce body weight. This effect is more robust (based on the magnitude of the change in both parameters and the greater slope of the regression line for obese mice) and is more closely correlated in obese mice compared to lean mice (based on p-values ​​from linear regression analysis).

[0500] Figure 5 Shown are the mean (+ / - SEM) numbers of metastatic lung lesions in obese and lean B16F10 melanoma / DIO mice following treatment with vehicle or 8 mg / kg or 24 mg / kg Compound 1 of the disclosure or 2 mg / kg of another MetAP2 inhibitor (Compound 4). Figure 5 The results demonstrated that obese mice had a greater number of metastases to the lungs than lean animals (3.6 + / - 1.4 lesions / mouse vs. 0.4 + / - 0.24 lesions / mouse for obese and lean mice, respectively, which was not statistically different). The results also showed that compound 1 reduced the number of lung metastases in obese mice in a dose-dependent manner (1.38 + / - 0.73 lesions / mouse and 0.5 + / - 0.22 lesions / mouse after 8 and 24 mg / kg treatment, respectively), although the differences were not statistically significant. Another MetAP2 inhibitor (compound 4) had only a small effect on the number of lung metastases in obese mice (2.4 + / - 0.8 lesions / mouse). No differences in lung metastases were found between the groups of lean mice (data not shown).

[0501] Table 3 shows the adipose tissue mass of obese mice bearing B16F10 melanoma after treatment with vehicle or 8 mg / kg or 24 mg / kg Compound 1 of the present disclosure or another MetAP2 inhibitor (Compound 4). One-way ANOVA was used to perform multiple comparison analysis of the data, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. The results of Table 3 confirm that obese tumor-bearing mice have significantly greater adipose tissue mass than thin tumor-bearing animals. They also show that Compound 1 reduces the body fat of obese animals (the result is that there is statistical significance only in epididymal adipose tissue). Note that the adipose tissue mass of DIO mice that do not carry tumors is 2-5 times (not shown) of control, vehicle-treated animals.

[0502] Table 3 also shows the adipose tissue mass of lean mice bearing B16F10 melanoma after treatment with vehicle or 8 mg / kg or 24 mg / kg of compound 1 of the present disclosure or another MetAP2 inhibitor (compound 4). One-way ANOVA was used to perform multiple comparison analysis of data, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results of Table 3 confirm that the adipose tissue accumulation in lean mice is not affected by treatment with compound 1.

[0503] Table 3

[0504]

[0505] Fig. 6 is shown in the white blood cell count of obese and thin B16F10 melanoma / DIO mice after treatment with vehicle or 8 mg / kg or 24 mg / kg of compound 1 of the present disclosure or another MetAP2 inhibitor (compound 4). One-way ANOVA is used to perform multiple comparison analysis on data, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results of Fig. 6 confirm that obese mice show leukocytosis (the level of circulating white blood cells (WBC) increases), and compound 1 reduces WBC. Fig. 6 also confirms that obese mice show greater sensitivity to the effect of WBC, because there is a significant effect in response to 8 mg / kg compound 1 in obese mice but not in thin mice.

[0506] Figure 7 Shown are B16F10 melanoma tumor growth in obese and lean mice following treatment with vehicle or 2 mg / kg unconjugated small molecule MetAP2 inhibitor (Compound 4). Figure 7The results demonstrated that compound 4 significantly inhibited tumor growth in obese mice (by 28%), although the magnitude of the effect was smaller than that observed with compound 1 (57% reduction at 8 mg / kg). In contrast to that observed with compound 1, compound 4 had no effect on tumor growth in lean mice.

[0507] To directly compare the amount of active MetAP2 inhibitor delivered by 8 mg / kg Compound 1 versus 2 mg / kg Compound 4, it is necessary to account for the amount of active agent in Compound 1, which is approximately 20% by weight, or 1.6 mg / kg of active agent delivered at an 8 mg / kg dose. Furthermore, Compound 1 was dosed once every four days; half the frequency of Compound 4. Therefore, the dose of active MetAP2 inhibitor delivered to mice from Compound 1 was approximately 1 / 2.5 of the active MetAP2 inhibitor delivered from Compound 4 (based on mg / kg per dose). However, to compare the total amount of active MetAP2 inhibitor delivered during the study period (17 days), the difference in dosing frequency (Compound 4 administered every two days versus Compound 1 administered every four days) must also be considered. Overall, nine doses of Compound 4 were equivalent to five doses of Compound 1, meaning that Compound 4 delivered 2.25 times more active MetAP2 inhibitor than Compound 1. Although the amount of active MetAP2 delivered was greater with Compound 4, its efficacy was lower than Compound 1, highlighting the superior and unexpected benefits provided by the compounds of the present disclosure.

[0508] Figure 8 Shown are body weights of tumor-bearing obese and lean mice after treatment with vehicle or 2 mg / kg of another small molecule MetAP2 inhibitor (Compound 4). Figure 8 The results demonstrated that although larger amounts of Compound 4 were delivered during the study (as discussed above), Compound 4 significantly reduced the body weight of obese mice (-7.9% after 2 mg / kg), but the magnitude of the effect was less than that observed with Compound 1 (-18.9% after 8 mg / kg). In contrast to the effect observed with Compound 1, Compound 4 had no effect on the body weight of lean mice.

[0509] Example 2 - In vivo testing in DIO mice - Leptin and adiponectin

[0510] Leptin is an adipocyte-derived hormone discovered based on its ability to inhibit caloric intake through signaling from receptors located on neurons in the hypothalamus of the central nervous system (CNS). Genetic deletion of leptin in mice and humans leads to severe obesity, which is reversed by exogenous delivery of recombinant leptin. Circulating levels of leptin are positively correlated with host adipose tissue mass, and elevated leptin levels have been observed in obese animals and humans. Unlike animals and humans of normal weight, obese animals and humans are unable to sense elevated levels of their endogenous leptin and are resistant to its anorectic, anti-obesity effects. Given the long and persistent course of obesity development, peripheral tissues and organs are exposed to elevated levels of leptin for years. Since leptin is now recognized to regulate several biological processes outside the CNS (e.g., immune function, angiogenesis, endothelial homeostasis, stem cell renewal), the adverse consequences of exposure to abnormally high leptin levels are now recognized. In particular, leptin has been shown to activate survival pathways in cancer stem cells (e.g., Oct4) and may therefore be responsible for 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 can directly increase cancer cell proliferation and also lead to metastatic disease. Importantly, the effect of ASC-derived leptin was significantly greater when ASCs were isolated from obese human donors than when they were isolated from lean human donors (Strong et al. Breast Can. Res. , 2015, 17:112). Leptin has therefore been implicated as part of the mechanistic link between obesity and cancer (Park et al, Nat Rev Endocrinol . 2014, 10(8): 455-465).

[0511] Another interesting endpoint in metabolic diseases and now (from a mechanistic and predictive perspective) in cancer is the adipocyte-derived hormone adiponectin. This protein is released from adipocytes into the circulation, where it acts on liver and muscle tissue to induce beneficial responses by enhancing the action of insulin. Adiponectin has recently been found to directly regulate 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 / cyclins) in an LKB1-dependent manner in mouse MCA38 and human HT29, HCT116, and LoVo colon cancer cell lines, suggesting that adiponectin may be protective in colorectal cancer (Moon et al, Gut, 2013, 2(4):561-70). Recent clinical studies have shown that adiponectin may have a protective effect against cancer recurrence, as increased levels are positively correlated with disease-free survival in breast cancer (Duggan et al, J Clin Oncol,. 2011, 29(1):32-9). Given the potential role of the two hormones leptin and adiponectin in metabolic diseases and cancer, plasma levels of leptin and adiponectin were measured (using ELISA) in samples obtained from in vivo studies in obese animals after administration of compound 1 to obese and lean mice bearing syngeneic B16F10 melanoma, or to obese mice without tumors.

[0512] Male C57BL / 6 mice were given free access to TD.06414, a high-fat diet (HFD) containing 60% Kcal from fat (DIO) for 16 weeks until the average body weight was >40 g.

[0513] Mice were treated with 5% mannitol in water (vehicle control) and Compound 1. Treatment was via subcutaneous injection of 5 ml / kg every 4 days (q4d) at either 2.0 mg / kg or 6.0 mg / kg of Compound 1.

[0514] Figure 9A Shown are 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. Figure 9B Shown are serum adiponectin in obese DIO mice after treatment with vehicle or 2 mg / kg or 6 mg / kg of Compound 1 of the present disclosure. Data were analyzed using one-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 9A and Figure 9BThe results demonstrated that compound 1 reduced serum leptin levels and increased serum adiponectin at each dose tested. In particular, compound 1 had a significant effect in reducing serum leptin levels.

[0515] Figure 9C Shown are the serum leptin:adiponectin ratios from obese DIO mice following treatment with vehicle or 2 mg / kg or 6 mg / kg of Compound 1. Data were analyzed using one-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 9C The results showed that each dose tested reduced the leptin:adiponectin ratio. In particular, compound 1 had a significant effect in reducing leptin:adiponectin serum levels at a dose of 6 mg / kg.

[0516] Figure 9D Shown are serum adiponectin levels in lean mice bearing B16F10 melanoma tumors following treatment with vehicle, 8 mg / kg or 24 mg / kg Compound 1, or 2 mg / kg Compound 4. Figure 9E Shown are serum adiponectin levels in obese DIO mice bearing B16F10 melanoma after treatment with vehicle, 8 mg / kg or 24 mg / kg Compound 1, or 2 mg / kg Compound 4. Data show one-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 9D and Figure 9E The results demonstrated that compound 1 significantly increased serum adiponectin levels 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.

[0517] Example 3 - In vivo testing EO771 breast tumor / DIO mice - tumor growth, body weight

[0518] 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 subsequently induced by injecting syngeneic EO771 cells into the fourth mammary gland (50,000 cells / mouse). When tumors became palpable, compound 1 (24 mg / kg) or vehicle (5% mannitol / water) was administered subcutaneously every 4 days for a total of 4 doses.

[0519] Figure 10A Shown is tumor growth in lean EO771 breast tumor / DIO mice after treatment with vehicle or 24 mg / kg Compound 1 of the present disclosure. Figure 10BShown is tumor growth in obese EO771 breast tumor / DIO mice after treatment with vehicle or 24 mg / kg Compound 1 of the present disclosure. Data were analyzed by two-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 10A and 10B The results demonstrated that EO771 tumors in obese female mice were 71% larger than those in lean female mice at day 15. The results also showed that compound 1 reduced tumor growth in both lean and obese female mice, with similar effects on tumor size (52% reduction in obese mice versus 53% reduction in lean mice).

[0520] Figure 11A Shown are body weights of lean EO771 mammary tumor-bearing mice after treatment with vehicle or 24 mg / kg Compound 1 of the present disclosure. Figure 11B Shown are changes in body weight relative to baseline in lean EO771 mammary tumor-bearing mice following treatment with vehicle or 24 mg / kg Compound 1 of the Disclosure. Figure 11C Shown are body weights of obese EO771 mammary tumor-bearing mice after treatment with vehicle or 24 mg / kg Compound 1 of the present disclosure. Figure 11D Shown are changes in body weight of obese EO771 mammary tumor-bearing mice after treatment with vehicle or 24 mg / kg Compound 1 of the present disclosure. Data were analyzed by two-way ANOVA for multiple comparisons, *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001. Figure 11A Results from –11D demonstrated that compound 1, administered at a dose of 24 mg / kg every 4 days, reduced body weight in 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).

[0521] Table 4 shows that Compound 1 significantly reduced adipose tissue mass (3 depots - parauterine, retroperitoneal, and inguinal - measured at necropsy) in obese mice after 2 weeks of every other day treatment. Similar, though less pronounced, effects of Compound 1 were observed in lean mice.

[0522] Table 4

[0523]

[0524] Example 4 - Phase 1 Dose Escalation Study of Compound 1 to Evaluate Safety and Tolerability in Patients with Advanced Refractory or Advanced-Stage Solid Tumors - Study Design

[0525] The Phase 1 clinical trial of Compound 1 had several objectives.

[0526] The main purposes are:

[0527] • Determine the safety and tolerability of Compound 1 in patients with advanced refractory or advanced-stage solid tumors.

[0528] • Determine the maximum tolerated dose (MTD) of compound 1 in patients with advanced refractory or advanced-stage solid tumors.

[0529] • To determine the recommended Phase 2 dose (RP2D) of Compound 1 in patients with advanced refractory or advanced-stage solid tumors.

[0530] The secondary purposes are:

[0531] • To evaluate the pharmacokinetic (PK) properties of Compound 5, the active moiety and metabolites of Compound 1 in patients with advanced refractory or advanced-stage solid tumors.

[0532] • Document evidence of anti-tumor activity of Compound 1 in patients with advanced refractory or advanced-stage solid tumors.

[0533] Exploratory objectives include:

[0534] • Evaluate the effect of Compound 1 in patients with advanced refractory or advanced-stage solid tumors by biomarker analysis, and by PET scan imaging (where clinically relevant and approved by the investigator and medical supervisor).

[0535] • The pharmacodynamic (PD) effects of Compound 1 in patients with advanced refractory or advanced-stage solid tumors will be evaluated by the MetAP2 assay and by DCE MRI scan imaging (where clinically relevant and approved by the investigator and medical supervisor).

[0536] • Document the effects of Compound 1 on metabolic parameters in patients with advanced refractory or advanced-stage solid tumors.

[0537] •Evaluation of muscle and fat tissue volume in selected patients using MRI or CT scan imaging.

[0538] Study Description

[0539] This is a Phase 1 dose escalation study evaluating the safety and tolerability of subcutaneously administered Compound 1 in patients with advanced refractory or advanced-stage solid tumors. Using an accelerated titration dose escalation design, one patient is used per dose level until the patient has a grade 2 toxicity that is deemed by the investigator to be possibly, probably, or definitely related to the study drug in their first treatment cycle. The cycle is 28 days, including a total of 4 weeks of treatment and including pre-dose safety testing before the start of the next treatment cycle. Once a secondary toxicity that is considered at least possibly related to the study drug is observed in the patient's first treatment cycle, the accelerated phase of the study will end and the non-accelerated phase (3+3 dose escalation design) will begin. At the dose that triggered the switch to the non-accelerated design and at each subsequent dose level, at least 3 evaluable patients will naturally increase the dose until dose-limiting toxicity (DLT) is found.

[0540] During the accelerated titration dose-escalation design, the sponsor, medical monitor, and safety review committee (SRC) may decide to move to a 3+3 non-accelerated dose-escalation phase before any grade 2 toxicity is observed that is considered at least possibly related to the study drug during the patient's first treatment cycle.

[0541] In the 3+3 non-accelerated phase, if one of the 3 patients has DLT (defined as follows), the colony will be expanded to a maximum of 6 patients. If only one of the 6 patients has DLT, dose escalation will continue. If 2 patients have DLT, dose escalation will stop, regardless of the number of patients treated in this group of colonies (for example, if patients 1 and 4 have DLTs, then patients 5 and 6 will no longer be treated). 2 of the 6 patients who have DLT at this dosage will be considered at least one dosage level above the MTD. The next lower dosage will be fully evaluated by treating a total of 6 patients. If two or more patients have DLTs at this lower dosage level, de-escalation dose will continue until identifying that 6 patients do not have or have only one dosage level with DLT. This dosage will be identified as MTD.

[0542] Once the MTD is determined, up to 6 additional patients, for a total of up to 12 patients, can be treated at this dose level to further summarize treatment-emergent adverse events (TEAEs).

[0543] Patients who experience Grade 3 or higher toxicity that the investigator determines is possibly, probably, or definitely related to the administration of Compound 1 may have their next dose withheld for up to 14 days (the day the dose is due is considered the first day of dose delay), and treatment may be repeated at the same dose level when the patient's toxicity returns to Grade 1 or to the patient's pre-event baseline. Patients who have their dose withheld for longer than 14 days will be discontinued from the study. A dose delay of up to two weeks from the scheduled first day of treatment may be considered for a patient's clinical problem, which may be considered unrelated to the study drug based on agreement between the investigator, medical monitor, and patient.

[0544] During the study, the SRC may determine whether additional dose groups should be opened. New dose groups above or below the highest dose used may be added with the approval of the Investigator, Medical Supervisor, and SRC.

[0545] Intra-patient dose escalation to the next higher cohort will consider those patients who have not demonstrated Grade 2 toxicity that is considered at least possibly related to the study drug in their first cycle and who have successfully completed their Tumor Burden Assessment after the second cycle. This type of dose escalation will only allow patients in the next higher dose cohort to successfully complete their first cycle safety evaluation by not demonstrating Grade 2 toxicity that is considered at least possibly related to the study drug. The decision to escalate the dose will be made in discussions between the investigator, medical monitor, and sponsor, taking into account the patient's input. If a patient is escalated to the next higher dose level in cycles 4, 5, or 7 and higher, additional plasma PK samples will be collected according to the defined protocol.

[0546] Patients will be allowed to continue treatment:

[0547] • If there is a clinical response, or

[0548] • If they have stable disease as assessed by imaging studies after C2, C4, C6 and every 3 cycles thereafter, or

[0549] •If the investigator and medical monitor believe the patient will benefit from treatment.

[0550] Each patient will be dosed once weekly for 4 weeks (Days 1, 8, 15, and 22) and include a safety follow-up before the start of the next treatment cycle. RECIST 1.1 Standard disease evaluation will be preceded by 2 cycles. The following dose levels will be used:

[0551]

[0552] Toxicity was determined using the Common Terminology Criteria for Adverse Events (CTCAE) v4.02.

[0553] A DLT was defined as any of the following adverse events that were clinically significant and considered by the Investigator to be possibly, probably, or definitely related to continued administration of Compound 1 despite best medical support:

[0554] • Any non-hematologic toxicity of Grade 3 or higher; persisting for seven (7) days, or

[0555] • Any Grade 3 or greater nausea, diarrhea, and / or vomiting that persists for three (3) days, provided the patient receives maximal medical intervention and / or prophylactic anti-emetic medication; or

[0556] • Any Grade 3 or higher hematologic toxicity lasting three (3) days, or

[0557] •Any neutropenic fever of Grade 3 or higher.

[0558] Research group : Approximately 30 patients

[0559] Study drug administration : Compound 1 will be administered by subcutaneous injection on days 1, 8, 15, and 22 of each cycle, and safety follow-up will be included before the start of the next treatment cycle.

[0560] Admission criteria:

[0561] The patient has the ability to provide written, informed consent to understand the requirements of the study and agrees to comply with the requirements of the study.

[0562] Male or female aged ≥21 to ≤85 years.

[0563] It is available for patients with histologically or cytologically confirmed advanced refractory, late-stage solid tumors who have progressed on standard treatment or have no effective anti-cancer therapy.

[0564] Patients with at least one radiographically measurable disease ≥1 cm in the greatest dimension on conventional computed tomography (CT) scanning (per RECIST 1.1 criteria) or, in the investigator's opinion, if evaluable disease can be reliably and continuously followed, may be eligible after approval by the medical monitor.

[0565] Eastern Cooperative Oncology Group (ECOG) status ≤1.

[0566] Life expectancy ≥3 months.

[0567] Women of childbearing potential must not be breastfeeding or lactating and must have a negative seronegative pregnancy test within 72 hours of the start of the study. Female and male study patients must be willing to use a double-barrier birth control method such as condoms or an occlusive cap (e.g., diaphragm or cervical cap / suppository) plus a spermicide (e.g., foam, gel, film, cream, suppository) throughout their participation in the study, including a period of 90 days after their last treatment, if the female partner is not postmenopausal or surgically sterilized.

[0568] The laboratory data are specified as follows:

[0569] • Hematology: ANC > 1500 cells / mm 3 , platelet count >100,000 cells / mm 3 and hemoglobin >9 g / dL.

[0570] • Urinalysis: No clinically significant abnormalities.

[0571] •Hemostasis: INR and PTT are within normal limits.

[0572] • HIV-positive patients are eligible if they meet the following criteria: CD4 count ≥100 / mm 3 , undetectable viral load in the past three months, receiving a stable antiretroviral regimen for ≥4 weeks prior to study entry.

[0573] Patients eligible for imaging studies had to be able to lie flat for up to 45 minutes.

[0574] Exclusion criteria

[0575] Patients who have undergone organ transplant surgery.

[0576] Patients with known primary brain malignancies, brain metastases, or active CNS lesions.

[0577] Patients with a known history of hepatitis A, B, or C receiving active antiviral therapy

[0578] Patients receiving anticoagulant medications; however, standard-dose ASA, antiplatelet agents, are permitted when approved in advance by the medical supervisor.

[0579] Patients with a history of gastric bypass or band surgery.

[0580] Patients who require insulin to control their diabetes. Subjects taking insulin secretagogues that act in a glucose-independent manner – sulfonylureas such as glyburide and any other drugs in this class.

[0581] Patients on corticosteroids above physiologic replacement levels; for example, prednisone 5 mg, dexamethasone 0.75 mg, hydrocortisone 20 mg, betamethasone 0.6 mg, methylprednisolone 4 mg, cortisone 25 mg, etc. daily. Nasal, inhaled, and topical corticosteroids are permitted.

[0582] Patients with uncontrolled or refractory hypertension: systolic blood pressure >180 or diastolic blood pressure >110, or hypotension: systolic blood pressure <90 or diastolic blood pressure <50, regardless of medical treatment.

[0583] During the screening period, a resting 12-lead electrocardiogram (ECG) was obtained showing a QTc (Bazett's correction) ≥470 ms or patients with congenital long QT syndrome. Isolated right bundle branch block (RBBB), incomplete right bundle branch block (IRBBB), and left anterior fascicular hemiblock (LAH) were acceptable. Any uncontrolled arrhythmia (patients with rate-controlled atrial fibrillation were not excluded unless they were on chronic anticoagulation per exclusion criterion #4) was also considered.

[0584] Renal: Serum creatinine > 1.5X upper limit of normal (ULN), or calculated creatinine clearance < 50 mL / min / 1.73 m2 for patients with creatinine levels above the prescribed normal level 2 .

[0585] Liver: Total bilirubin ≥1.5X ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5X ULN. For patients with known liver metastases or liver tumors, ALT or AST ≤5.0X ULN is permitted.

[0586] Participation in any other trial of an investigational drug within 30 days prior to the first dose of study drug.

[0587] Previous treatment:

[0588] • Treatment with the following drugs for ≤ 4 weeks or 5 half-lives, whichever is shorter, before the first dose of study drug:

[0589] • Any treatment with cytotoxic or cytostatic chemotherapy, monoclonal antibody therapy, radiation therapy, molecularly targeted therapy, hormonal drugs, TKIs (tyrosine kinase inhibitors), angiogenesis and VEGF inhibitors.

[0590] • Major surgery ≤ 4 weeks prior to the first dose of study drug.

[0591] •Any radioimmunotherapy ≤ 12 weeks before the first dose of study drug.

[0592] Any other coexisting medical condition or social condition that, in the opinion of the investigator, would prevent the patient from participating in the study or interfere with the patient's compliance with the study.

[0593] Any serious medical condition, laboratory abnormality, or psychiatric condition that would prevent the patient from participating in the following study procedures or that would place the patient at unacceptable risk if she / he participated in the study or would confound the ability to interpret data from the study.

[0594] Patients with a known history of hypersensitivity to any test material or related compounds.

[0595] Given that the biologically active small molecule moieties of Compound 1 and Compound 5 are CYP3A 4&5 substrates, patients who require long-term concurrent treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4 / 5) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, and St. John's Wort).

[0596] Patients who have had localized radiation therapy (e.g., for analgesia or to prevent cytolytic injury with risk of fracture) ≤ 4 weeks prior to starting study drug, or radiation therapy ≤ 2 weeks prior to starting study drug, or have not recovered from radiation therapy toxicity.

[0597] Prior use of prescription or over-the-counter appetite stimulants (appetites) (i.e., megestrol acetate, mirtazapine, dronabinol, anabolic steroids) within 2 months of the first dose of study drug.

[0598] Research evaluation

[0599] The following is an overview of the requirements and tests required prior to enrollment and that will be performed during patient participation in this Phase 1 study.

[0600] Screening phase (up to 14 days before Day 1)

[0601] •Signed informed consent

[0602] •Medical history

[0603] • Physical examination (all body systems); rectal and genital examinations may be deferred if not clinically indicated

[0604] • Height and weight

[0605] • ECOG performance status

[0606] • Vital signs (temperature, blood pressure, pulse, and respiratory rate)

[0607] • Parallel drug evaluation

[0608] • 12-lead electrocardiogram (repeated 3 times)

[0609] • Serum pregnancy test (for non-infertile women of reproductive potential)

[0610] •hematology

[0611] •Clinical chemistry, coagulation, lipids, and urinalysis (microscopy if dipstick positive)

[0612] • Tumor burden was assessed radiographically using RECIST 1.1 Standard (CT scan may be used if captured no more than 130 days before treatment day 1)

[0613] •PET and DCE MRI scans were performed when clinically indicated and approved by the investigator and medical supervisor

[0614] • MRI or CT scans for body composition analysis on selected patients approved by the investigator and medical supervisor; see Imaging Manual

[0615] • Document any clinically acceptable analytical results available for protein biomarkers relevant to the patient's specific tumor type (e.g., PSA, CA-125, AFP, CEA, β-hCG, CA19-9, etc.)

[0616] Treatment period (except for PK, PD, biomarkers, and retention, pre-dose testing can be performed within 72 hours of treatment)

[0617] • Medical history

[0618] • Body weight (previous to each treatment day for study drug dose calculations - body weight from previous visits can be used for study drug dose calculations)

[0619] • Questions about eating habits, food, and physical activity

[0620] • ECOG performance status (1 day before dose of each cycle)

[0621] • Vital signs (temperature, blood pressure, pulse, and respiratory rate)

[0622] • Parallel drug evaluation

[0623] •12-lead electrocardiogram (repeated 3 times).

[0624] • Local tolerance at the injection site of subcutaneous therapy

[0625] • Serum pregnancy test for female patients of reproductive potential (1 day prior to dose)

[0626] •hematology

[0627] •Clinical chemistry, coagulation, lipids, and urinalysis (microscopy if dipstick positive)

[0628] • Blood sample collection for PK and PD analysis

[0629] • Blood sample collection for biomarker and retention exploration

[0630] •PET and DCE MRI scans were performed as clinically indicated and approved by the investigator and medical supervisor; see the Imaging Manual

[0631] • MRI or CT scans for body composition analysis on selected patients approved by the investigator and medical supervisor; see Imaging Manual

[0632] •use RECIST 1.1 Tumor burden assessments will be performed every other cycle (i.e., at the end of cycles 2, 4, and 6). After completion of cycle 6, tumor burden assessments will be performed every 3 cycles. If a stable or positive response is found, a follow-up (4-week) confirmatory radiological assessment will be performed.

[0633] • Document any available, clinically acceptable analytical results for the patient's specific tumor type-associated protein biomarkers (e.g., PSA, CA-125, AFP, CEA, β-hCG, CA19-9, etc.)

[0634] • Review of adverse events (including symptom review)

[0635] End-of-Treatment (EOT) evaluation (EOT visit will be scheduled as soon as possible after the investigator determines that study drug treatment is no longer an option, or after the patient withdraws from the study)

[0636] •weight

[0637] • Questions about food, eating habits, and physical activity

[0638] • ECOG performance status

[0639] • Vital signs (temperature, blood pressure, pulse, and respiratory rate)

[0640] • Parallel drug evaluation

[0641] • 12-lead electrocardiogram (repeated 3 times)

[0642] • Local tolerance at the injection site of subcutaneous therapy

[0643] •hematology

[0644] •Clinical chemistry, coagulation, lipid, and urinalysis (microscopy)

[0645] • Blood sample collection for PK and PD analysis

[0646] • Blood sample collection for biomarker and retention exploration

[0647] •use RECIST 1.1 Tumor burden assessment

[0648] • Document any available, clinically acceptable analytical results for the patient's specific tumor type-associated protein biomarkers (e.g., PSA, CA-125, AFP, CEA, β-hCG, CA19-9, etc.)

[0649] • Review of adverse events (including symptom review)

[0650] End-of-Study (EOS) Assessment (EOS 30 days after EOT (±3 days) visit)

[0651] • Physical examination

[0652] • Height and weight

[0653] • Questions about food, eating habits, and physical activity

[0654] • ECOG performance status

[0655] • Vital signs (temperature, blood pressure, pulse, and respiratory rate)

[0656] • Parallel drug evaluation

[0657] • 12-lead electrocardiogram (repeated 3 times)

[0658] • Local tolerance at the injection site of subcutaneous therapy

[0659] • Serum pregnancy test (for non-infertile women of childbearing potential)

[0660] •hematology

[0661] •Clinical chemistry, coagulation, lipid, and urinalysis (microscopy)

[0662] • Blood sample collection for PK and PD analysis

[0663] • Blood sample collection for exploratory biomarkers and retention

[0664] • Tumor burden assessment using RECIST 1.1conduct

[0665] • Record any available clinically acceptable analytical results for the patient's specific tumor type-associated protein biomarkers (e.g., PSA, CA-125, AFP, CEA, β-hCG, CA19-9, etc.)

[0666] • Review of adverse events

[0667] Study endpoints

[0668] Safety endpoints

[0669] • Incidence, grade, and duration of AEs

[0670] • Global and local tolerance evaluation

[0671] • Laboratory evaluation

[0672] •Physical examination, vital signs and ECG parameters

[0673] Pharmacokinetic and tumor burden endpoints

[0674] • PK profile from dose 1 until the patient is no longer taking the drug

[0675] • Changes in disease status, overall response rate (CR + PR) and disease control rate (CR + PR + SD)

[0676] Explore the End

[0677] •PET and DCE MRI evaluation

[0678] • Distribution of PD (MetAP2) from Dose 1 until patients were no longer taking study drug

[0679] • MRI or CT evaluation of body composition changes

[0680] • Biomarker assessments (TNF-α, IL-6, MCP-1, IGF-1, hsCRP, leptin, insulin, SHBG (for selected patients), VEGF, bFGF, and adiponectin) from Dose 1 until patients were no longer taking study drug

[0681] • Metabolic evaluations (glucose, total cholesterol, LDL, HDL, free fatty acids, lipids, triglycerides, and VLDL) and diet and food evaluations from dose 1 until the patient is no longer taking study drug

[0682] Statistical analysis

[0683] Given the small sample size of patients in this Phase 1 trial, descriptive statistics will be used for all safety, efficacy, and pharmacokinetic parameters. Categorical variables will be summarized by frequency distribution (number and percentage of patients), continuous variables will be summarized by mean, standard deviation, median, minimum, maximum, and time-to-event variables will be summarized using the Kaplan-Meier method and estimated median time numbers.

[0684] The frequency with which patients experienced at least one AE will be displayed by body system and preferred term according to MedDRA nomenclature. Detailed information collected for each AE will include: description of the event, duration, whether the AE was serious, severity, relationship to study drug, action taken, clinical consequences, and whether it was a DLT. The severity of AEs will be graded according to CTCAE v4.02. AEs graded as dose-limiting will be listed.

[0685] The summary table will show the number of patients (per dose group) in whom AEs were observed and the corresponding percentage. The denominator used to calculate the incidence percentage includes patients who received at least one dose of Compound 1 in each dose group. Within each table, AEs will be classified by MedDRA body system and preferred term. Additional subcategories will be based on the severity of the event and its relationship to the study drug.

[0686] Adverse events leading to treatment discontinuation or withdrawal from the study, serious adverse events, and deaths will be tabulated. All DLTs will be reported and the MTD identified.

[0687] Vital signs and ECGs will be summarized using descriptive statistics. Summary tables will be prepared to examine the distribution of laboratory measurements over time. Conversion tables will be provided to examine the distribution of laboratory toxicities. In addition, patient listings will list adverse events, vital signs, clinical laboratory test results, physical examinations, and ECGs (before and after treatment).

[0688] Example 5 – Phase 1 Study – Metabolic Dysfunction

[0689] Metabolic dysfunction, defined as elevated levels of hormones such as insulin, leptin, IGF-1, or decreased levels of hormones such as adiponectin or an elevated leptin:adiponectin ratio, is often associated with obesity (defined as having a body mass index >30 kg / m2). The most common causes of obesity are overnutrition and a sedentary lifestyle, which over time lead to increased storage of nutrients as triglycerides within adipose tissue. In this setting, adipocytes within adipose tissue undergo excessive enlargement as more triglycerides are deposited and obesity develops, but these cells eventually reach a critical size beyond which they cannot expand. Excessively enlarged adipocytes exhibit increased leptin secretion (which leads to increased levels of circulating leptin relative to adipose tissue mass) and decreased adiponectin secretion (which leads to decreased levels of circulating adiponectin, indicative of metabolic dysfunction).

[0690] In addition, excessively enlarged adipocytes cause local hypoxia, which causes cell stress, cell death, and simultaneous immune cell infiltration (macrophages and lymphocytes) to digest excess triglycerides and cellular debris. Subsequent events include persistent inflammation within adipose tissue, proliferation of adipose stem cells due to excessive adipocyte enlargement, and increased angiogenesis, all of which lead to the development of metabolic dysfunction.

[0691] These events occur primarily in visceral (abdominal) adipose tissue, rather than subcutaneous adipose tissue, and the association of visceral adipose tissue mass (but to a lesser extent, subcutaneous adipose tissue) with metabolic dysfunction is well known. However, because the measurement of BMI does not capture the distribution of adipose tissue within the body, nor does it take into account muscle mass, excess fat and pathological abnormalities in adipose tissue that lead to metabolic dysfunction as defined above can all occur in patients with a BMI in the normal (e.g., 20-25 kg / m2) or overweight (e.g., 25-30 kg / m2) categories. To determine whether a patient has metabolic dysfunction, BMI is inaccurate for the reasons mentioned above, and a more accurate test would include measuring the levels of circulating hormones such as insulin, leptin, adiponectin, and IGF-1.

[0692] In this study, circulating hormones such as insulin, leptin, adiponectin, and IGF-1 were measured in cancer patients (fasting state) who responded to once-weekly subcutaneous administration of Compound 1 (using a range of doses). It was noted that patients with carcinoid, colorectal, cervical, endometrial, and breast cancer showed baseline levels of these hormones that indicate varying degrees of metabolic dysfunction. In addition, after weekly administration of Compound 1, the direction of change in the levels of these hormones indicated improvement in metabolic dysfunction.

[0693] Figure 12 shows circulating levels of the metabolic biomarkers insulin, adiponectin, leptin, IGF-1, and leptin:adiponectin ratio (LAR) at baseline and following weekly administration of Compound 1 to male patients with carcinoid tumors and a BMI of 24.5 kg / m2 (e.g., normal). Figure 12A Displays the absolute and Figure 12B Shown are % changes from baseline over time. Figure 12A and 12B Results demonstrated that fasting insulin levels were abnormally high at baseline but decreased by 89% (relative to baseline) after four weekly doses of Compound 1. Furthermore, leptin levels and the leptin:adiponectin ratio (LAR) decreased, indicating improved metabolic function following Compound 1 administration.

[0694] In another example shown in FIG13 , a female patient with colon cancer (BMI = 23.5, or normal) was administered 6 mg / m 2 once weekly. 2 Compound 1 for 12 weeks, followed by dose escalation (DE) to 8.5 mg / m 2 , for an additional 6 weeks. Figure 13A Displays the absolute and Figure 13B Shows % change over time. Figure 13A and 13B The results demonstrated that leptin decreased from baseline, while adiponectin increased at the same time, such that LAR decreased by 62% from a high value of 4.7 at baseline, indicating improvement of metabolic dysfunction after administration of Compound 1.

[0695] In another example shown in FIG14 , a female patient with endometrial cancer (BMI = 25.1, or overweight) was administered 8.5 mg / m 2 once weekly. 2 Compound 1 for 12 weeks followed by dose escalation (DE) to 11.9 mg / m 2 , for an additional 5 weeks. Figure 14A Displays the absolute and Figure 14B Shows % change over time. Figure 14A and 14B The results demonstrated that leptin decreased from baseline, while adiponectin increased over the same time period, such that LAR decreased by 85% from a high value of 4.5 at baseline, indicating improved metabolic dysfunction following administration of Compound 1. Insulin data were not available at baseline, so a % change from baseline was not calculated, but insulin did decrease by 80% from 4 weeks after the start of dosing (when insulin data first became available) to 8 weeks after the start of dosing.

[0696] In another example shown in FIG15 , 11.9 mg / m 2 was administered once weekly to a female patient with cervical cancer (BMI = 22.5, or normal). 2 Compound 1 for 8 weeks. Figure 15A Displays the absolute and Figure 15B Shows % change over time. Figure 15A and 15B The results demonstrated that leptin decreased by 88% from baseline and LAR decreased by 78% from baseline, indicating that metabolic dysfunction improved after eight weeks of administration of Compound 1. Insulin decreased by 50% from baseline to eight weeks after administration, also indicating that metabolic dysfunction improved after administration of Compound 1.

[0697] In another example shown in FIG16 , 15.3 mg / m was administered once weekly to a female patient with hormone receptor-positive breast cancer (BMI = 27.5, or overweight). 2 Compound 1 for 8 weeks. Figure 16A Displays the absolute and Figure 16B Shows % change over time. Figure 16A and 16B The results demonstrated that leptin decreased by 70% from baseline, indicating improvement in metabolic dysfunction after eight weeks of administration of Compound 1.

Claims

1. Use of a therapeutically effective amount of at least one compound of the formula: or a pharmaceutically acceptable salt thereof, and at least one second active agent in the preparation of a medicament for treating metabolically sensitive tumors in obese subjects suffering from at least one metabolic dysfunction: in x is in the range of 1 to 450; y is in the range of 1 to 30; and n is in the range of 1 to 100, wherein the metabolic dysfunction is excessive visceral adiposity, elevated leptin levels, decreased adiponectin levels, a high leptin to adiponectin ratio, elevated fasting insulin, or any combination thereof; The metabolically sensitive tumor is breast cancer or melanoma.

2. The method of claim 1, wherein the second active agent comprises at least one kinase inhibitor.

3. The use according to claim 2, wherein the at least one kinase inhibitor is a multi-kinase inhibitor.

4. The use of claim 2, wherein the at least one kinase inhibitor is a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, an MTOR inhibitor, or any combination thereof.

5. The use of claim 1, wherein the second active agent comprises fulvestrant.

6. The use of claim 1, wherein the second active agent comprises a chemotherapeutic agent.

7. The use of claim 6, wherein the chemotherapeutic agent comprises an alkylating agent, an antibiotic, an antimetabolite, an antidote, an interferon, a polyclonal or monoclonal antibody, or any combination thereof.

8. The method of claim 6, wherein the chemotherapeutic agent comprises an EGFR inhibitor, a FGFR inhibitor, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitotic inhibitor, an MTOR inhibitor, a multikinase inhibitor, or any combination thereof.

9. The use of claim 6, wherein the chemotherapeutic agent comprises a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, a VEGF / VEGFR inhibitor, or any combination thereof.

10. The use of claim 6, wherein the chemotherapeutic agent comprises a taxane or a taxane derivative, an anthracycline, or any combination thereof.

11. The use of claim 6, wherein the chemotherapeutic agent comprises an aromatase inhibitor, a microtubule-targeting drug, a topoisomerase poison, a cytidine analog drug, an anti-tumor agent, an anti-proliferative agent, or any combination thereof.

12. The use according to claim 1, wherein the metabolically sensitive tumor is breast cancer.

13. The use according to claim 12, wherein the breast cancer is hormone receptor positive (HR+) breast cancer. The use according to claim 13 , wherein the HR+ breast cancer is HR+ / Her2- breast cancer.

15. The use according to claim 1, wherein the metabolically sensitive tumor is melanoma.

16. The method of claim 1, wherein the therapeutically effective amount of the at least one compound or a pharmaceutically acceptable salt thereof is 1 mg / m 2 Up to 50 mg / m 2 .

17. The method of claim 1, wherein the therapeutically effective amount of the at least one compound or a pharmaceutically acceptable salt thereof is 5 mg / m 2 Up to 25 mg / m 2 .

18. The method of claim 1, wherein the therapeutically effective amount of the at least one compound or a pharmaceutically acceptable salt thereof is 5 mg / m 2 Up to 50 mg / m 2 .

19. The method of claim 1, wherein the therapeutically effective amount of the at least one compound or a pharmaceutically acceptable salt thereof is 5 mg / m 2 Up to 15 mg / m 2 .

20. The method of claim 1, wherein the therapeutically effective amount of the at least one compound or a pharmaceutically acceptable salt thereof is 5 mg / m 2 Up to 10 mg / m 2 .

21. The use of claim 1, wherein the at least one compound or a pharmaceutically acceptable salt thereof is provided as a pharmaceutical composition comprising the at least one compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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