METAP2 inhibitors for the treatment of pulmonary fibrosis

Abstract

The present disclosure provides pharmaceutical combinations comprising a MetAP2 inhibitor for the treatment of interstitial lung diseases, including pulmonary fibrosis.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 396,836, filed August 10, 2022, and U.S. Provisional Application No. 63 / 405,973, filed September 13, 2022. The contents of each of the above patent applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Interstitial lung disease (ILD) refers to a large group of disorders that cause progressive scarring of lung tissue, mostly due to fibrosis. The scarring associated with ILD ultimately affects a person's ability to breathe and get enough oxygen into the bloodstream, resulting in a series of adverse health effects. ILD can be caused by long-term exposure to harmful substances such as asbestos. Some types of autoimmune diseases, such as rheumatoid arthritis, can also cause ILD. Interstitial lung disease can also be induced by the administration of certain drugs, including anticancer drugs (Schwaiblmair et al. Drug-induced interstitial lung disease. Open Respir Med J. 2012;6:63-74. doi:10.2174 / 1874306401206010063. Epub 2012 Jul 27. PMID:22896776; PMCID:PMC3415629; Camus et al. Interstitial lung disease associated with drug therapy. Br J Cancer. 2004;91 Suppl 2(Suppl 2):S 18-S 23; Conte et al. Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment. ESMO Open. 2022;7(2):100404; which are incorporated by reference in their entireties for all purposes). For example, Enhertz, an antibody-drug conjugate used to treat HER2-positive metastatic breast cancer, has been shown to induce ILD, including pneumonitis, in certain patients, although in some cases the cause remains unknown (i.e., idiopathic).

[0003] Pulmonary fibrosis, also known as lung fibrosis, is a complex disease with multiple subtypes, including idiopathic pulmonary fibrosis (IPF), which is progressive, chronic, and one of the most lethal interstitial lung diseases. Pulmonary fibrosis, including IPF, is characterized by extracellular matrix (ECM) remodeling and abnormal fibroblast proliferation in the lung parenchyma (lung lesions), resulting in edema and tissue scarring. Pulmonary fibrosis is thought to be caused by long-term exposure to substances harmful to alveolar epithelial cells and genetic factors. Although the pathogenesis of pulmonary fibrosis is not yet fully understood, various cytokines and other molecules have been reported to play important roles in disease progression. Activated lung epithelium can also produce mediators for fibroblast migration, proliferation, and differentiation into activated myofibroblasts. These myofibroblasts secrete increased amounts of molecules that promote extracellular matrix fluid and lung structural remodeling.

[0004] Inflammatory signaling pathways have been implicated in the pathophysiology of pulmonary fibrosis. Acute inflammatory responses play a key role in inducing pulmonary fibrosis, for example, in the bleomycin-induced pulmonary fibrosis model, an animal model used to study pulmonary fibrosis. Brief exposure to bleomycin induces epithelial cell apoptosis and activates an inflammatory wound-healing response that can result in the transient excessive deposition of ECM components in the affected tissue. Therefore, reducing the inflammatory response can halt or slow the progression of tissue remodeling and restore normal tissue architecture after injury. Fibrosis is promoted by many signaling molecules, including inflammatory cytokines.

[0005] Although the pathogenesis of pulmonary fibrosis is not fully understood, evidence suggests that several classes of proteases may play important roles in the pathogenesis of the disease. For example, the expression of matrix metalloproteinases (e.g., MMP-7 and MMP-9) and certain cathepsins (e.g., cathepsins B and H) is increased in lung samples from patients with pulmonary fibrosis, and promotes the development of pulmonary fibrosis and / or extracellular matrix remodeling in experimental models. Another class of proteases, including the aminopeptidase family, has also been implicated in several disease models of fibrosis, with increased aminopeptidase activity found in bronchoalveolar lavage fluid from patients with IPF and patients with interstitial lung lesions resulting from connective tissue disease compared with normal volunteers. One member of the aminopeptidase family is methionine aminopeptidase type 2 (MetAP2, or p67), which catalyzes the removal of N-terminal methionine from nascent polypeptides.

[0006] There is a need in the art for compositions and methods for the treatment of ILD. Additionally, there is a need in the art for compositions and methods for preventing and / or alleviating treatment-induced ILD. The present disclosure provides MetAP2 inhibitors and combinations comprising MetAP2 inhibitors for the treatment of ILD, including pulmonary edema, pleural effusion, pulmonary fibrosis, and pneumonia, and for preventing and / or alleviating treatment-induced ILD. Summary of the Invention

[0007] The present disclosure provides at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating pulmonary fibrosis in a subject.

[0008] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0009] The present disclosure provides a combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof for use in treating pulmonary fibrosis in a subject.

[0010] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0011] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis in a subject, the method further comprising administration of nintedanib or a pharmaceutically acceptable salt thereof.

[0012] The present disclosure provides nintedanib, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis in a subject, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure provides a combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof for use in treating pulmonary fibrosis in a subject.

[0014] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0015] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis in a subject, the method further comprising administration of pirfenidone or a pharmaceutically acceptable salt thereof.

[0016] The present disclosure provides pirfenidone, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis in a subject, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0017] Any of the above aspects, or any other aspect described herein, can be combined with any other aspect.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular includes the plural unless the context clearly dictates otherwise; for example, the terms "a," "an," and "the" are understood to be singular or plural, and the term "or" is understood to be inclusive. For example, "an element" means one or more elements. Throughout this specification, the term "comprising," or variations such as "comprises" or "comprising," are understood to imply the inclusion of a stated element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps. The term "about" or "approximately" may be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term "about."

[0019] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0020] The above and further features will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings.

[0021] [Figure 1] FIG. 1 is a series of graphs showing PenH values (left panel) and respiratory rates (right panel) of mice in each treatment group on day 6 of the study described in Example 1 of the present disclosure, after the mice were randomized into different treatment groups and prior to the start of treatment.

[0022] [Figure 2] 1 is a series of graphs showing PenH values on day 13 of the study described in Example 1 of the present disclosure (top left panel), the change in PenH values from day 6 to day 13 of the study described in Example 1 of the present disclosure (bottom left panel), the respiratory rate on day 13 of the study described in Example 1 of the present disclosure (top right panel), and the change in respiratory rate from day 6 to day 13 of the study described in Example 1 of the present disclosure (bottom respiratory rate panel) for each treatment group described in Example 1 of the present disclosure.

[0023] [Figure 3]1 is a series of graphs showing PenH values at day 20 of the study described in Example 1 of the present disclosure (top left panel), the change in PenH values from day 6 to day 20 of the study described in Example 1 of the present disclosure (bottom left panel), the respiratory rate at day 20 of the study described in Example 1 of the present disclosure (top right panel), and the change in respiratory rate from day 6 to day 20 of the study described in Example 1 of the present disclosure (bottom respiratory rate panel) for each treatment group described in Example 1 of the present disclosure.

[0024] [Figure 4] 1 is a series of graphs showing PenH values (left panel) and respiratory rate (right panel) in each treatment group over the course of the study described in Example 1 of the present disclosure.

[0025] [Figure 5A] 1 is a series of graphs showing blood oxygen tension (pO2), blood bicarbonate (HCO3-) ion levels, and blood lactate levels in each treatment group at the end of the study described in Example 1 of the present disclosure (left panel to right panel, respectively).

[0026] [Figure 5B] 1 is a graph showing arterial blood saturation (SpO2) in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0027] [Figure 6] 1 is a graph showing lung weights in each treatment group at the end of the study described in Example 1 of the present disclosure.

[0028] [Figure 7] 1 is a graph showing pressure-volume curves (PV loops) in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0029] [Figure 8] 1 is a graph showing static compliance (Cst) in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0030] [Figure 9]1 is a series of graphs showing inflation volumes (tidal volumes) and lung volumes (total lung capacity) in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0031] [Figure 10] 1 is a series of graphs showing respiratory system resistance (Rrs) and tissue dumping (G) in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0032] [Figure 11] 1 is a series of graphs showing respiratory system elastance (Ers) and lung elastance (H) in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0033] [Figure 12] 1 is a series of graphs showing the results of automated histopathological analysis of lung samples obtained from each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0034] [Figure 13] 1 is a series of graphs showing body weight and body weight change in each treatment group over the course of the study described in Example 2 of the present disclosure.

[0035] [Figure 14] 1 is a graph showing left lung weights in each treatment group at the end of the study described in Example 2 of the present disclosure.

[0036] [Figure 15] 1 is a graph showing post-caval lobe weights in each treatment group at the end of the study described in Example 2 of the present disclosure.

[0037] [Figure 16] 1 is a graph showing survival of mice in each treatment group over the course of the study described in Example 2 of the present disclosure.

[0038] 17-19 are a series of graphs showing the results of automated histopathological analysis of lung samples obtained from each treatment group at the end of the study as described in Example 2 of the present disclosure.

[0039] [Figure 17] 1 is a graph depicting the results of automated histopathological analysis quantifying tissue density in lung samples from mice from each treatment group at the end of the study as described in Example 2 of the present disclosure.

[0040] [Figure 18] 1 is a graph depicting the results of automated histopathological analysis quantifying fibrotic foci in lung samples from mice from each treatment group at the end of the study as described in Example 2 of the present disclosure.

[0041] [Figure 19] 1 is a graph depicting the results of automated histopathological analysis quantifying collagen levels in lung samples from mice from each treatment group at the end of the study as described in Example 2 of the present disclosure.

[0042] [Figure 20] 1 is a table showing the results of automated histopathological analysis quantifying mean airspace circularity in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0043] [Figure 21] 1 is a table showing the results of automated histopathological analysis quantifying the mean airspace contact in each treatment group at the end of the study as described in Example 1 of the present disclosure.

[0044] [Figure 22] 1 is a graph showing the results of automated histopathological analysis of lung samples obtained from each treatment group at the end of the study described in Example 1, depicting collagen area (COL1A1 area (%)). Values are expressed as mean ± SD, and icons represent the average value per animal. DETAILED DESCRIPTION OF THE INVENTION

[0045] The present disclosure provides methods of treating interstitial lung diseases, including, inter alia, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF) and treatment-induced interstitial lung disease, the methods comprising administering to a subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, or comprising administering to a subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent.

[0046] Methods and combinations of the present disclosure The present disclosure provides methods for treating pulmonary fibrosis in a subject in need thereof, the methods comprising administering to the subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0047] The present disclosure provides a method of treating pulmonary fibrosis in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0048] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating pulmonary fibrosis in a subject in need thereof.

[0049] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating pulmonary fibrosis in a subject in need thereof.

[0050] The present disclosure provides methods for preventing pulmonary fibrosis in a subject in need thereof, the methods comprising administering to a subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0051] The present disclosure provides a method for preventing pulmonary fibrosis in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0052] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing pulmonary fibrosis in a subject in need thereof.

[0053] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing pulmonary fibrosis in a subject in need thereof.

[0054] The present disclosure provides a combination therapy comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0055] The present disclosure provides a combination therapy comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the combination therapy comprises a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone.

[0057] In some embodiments, the combination therapy comprises a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib.

[0058] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0059] The present disclosure provides a method of preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0060] The present disclosure provides pharmaceutical compositions comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0061] The present disclosure provides a pharmaceutical composition comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and pirfenidone or a pharmaceutically acceptable salt thereof.

[0062] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0063] The present disclosure provides a method for preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0064] The present disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0065] The present disclosure provides a kit comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and pirfenidone or a pharmaceutically acceptable salt thereof.

[0066] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0067] The present disclosure provides a method of preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0068] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0069] The present disclosure provides a method for treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof.

[0070] The present disclosure provides a method for preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0071] The present disclosure provides a method for preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof.

[0072] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating pulmonary fibrosis.

[0073] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing pulmonary fibrosis.

[0074] The present disclosure provides the use of pirfenidone or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for treating pulmonary fibrosis.

[0075] The present disclosure provides the use of pirfenidone or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for preventing pulmonary fibrosis.

[0076] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating pulmonary fibrosis.

[0077] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing pulmonary fibrosis.

[0078] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the treatment of pulmonary fibrosis.

[0079] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the prevention of pulmonary fibrosis.

[0080] The present disclosure provides pirfenidone or a pharmaceutically acceptable salt thereof for use in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the treatment of pulmonary fibrosis.

[0081] The present disclosure provides pirfenidone or a pharmaceutically acceptable salt thereof for use in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the prevention of pulmonary fibrosis.

[0082] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in the treatment of pulmonary fibrosis.

[0083] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in preventing pulmonary fibrosis.

[0084] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis, wherein the combination further comprises pirfenidone or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising pirfenidone or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0085] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof for use in preventing pulmonary fibrosis. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in preventing pulmonary fibrosis, wherein the combination further comprises pirfenidone or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising pirfenidone or a pharmaceutically acceptable salt thereof for use in preventing pulmonary fibrosis, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0086] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis, the method further comprising administration of pirfenidone or a pharmaceutically acceptable salt thereof.

[0087] The present disclosure provides pirfenidone, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0088] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for preventing pulmonary fibrosis, the method further comprising administration of pirfenidone or a pharmaceutically acceptable salt thereof.

[0089] The present disclosure provides pirfenidone or a pharmaceutically acceptable salt thereof for use in a method for preventing pulmonary fibrosis, the method further comprising administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered by the same route of administration. In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered by different routes of administration.

[0091] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered simultaneously.

[0092] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered in close temporal proximity.

[0093] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered in any order.

[0094] The present disclosure provides combination therapies comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0095] The present disclosure provides a combination therapy comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof.

[0096] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0097] The present disclosure provides a method of preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0098] The present disclosure provides a medicament comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0099] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0100] The present disclosure provides a method for preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0101] The present disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0102] The present disclosure provides a kit comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and nintedanib or a pharmaceutically acceptable salt thereof.

[0103] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0104] The present disclosure provides a method of preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0105] The present disclosure provides a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0106] The present disclosure provides a method of treating pulmonary fibrosis in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof.

[0107] The present disclosure provides a method for preventing pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0108] The present disclosure provides a method for preventing pulmonary fibrosis in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof.

[0109] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with nintedanib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pulmonary fibrosis.

[0110] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with nintedanib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing pulmonary fibrosis.

[0111] The present disclosure provides the use of nintedanib or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for treating pulmonary fibrosis.

[0112] The present disclosure provides the use of nintedanib or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for preventing pulmonary fibrosis.

[0113] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating pulmonary fibrosis.

[0114] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing pulmonary fibrosis.

[0115] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with nintedanib or a pharmaceutically acceptable salt thereof in the treatment of pulmonary fibrosis.

[0116] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with nintedanib or a pharmaceutically acceptable salt thereof in the prevention of pulmonary fibrosis.

[0117] The present disclosure provides nintedanib, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, of the present disclosure in the treatment of pulmonary fibrosis.

[0118] The present disclosure provides nintedanib or a pharmaceutically acceptable salt thereof for use in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the prevention of pulmonary fibrosis.

[0119] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in the treatment of pulmonary fibrosis.

[0120] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in preventing pulmonary fibrosis.

[0121] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis, wherein the combination further comprises nintedanib or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising nintedanib or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0122] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof for use in the prevention of pulmonary fibrosis. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the prevention of pulmonary fibrosis, wherein the combination further comprises nintedanib or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising nintedanib or a pharmaceutically acceptable salt thereof for use in the prevention of pulmonary fibrosis, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0123] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis, the method further comprising administration of nintedanib or a pharmaceutically acceptable salt thereof.

[0124] The present disclosure provides nintedanib, or a pharmaceutically acceptable salt thereof, for use in a method for treating pulmonary fibrosis, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0125] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for preventing pulmonary fibrosis, the method further comprising administration of nintedanib or a pharmaceutically acceptable salt thereof.

[0126] The present disclosure provides nintedanib, or a pharmaceutically acceptable salt thereof, for use in a method for preventing pulmonary fibrosis, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0127] The present disclosure provides methods of treating interstitial lung disease in a subject in need thereof, the methods comprising administering to the subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0128] The present disclosure provides a method of treating interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0129] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating interstitial lung disease in a subject in need thereof.

[0130] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating interstitial lung disease in a subject in need thereof.

[0131] The present disclosure provides methods for preventing interstitial lung disease in a subject in need thereof, the methods comprising administering to a subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0132] The present disclosure provides a method for preventing interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0133] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing interstitial lung disease in a subject in need thereof.

[0134] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing interstitial lung disease in a subject in need thereof.

[0135] The present disclosure provides methods of treating treatment-induced interstitial lung disease in a subject in need thereof, the methods comprising administering to the subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0136] The present disclosure provides a method of treating treatment-induced interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0137] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating treatment-induced interstitial lung disease in a subject in need thereof.

[0138] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating treatment-emergent interstitial lung disease in a subject in need thereof.

[0139] The present disclosure provides methods for preventing treatment-induced interstitial lung disease in a subject in need thereof, the methods comprising administering to a subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0140] The present disclosure provides a method for preventing treatment-induced interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0141] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing treatment-induced interstitial lung disease in a subject in need thereof.

[0142] The present disclosure provides use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing treatment-emergent interstitial lung disease in a subject in need thereof.

[0143] The present disclosure provides methods for preventing and / or alleviating treatment-induced interstitial lung disease in a subject in need thereof, the methods comprising administering to the subject in need thereof at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0144] The present disclosure provides a method for preventing and / or alleviating treatment-induced interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0145] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing and / or alleviating treatment-emergent interstitial lung disease in a subject in need thereof.

[0146] The present disclosure provides use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing and / or alleviating treatment-induced interstitial lung disease in a subject in need thereof.

[0147] The present disclosure provides a combination therapy comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0148] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0149] The present disclosure provides a method of preventing interstitial lung disease in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0150] The present disclosure provides a pharmaceutical composition comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0151] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0152] The present disclosure provides a method for preventing interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0153] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0154] The present disclosure provides a method for preventing interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0155] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0156] The present disclosure provides a method for treating interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and apirfenidone or a pharmaceutically acceptable salt thereof.

[0157] The present disclosure provides a method for preventing interstitial lung disease in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt thereof.

[0158] The present disclosure provides a method for preventing interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and apirfenidone or a pharmaceutically acceptable salt thereof.

[0159] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating interstitial lung disease.

[0160] The present disclosure provides use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing interstitial lung disease.

[0161] The present disclosure provides the use of pirfenidone or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for treating interstitial lung disease.

[0162] The present disclosure provides the use of pirfenidone or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for preventing interstitial lung disease.

[0163] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating interstitial lung disease.

[0164] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing interstitial lung disease.

[0165] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the treatment of interstitial lung disease.

[0166] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with pirfenidone or a pharmaceutically acceptable salt thereof in the prevention of interstitial lung disease.

[0167] The present disclosure provides pirfenidone, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, of the present disclosure in the treatment of interstitial lung disease.

[0168] The present disclosure provides pirfenidone or a pharmaceutically acceptable salt thereof for use in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the prevention of interstitial lung disease.

[0169] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in treating interstitial lung disease.

[0170] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and pirfenidone, or a pharmaceutically acceptable salt thereof, for use in preventing interstitial lung disease.

[0171] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial lung disease. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial lung disease, wherein the combination further comprises pirfenidone or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising pirfenidone or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial lung disease, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0172] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof for use in preventing interstitial lung disease. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in preventing interstitial lung disease, wherein the combination further comprises pirfenidone or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising pirfenidone or a pharmaceutically acceptable salt thereof for use in preventing interstitial lung disease, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0173] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating interstitial lung disease, the method further comprising administration of pirfenidone or a pharmaceutically acceptable salt thereof.

[0174] The present disclosure provides pirfenidone, or a pharmaceutically acceptable salt thereof, for use in a method for treating interstitial lung disease, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0175] The present disclosure provides a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in a method for preventing interstitial lung disease, the method further comprising administration of pirfenidone or a pharmaceutically acceptable salt thereof.

[0176] The present disclosure provides pirfenidone or a pharmaceutically acceptable salt thereof for use in a method for preventing interstitial lung disease, the method further comprising administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered by the same route of administration. In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered by different routes of administration.

[0178] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered simultaneously.

[0179] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered in close temporal proximity.

[0180] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof may be administered in any order.

[0181] The present disclosure provides combination therapies comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0182] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0183] The present disclosure provides a method of treating interstitial lung disease in a subject, the method comprising administering a combination therapy to the subject.

[0184] The present disclosure provides a method of preventing interstitial lung disease in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0185] The present disclosure provides pharmaceutical compositions comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0186] The present disclosure provides a pharmaceutical composition comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and nintedanib or a pharmaceutically acceptable salt thereof.

[0187] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0188] The present disclosure provides a method for preventing interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0189] The present disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0190] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0191] The present disclosure provides a method for preventing interstitial lung disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0192] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0193] The present disclosure provides a method of treating interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof.

[0194] The present disclosure provides a method for preventing interstitial lung disease in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.

[0195] The present disclosure provides a method for preventing interstitial lung disease in a subject, the method comprising administering to the subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof.

[0196] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with nintedanib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating interstitial lung disease.

[0197] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with nintedanib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing interstitial lung disease.

[0198] The present disclosure provides the use of nintedanib or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating interstitial lung disease.

[0199] The present disclosure provides the use of nintedanib or a pharmaceutically acceptable salt thereof in combination with at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure in the manufacture of a medicament for preventing interstitial lung disease.

[0200] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating interstitial lung disease.

[0201] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing interstitial lung disease.

[0202] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with nintedanib or a pharmaceutically acceptable salt thereof in the treatment of interstitial lung disease.

[0203] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with nintedanib or a pharmaceutically acceptable salt thereof in the prevention of interstitial lung disease.

[0204] The present disclosure provides nintedanib or a pharmaceutically acceptable salt thereof for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the treatment of interstitial lung disease.

[0205] The present disclosure provides nintedanib or a pharmaceutically acceptable salt thereof for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the prevention of interstitial lung disease.

[0206] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in the treatment of interstitial lung disease.

[0207] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof, for use in preventing interstitial lung disease.

[0208] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial lung disease. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial lung disease, wherein the combination further comprises nintedanib or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising nintedanib or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial lung disease, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0209] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof for use in preventing interstitial lung disease. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in preventing interstitial lung disease, wherein the combination further comprises nintedanib or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising nintedanib or a pharmaceutically acceptable salt thereof for use in preventing interstitial lung disease, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0210] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating interstitial lung disease, the method further comprising administration of nintedanib or a pharmaceutically acceptable salt thereof.

[0211] The present disclosure provides nintedanib, or a pharmaceutically acceptable salt thereof, for use in a method for treating interstitial lung disease, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0212] The present disclosure provides a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in a method for preventing interstitial lung disease, the method further comprising administration of nintedanib or a pharmaceutically acceptable salt thereof.

[0213] The present disclosure provides nintedanib, or a pharmaceutically acceptable salt thereof, for use in a method for preventing interstitial lung disease, the method further comprising administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof may be administered by the same route of administration. In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof may be administered by different routes of administration.

[0215] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof may be administered simultaneously.

[0216] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof may be administered closely in time.

[0217] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof may be administered in any order.

[0218] The present disclosure provides a combination therapy comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one anti-cancer agent or a pharmaceutically acceptable salt thereof.

[0219] The present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0220] The present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a combination therapy of the present disclosure.

[0221] The present disclosure provides a method of preventing cancer in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the aforementioned combination therapies.

[0222] The present disclosure provides a method of preventing cancer in a subject, the method comprising administering to the subject a combination therapy of the present disclosure.

[0223] The present disclosure provides pharmaceutical compositions comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one anti-cancer agent or a pharmaceutically acceptable salt thereof.

[0224] The present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0225] The present disclosure provides a method for preventing cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned pharmaceutical compositions.

[0226] The present disclosure provides a kit comprising at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one anticancer agent or a pharmaceutically acceptable salt thereof.

[0227] The present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0228] The present disclosure provides a method of preventing cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one of the aforementioned kits.

[0229] The present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one anti-cancer agent or a pharmaceutically acceptable salt thereof.

[0230] The present disclosure provides a method for treating cancer, the method comprising administering to a subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof.

[0231] The present disclosure provides a method for preventing cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of at least one anti-cancer agent or a pharmaceutically acceptable salt thereof.

[0232] The present disclosure provides a method for preventing cancer, the method comprising administering to a subject a MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof.

[0233] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0234] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing cancer.

[0235] The present disclosure provides the use of at least one anticancer agent, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, of the present disclosure in the manufacture of a medicament for treating cancer.

[0236] The present disclosure provides use of at least one anticancer agent, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, of the present disclosure in the manufacture of a medicament for preventing cancer.

[0237] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one anticancer agent, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating cancer.

[0238] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one anticancer agent, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for preventing cancer.

[0239] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.

[0240] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, in the prevention of cancer.

[0241] The present disclosure provides at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.

[0242] The present disclosure provides at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, of the present disclosure in the prevention of cancer.

[0243] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0244] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in preventing cancer.

[0245] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one anticancer agent or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, the combination further comprising at least one anticancer agent or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising at least one anticancer agent or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, the combination further comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0246] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof and at least one anticancer agent or a pharmaceutically acceptable salt thereof for use in preventing cancer. The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof for use in preventing cancer, wherein the combination further comprises at least one anticancer agent or a pharmaceutically acceptable salt thereof. The present disclosure provides a combination comprising at least one anticancer agent or a pharmaceutically acceptable salt thereof for use in preventing cancer, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof.

[0247] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer, the method further comprising administration of at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof.

[0248] The present disclosure provides at least one anticancer agent, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer, the method further comprising administering at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0249] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for preventing cancer, the method further comprising administration of at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof.

[0250] The present disclosure provides at least one anticancer agent or a pharmaceutically acceptable salt thereof for use in a method for preventing cancer, the method further comprising administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one anticancer agent or a pharmaceutically acceptable salt thereof may be administered by the same route of administration, or in some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one anticancer agent or a pharmaceutically acceptable salt thereof may be administered by different routes of administration.

[0252] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one anti-cancer agent or a pharmaceutically acceptable salt thereof may be administered simultaneously.

[0253] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one anti-cancer agent or a pharmaceutically acceptable salt thereof may be administered in close temporal proximity.

[0254] In some embodiments, the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one anti-cancer agent or a pharmaceutically acceptable salt thereof may be administered in any order.

[0255] In some embodiments, when a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure is administered alone or in combination with nintedanib and / or an anti-cancer agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, the subject exhibits decreased pulmonary congestion, decreased pulmonary inflammation, decreased respiratory rate, increased SpO2, increased pO2 levels, decreased blood lactate levels, increased blood bicarbonate levels, decreased lung weight, decreased respiratory system tissue resistance, decreased tissue dumping, decreased respiratory system elastance, decreased lung elastance, decreased parenchymal tissue density, shrinkage of lung lesions, decreased collagen content, decreased collagen deposition, and / or decreased tissue density, compared to a subject who was not administered a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure alone or in combination with nintedanib and / or an anti-cancer agent or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure results in a subject exhibiting decreased pulmonary congestion, decreased pulmonary inflammation, decreased respiratory rate, increased SpO2, increased pO2 levels, decreased blood lactate levels, increased blood bicarbonate levels, decreased lung weight, decreased respiratory system tissue resistance, decreased tissue dumping, decreased respiratory system elastance, decreased lung elastance, decreased parenchymal tissue density, shrinkage of lung lesions, decreased collagen content, decreased collagen deposition, and / or decreased tissue density, compared to a subject not administered a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure.

[0257] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof results in a subject exhibiting decreased pulmonary congestion, decreased pulmonary inflammation, decreased respiratory rate, increased SpO2, increased pO2 levels, decreased blood lactate levels, increased blood bicarbonate levels, decreased lung weight, decreased respiratory system tissue resistance, decreased tissue dumping, decreased respiratory system elastance, decreased lung elastance, decreased parenchymal tissue density, shrinkage of lung lesions, decreased collagen content, decreased collagen deposition, and / or decreased tissue density, compared to a subject not administered a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof results in a subject exhibiting decreased pulmonary congestion, decreased pulmonary inflammation, decreased respiratory rate, increased SpO2, increased pO2 levels, decreased blood lactate levels, increased blood bicarbonate levels, decreased lung weight, decreased respiratory system tissue resistance, decreased tissue dumping, decreased respiratory system elastance, decreased lung elastance, decreased parenchymal tissue density, shrinkage of lung lesions, decreased collagen content, decreased collagen deposition, and / or decreased tissue density, compared to a subject not administered a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and an anticancer agent or a pharmaceutically acceptable salt thereof in a subject exhibits decreased pulmonary congestion, decreased pulmonary inflammation, decreased respiratory rate, increased SpO2, increased pO2 levels, decreased blood lactate levels, increased blood bicarbonate levels, decreased lung weight, decreased respiratory system tissue resistance, decreased tissue dumping, decreased respiratory system elastance, decreased lung elastance, decreased parenchymal tissue density, shrinkage of lung lesions, decreased collagen content, decreased collagen deposition, and / or decreased tissue density in a subject compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and an anticancer agent or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, bleomycin (BLM) is administered intratracheally. In some embodiments, exposure to bleomycin results in an inflammatory response and increased epithelial apoptosis. In some embodiments, this inflammatory response and epithelial apoptosis occur within the first 7 days after exposure. In some embodiments, exposure to bleomycin induces symptoms similar to acute lung injury (ALI). In some embodiments, the fibrosis stage begins 7 days after exposure to BLM. In some embodiments, the fibrosis stage persists for 3-4 weeks after exposure to BLM.

[0261] In some embodiments, treatment with bleomycin results in a decrease in pulmonary function, as indicated by increased pulmonary congestion, increased pulmonary inflammation, increased respiratory rate, decreased SpO2, elevated blood lactate levels, decreased blood bicarbonate levels, increased edema, increased vascular leakage and extracellular matrix deposition, increased lung tissue resistance and stiffness, increased parenchymal tissue density, increased lung lesions, and increased lung collagen content.

[0262] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure results in improved pulmonary function, as indicated by decreased pulmonary congestion, decreased pulmonary inflammation, increased blood bicarbonate levels, decreased edema, decreased vascular leakage and extracellular matrix deposition, increased SpO2 levels, decreased blood lactate levels, decreased lung tissue resistance and stiffness, decreased parenchymal tissue density, regression of lung lesions, decreased lung collagen content, and decreased respiratory rate, compared to subjects not administered a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure. In some embodiments, the improved pulmonary function occurs within one week of administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure. In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure follows exposure to bleomycin.

[0263] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof results in improved pulmonary function as indicated by decreased pulmonary congestion, decreased pulmonary inflammation, increased SpO2 values, decreased blood lactate levels, increased blood bicarbonate levels, decreased edema, decreased vascular leakage and extracellular matrix deposition, decreased lung tissue resistance and stiffness, decreased parenchymal tissue density, regression of lung lesions, decreased lung collagen content, and decreased respiratory rate, compared to subjects who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof. In some embodiments, the improved pulmonary function occurs within one week of administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof occurs after exposure to bleomycin.

[0264] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof results in improved pulmonary function as indicated by decreased pulmonary congestion, decreased pulmonary inflammation, increased SpO2 values, decreased blood lactate levels, increased blood bicarbonate levels, decreased edema, decreased vascular leakage and extracellular matrix deposition, decreased lung tissue resistance and stiffness, decreased parenchymal tissue density, regression of lung lesions, decreased lung collagen content, and decreased respiratory rate, compared to subjects not administered a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof. In some embodiments, the improved pulmonary function occurs within one week of administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof occurs after exposure to bleomycin.

[0265] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure inhibits collagen deposition in lung tissue.

[0266] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof disclosed herein and nintedanib or a pharmaceutically acceptable salt thereof inhibits collagen deposition in lung tissue. In some embodiments, administration of a combination of MetAP2 or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof enhances the reduction of collagen deposition compared to administration of MetAP2 alone.

[0267] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof inhibits collagen deposition in lung tissue.

[0268] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure reduces collagen deposition in lung tissue compared to a subject who does not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure.

[0269] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure after exposure to bleomycin reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure.

[0272] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof after exposure to bleomycin reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and nintedanib or a pharmaceutically acceptable salt thereof after exposure to bleomycin reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure.

[0274] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof after exposure to bleomycin reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, administration of a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure and pirfenidone or a pharmaceutically acceptable salt thereof after exposure to bleomycin reduces collagen deposition in lung tissue compared to a subject who did not receive a MetAP2 inhibitor or a pharmaceutically acceptable salt thereof of the present disclosure.

[0276] MetAP2 inhibitors Any of the MetAP2 inhibitors described herein can be used in the kits, pharmaceutical compositions, uses and methods described herein.

[0277] In some embodiments, the MetAP2 inhibitor may be Compound 1, or a pharmaceutically acceptable salt, analog, derivative, salt, or ester thereof, wherein Compound 1 is represented by the formula: [ka] wherein x ranges from 1 to about 450, y ranges from 1 to about 30, and n ranges from 1 to about 100. In some embodiments, n ranges from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 55, or from about 1 to about 50. In some embodiments, the ratio of x to y can range from about 30:1 to about 3:1.

[0278] In some embodiments, the MetAP2 inhibitor may be Compound 2, or a pharmaceutically acceptable salt, analog, derivative, salt, or ester thereof, wherein Compound 2 is represented by the formula: [ka] wherein x ranges from 1 to about 450, y ranges from 1 to about 30, and n ranges from 1 to about 100. In some embodiments, n ranges from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 55, or from about 1 to about 50. In some embodiments, the ratio of x to y can range from about 30:1 to about 3:1.

[0279] In some embodiments, the MetAP2 inhibitor may be compound 3, or a pharmaceutically acceptable salt, analog, derivative, salt, or ester thereof, wherein compound 3 is represented by the formula: [ka] wherein x ranges from 1 to about 450, y ranges from 1 to about 30, and n ranges from 1 to about 100. In some embodiments, n ranges from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 55, or from about 1 to about 50. In some embodiments, the ratio of x to y can range from about 30:1 to about 3:1.

[0280] In some embodiments, the MetAP2 inhibitor may be compound 4, or a pharmaceutically acceptable salt, analog, derivative, salt, or ester thereof, wherein compound 4 is represented by the formula: [ka] wherein x ranges from 1 to about 450, y ranges from 1 to about 30, and n ranges from 1 to about 100. In some embodiments, n ranges from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 55, or from about 1 to about 50. In some embodiments, the ratio of x to y can range from about 30:1 to about 3:1.

[0281] In some embodiments, the MetAP2 inhibitor is [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0282] In some embodiments, the MetAP2 inhibitor is [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0283] In some embodiments, the MetAP2 inhibitor is [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0284] In some embodiments, the MetAP2 inhibitor is [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0285] In some embodiments, the MetAP2 inhibitor is [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0286] In some embodiments, the MetAP2 inhibitor is cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid, cis-(3aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid, cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonyl-amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid, 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, cis-(3aR,9bR)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid, tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid, cis-(3aS,9bS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid, 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate, 7-(benzenesulfonylamino)-1,2- Dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate, cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid, (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6, cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6, cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6 -carboxylic acid, (1aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl) -4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-Tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[ (Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-(3-dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2-(3- dimethylaminopropyl-amino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2-(4-dimethylaminobutylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(5-dimethylaminopentylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclo Cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro- ... c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid -1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-Tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azetidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- Carboxylic acid, (1aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarba (1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a a,2,7b-Tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-(pyrrolidin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4-fluorobenzene-sulfonylamino}-1, 1a,2,7b-Tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-((S)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)- 5-[2-(3-dimethylaminopropylcarbamoyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{[N-((S)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{[N-((R)-1-ethyl-pyrrolidin-3-yl)-N- Methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a ,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(3-N,N-diethylaminopropylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidin-2-yl)carbonyl-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-amino-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetra Hydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((S)-1- 1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-Tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, bSR)-5-{2-[((R)-1-azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidine-3 -ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, Propa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-((R)-1 The compound may be selected from (1aR,7bS)-5-[2-(1-ethylpiperidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid, and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

[0287] In some embodiments, the MetAP2 inhibitor is [ka] [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0288] In some embodiments, the MetAP2 inhibitor is [ka] or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.

[0289] In some embodiments, the MetAP2 inhibitor can be administered by subcutaneous injection (SC). In some embodiments, the MetAP2 inhibitor can be administered by subcutaneous injection into the mid-abdomen (around the umbilicus). In some embodiments, the subcutaneous injection of the MetAP2 inhibitor can be administered at a constant infusion rate over a time frame of about 30 to about 45 seconds. In some embodiments, the maximum injection volume of the MetAP2 inhibitor is less than about 1.7 ml.

[0290] In some embodiments, the MetAP2 inhibitor can be administered approximately every four days (Q4D).

[0291] In some embodiments, the MetAP2 inhibitor can be administered approximately once per day (QD), approximately once per 2 days (Q2D), approximately once per 3 days (Q3D), approximately once per 4 days (Q4D), approximately once per 5 days (Q5D), approximately once per 6 days (Q6D), approximately once per 7 days (Q7D), approximately once per 8 days (Q8D), approximately once per 9 days (Q9D), approximately once per 10 days (Q10D), approximately once per 11 days (Q11D), approximately once per 12 days (Q12D), approximately once per 13 days (Q13D), approximately once per 14 days (Q14D), or approximately once per 15 days (Q15D). In some embodiments, the MetAP2 inhibitor may be administered approximately once per 7 days (Q7D). In some embodiments, the MetAP2 inhibitor may be administered approximately once per 14 days (Q14D).

[0292] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 1 mg / m 2 , or about 2 mg / m 2 , or about 3 mg / m 2 , or about 4 mg / m 2 , or about 5 mg / m 2 , or about 6 mg / m 2 , or about 7 mg / m 2 , or about 8 mg / m 2, or about 9 mg / m 2 , or about 10 mg / m 2 , or about 11 mg / m 2 , or about 12 mg / m 2 , or about 13 mg / m 2 , or about 14 mg / m 2 , or about 15 mg / m 2 , or about 16 mg / m 2 , or about 17 mg / m 2 , or about 18 mg / m 2 , or about 19 mg / m 2 , or about 20 mg / m 2 , or about 21 mg / m 2 , or about 22 mg / m 2 , or about 23 mg / m 2 , or about 24 mg / m 2 , or about 25 mg / m 2 , or about 26 mg / m 2 , or about 27 mg / m 2 , or about 28 mg / m 2 , or about 29 mg / m 2 , or about 30 mg / m 2 , or about 31 mg / m 2 , or about 32 mg / m 2 , or about 33 mg / m 2 , or about 34 mg / m 2 , or about 35 mg / m 2 , or about 36 mg / m 2 , or about 37 mg / m 2 , or about 38 mg / m 2 , or about 39 mg / m 2 , or about 40 mg / m 2 , or about 41 mg / m 2 , or about 42 mg / m 2 , or about 43 mg / m 2 , or about 44 mg / m 2 , or about 45 mg / m 2 , or about 46 mg / m 2 , or about 47 mg / m 2 , or about 48 mg / m 2 , or about 49 mg / m 2 , or about 50 mg / m 2 , or about 51 mg / m 2 , or about 52 mg / m2 , or about 53 mg / m 2 , or about 54 mg / m 2 , or about 55 mg / m 2 , or about 56 mg / m 2 , or about 57 mg / m 2 , or about 58 mg / m 2 , or about 59 mg / m 2 , or about 60 mg / m 2 , or approximately mg / m 2 , or about 61 mg / m 2 , or about 62 mg / m 2 , or about 63 mg / m 2 , or about 64 mg / m 2 , or about 65 mg / m 2 , or about 66 mg / m 2 , or about 67 mg / m 2 , or about 68 mg / m 2 , or about 69 mg / m 2 , or about 70 mg / m 2 , or about 81 mg / m 2 , or about 82 mg / m 2 , or about 83 mg / m 2 , or about 84 mg / m 2 , or about 85 mg / m 2 , or about 86 mg / m 2 , or about 87 mg / m 2 , or about 88 mg / m 2 , or about 89 mg / m 2 , or about 90 mg / m 2 , or about 91 mg / m 2 , or about 92 mg / m 2 , or about 93 mg / m 2 , or about 94 mg / m 2 , or about 95 mg / m 2 , or about 96 mg / m 2 , or about 97 mg / m 2 , or about 98 mg / m 2 , or about 99 mg / m 2 , or about 100 mg / m 2 can be administered in an amount of

[0293] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 49 mg / m 2In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 36 mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 65 mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 27 mg / m 2 may be administered in an amount of

[0294] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 49 mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 39 mg / m 2 ~about 59mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 44 mg / m 2 ~about 54mg / m 2 may be administered in an amount of

[0295] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 36 mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 26 mg / m 2 ~approximately 49 mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 31 mg / m 2 ~about 65mg / m 2 may be administered in an amount of

[0296] In some embodiments, the MetAP2 inhibitor is administered at a dose of about 65 mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 55 mg / m 2 ~about 75mg / m 2 In some embodiments, the MetAP2 inhibitor may be administered in an amount of about 60 mg / m 2 ~about 70mg / m 2 may be administered in an amount of

[0297] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 1 mg / m 2, or about 2 mg / m 2 , or about 3 mg / m 2 , or about 4 mg / m 2 , or about 5 mg / m 2 , or about 6 mg / m 2 , or about 7 mg / m 2 , or about 8 mg / m 2 , or about 9 mg / m 2 , or about 10 mg / m 2 , or about 11 mg / m 2 , or about 12 mg / m 2 , or about 13 mg / m 2 , or about 14 mg / m 2 , or about 15 mg / m 2 , or about 16 mg / m 2 , or about 17 mg / m 2 , or about 18 mg / m 2 , or 19 mg / m 2 , or about 20 mg / m 2 , or about 21 mg / m 2 , or about 22 mg / m 2 , or about 23 mg / m 2 , or about 24 mg / m 2 , or about 25 mg / m 2 , or about 26 mg / m 2 , or about 27 mg / m 2 , or about 28 mg / m 2 , or about 29 mg / m 2 , or about 30 mg / m 2 , or about 31 mg / m 2 , or about 32 mg / m 2 , or about 33 mg / m 2 , or about 34 mg / m 2 , or about 35 mg / m 2 , or about 36 mg / m 2 , or about 37 mg / m 2 , or about 38 mg / m 2 , or about 39 mg / m 2 , or about 40 mg / m 2 , or about 41 mg / m 2 , or about 42 mg / m 2 , or about 43 mg / m 2 , or about 44 mg / m 2 , or about 45 mg / m 2, or about 46 mg / m 2 , or about 47 mg / m 2 , or about 48 mg / m 2 , or about 49 mg / m 2 , or about 50 mg / m 2 , or about 51 mg / m 2 , or about 52 mg / m 2 , or about 53 mg / m 2 , or about 54 mg / m 2 , or about 55 mg / m 2 , or about 56 mg / m 2 , or about 57 mg / m 2 , or about 58 mg / m 2 , or about 59 mg / m 2 , or about 60 mg / m 2 , or approximately mg / m 2 , or about 61 mg / m 2 , or about 62 mg / m 2 , or about 63 mg / m 2 , or about 64 mg / m 2 , or about 65 mg / m 2 , or about 66 mg / m 2 , or about 67 mg / m 2 , or about 68 mg / m 2 , or about 69 mg / m 2 , or about 70 mg / m 2 , or about 81 mg / m 2 , or about 82 mg / m 2 , or about 83 mg / m 2 , or about 84 mg / m 2 , or about 85 mg / m 2 , or about 86 mg / m 2 , or about 87 mg / m 2 , or about 88 mg / m 2 , or about 89 mg / m 2 , or about 90 mg / m 2 , or about 91 mg / m 2 , or about 92 mg / m 2 , or about 93 mg / m 2 , or about 94 mg / m 2 , or about 95 mg / m 2 , or about 96 mg / m 2 , or about 97 mg / m 2 , or about 98 mg / m2 , or about 99 mg / m 2 , or about 100 mg / m 2 It could be.

[0298] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 49 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 39 mg / m 2 ~about 59mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 44 mg / m 2 ~about 54mg / m 2 It could be.

[0299] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 36 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 26 mg / m 2 ~approximately 49 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 31 mg / m 2 ~approximately 49 mg / m 2 It could be.

[0300] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 65 mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 55 mg / m 2 ~about 75mg / m 2 In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor is about 60 mg / m 2 ~about 70mg / m 2 It could be.

[0301] In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg. In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 80 mg. In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 70 mg to about 90 mg. In some embodiments, the MetAP2 inhibitor can be administered in an amount of about 75 mg to about 85 mg.

[0302] In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor can be about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg. In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor can be about 80 mg. In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor can be about 70 mg to about 90 mg. In some embodiments, the therapeutically effective amount of a MetAP2 inhibitor can be about 75 mg to about 85 mg.

[0303] Pirfenidone As will be appreciated by those skilled in the art, pirfenidone has the following chemical structure: [ka]

[0304] As will be appreciated by those skilled in the art, pirfenidone can be identified by any of the following names: 2(1H)-pyridinone, 5-methyl-1-phenyl-, 5-methyl-1-phenyl-2(1H)-pyridinone, 5-methyl-1-phenyl-2(1H)-pyridone, AMR 69, 5-methyl-1-phenyl-1H-pyridin-2-one, Deskar, Pirespa, Esbriet, RG6062, RG 6062, RG-6062. As will be appreciated by those skilled in the art, pirfenidone can be identified by CAS number 53179-13-8.

[0305] In some embodiments, pirfenidone can be administered orally.

[0306] In some embodiments, pirfenidone is about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 267 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 425 mg, or about 450 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 675 mg, or about 70 0 mg, or about 725 mg, or about 750 mg, or about 775 mg, or about 800 mg, or about 801 mg, or about 825 mg, or about 850 mg, or about 875 mg, or about 900 mg, or about 925 mg, or about 950 mg, or about 975 mg, or about 1000 mg, or about 1025 mg, or about 1050 mg, or about 1075 mg, or about 1100 mg, or about 1125 mg, or about 1150 mg, or about 1175 mg, or about 1200 mg, or about 1225 mg, or about 1250 mg, or about 1267 mg, or about 1275 mg, or about 130 0 mg, or about 1325 mg, or about 1350 mg, or about 1375 mg, or about 1400 mg, or about 1425 mg, or about 1450 mg, or about 1500 mg, or about 1525 mg, or about 1550 mg, or about 1575 mg, or about 1600 mg, or about 1625 mg, or about 1650 mg, or about 1675 mg, or about 1700 mg, or about 1725 mg, or about 1750 mg, or about 1775 mg, or about 1800 mg, or about 1801 mg, or about 1825 mg, or about 1850 mg, or about 1875 mg, or about 1900 mg, or about It can be administered in an amount of about 925 mg, or about 1950 mg, or about 1975 mg, or about 2000 mg, or about 2025 mg, or about 2050 mg, or about 2075 mg, or about 2100 mg, or about 2125 mg, or about 2150 mg, or about 2175 mg, or about 2200 mg, or about 2225 mg, or about 2250 mg, or about 2275 mg, or about 2300 mg, or about 2325 mg, or about 2350 mg, or about 2375 mg, or about 2400 mg, or about 2403 mg, or about 2425 mg, or about 2450 mg, or about 2475 mg.

[0307] In some embodiments, pirfenidone may be administered in an amount of about 801 mg. In embodiments in which pirfenidone is administered in an amount of about 801 mg, that amount can be administered by orally administering three 267 mg capsules.

[0308] In some embodiments, pirfenidone may be administered in an amount of about 2403 mg per day. In embodiments in which pirfenidone is administered in an amount of 2403 mg / day, that amount can be administered by orally administering three 267 mg capsules three times daily.

[0309] In some embodiments, the therapeutically effective amount of pirfenidone can be any of the amounts of pirfenidone described herein.

[0310] In some embodiments, pirfenidone can be administered as a pharmaceutical composition, the pharmaceutical composition comprising at least one of microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, gelatin, and titanium dioxide.

[0311] In some embodiments, pirfenidone may be administered approximately once a day. In some embodiments, pirfenidone may be administered approximately twice a day. In some embodiments, pirfenidone may be administered approximately three times a day.

[0312] Nintedanib As will be appreciated by those skilled in the art, nintedanib has the following chemical structure: [ka]

[0313] As will be appreciated by those skilled in the art, it will be understood that nintedanib may be identified by any of the following names: (3Z)-2,3-dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester, (3Z)-2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester, BIBF 1120, Vargatef, Ofev, methyl (Z)-3-[[[4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl]amino](phenyl)methylene]-2-oxoindoline-6-carboxylate, methyl (Z)-3-[[[4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl]amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate. As will be understood by those skilled in the art, pirfenidone can be identified by the CAS number 656247-17-5.

[0314] In some embodiments, nintedanib may be administered in the form of an ethanesulfonate salt, i.e., nintedanib esylate (CAS No. 656247-18-6).

[0315] In some embodiments, nintedanib may be administered orally.

[0316] In some embodiments, nintedanib is administered at a dose of about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 267 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 425 mg, or about 450 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 675 mg, or about 700 mg. mg, or about 725 mg, or about 750 mg, or about 775 mg, or about 800 mg, or about 801 mg, or about 825 mg, or about 850 mg, or about 875 mg, or about 900 mg, or about 925 mg, or about 950 mg, or about 975 mg, or about 1000 mg, or about 1025 mg, or about 1050 mg, or about 1075 mg, or about 1100 mg, or about 1125 mg, or about 1150 mg, or about 1175 mg, or about 1200 mg, or about 1225 mg, or about 1250 mg, or about 1267 mg, or about 1275 mg, or about 1300 mg, or about 1325 mg, or about 1350 mg, or about 1375 mg, or about 1400 mg, or about 1425 mg, or about 1450 mg, or about 1500 mg, or about 1525 mg, or about 1550 mg, or about 1575 mg, or about 1600 mg, or about 1625 mg, or about 1650 mg, or about 1675 mg, or about 1700 mg, or about 1725 mg, or about 1750 mg, or about 1775 mg, or about 1800 mg, or about 1801 mg, or about 1825 mg, or about 1850 mg, or about 1875 mg, or about 1900 mg, or about 19 The compound may be administered in an amount of about 25 mg, or about 1950 mg, or about 1975 mg, or about 2000 mg, or about 2025 mg, or about 2050 mg, or about 2075 mg, or about 2100 mg, or about 2125 mg, or about 2150 mg, or about 2175 mg, or about 2200 mg, or about 2225 mg, or about 2250 mg, or about 2275 mg, or about 2300 mg, or about 2325 mg, or about 2350 mg, or about 2375 mg, or about 2400 mg, or about 2403 mg, or about 2425 mg, or about 2450 mg, or about 2475 mg.

[0317] In some embodiments, nintedanib may be administered in an amount of about 150 mg.

[0318] In some embodiments, nintedanib may be administered in an amount of about 100 mg.

[0319] In some embodiments, nintedanib may be administered in an amount of about 300 mg / day. In embodiments in which nintedanib is administered in an amount of about 300 mg / day, this amount may be administered by orally administering one 150 mg capsule twice daily. In some embodiments, two capsules may be administered about 12 hours apart.

[0320] In some embodiments, nintedanib may be administered in an amount of about 200 mg / day. In embodiments in which nintedanib is administered in an amount of about 200 mg / day, this amount may be administered by orally administering one 100 mg capsule twice daily. In some embodiments, two capsules may be administered about 12 hours apart.

[0321] In some embodiments, the therapeutically effective amount of nintedanib can be any of the amounts of nintedanib described herein.

[0322] In some embodiments, nintedanib can be administered as a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one of triglycerides, hard fat, lecithin, gelatin, glycerol, titanium dioxide, red iron oxide, yellow iron oxide, and black ink.

[0323] In some embodiments, nintedanib may be administered approximately once a day. In some embodiments, nintedanib may be administered approximately twice a day. In some embodiments, nintedanib may be administered approximately three times a day.

[0324] Diseases and Disorders In some embodiments, the interstitial lung disease can be pulmonary fibrosis.

[0325] In some embodiments, the pulmonary fibrosis results from an interstitial lung disease.

[0326] As will be understood by those skilled in the art, pulmonary fibrosis is a disease that occurs when lung tissue becomes damaged and scarred, resulting in thick, stiff tissue that makes it more difficult for a subject's lungs to function properly.

[0327] In some embodiments, the interstitial lung disease can be one or more of asbestosis, COVID-19-associated pulmonary fibrosis, drug-induced pulmonary fibrosis, pneumonia, hypersensitivity pneumonitis (HP), idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (NSIP), pneumoconiosis, rheumatoid arthritis interstitial lung disease (RA-ILD), sarcoidosis, silicosis, pulmonary edema, pleural effusion, and systemic sclerosis. In some embodiments, the pulmonary fibrosis is IPF.

[0328] In some embodiments, the interstitial lung disease can be treatment-induced interstitial lung disease. Treatment-induced interstitial lung disease is an interstitial lung disease caused by the administration of one or more treatments to a subject (i.e., interstitial lung disease is an adverse side effect of one or more treatments, see Schwaiblmair et al.; Camus et al.; Conte et al.; Skeoch et al. Drug-Induced Interstitial Lung Disease: A Systematic Review, 2018, J. Clin. Med. 7(10):356; and Spagnolo et al. Drug-induced interstitial lung disease, 2022, European Respiratory Journal, 60(3). Each of the above publications is incorporated by reference in its entirety for all purposes. In some embodiments, the treatment-induced interstitial lung disease can be treatment-induced pulmonary fibrosis. In some embodiments, the treatment-induced interstitial lung disease can be treatment-induced pneumonitis.

[0329] In some embodiments, the interstitial lung disease is drug-induced.

[0330] In some embodiments, the one or more treatments that induce interstitial lung disease can be any treatment known in the art to include interstitial lung disease (Schwaiblmair et al.; Skeoch et al.; Spagnolo et al.; Camus et al.; and Conte et al.).

[0331] In some embodiments, the one or more therapies inducing the interstitial lung disease are selected from the group consisting of acetylsalicylic acid, amphotericin B, amiodarone, azathioprine, beta blockers, carbamazepine, clarithromycin, diclofenac, granulocyte colony-stimulating factor, phenytoin, fluoxetine, hydralazine, levofloxacin, contrast agents, minocycline, naproxen, nitrofurantoin, gold, paracetamol, penicillamine, penicillin, statins, sulfasalazine, abemaciclib, palbociclib, ribociclib, alectinib, crizotinib, ceritinib, nivolumab, pembroke venom, ribozyme, ribozyme, ribozyme-containing steroids ... The therapeutic agent may include at least one of lorizumab, atezolizumab, durvalumab, ipilimumab, osimertinib, vinorelbine, paclitaxel, docetaxel, bleomycin, gemcitabine, erlotinib, gefitinib, panitumumab, cetuximab, everolimus, temsirolimus, sirolimus, ipilimumab, nivolumab, irinotecan, rituximab, imatinib, pemetrexed, granulocyte colony-stimulating factor, methotrexate, tumor necrosis factor inhibitor, leflunomide, amiodarone, bepridil, statin, nitrofurantoin, daptomycin, and interferon.

[0332] In some embodiments, the one or more therapies that induce interstitial lung disease can include at least one of an anti-epidermal growth factor receptor agent, an anti-BRAF agent, a cyclin-dependent kinase 4 / 6 inhibitor, a poly(ADP-ribose) polymerase inhibitor, an immune checkpoint inhibitor, a PD-1 inhibitor, an EGFR inhibitor, a HER2 inhibitor, a BRC / ABL tyrosine kinase inhibitor, an ALK inhibitor, a BRAF inhibitor, a PI3K inhibitor, a FLT3 inhibitor, a TRK / ROS1 inhibitor, a VEGFR inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, and a PARP inhibitor.

[0333] In some embodiments, the one or more treatments that induce interstitial lung disease can include administration of at least one anti-cancer agent.

[0334] In some embodiments, the anti-cancer agent may comprise an antibody-drug conjugate.

[0335] In some embodiments, the anti-cancer agent may comprise irinotecan. In some embodiments, the anti-cancer agent may comprise an analog or irinotecan. In some embodiments, the anti-cancer agent may comprise a derivative of irinotecan. In some embodiments, the anti-cancer agent may comprise an antibody-drug conjugate, wherein the antibody-drug conjugate comprises irinotecan, an analog of irinotecan, or a derivative of irinotecan.

[0336] In some embodiments, the anti-cancer agent may comprise an antibody-drug conjugate, wherein the antibody-drug conjugate comprises deruxtecan.

[0337] In some embodiments, the anti-cancer drug can include Enhertu (trastuzumab deruxtecan).

[0338] In some embodiments, the anticancer agent can comprise at least one of abemaciclib, palbociclib, ribociclib, alectinib, crizotinib, ceritinib, nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, osimertinib, vinorelbine, paclitaxel, docetaxel, bleomycin, gemcitabine, erlotinib, gefitinib, panitumumab, cetuximab, everolimus, temsirolimus, sirolimus, ipilimumab, nivolumab, irinotecan, rituximab, imatinib, pemetrexed, and granulocyte colony-stimulating factor.

[0339] In some embodiments, the anti-cancer agent may comprise at least one of an anti-epidermal growth factor receptor agent, an anti-BRAF agent, a cyclin-dependent kinase 4 / 6 inhibitor, a poly(ADP-ribose) polymerase inhibitor, an immune checkpoint inhibitor, a PD-1 inhibitor, an EGFR inhibitor, a HER2 inhibitor, a BRC / ABL tyrosine kinase inhibitor, an ALK inhibitor, a BRAF inhibitor, a PI3K inhibitor, an FLT3 inhibitor, a TRK / ROS1 inhibitor, a VEGFR inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, and a PARP inhibitor.

[0340] In some embodiments, the one or more treatments that induce interstitial lung disease can include administration of at least one anti-cancer agent.

[0341] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. This definition includes both benign and malignant cancers. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or germ cell tumors. More specific examples of such cancers include adrenocortical tumors, bladder urothelial carcinoma, breast cancer including Her2-positive or Her2-low expressing, triple-negative, hormone receptor-positive, and invasive cancers, cervical squamous cell carcinoma, cervical adenocarcinoma, bile duct cancer, colon adenocarcinoma, lymphoid tumors diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, chromophobe renal carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, acute myeloid leukemia, brain low-grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate cancer, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, uterine carcinosarcoma, and uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer or stomach cancer.Further examples of cancers include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, colorectal cancer, brain tumor, breast cancer, cancer of unknown primary site (CUP), bone metastasis, brain metastasis, liver metastasis, lung metastasis, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromaffin myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, gastric cancer cancer), gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, scirrhous gastric cancer, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumors, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, hydatidiform mole, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancers, signet ring cell carcinoma, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer Cancers include T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal gland tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, Womb cancer, and gynecological cancers.Examples of cancer also include, but are not limited to, cancers expressing a human epidermal growth factor family receptor (e.g., Her2) or tumors expressing a Trop2 receptor, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chromaffin lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0342] In some embodiments, the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, renal cancer, kidney cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cavity cancer, pharyngeal cancer, or colorectal cancer.

[0343] In some embodiments, the cancer is breast cancer.

[0344] In some embodiments, the breast cancer is metastatic breast cancer. As used herein, metastatic breast cancer is stage III or IV breast cancer that has spread to other parts of the body, including but not limited to the liver, brain, bone, etc.

[0345] In some embodiments, the breast cancer is human epidermal growth factor 2 (HER2)-negative breast cancer.

[0346] In some embodiments, the breast cancer is HR+HER2- breast cancer.

[0347] In some embodiments, the breast cancer may be luminal A breast cancer. In some embodiments, the breast cancer may be luminal B breast cancer. In some embodiments, the breast cancer may be triple-negative or basal-like breast cancer. In some embodiments, the breast cancer may be HER2-enriched breast cancer.

[0348] In some embodiments, the cancer is head and neck cancer.

[0349] In some embodiments, the lung cancer is non-small cell lung cancer.

[0350] In some embodiments, the cancer is brain cancer. In some embodiments, the brain cancer can be recurrent brain metastasis.

[0351] In some embodiments, the cancer is squamous cell carcinoma.

[0352] In some embodiments, the cancer is a central nervous system tumor.

[0353] In some embodiments, the cancer is liposarcoma.

[0354] In some embodiments, the cancer is endometrial cancer.

[0355] In some embodiments, the cancer is a neuroendocrine tumor.

[0356] In some embodiments, the cancer is small cell lung cancer (SCLC).

[0357] subject In some embodiments, the subject in need is an animal. In some embodiments, the animal is a mammal. In some embodiments, the subject in need is a human.

[0358] In some embodiments, the subject in need is a human aged 18 years or older, or 25 years or older, or 50 years or older, or 60 years or older, or 65 years or older, or 70 years or older, or 75 years or older, or 80 years or older, or 85 years or older.

[0359] General definition Certain compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates that all such compounds are within the scope of the present disclosure, including cis and trans isomers, R and S-enantiomers, diastereomers, d-isomers, l-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present disclosure. Any representation of a specific isomer is merely exemplary (e.g., a representation of a trans isomer also encompasses the cis isomer).

[0360] For example, if a particular enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary to separate the resulting diastereomeric mixture and cleavage of the auxiliary to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic means known in the art to recover the pure enantiomers.

[0361] In this specification, the structural formula of a compound may conveniently represent a specific isomer in some cases, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, and tautomers. Furthermore, the compounds represented by the formula may exist in crystalline polymorphism. It should be noted that any crystalline form, a mixture of crystalline forms, or anhydrous or hydrated forms thereof are included within the scope of the present disclosure. Furthermore, so-called metabolites produced by decomposition of the compounds of the present invention in vivo are also included within the scope of the present invention.

[0362] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0363] A carbon atom bonded to four nonidentical substituents is termed a "chiral center."

[0364] "Chiral isomer" means a compound having at least one chiral center. Compounds with two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereoisomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the ranking rules of Cahn, Ingold, and Prelog. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385;errata 511, Cahn et al.,Angew.Chem.1966,78,413;Cahn and Ingold,J.Chem.Soc.1951(London),612, Cahn et al.,Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0365] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about double bonds. These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0366] Furthermore, the structures and other compounds discussed in this disclosure include all atropisomers thereof. An "atropisomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers owe their existence to rotational constraints caused by the hindrance of rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers in selected cases.

[0367] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion involves the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are capable of interconversion by tautomerization is called tautomerism.

[0368] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of an electron and a hydrogen atom occurs; and ring-chain tautomerism, which occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic (ring-shaped) form, such as that exhibited by glucose.

[0369] Common tautomeric pairs include ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine.

[0370] It is understood that the compounds of the present disclosure may be represented as various tautomeric forms. It should also be understood that where a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form.

[0371] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0372] Additionally, compounds of the present disclosure, such as salts of the compounds, can exist in either hydrated or non-hydrated (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.

[0373] "Solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance, where the water retains its molecular state as HO.

[0374] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but differs in structure or origin.

[0375] The term "derivative," as defined herein, refers to compounds that share a common core structure and are substituted with various groups as described herein.

[0376] The term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms with another generally similar atom or group of atoms. The purpose of bioisosteric substitution is to create a new compound with similar biological properties to the parent compound. Bioisosteric substitutions can be physicochemically or topologically based. Examples of bioisosteres of carboxylic acids include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0377] As used herein, the term "temporal proximity" refers to the administration of one therapeutic agent (e.g., a MetAP2 inhibitor compound disclosed herein) occurring within a time frame before or after the administration of another therapeutic agent (e.g., pirfenidone or nintedanib) such that the therapeutic effects of one therapeutic agent overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, the therapeutic effects of one therapeutic agent completely overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, "temporal proximity" refers to the administration of one therapeutic agent occurring within a time frame before or after the administration of another therapeutic agent such that a synergistic effect exists between the one therapeutic agent and the other therapeutic agent. "Temporal proximity" can vary depending on various factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is administered, the disease or symptom being treated or ameliorated, the therapeutic result to be achieved, the dosage, frequency, and duration of administration of the therapeutic agent, the pharmacokinetics and pharmacodynamics of the therapeutic agent, and the route by which the therapeutic agent is administered. In some embodiments, "proximity in time" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may occur in close temporal proximity to a single administration of another therapeutic agent. In some embodiments, the temporal proximity may vary during a treatment cycle or dosing regimen.

[0378] The terms "effective amount" and "therapeutically effective amount" of an agent or compound are used in the broadest sense and refer to a nontoxic but sufficient amount of an active agent or compound to provide a desired effect or benefit.

[0379] The term "benefit" is used in the broadest sense to refer to any desired effect, and specifically includes clinical benefit as defined herein. Clinical benefit can be measured by assessing various endpoints, for example, inhibition to some extent of disease progression, including delay and / or complete halt, reduction in the number of disease events and / or symptoms, shrinkage in lesion size, inhibition (i.e., reduction, delay or complete halt) of disease cell invasion into adjacent peripheral organs and / or tissues, inhibition (i.e., reduction, delay or complete halt) of disease metastasis, reduction in the autoimmune response which may, but not necessarily, result in regression or elimination of disease lesions, alleviation to some extent of one or more symptoms associated with the disorder, length of symptom-free period after treatment such as increased progression-free survival, increased overall survival, higher response rate, reduced mortality at a given time point after treatment, and / or improvement in one of the following symptoms: congestion, fluid / edema, wheezing, cough, hypoxemia, hypoxia, lung stiffness, shortness of breath, shortness of breath during exercise, dry cough, rapid, shallow breathing, weight loss, fatigue, joint pain, muscle pain, and finger clubbing.

[0380] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0381] As used herein, the terms "combination therapy" or "cotherapy" include the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, a pharmacokinetic or pharmacodynamic interaction resulting from the combination of therapeutic agents.

[0382] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0383] Unless otherwise indicated, all references to methods of treatment will be understood to include the use of the compounds to provide the treatment or prophylaxis, etc. described herein, as well as the use of the compounds to prepare medicaments for treating or preventing such conditions. Treatment includes treatment of humans or non-human animals, including rodents, and other disease models.

[0384] As used herein, the term "subject" is interchangeable with the term "subject in need," both of which refer to a subject having a disease or at risk of developing a disease. "Subject" includes mammals. A mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. A subject can also be a bird or poultry. In one embodiment, the mammal is a human.

[0385] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include treatment of a cell or animal model in vitro.

[0386] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may also be used to prevent the associated disease, condition or disorder, or to identify suitable candidates for such purposes.

[0387] As used herein, the terms "preventing," "prevent" or "protecting from" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition or disorder. [Example]

[0388] The methods and combinations described herein are based on the surprising discovery that Compound 1 of the present disclosure significantly improved lung histology and lung function in elderly male bleomycin-treated mice. The combination of Compound 1 and nintedanib had significantly greater effects on functional (PenH, SpO2, lung stiffness) and histological (tissue density, fibrotic lesions) endpoints compared with either compound alone. A study in young female mice with bleomycin-induced disease showed benefits of Compound 1 + nintedanib compared with either drug alone (lung weight, tissue density, fibrotic lesions). Compound 1 also increased plasma levels of adiponectin. These and other findings are described in more detail in the Examples provided below.

[0389] Example 1 - Treatment of Pulmonary Fibrosis with Compound 1 and Combinations of Compound 1 with Nintedanib or Pirfenidone The following are non-limiting examples demonstrating the treatment of pulmonary fibrosis in an aged C57BL / 6 male mouse model using Compound 1 (referred to herein and in Figures 1-12 and 22 as "SDX-7320" or "SDX") and a combination of Compound 1 with either nintedanib (Nin), the current standard of care for patients with interstitial pulmonary fibrosis, or pirfenidone.

[0390] Pulmonary fibrosis was modeled by treating mice with bleomycin (BLM). As will be appreciated by those skilled in the art, BLM sulfate is a mixture of cytotoxic glycopeptide antibiotics isolated from Streptomyces verticillus and is used as an anti-cancer / antibiotic drug to treat various cancers. BLM disrupts DNA in tumor cells and induces apoptosis. BLM has been shown to have deleterious effects on tissues such as the lung and is associated with pulmonary side effects, including inflammation and fibrosis. The most common route of BLM administration to induce pulmonary fibrosis is intratracheal, which generally causes an inflammatory response and increased epithelial apoptosis within the first 7 days, closely resembling acute lung injury (ALI). This is followed by a 3-day transitional phase, during which inflammation resolves and the earliest fibrotic changes are detected. The fibrotic phase persists for 3-4 weeks after BLM and is characterized by excessive deposition of extracellular matrix, which causes areas of fibrosis. As will be appreciated by those skilled in the art, BLM-induced lung injury in mice is a well-documented model of pulmonary fibrosis and is a particularly useful model for studying compounds effective in reducing pulmonary fibrosis and improving lung function after injury.

[0391] Animals: Jackson Laboratory male C57BL / 6 mice aged 72 weeks at the time of randomization were used in this study.

[0392] Treatment: Seven groups of mice were treated as shown in Table A. Mice in groups 2-7 were challenged on day 0 of the study with bleomycin solution by a single oropharyngeal dose of bleomycin solution, such that mice received 1.5 U / kg based on the animals' average body weight. On day 6 of the study, all mice were randomized based on weight loss measured on day 6 and their PenH values (see below).

[0393] Mice in treatment groups 1 and 2 received a vehicle control subcutaneously once every four days (Q4D) from days 7 to 21. Mice in treatment group 3 received SDX-7320 subcutaneously at a dose of 8 mg / kg Q4D from days 7 to 21 (i.e., four doses). Mice in treatment group 4 received pirfenidone orally (PO) at a dose of 100 mg / kg twice daily (BID) from days 7 to 21. Mice in treatment group 5 received nintedanib orally (PO) at a dose of 50 mg / kg once daily (QD) from days 7 to 21. Mice in treatment group 6 received SDX-7320 subcutaneously at a dose of 8 mg / kg Q4D from days 7 to 21 and pirfenidone orally (PO) at a dose of 100 mg / kg twice daily (BID) from days 7 to 21. Mice in treatment group 7 received SDX-7320 subcutaneously at a dose of 8 mg / kg Q4D from days 7 to 21 and nintedanib orally (PO) at a dose of 50 mg / kg once daily (QD) from days 7 to 21. Food and water were provided ad libitum. [Table 1]

[0394] Observations and Measurements: Daily observations of the animals' behavior and general health were recorded. Body weights were also measured daily.

[0395] Respiratory function: Respiratory function of mice was measured using plethysmography. All mice were acclimated to the plethysmograph chamber environment. After the acclimation period, baseline functional respiratory parameters were measured using a whole-body plethysmograph (SCIREQ VivoFlow) on days 6 (before treatment introduction and randomization), 13, and 20 after BLM administration. Respiratory function was measured using mice placed singly in unrestrained whole-body plethysmography (WBP) chambers (Buxco Systems). WBP tracings provide specific information about breathing patterns that correlate with the development of inflammation and fibrosis. Functional respiratory parameters analyzed included respiratory rate and PenH (pulmonary congestion index). PenH is used as an index of edema, inflammation, or congestion (bronchoconstriction). As understood by those skilled in the art, PenH is related to the pulmonary reactivity to injury. In pulmonary fibrosis studies, PenH is used as an index of the animal's pulmonary condition. Absence of elevated PenH values suggests that the animal is not diseased.

[0396] Hypoxia Measurement: On day 20 of the study, hypoxia-related parameters were assessed using an Abbott Vet-scan i-STAT system. Blood gas measurements of arterial blood, including partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), oxygen saturation (SpO2), bicarbonate ion, and lactate levels (indicating hypoxia), were assessed using a single-use CG4+ cartridge. Approximately 4-5 drops of arterial blood were collected from the tail to minimize impact on blood homeostasis.

[0397] PV Loop Assay: Prior to sacrifice on day 21 (after BLM administration), all mice were anesthetized with ketamine / xylazine. Anesthesia was confirmed by the absence of reflex movements. Mice were tracheotomized with a 20G stub needle cannula and ventilated with SCIREQ's FlexiVent automated system. To prevent spontaneous breathing, mice were injected with vecuronium (1 mg / kg), a skeletal muscle relaxant, and allowed to stabilize for at least 2 minutes. After stabilization, all animals were ventilated with the FlexiVent (SCIREQ). Default mouse ventilation parameter settings were entered into the Mouse Mechanics Scan script protocol, including SnapShot-150, Quickprime-3, PV Loop, and Deep Inflation ventilatory pattern protocols. All pulmonary function data acquisition and editing were performed using FlexiWare software V8 to determine phenotypic changes in lung parenchyma that occur with various pulmonary pathologies. Lung compliance or pulmonary compliance is a measure of the lung's ability to stretch and expand (the elastic tissue's distensibility), i.e., reflects the change in volume for any given applied pressure. As will be understood by those skilled in the art, low compliance indicates a stiff lung (with high elastic recoil), which is often observed in fibrosis. High compliance indicates a flexible lung (with low elastic recoil), which is often observed in emphysema.

[0398] Lung weight: The lungs were removed and wet lung weight (indicating edema) was recorded.

[0399] Histopathological preparation: The whole lungs of each mouse were removed, weighed, flushed with 0.9% NaCl, and inflated with 10% neutral buffered formalin (NBF). The left lobe was kept in fixative for 48 hours and sent to the Histopathology Laboratory Althisia (Troyes, France) for preparation of slides for histopathological analysis. For each animal, three sections (5 μm thick) were cut (100 μm apart) onto a single slide and stained with picrosirius red (PSR). Alternatively, sections were labeled with the ab270993 antibody (a rabbit monoclonal antibody against type I collagen). After fixation and sectioning, slides labeled with ab270994Th underwent EDTA-based epitope retrieval and serum blocking for 20 minutes. They were then incubated with the ab270993 primary antibody (concentration, 1 / 1000) for 1 hour, followed by incubation with the secondary antibody for 45 minutes. All slides were scanned at 20x magnification (0.452 μm / pixel) using a NanoZoomer®-SQ scanner (Hamamatsu Photonics), and digital slides of the entire sections were captured using NDP view 2 Hamamatsu software. Images were then processed for automated analysis of pulmonary fibrosis (parenchymal density, percentage of fibrotic foci, and percentage collagen content).

[0400] Histopathological analysis: Automated quantification of morphological features of pulmonary fibrosis was performed from digitized images (scans) of PSR-stained or antibody-labeled lung sections using MorphoQuant™ (Biocellvia, France), an automated, AI-based digital pathology software for quantification. MorphoQuant™ uses the principles of morphological analysis to detect and quantify specific lung disease features from histological slides (Gilhodes et al. 2017; Michaudel, Fauconnier, et al. 2018). The following morphological endpoints were quantitatively assessed: a) Parenchymal tissue density (expressed as "tissue density (%)"), PSR staining: Tissue density is the ratio of the area occupied by lung tissue to the total section area, expressed as a percentage. The lumens derived from alveoli, bronchi, bronchioles, and blood vessels are not taken into account. b) Dense lung tissue (expressed as "fibrous foci (%)"), PSR staining: fibrous foci correspond to fibrous thickening of the alveolar parenchyma and are therefore characterized by specific high density values throughout the lung section. Fibrotic foci are expressed as the percentage ratio of the area occupied by dense lung tissue of the section to the total section area. c) Total collagen (expressed as "Collagen (%)"), PSR staining: Total collagen corresponds to the ratio of the area occupied by collagen to the total section area, expressed as a percentage. d) Collagen type I, α1 (expressed as "COL1A1 area (%)"), ab270993 antibody labeled: Collagen type I, α1 corresponds to the ratio of the area occupied by collagen type I, α1 to the total section area, expressed as a percentage.

[0401] Statistical analysis: All parameters were analyzed similarly, and results were expressed as mean ± SEM using Graph Pad Prism Software version 8.0 (San Diego, CA, USA). Equality of variance was tested using the Bartlett test. ANOVA was performed, followed by a post-hoc test (uncorrected Fisher's LSD). When distributions were not normalized, nonparametric analysis (Kruskal-Wallis test) was performed, followed by an uncorrected Dunn's test. Statistical comparisons were made between sham and BLM / vehicle, followed by comparisons between BLM / vehicle and treatment groups. Differences were considered statistically significant if the P value was less than 0.05. * indicates difference relative to sham animals, # indicates difference relative to BLM+vehicle group, and $ indicates difference relative to BLM+nintedanib. * P<0.05, ** P<0.01, ***P<0.001, # P<0.05, ## P<0.01, ### P<0.001, while $ P<0.05, $$ P<0.01 and $$$ P<0.001.

[0402] Results: Figure 1 shows the PenH values (left panel) and respiratory rates (right panel) of mice in each treatment group on day 6 of the study after randomization of the mice into the different treatment groups. As will be appreciated by those skilled in the art, randomization allows for a relatively equal distribution of each group with respect to disease severity before the start of treatment.

[0403] Figure 2 shows the PenH values on day 13 of the study (upper left panel), the change in PenH values from day 6 to day 13 of the study (lower left panel), the respiratory rate on day 13 of the study (upper right panel), and the change in respiratory rate from day 6 to day 13 of the study (lower respiratory rate panel) for each treatment group.

[0404] Figure 3 shows the PenH values on study day 20 (upper left panel), the change in PenH values from study days 6 to 20 (lower left panel), the respiratory rate on study day 20 (upper right panel), and the change in respiratory rate from study days 6 to 20 (lower respiratory rate panel) for each treatment group. As shown in Figure 3, 20 days after BLM administration, the reduction in lung function was maintained in the BLM-treated group compared to the sham group. As observed on days 6 and 13, BLM administration increased pulmonary congestion (as indicated by PenH values) in BLM-treated animals. While nintedanib alone increased pulmonary congestion, SDX-7320 monotherapy reduced pulmonary congestion, and treatment with the combination of SDX-7320 and nintedanib or SDX-7320 and pirfenidone reduced congestion / inflammation. Furthermore, as shown in Figure 3, the mean respiratory rate was significantly greater in the BLM-treated group. Treatment with the combination of SDX-7320 and nintedanib or the combination of SDX-7320 and pirfenidone reduced respiratory rate.

[0405] Figure 4 shows the PenH values (left panel) and respiratory rate (right panel) for each treatment group over the study period. As shown in Figure 4, after one week of treatment, the condition of mice treated with SDX-7320 monotherapy, the combination of SDX-7320 and nintedanib, or the combination of SDX-7320 and pirfenidone improved. As shown in Figure 4, 21 days after the BLM injury and 14 days after the start of treatment, the condition of mice treated with either SDX-7320 monotherapy, the combination of SDX-7320 and nintedanib, or the combination of SDX-7320 and pirfenidone improved.

[0406] On day 21 of the study, respiratory capacity was assessed by measuring key blood / gas exchange parameters, including arterial blood saturation (SpO2), blood oxygen tension (pO2), blood lactate levels, and blood bicarbonate (HCO3-) ion levels. Blood oxygen tension (pO2), blood bicarbonate (HCO3-) ion levels, and blood lactate levels are shown in Figure 5A (from left to right panels, respectively), and SpO2 values are shown in Figure 5B. As will be appreciated by those skilled in the art, in pulmonary fibrosis, arterial saturation is considered an important parameter representing the status of the lungs. As shown in Figure 5B, SpO2 values were significantly lower in BLM-treated animals compared to sham animals, indicating further evidence of impaired lung function. As shown in Figure 5B, treatment with either SDX-7320 alone or in combination with pirfenidone or nintedanib improved SpO2 values. This improvement was further supported by the improvement in pO2 levels, shown in the left panel of Figure 5A.

[0407] As will be appreciated by those skilled in the art, one of the physiological effects of hypoxia is systemic anaerobic metabolism, resulting in elevated blood lactate levels. As shown in the right panel of Figure 5A, BLM-treated mice had higher blood lactate levels compared to sham mice. SDX-7320 treatment tended to reduce these levels, directly correlating with SpO2 and pO2. Treatment with SDX-7320 alone or in combination with pirfenidone or nintedanib reduced blood lactate levels. These improvements are further supported by the blood bicarbonate levels shown in the center panel of Figure 5A, which correlate with blood bicarbonate levels.

[0408] As will be understood by those skilled in the art, edema is a characteristic of pulmonary inflammation and is associated with vascular leakage and extracellular matrix deposition, which can increase lung weight through interstitial fluid retention and collagen deposition. After 21 days of study, the mice were sacrificed, and the lungs were removed, carefully blotted with sponges, and weighed. Pulmonary edema was assessed by measuring wet lung weight, and the results are shown in Figure 6. As shown in Figure 6, BLM injury induced a significant increase in lung weight. Treatment with SDX-7320 alone or in combination with pirfenidone or nintedanib reduced lung weight compared to BLM-treated mice. Nintedanib or pirfenidone alone did not significantly reduce lung weight.

[0409] Just prior to sacrifice on the final surgical day, a series of studies were performed on mice using the FlexiVent automated system (SCIREQ) to assess various parameters of pulmonary function. Pressure-volume loops (PV loops) were assessed for all mice using a series of automated predetermined pressure steps from 0 to 30 cmH2O, and the analysis is shown in Figure 7.

[0410] Static compliance (Cst) was also measured for each treatment group, and the analysis is shown in FIG.

[0411] Inflation volumes (tidal volumes) and lung volumes (total lung capacity) were also measured for each treatment group, and the analysis is shown in FIG.

[0412] Respiratory system resistance (Rrs) and tissue dumping (G) were also measured in each treatment group, and the analysis is shown in Figure 10. As will be understood by those skilled in the art, tissue dumping is related to alveolar resistance and is primarily responsible for the resistance of the entire pulmonary system. As shown in Figure 10, tissue resistance was significantly increased in mice on BLM + vehicle. Treatment with either SDX-7320 alone or in combination with pirfenidone or nintedanib improved this alveolar resistance to pressure fluctuations.

[0413] Respiratory system elastance (Ers) and lung elastance (H) were also measured in each treatment group, and the analysis is shown in Figure 11. As will be understood by those skilled in the art, lung elastance (H) represents the elastic energy stored in tissue after an applied deformation and therefore the ability of the tissue to recover and return to its original shape. This is an indicator of tissue stiffness. As shown in Figure 11, tissue stiffness was increased in BLM mice and was improved by treatment with SDX-7320, with or without the addition of nintedanib.

[0414] Automated histopathological analysis of lung samples was performed to determine parenchymal density, fibrotic foci (lung foci), and total collagen, as described above. The results of this analysis are shown in Figure 12 (parenchymal density, fibrotic foci, and total collagen), Figure 22 (type I collagen, α1), and the corresponding Table C. [Table 2]

[0415] As shown in Figure 12, treatment with SDX-7320 alone or in combination with nintedanib or pirfenidone improved both lung lesions and parenchymal tissue density and collagen content.

[0416] As shown in Figure 22 and corresponding Table C, treatment with SDX-7320 alone or in combination with nintedanib significantly inhibits collagen deposition in lung tissue after exposure to bleomycin. SDX-7320 in combination with nintedanib further improved the SDX-7320 response, almost completely inhibiting collagen deposition. In contrast, nintedanib alone had little activity on collagen deposition.

[0417] Finally, automated histopathological analysis of lung samples was performed to determine the mean airspace circularity and mean airspace contact in each treatment group. The results of this analysis are summarized in Figures 20 and 21, respectively. As shown in Figures 20 and 21, differences were observed in mice treated with the vehicle control compared to mice treated with the combination of SDX-7320 and pirfenidone or the combination of SDX-7320 and nintedanib.

[0418] Taken together, these results demonstrate that SDX-7320 and the combination of SDX-7320 with either nintedanib or pirfenidone can be used to effectively treat pulmonary fibrosis and improve lung function after induction of pulmonary fibrosis.

[0419] Example 2 - Treatment of Pulmonary Fibrosis with Compound 1 and a Combination of Compound 1 and Nintedanib The following are non-limiting examples demonstrating the treatment of pulmonary fibrosis in an 8-week-old female C57BL / 6 mouse model using Compound 1 (referred to herein and in Figures 13-19 as "SDX-7320" or "SDX") and a combination of Compound 1 and nintedanib.

[0420] Pulmonary fibrosis was modeled by treating mice with bleomycin (BLM). To induce pulmonary fibrosis, a single dose of bleomycin (3 mg / kg in a volume of 50 μl) was instilled intratracheally on day 0 of the study.

[0421] Treatment: Five groups of mice were treated as described in Table B. Mice in groups 2-5 were challenged with bleomycin solution on day 0 of the study, as described above. Mice were randomized into different treatment groups on day 7 of the study based on change in body weight from baseline.

[0422] Mice in treatment group 2 received a vehicle control subcutaneously once every four days (Q4D) from days 7 to 20. Mice in treatment group 3 received SDX-7320 subcutaneously at a dose of 8 mg / kg Q4D from days 7 to 21. Mice in treatment group 4 received nintedanib orally (PO) at a dose of 100 mg / kg once daily (QD) from days 7 to 20. Mice in treatment group 5 received SDX-7320 subcutaneously at a dose of 8 mg / kg Q4D from days 7 to 20 and nintedanib orally (PO) at a dose of 100 mg / kg once daily (QD) from days 7 to 21. All mice were sacrificed on day 21 of the study. [Table 3]

[0423] Results: Figure 13 shows the body weight and body weight change in each treatment group over the course of the study.

[0424] Figure 14 shows the weight of the left lung at the end of the study for each treatment group. As shown in Figure 14, mice treated with a combination of SDX-7320 and nintedanib showed a decrease in mean left lung weight compared to the vehicle control group. Furthermore, the mean left lung weight in mice treated with SDX-7320 alone also tended to be decreased compared to the vehicle control group.

[0425] Figure 15 shows the post-caval lobe weights at the end of the study for each treatment group. As shown in Figure 15, mice treated with a combination of SDX-7320 and nintedanib showed a decrease in post-caval lobe weight compared to the vehicle control group. Furthermore, the post-caval lobe weights in mice treated with SDX-7320 alone also tended to be decreased compared to the vehicle control group.

[0426] Figure 16 shows the survival of mice in each of the control groups over the course of the study.

[0427] Additionally, automated histopathological analysis was performed on lung samples obtained from mice at the end of the study. Briefly, formalin-fixed, paraffin-embedded blocks were processed. For each mouse, a series of three sections (5 μm thick) was cut, spaced 50 μm apart. Because each block contained three lobes, nine sections were placed on slides and stained with PSR. Digital slides of all sections were imaged at 20x magnification using Hamamatsu Photonics' NDP.view 2 software. Automated quantification of pulmonary PF morphological features was performed from digitized images (scans) of PSR-stained lung sections using Biocellvia's imaging assay, MorphoQuant®-Lung. The following endpoints were quantitatively assessed as described in Example 1: a) Tissue density (%) b) Fibrotic foci (%) c) Collagen (%).

[0428] The results of tissue density, fibrous lesions, and collagen analysis are shown in Figures 17-19, respectively. Tissue density and collagen content were reduced in the combination group compared to vehicle and each treatment alone. As shown in Figure 18, treatment with the combination of SDX-7320 and nintedanib reduced fibrous lesions compared to both the vehicle control group and treatment with nintedanib alone.

[0429] Taken together, these results demonstrate that SDX-7320 and the combination of SDX-7320 with either nintedanib or pirfenidone can be used to effectively treat pulmonary fibrosis and improve lung function after induction of pulmonary fibrosis.

Claims

1. 1. A combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof for use in the treatment of pulmonary fibrosis in a subject.

2. 1. A method of treating pulmonary fibrosis in a subject in need thereof, comprising administering to the subject at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof.

3. 1. A MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in a method for treating pulmonary fibrosis in a subject, the method further comprising administration of nintedanib or a pharmaceutically acceptable salt thereof.

4. 1. Nintedanib or a pharmaceutically acceptable salt thereof for use in a method for treating pulmonary fibrosis in a subject, said method further comprising administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

5. 10. The combination for use according to claim 1, the method according to claim 2, the MetAP2 inhibitor for use according to claim 3, or the nintedanib for use according to claim 4, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the nintedanib or a pharmaceutically acceptable salt thereof are administered simultaneously or closely in time.

6. The MetAP2 inhibitor is 【Chemical 1】 10. The combination for use according to claim 1 or 5, the method of claim 2 or 5, the MetAP2 inhibitor for use according to claim 3 or 5, or nintedanib for use according to claim 4 or 5, selected from: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably the ratio of x to y is in the range of about 30:1 to about 3:1, preferably the ratio of x to y is about 11:1; or a pharmaceutically acceptable salt thereof.

7. The MetAP2 inhibitor is 【Chemistry 2】 wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, preferably the ratio of x to y is about 11:1, or a pharmaceutically acceptable salt thereof.

8. The combination for use according to any one of claims 1 or 5 to 7, the method according to any one of claims 2 or 5 to 7, the MetAP2 inhibitor for use according to any one of claims 3 or 5 to 7, or nintedanib for use according to any one of claims 4 or 5 to 7, wherein said nintedanib is nintedanib esylate.

9. The combination for use according to any one of claims 1 or 5 to 8, the method according to any one of claims 2 or 5 to 8, the MetAP2 inhibitor for use according to any one of claims 3 or 5 to 8, or nintedanib for use according to any one of claims 4 or 5 to 8, wherein the pulmonary fibrosis is asbestosis, COVID-19-associated pulmonary fibrosis, drug-induced pulmonary fibrosis, hypersensitivity pneumonitis (HP), idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (NSIP), pneumoconiosis, rheumatoid arthritis interstitial lung disease (RA-ILD), sarcoidosis, silicosis, systemic sclerosis, or therapy-induced pulmonary fibrosis, preferably wherein the pulmonary fibrosis is IPF or therapy-induced pulmonary fibrosis.

10. A combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof for use in treating pulmonary fibrosis in a subject.

11. 1. A method for treating pulmonary fibrosis in a subject in need thereof, comprising administering to the subject at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and pirfenidone or a pharmaceutically acceptable salt thereof.

12. 1. A MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in a method for treating pulmonary fibrosis in a subject, the method further comprising administration of pirfenidone or a pharmaceutically acceptable salt thereof.

13. 1. Pirfenidone or a pharmaceutically acceptable salt thereof for use in a method for treating pulmonary fibrosis in a subject, said method further comprising administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

14. 14. The combination for use according to claim 10, the method according to claim 11, the MetAP2 inhibitor for use according to claim 12, or the pirfenidone for use according to claim 13, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the pirfenidone or a pharmaceutically acceptable salt thereof are administered simultaneously or closely in time.

15. The MetAP2 inhibitor is 【Chemistry 3】 15. The combination for use according to claim 10 or 14, the method of claim 11 or 14, the MetAP2 inhibitor for use according to claim 12 or 14, or the pirfenidone for use according to claim 13 or 14 selected from: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably the ratio of x to y is in the range of about 30:1 to about 3:1, preferably the ratio of x to y is about 11:1; or a pharmaceutically acceptable salt thereof.

16. The MetAP2 inhibitor is 【Chemistry 4】 wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, preferably the ratio of x to y is about 11:1, or a pharmaceutically acceptable salt thereof.

17. The combination for use according to any one of claims 10 or 14 to 16, the method according to any one of claims 11 or 14 to 16, the MetAP2 inhibitor for use according to any one of claims 12 or 14 to 16, or the pirfenidone for use according to any one of claims 13 or 14 to 16, wherein the pulmonary fibrosis is asbestosis, COVID-19-associated pulmonary fibrosis, drug-induced pulmonary fibrosis, hypersensitivity pneumonitis (HP), idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (NSIP), pneumoconiosis, rheumatoid arthritis interstitial lung disease (RA-ILD), sarcoidosis, silicosis, systemic sclerosis, therapy-induced pulmonary fibrosis, preferably the pulmonary fibrosis is IPF or therapy-induced pulmonary fibrosis.

18. A combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-cancer agent or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject.

19. 1. A method for treating cancer in a subject in need thereof, comprising administering to the subject at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one anticancer agent or a pharmaceutically acceptable salt thereof.

20. 1. A MetAP2 inhibitor or a pharmaceutically acceptable salt thereof for use in a method for treating cancer in a subject, the method further comprising administration of at least one anticancer agent or a pharmaceutically acceptable salt thereof.

21. 1. At least one anti-cancer agent or a pharmaceutically acceptable salt thereof for use in a method for treating pulmonary fibrosis in a subject, said method further comprising administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

22. 22. The combination for use according to claim 18, the method according to claim 19, the MetAP2 inhibitor for use according to claim 20, or the at least one anti-cancer agent for use according to claim 21, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the at least one anti-cancer agent or a pharmaceutically acceptable salt thereof are administered simultaneously or closely in time.

23. The MetAP2 inhibitor is 【Chemistry 5】 23. The combination for use according to claim 18 or 22, the method of claim 19 or 22, the MetAP2 inhibitor for use according to claim 20 or 22, or the at least one anti-cancer agent for use according to claim 21 or 22 selected from: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, and preferably the ratio of x to y is in the range of about 30:1 to about 3:1, preferably the ratio of x to y is about 11:1; or a pharmaceutically acceptable salt thereof.

24. The MetAP2 inhibitor is 【Chemistry 6】 24. The combination for use according to any one of claims 18 or 22-23, the method of any one of claims 19 or 22-23, the MetAP2 inhibitor for use according to any one of claims 20 or 22-23, or the at least one anti-cancer agent for use according to any one of claims 21 or 22-23, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably the ratio of x to y is in the range of about 30:1 to about 3:1, preferably the ratio of x to y is about 11:1, or a pharmaceutically acceptable salt thereof.

25. 24. The combination for use according to any one of claims 18 or 22-23, the method of any one of claims 19 or 22-234, the MetAP2 inhibitor for use according to any one of claims 20 or 22-24, or the at least one anti-cancer agent for use according to any one of claims 21 or 22-24, wherein the at least one anti-cancer agent comprises Enhertz and the cancer is breast cancer.

26. 26. The combination for use, the method, the MetAP2 inhibitor for use, or the anti-cancer agent for use according to claim 25, wherein the breast cancer is HER2-negative breast cancer.

27. Administration of the MetAP2 inhibitor alone or in combination with nintedanib reduces pulmonary congestion, reduces pulmonary inflammation, reduces respiratory rate, and reduces SpO2 in a subject. ２ Increase in pO ２ 9. The combination for use according to any one of claims 1 or 5 to 8, the method of any one of claims 2 or 5 to 8, the MetAP2 inhibitor for use according to any one of claims 3 or 5 to 8, or nintedanib for use according to any one of claims 4 or 5 to 8, which results in increased lung tissue levels, decreased blood lactate levels, increased blood bicarbonate levels, decreased lung weight, decreased respiratory tissue resistance, decreased lung tissue dumping, decreased respiratory system elastance, decreased lung elastance, decreased parenchymal tissue density, regression of lung lesions, decreased collagen content, decreased collagen deposition and / or decreased tissue density.

28. The combination for use according to any one of claims 1 or 5 to 8, the method of any one of claims 2 or 5 to 8, the MetAP2 inhibitor for use according to any one of claims 3 or 5 to 8, or nintedanib for use according to any one of claims 4 or 5 to 8, wherein administration of the MetAP2 inhibitor alone or in combination with nintedanib results in a decrease in collagen deposition in lung tissue compared to a subject who does not receive the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.

29. 29. The combination for use, the method, the MetAP2 inhibitor for use, or the nintedanib for use according to claim 28, wherein administering both the MetAP2 inhibitor and nintedanib results in a greater reduction in collagen deposition in lung tissue compared to administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof alone.

30. The combination for use according to any one of claims 1 or 5 to 8, the method of any one of claims 2 or 5 to 8, the MetAP2 inhibitor for use according to any one of claims 3 or 5 to 8, or nintedanib for use according to any one of claims 4 or 5 to 8, wherein the pulmonary fibrosis results from an interstitial lung disease.

31. 31. The combination for use, method, MetAP2 inhibitor for use, or nintedanib for use according to claim 30, wherein the interstitial lung disease is drug-induced.

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