Methods for treating acute respiratory distress syndrome with TIE-2 activators

Abstract

Disclosed herein are methods for treating acute respiratory distress syndrome, lung injury, respiratory failure, and related conditions using a Tie-2 activator and an HPTPβ inhibitor. The methods include reducing vascular leakage and permeability, reducing edema, reducing inflammation, and increasing oxygen exchange capacity in the lung. In some embodiments, the present invention provides a method for treating a pulmonary condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a Tie-2 activator to the subject, wherein the administration increases the subject's oxygenation index by about 1 to about 20, compared to the absence of administration.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 028,317, filed May 21, 2020, the contents of which are incorporated herein by reference. [Background technology]

[0002] background Acute respiratory distress syndrome (ARDS) is a severe lung injury characterized by disruption of pulmonary endothelial homeostasis, bilateral pulmonary infiltrates, and hypoxemia. The microvascular barrier separating blood cells from airspaces ruptures. The resulting inflammatory infiltrate and pulmonary edema severely impair gas exchange, leading to multiple organ failure and death. A common cause of ARDS is sepsis, in which a dysfunctional immune response to infection leads to systemic inflammation and organ damage. Summary of the Invention [Means for solving the problem]

[0003] overview In some embodiments, the invention provides methods of treating a pulmonary condition in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a Tie-2 activator to the subject, wherein the administration increases the oxygenation index of the subject by about 1 to about 20, compared to the absence of administration.

[0004] In some embodiments, the invention provides a method of treating acute respiratory distress syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein the administration increases the subject's oxygenation index by about 1 to about 20 within 7 days after administration compared to no administration, the therapeutically effective amount is about 0.1 mg to about 30 mg per kg of subject per dose, and the therapeutically effective amount is about 10 mg to about 40 mg per kg of subject, the Tie-2 activator is present in the unit dosage form at a concentration of about 20 mg / mL, the subject is infected with SARS-CoV-2, and the administration treats acute respiratory distress syndrome in the subject.

[0005] In some embodiments, the invention provides a method of treating acute respiratory distress syndrome in a subject having COVID-19, comprising administering to the subject a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein the administration increases the subject's oxygenation index by about 1 to about 20 within 7 days after administration compared to no administration, the therapeutically effective amount is about 0.1 mg to about 30 mg per kg of subject per dose, and the therapeutically effective amount is about 10 mg to about 40 mg per kg of subject per dose, the Tie-2 activator is present in the unit dosage form at a concentration of about 20 mg / mL, the subject is infected with SARS-CoV-2, and the administration treats acute respiratory distress syndrome in the subject.

[0006] In some embodiments, the invention provides a method of treating COVID-19 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein the administration increases the subject's oxygenation index by about 1 to about 20 within 7 days after administration compared to no administration, the therapeutically effective amount is about 0.1 mg to about 30 mg per kg of subject per dose, and the therapeutically effective amount is about 10 mg to about 40 mg per kg of subject, the Tie-2 activator is present in the unit dosage form at a concentration of about 20 mg / mL, the subject is infected with SARS-CoV-2, and the administration treats acute respiratory distress syndrome in the subject.

[0007] Incorporation by Reference Each patent, publication, and non-patent document cited in this application is incorporated herein by reference in its entirety, as if each were individually incorporated by reference. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method of treating a pulmonary condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a Tie-2 activator to the subject, wherein the administration increases the oxygenation index of the subject by about 1 to about 20 compared to the absence of administration. (Item 2) 2. The method of claim 1, wherein the administration increases the oxygenation index of the subject by about 1 to about 10. (Item 3) 2. The method according to item 1, wherein the administration increases the oxygenation index of the subject by about 1 to about 20 within 72 hours after administration. (Item 4) 2. The method according to item 1, wherein the administration increases the oxygenation index of the subject by about 1 to about 20 within 48 hours after administration. (Item 5) 2. The method according to item 1, wherein the administration increases the oxygenation index of the subject by about 1 to about 20 within 24 hours after administration. (Item 6) said administration reduces the mean airway pressure required to be applied to said subject by a ventilator by about 1 cmH compared to no administration; 2 O~about 30cmH 2 The method according to item 1, wherein O is reduced. (Item 7) The administration reduces the mean airway pressure required to be applied to the subject by a ventilator to about 1 cmH within 72 hours after administration. 2 O~about 30cmH 2 The method according to item 1, wherein O is reduced. (Item 8) The administration reduces the mean airway pressure required to be applied to the subject by a ventilator to about 1 cmH within 48 hours after administration. 2 O~about 30cmH 2 The method according to item 1, wherein O is reduced. (Item 9) The administration reduces the mean airway pressure required to be applied to the subject by a ventilator to about 1 cmH within 24 hours after administration. 2 O~about 30cmH 2 The method according to item 1, wherein O is reduced. (Item 10) the administration reduces PaO in the subject compared to not administering 2 / FiO 2 2. The method according to item 1, wherein the ratio is increased by about 1 to about 100. (Item 11) the administration reduces PaO2 of the subject within 72 hours after administration 2 / FiO 2 2. The method according to item 1, wherein the ratio is increased by about 1 to about 100. (Item 12) wherein the administration reduces PaO2 of the subject within 48 hours after administration. 2 / FiO 2 2. The method according to item 1, wherein the ratio is increased by about 1 to about 100. (Item 13) the administration reduces PaO2 of the subject within 24 hours after administration 2 / FiO 2 2. The method according to item 1, wherein the ratio is increased by about 1 to about 100. (Item 14) Item 1, wherein the administration reduces the acute lung injury score of the subject by 1 to 4 compared to the case where the administration is not performed. (Item 15) Item 10. The method of item 1, wherein the administration reduces the subject's acute lung injury score by 1 to 4 within 72 hours after administration. (Item 16) Item 10. The method of item 1, wherein the administration reduces the subject's acute lung injury score by 1 to 4 within 48 hours after administration. (Item 17) 2. The method of claim 1, wherein the administration reduces the subject's acute lung injury score by 1 to 4 within 24 hours of administration. (Item 18) 2. The method of item 1, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 compared to when the administration is not performed. (Item 19) 2. The method of item 1, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 within 72 hours after administration. (Item 20) 2. The method of item 1, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 within 48 hours after administration. (Item 21) 2. The method of item 1, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 within 24 hours after administration. (Item 22) 2. The method of claim 1, wherein the administration regulates a change in the level of plasma Ang-2 concentration in the subject after administration. (Item 23) 2. The method of claim 1, wherein the administration regulates a change in the level of plasma Ang-2 / Ang-1 ratio in the subject after administration. (Item 24) 2. The method of claim 1, wherein the administration regulates a change in the level of plasma IL-6 concentration in the subject after administration. (Item 25) 2. The method of claim 1, wherein the administration regulates a change in the level of plasma IL-8 concentration in the subject after administration. (Item 26) 2. The method of claim 1, wherein the administration modulates a change in the level of plasma TNFα concentration in the subject after administration. (Item 27) 2. The method of claim 1, wherein the administration regulates a change in the level of plasma D-dimer concentration in the subject after administration. (Item 28) 2. The method of claim 1, wherein the administration regulates a change in the level of plasma CRP concentration in the subject after administration. (Item 29) 2. The method of claim 1, wherein the administration reduces systemic inflammation in the subject after administration. (Item 30) 2. The method of claim 1, wherein the administration activates endothelial nitric oxide synthase (eNOS) in the subject after administration. (Item 31) 2. The method of claim 1, wherein the administration increases the production of nitric oxide (NO) in the subject after administration. (Item 32) 2. The method of claim 1, wherein the Tie-2 activator is administered to the subject in a unit dosage form. (Item 33) 33. The method of claim 32, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient. (Item 34) 34. The method of claim 33, wherein the pharmaceutically acceptable excipient is a cyclodextrin. (Item 35) 34. The method of claim 33, wherein the pharmaceutically acceptable excipient is HPβCD. (Item 36) 34. The method of claim 33, wherein the pharmaceutically acceptable excipient is D-mannitol. (Item 37) 34. The method of claim 33, wherein the pharmaceutically acceptable excipient is dextrose. (Item 38) 33. The method of claim 32, wherein the unit dosage form further comprises HPβCD in an amount of about 10% by weight of the unit dosage form. (Item 39) 33. The method of claim 32, wherein the unit dosage form further comprises D-mannitol in an amount of about 4.5% by weight of the unit dosage form. (Item 40) 33. The method of claim 32, wherein the unit dosage form further comprises dextrose in an amount of about 5% by weight of the unit dosage form. (Item 41) 2. The method of claim 1, wherein the administration is by continuous infusion for 1 hour. (Item 42) 10. The method of claim 1, wherein the administration is a 2-hour continuous infusion. (Item 43) 2. The method of claim 1, wherein the administration is by continuous infusion for 2 to 2.5 hours. (Item 44) 2. The method of item 1, wherein the administration is twice daily. (Item 45) 2. The method of item 1, wherein the administration is three times daily. (Item 46) 10. The method of claim 1, wherein the administration is three times daily for seven days. (Item 47) 10. The method of claim 1, wherein the administration is every 8 hours for 72 hours. (Item 48) Item 2. The method according to item 1, wherein the therapeutically effective amount is about 0.1 mg to about 30 mg per kg of the subject per dose. (Item 49) Item 10. The method according to item 1, wherein the therapeutically effective amount is about 0.1 mg to about 20 mg per kg of the subject per dose. (Item 50) 2. The method of claim 1, wherein the therapeutically effective amount is about 750 ng·hr / mL / day. (Item 51) 2. The method of claim 1, wherein the therapeutically effective amount is about 510.2 ng·hr / mL / day. (Item 52) 2. The method of claim 1, wherein the therapeutically effective amount of the Tie-2 activator is about 10 mg. (Item 53) 2. The method of claim 1, wherein the therapeutically effective amount of the Tie-2 activator is about 15 mg. (Item 54) 2. The method of claim 1, wherein the therapeutically effective amount of the Tie-2 activator is about 30 mg. (Item 55) 2. The method of claim 1, wherein the therapeutically effective amount of the Tie-2 activator is about 45 mg. (Item 56) 2. The method of claim 1, wherein the Tie-2 activator is administered in a formulation having a concentration of about 20 mg / mL. (Item 57) 2. The method of claim 1, wherein the administration is subcutaneous. (Item 58) 2. The method of claim 1, wherein the administration is intravenous. (Item 59) 2. The method of item 1, wherein the administration is by bolus intravenous injection. (Item 60) 2. The method of claim 1, wherein the administration is by continuous intravenous infusion. (Item 61) 2. The method of claim 1, wherein the pulmonary condition is acute lung injury. (Item 62) 2. The method of claim 1, wherein the pulmonary condition is acute hypoxemic respiratory failure. (Item 63) 2. The method of claim 1, wherein the pulmonary condition is acute respiratory distress syndrome (ARDS). (Item 64) Item 64. The method of item 63, wherein the ARDS is mild ARDS. (Item 65) Item 64. The method of item 63, wherein the ARDS is moderate ARDS. (Item 66) Item 64. The method of item 63, wherein the ARDS is severe ARDS. (Item 67) 2. The method of claim 1, wherein the pulmonary condition is COVID-19. (Item 68) The subject has a PaO of less than about 300 as determined from arterial blood of the subject. 2 / FiO 2 Item 1, wherein the ratio is: (Item 69) The subject has a PaO of about 200 to about 300 as determined from arterial blood of the subject. 2 / FiO 2 Item 1, wherein the ratio is: (Item 70) The subject has a PaO of about 100 to about 200 as determined from arterial blood of the subject. 2 / FiO 2 Item 1, wherein the ratio is: (Item 71) The subject has a PaO of less than about 100 as determined from arterial blood of the subject. 2 / FiO 2 Item 1, wherein the ratio is: (Item 72) Item 10. The method of item 1, wherein the subject has bilateral pulmonary infiltrates as determined by chest x-ray. (Item 73) 2. The method of claim 1, wherein the subject does not have bilateral pulmonary infiltrates as determined by chest x-ray. (Item 74) Item 10. The method of item 1, wherein the subject has a viral infection. (Item 75) 75. The method of item 74, wherein the viral infection is a coronavirus infection. (Item 76) 75. The method of claim 74, wherein the viral infection is SARS-CoV-2. (Item 77) Item 10. The method of item 1, wherein the subject has hypertension. (Item 78) Item 10. The method of item 1, wherein the subject has pulmonary hypertension. (Item 79) Item 10. The method of item 1, wherein the subject is a human. (Item 80) The Tie-2 activator is a compound of the formula

change

change

change

change

change

change

change

change

change

change

change

change

change

[0008] [Figure 1] Figure 1 shows Tie-2 signaling effects in health, sepsis, and ARDS.

[0009] [Figure 2] Figure 2 shows the effects of Tie-2, Ang-1, Ang-2, and VE-PTP signaling in COVID-19.

[0010] [Figure 3]Panel A of Figure 3 shows human RNA expression data for VE-PTP. Panel B shows immunoblots and corresponding expression levels of VE-PTP (upper panel) or Tie2 (lower panel) immunoprecipitated from whole lung lysates of Akita / Ren diabetic hypertensive mice. Panel C shows Western blot analysis of lysates from cultured endothelial cells demonstrating VE-PTP induction by hypoxia.

[0011] [Figure 4] Panel A of Figure 4 shows Western blot analysis of cultured endothelial cell lysates demonstrating Tie-2 activation by Compound 1. Panel B shows the effect of Compound 1 on LPS-induced lung permeability. Panel C shows the effect of Compound 1 on VEGF-induced and histamine-induced skin vascular permeability.

[0012] [Figure 5] FIG. 5 is a schematic diagram of the cecal ligation and puncture (CLP) sepsis model.

[0013] [Figure 6] FIG. 6 shows the effect of Compound 1 on polymicrobial septic shock.

[0014] [Figure 7] FIG. 7 shows human pharmacokinetic results for SQ Compound 1 twice daily (BID) at the doses indicated.

[0015] [Figure 8] Panel A of Figure 8 shows the effect of Compound 1 on lowering systolic blood pressure in patients with DME. Panel B shows the effect of Compound 1 alone and in combination with ranibizumab on lowering systolic blood pressure in patients with DME. Panel C shows the effect of Compound 1 on lowering systolic blood pressure in patients with a baseline systolic blood pressure of 140 mmHg or greater versus patients with a baseline systolic blood pressure of less than 140 mmHg.

[0016] [Figure 9]FIG. 9 shows the effect of Compound 1 alone and in combination with ranibizumab on reducing central retinal subfield thickness in patients with DME.

[0017] [Figure 10] FIG. 10 shows the effect of Compound 1 on the urinary albumin / creatinine ratio (UACR).

[0018] [Figure 11] FIG. 11 shows the pathophysiological progression of lung injury.

[0019] [Figure 12] FIG. 12 shows exemplary oxygenation index data from three ARDS network trials.

[0020] [Figure 13] FIG. 13 shows the study design to evaluate the safety and efficacy of Compound 1 in subjects with moderate to severe COVID-19. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description For example, therapies using Tie-2 activators for the treatment of ARDS, acute lung injury (ALI), chronic lung injury, pulmonary inflammation, pulmonary hypoxemia, and respiratory failure are described herein. The Tie-2 activators of the present disclosure can activate Tie-2 signaling by promoting protein phosphorylation, such as Tie-2 phosphorylation. Such activation can play a crucial role in protecting against microvascular rupture in ARDS or COVID-19.

[0022] ARDS and respiratory failure ARDS is an acute inflammatory syndrome characterized by increased permeability of the alveolar-capillary membrane. Clinically, ARDS can present as acute-onset bilateral pulmonary infiltrates with severe hypoxemia. In the general population, the most common cause of ARDS is sepsis. Pneumonia and / or aspiration of oral gastric contents are the second leading causes, followed by trauma and burns. Other causes include pancreatitis, smoke inhalation, circulatory shock in the absence of sepsis, blood transfusion (transfusion-related acute lung injury, or TRALI), cardiothoracic surgery, chest or pulmonary contusion, fracture, and drug toxicity. Symptoms of ARDS include severe shortness of breath, muscle fatigue, generalized weakness, hypotension, skin or nail discoloration, dry and hacking cough, fever, headache, elevated heart rate, and altered mental status.

[0023] Non-limiting examples of conditions associated with ARDS include ALI, chronic lung injury, sepsis, septic shock, pneumonia, lung inflammation, fluid accumulation in the lungs, pulmonary edema, hypotension, and bronchitis. Sepsis is characterized by an extreme immune response to infection that results in damage to tissues and organs, such as the lungs, abdominal organs, and urinary tract. Under normal conditions, the immune system is triggered to release cytokines and other immunomodulators into the bloodstream to combat infection. Sepsis occurs when the immune response becomes dysregulated, causing systemic inflammation and immune cell hyperactivation, for example, during chronic infection. Non-limiting examples of sepsis symptoms include fever, hypothermia, hypotension, elevated heart rate, elevated respiratory rate, elevated blood glucose, metabolic acidosis, low blood volume, heart failure, anaphylaxis, adrenal insufficiency, pulmonary embolism, edema, decreased urination, and altered mental status.

[0024] ARDS, sepsis, and pneumonia can be caused by pathogenic infections such as bacteria, viruses, or parasites. These infections can specifically target the lungs, causing lung injury and ARDS. Non-limiting examples of pathogenic viruses include coronavirus, influenza, rhinovirus, hantavirus, Nipah virus, Hendra virus, and human immunodeficiency virus (HIV). Non-limiting examples of conditions that cause or are associated with ARDS include hantavirus pulmonary syndrome (HPS), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and 2019 novel coronavirus disease (COVID-19).

[0025] Coronaviruses are a group of closely related viruses that infect the respiratory tract. Non-limiting examples of coronaviruses include SARS-CoV (SARS-CoV-1), SARSr-CoV, HCoV-NL63, HCoV-HKU1, MERS-CoV, and SARS-CoV-2 (2019-nCoV).

[0026] Human influenza A and B viruses cause seasonal epidemics of influenza disease. Influenza A viruses are known to cause influenza pandemics. Influenza A viruses are classified into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1-H18 and N1-N11, respectively). Influenza A virus subtypes that routinely circulate in humans include A(H1N1) and A(H3N2). Non-limiting examples of pathogenic influenza viruses include swine influenza, avian influenza, equine influenza, canine influenza, H1N1, H1N1 / 09, H1N2, H2N2, H3N2, H3N8, H5N1, H7N2, H7N3, H7N3, H7N7, H7N9, H9N2, and H10N7.

[0027] Rhinoviruses are the most common viral infectious agents in humans and are the primary cause of the common cold. There are three species of rhinoviruses (A, B, and C), which differ based on their surface proteins (serotypes).

[0028] Current treatments for ARDS only manage the underlying causes or symptoms of ARDS, such as antibiotics to treat infection, corticosteroids to reduce inflammation, bronchodilators to dilate airways, and diuretics to reduce fluid accumulation in the lungs. The cornerstones of ARDS management are supportive care and mechanical respiratory support. Supportive care is designed to reduce further harm as the lungs recover from ARDS. For example, low-tidal-volume ventilation strategies reduce the likelihood of ventilator-induced lung injury, and conservative fluid strategies maintain drier lungs, resulting in better oxygenation and clinical outcomes. However, substantial improvements in outcomes for patients with ARDS depend on therapies that directly address the pathophysiology of ARDS. Such targeted therapies could reduce the long-term disease burden by attenuating the late fibroproliferative phase and more fully restoring normal lung function.

[0029] COVID-19 COVID-19 is a rapidly progressing respiratory infection caused by the coronavirus SARS-CoV-2, leading to ARDS and respiratory failure. Individuals with pre-existing conditions are at higher risk for complications associated with COVID-19. Non-limiting examples of these pre-existing conditions include heart failure, diabetes, hypertension, coronary heart disease, asthma, chronic liver disease, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD). For example, patients with CKD who contract COVID-19 are at higher risk for acute kidney injury.

[0030] Conditions associated with chronic endothelial dysfunction and vascular injury, such as diabetes and hypertension, increase VE-PTP expression and decrease Tie-2 activation. This biological context may explain the predisposition of diabetic and hypertensive patients to increased COVID-19 severity. Furthermore, hypoxia increases VE-PTP expression and decreases Tie-2 activation, further contributing to the endothelial dysfunction and multiple organ failure that occur in COVID-19 patients with severe respiratory failure.

[0031] Angiotensin-converting enzyme 2 (ACE2), the functional receptor for SARS-CoV-2, is expressed in the lung epithelium and endothelium. This phenomenon suggests that the pulmonary vasculature is a direct target in the development of COVID-19 lung pathology. SARS-CoV-2 can also infect and replicate in human capillary organoids. In some cases, lymphocytic endotheliitis can occur in the lungs, heart, kidneys, and liver of COVID-19 patients. COVID-19 endotheliitis may be the cause of systemic microcirculatory dysfunction in different vascular beds and clinical sequelae in patients with COVID-19.

[0032] Viral inclusion bodies and elements can be found in the endothelial lining of the heart, liver, kidney, intestine, and lungs of patients with COVID-19. These endothelial cells harbor inflammatory cell accumulation and show evidence of endothelial and inflammatory cell death. Collectively, these findings suggest that SARS-CoV-2 infection promotes the induction of endotheliitis in several organs as a direct result of viral involvement and the host inflammatory response.

[0033] Furthermore, induction of apoptosis and pyroptosis may play a key role in endothelial cell injury in patients with COVID-19. This strategy may be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction associated with male gender, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19. Therefore, restoring Tie-2 activation in the pulmonary vasculature represents a promising host-directed approach for treating COVID-19-associated lung pathology. Described herein are Tie-2 activators useful for reducing the severity of COVID-19.

[0034] Tie-2 activation and pulmonary endothelial stabilization Among all organs in the body, the lung contains the highest proportion of endothelial cells and the largest cross-sectional area of ​​vasculature. Therefore, the lung is a prime target for therapeutic modulation of Tie-2. Tie-2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2) is a membrane receptor tyrosine kinase expressed primarily in vascular endothelial cells and a subset of hematopoietic stem cells (HSCs) and macrophages. The Tie-2 receptor is largely endothelial-specific and essential for vascular maturation. Phosphorylation of Tie-2 leads to Tie-2 activation. Upstream factors control Tie-2 phosphorylation and affect downstream signaling pathways. Non-limiting examples of factors that regulate Tie-2 include angiopoietin 1 (Ang-1 or Angpt-1), angiopoietin 2 (Ang-2 or Angpt-2), and human protein tyrosine phosphatase β (often abbreviated as HPTPβ or HPTP-beta).

[0035] Ang-1 is an agonist of Tie-2, and its binding to Tie-2 promotes receptor phosphorylation. Ang-2 is a Tie-2 ligand that acts in a context-dependent antagonistic or agonistic manner. Ang-1 binding to Tie-2 increases the level of endogenous Tie-2 receptor phosphorylation. This binding initiates a signaling cascade that can induce characteristic vascular remodeling through highly ordered angiogenesis and the strengthening of endothelial cell junctions (endothelial cell proximity). These signaling pathways include downstream PI3K / Akt signaling, eNOS signaling, Rac1 signaling, survivin signaling, NF-κB signaling, and the Ras / Raf / MEK / ERK pathway. Rac1 signaling mediates stabilization of cell junctions. Survivin can improve endothelial cell survival. Ang-1-Tie-2 signaling can inhibit NF-κB signaling, which regulates inflammation. Within the vascular endothelium, Ang-1-Tie-2 signaling promotes endothelial cell proximity. In the hematopoietic stem cell (HSC) microenvironment, Ang-1-Tie-2 signaling contributes to the long-term repopulation of HSCs in a paracrine manner.

[0036] Under physiological conditions, the duration of Tie-2 phosphorylation is controlled by HPTPβ, which removes phosphate groups from the Tie-2 receptor. By inhibiting HPTPβ, Tie-2 phosphorylation levels are substantially increased, restoring proper cell proximity. Compounds of the present disclosure can activate Tie-2 downstream signaling by inhibiting HPTPβ / VE-PTP.

[0037] HPTPβ and vascular endothelial protein tyrosine phosphatase (VE-PTP; the mouse orthologue of HPTPβ) are expressed in vascular endothelial cells throughout development and in adult blood vessels. HPTPβ plays a functional role in endothelial cell proliferation, endothelial cell viability, endothelial cell differentiation, endothelial cell permeability, angiogenesis, and neovascularization. HPTPβ also regulates inflammation and interactions with endothelial support cells, such as pericytes, podocytes, and smooth muscle cells. HPTPβ maintains endothelial barrier integrity by controlling the phosphorylation of proteins within endothelial cell junctions, including Tie-2, adherens junction components, VE-cadherin, plakoglobin, and vascular endothelial growth factor receptor 2 (VEGFR2). HPTPβ expression is upregulated by hypoxia, diabetes, and renin-induced hypertension, resulting in decreased Tie-2 signaling and loss of endothelial cell barrier integrity. Therefore, Tie-2 inhibition causes vascular leakage in the lung.

[0038] In vascular leakage, the endothelial cells lining blood vessels separate, allowing fluid to leak from the circulatory system into the interstitial space. Symptoms of vascular leakage include hemoconcentration, hypotension, hypoalbuminemia, segmental or generalized edema, monoclonal gammopathy of undetermined significance (MGUS), fatigue, and syncope. Arteries, veins, and capillaries are susceptible to increased vascular permeability, resulting in pulmonary vascular leakage.

[0039] Targeting HPTPβ can activate Tie-2 and restore downstream signaling in pulmonary endothelial cells. As shown in Figure 1, Tie-2 regulation can play an important role in controlling host vascular responses in ARDS and related pathogenesis. For example, Tie-2 activation is inhibited in sepsis, and ARDS results from elevated Ang-2 levels and decreased TIE2 gene expression. Circulating Ang-2 is also associated with the severity of chronic renal failure. Furthermore, intact Tie-2 signaling promotes endothelial cell integrity during inflammation. Loss of Tie-2 signaling in inflamed vasculature transitions the normal anticoagulant surface to a procoagulant phenotype. Conversely, Tie-2 activation can reduce both spontaneous and injury-induced fibrin formation in sepsis models. Suppression of Ang-2 expression can increase total Tie-2 levels, while reduction of Tie-2 signaling can downregulate Ang-2 biosynthesis. Therefore, the initial release of Ang-2 from activated endothelial cells can suppress Tie-2 signaling, downregulating Ang-2 biosynthesis and further reducing Tie-2 signaling. HPTPβ / VE-PTP inhibition can activate Tie-2 signaling, thereby maintaining endothelial barrier defense and homeostasis. Therefore, Tie-2 activation may be a treatment mechanism for ARDS and systemic inflammatory conditions such as acute kidney injury (AKI), septic shock, and disseminated intravascular coagulation (DIC).

[0040] Furthermore, phosphorylated Tie-2 can suppress the canonical inflammatory transcription factor NF-kB, thereby enhancing vascular inflammation through this high Ang-2 / low Tie-2 feed-forward loop. Loss of protective Tie-2 signaling leads to nuclear translocation of NF-kB and transcription of leukocyte adhesion molecules. Conversely, Tie-2 stimulation can attenuate pulmonary inflammation during endotoxic shock. Tie-2 signaling can also restore vascular wall homeostasis by stabilizing pericytes and vascular smooth muscle cells. This effect is achieved by restoring production of the vasodilator nitric oxide (NO) from endothelial nitric oxide synthase (eNOS). NO transiently reduces blood pressure.

[0041] Circulating Ang-2 concentrations may reflect disease severity and progression toward death or recovery over time. Circulating and bronchoalveolar lavage (BAL) levels of Ang-2 are elevated in patients with ALI and ARDS. Circulating Ang-2 is also elevated in future non-survivors of ALI / ARDS among surgical patients and may quantitatively correlate with extravascular lung water content and fluid balance in both septic and non-septic ALI / ARDS, as well as with total body fluid overload in patients with septic shock. Decreased Ang-1 and elevated Ang-2 levels may be associated with ICU mortality from severe sepsis. Ang-2 levels may be an effective metric for predicting ARDS mortality. Furthermore, genetic variants of ANG2 may be associated with an increased risk of ARDS. Targeting dysfunctional Tie-2 signaling offers a promising approach for the treatment of ARDS.

[0042] As shown in Figure 2, in stable, normal vasculature, Ang-1 is responsive and can activate Tie-2. Conversely, in destabilized COVID-19 (or ALI / ARDS) vasculature, Ang-1 activity is impaired or resistant and therefore unable to activate Tie-2. Ang-2 levels and activity are elevated relative to Ang-1, leading to further inactivation of Tie-2 signaling. Enhanced Tie-2 signaling can then regulate hypoxic pulmonary vasoconstriction associated with ARDS and induce beneficial effects on oxygenation index.

[0043] Tie-2 activation by the compounds disclosed herein can counter various forms of lung injury, including ALI or chronic lung injury. For example, Tie-2 signaling can protect barrier function, attenuate inflammation, restore vascular wall homeostasis, promote lymphatic integrity, counteract thrombogenicity, reduce lung injury caused by hyperoxia, reduce lipopolysaccharide induction, treat abdominal sepsis caused by cecal ligation and puncture (CLP), systemic anthrax toxin, and phosgene, and treat pulmonary hypertension caused by monocrotaline, serotonin, or IL-6. Tie-2 activation in ARDS can restore the vascular barrier, blunt inflammation, reduce pulmonary vascular resistance, and attenuate thrombosis, thereby improving ventilation / perfusion mismatch (V / Q ratio) and promoting lymphatic function for the clearance of pulmonary edema. Each of these effects can improve the physiology and outcomes of patients with ARDS.

[0044] The primary mechanism for Tie-2 activation in the treatment of lung injury may be defense against vascular hyperpermeability. During inflammation, vascular leakage can occur due to a decrease in Tie-2 signaling, which shifts the balance of intraendothelial GTPases that control endothelial structure and junctions. As a result, endothelial structures contract and junctions lose the barrier effector protein VE-cadherin. Therefore, genetic or biological manipulations that activate Tie-2 signaling, for example, through excessive Ang-1, Ang-1 activation, Ang-2 inhibition, or VE-PTP inhibition, may have a protective effect on microvascular barrier function.

[0045] In some embodiments, activation of Tie-2 or inhibition of HPTPβ by compounds of the present disclosure promotes activation of eNOS in endothelial cells, which in turn activates guanylate cyclase in smooth muscle cells to produce cyclic guanosine monophosphate (cGMP). cGMP can relax smooth muscle cells and cause vasodilation. In some embodiments, Tie-2 activators or HPTPβ inhibitors promote vascular density by increasing NO concentration and reducing vascular leakage.

[0046] The host response to primary lung injury includes the release of cytokines such as IFN-αβ, IFN-γ, granulocyte colony-stimulating factor (G-CSF), monocyte chemotactic protein 1 (MCP1), macrophage inflammatory protein 1α (MIP1A), platelet-derived growth factor (PDGF), TNFα, IL-6, IL-7, and IL-8. IFN-αβ and IFN-γ induce inflammatory cell infiltration and trigger apoptosis of airway and alveolar epithelial cells via Fas / FasL-dependent or TRAIL-DR5-dependent mechanisms. Furthermore, TNF, released by immune regulators, promotes apoptosis of both pulmonary epithelial and endothelial cells. Apoptosis of epithelial and endothelial cells impairs the pulmonary microvascular and alveolar epithelial barrier. Disruption of the epithelial barrier leads to vascular leakage and alveolar edema, ultimately resulting in hypoxia. Cytokines also attract leukocytes to the injured lung and cause their activation. Activated leukocytes secrete a series of molecules that secondarily damage the alveolar epithelium and capillary endothelium. Endothelial damage leads to microvascular barrier disruption and vascular leakage. The outflow of protein-rich fluid from the vascular space into the interstitium creates an unfavorable swelling gradient, further accumulating water in the alveolar space. The lymphatics then reach their limit of capacity to remove fluid from the alveolar space. Alveolar congestion with proteinaceous fluid and debris from dead cells impairs gas exchange, leading to hypoxic alveoli. As a result, blood is physiologically shunted around the hypoxic alveoli. At this stage, ventilation is inefficient due to the high dead space fraction. Left untreated, lung compliance decreases, thereby requiring greater positive pressure for ventilation, thereby increasing the risk of ventilator-induced lung injury. Pulmonary hypertension often develops through a combination of hypoxic pulmonary vasoconstriction, increased airway pressure required for ventilation, and the effects of vasoconstrictive drugs.

[0047] Evaluation of ARDS Treatment of ARDS and / or COVID-19 with the compounds described herein, or restoration of respiratory function, can be assessed by, for example, the Berlin Criteria, oxygenation index, acute lung injury score, pulmonary dead space fraction, chest radiography assessment, quantification of ventilator weaning duration, duration of assisted ventilation, incidence of infection, sequential organ failure assessment, COVID-19 ordinal scale, or occurrence of thromboembolic events in a subject after administration of a treatment described herein. The Berlin Criteria (Berlin Definition) are diagnostic features of ARDS. The Berlin Criteria exclude the use of a pulmonary artery catheter to measure pulmonary artery occlusion pressure. The Berlin Criteria classify ARDS as follows: a PaO2 / FiO2 ratio of 300 or less and greater than 200 is mild ARDS; a PaO2 / FiO2 ratio of 100-200 is moderate ARDS; and a PaO2 / FiO2 ratio of less than 100 is severe ARDS. ARDS may also be characterized by acute hypoxemia (PaO2 / FiO2 ratio less than 200 mmHg), bilateral infiltrates seen on chest x-ray, and no evidence of left atrial hypertension. ALI has similar criteria to ARDS, but with a lower degree of hypoxemia (PaO2 / FiO2 ratio less than 300 mmHg). ALI is defined as an acute inflammatory syndrome accompanied by increased permeability of the alveolar-capillary membrane. The cutoff value for distinguishing ALI from ARDS is 200 mmHg.

[0048] To ensure adequate oxygen delivery to the blood, subjects with respiratory failure can receive supplemental oxygen using a mechanical ventilator or artificial respirator. The two main types of mechanical ventilation are noninvasive and invasive ventilation. Noninvasive ventilation provides ventilatory support to subjects via a tightly fitted face or nose mask. Invasive ventilation provides ventilatory support to subjects via a tube inserted into the trachea through the mouth or nose, or through a hole created in the trachea through the front of the throat. Lung-protective ventilation strategies include low tidal volumes / low plateau pressures and alveolar recruitment / positive end-expiratory pressure (PEEP) titration. These strategies aim to reduce tension and stress at the alveolar level: the former by avoiding excessive hyperextension at the end of inspiration, and the latter by achieving and maintaining an open lung at the end of expiration.

[0049] PEEP is a measure of the pressure in the lungs at the end of expiration (alveolar pressure). Exogenous PEEP is PEEP applied by the ventilator. Intrinsic PEEP is caused by incomplete expiration. To mitigate end-expiratory alveolar collapse, low levels of PEEP (e.g., 4-5 cmH2O) can be applied to most mechanically ventilated patients. For example, in patients with ARDS, ALI, or other types of hypoxemic respiratory failure, high levels of applied PEEP (less than 5 cmH2O) can be used to improve hypoxemia or reduce ventilator-associated lung injury. The minimum level of PEEP required for the diagnosis of ARDS is 5 cmH2O. The Tie-2 activators described herein can reduce the PEEP required by a subject. In some embodiments, the Tie-2 activators described herein reduce the PEEP required by a subject by about 1 cmH2O to about 20 cmH2O, about 1 cmH2O to about 10 cmH2O, about 1 cmH2O to about 5 cmH2O, 5 cmH2O to about 10 cmH2O, or about 10 cmH2O to about 20 cmH2O. In some embodiments, the Tie-2 activators described herein reduce the PEEP required by a subject by about 1 cmH2O, about 2 cmH2O, about 3 cmH2O, about 4 cmH2O, about 5 cmH2O, about 6 cmH2O, about 7 cmH2O, about 8 cmH2O, about 9 cmH2O, about 10 cmH2O, about 11 cmH2O, about 12 cmH2O, about 13 cmH2O, about 14 cmH2O, about 15 cmH2O, about 16 cmH2O, about 17 cmH2O, about 18 cmH2O, about 19 cmH2O, or about 20 cmH2O.

[0050] Mean airway pressure (MAP) is the average pressure applied during positive pressure mechanical ventilation. The Tie-2 activators described herein can reduce the MAP required by a subject. In some embodiments, the Tie-2 activators described herein reduce the MAP required by a subject by about 1 cmH2O to about 20 cmH2O, about 1 cmH2O to about 10 cmH2O, about 1 cmH2O to about 5 cmH2O, about 5 cmH2O to about 10 cmH2O, or about 10 cmH2O to about 20 cmH2O. In some embodiments, the Tie-2 activators described herein reduce the MAP required by a subject by about 1 cmH2O, about 2 cmH2O, about 3 cmH2O, about 4 cmH2O, about 5 cmH2O, about 6 cmH2O, about 7 cmH2O, about 8 cmH2O, about 9 cmH2O, about 10 cmH2O, about 11 cmH2O, about 12 cmH2O, about 13 cmH2O, about 14 cmH2O, about 15 cmH2O, about 16 cmH2O, about 17 cmH2O, about 18 cmH2O, about 19 cmH2O, or about 20 cmH2O.

[0051] The ratio of arterial oxygen pressure (PaO2) to inspired oxygen fraction (FiO2) can be used to assess pulmonary gas exchange abnormalities. FiO2 is the molar or volume fraction of oxygen in the inhaled gas. For example, natural air contains 21% oxygen, which corresponds to an FiO2 of 0.21. Subjects experiencing respiratory distress are supplemented with pressurized oxygen, an FiO2 higher than atmospheric pressure, and therefore an FiO2 > 0.21. The PaO2 / FiO2 ratio can be used to determine the severity of lung injury and the diagnosis of ARDS.

[0052] The Tie-2 activators described herein can increase a subject's PaO2 / FiO2 ratio. The change in PaO2 / FiO2 ratio can be determined from baseline compared to 6, 24, 36, 48, 72 hours, or 7 days after administration of a treatment described herein. In some embodiments, the change in PaO2 / FiO2 ratio is about 1 to about 400, or about 1 to about 100, compared to no administration. In some embodiments, the change in the PaO2 / FiO2 ratio is about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, or about 450.

[0053] In some embodiments, administration of a Tie-2 activator described herein to a subject increases the PaO2 / FiO2 ratio of the subject to about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 610, about 620, about 630, about 640, about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, about 760, about 770, about 780, about 790, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 89 The PaO2 / FiO2 ratio, which can be increased to about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, or about 600, can be determined after administration of the therapies described herein, for example, 6, 24, 36, 48, 72 hours, or 7 days after administration.

[0054] The oxygenation index (OI) is a measure of the efficiency of oxygen exchange in the lungs, with higher scores indicating more severe pulmonary dysfunction and a higher risk of death. OI is calculated as (FiO2 * mean airway pressure) / PaO2. Like the PaO2 / FiO2 ratio, OI is a measure of oxygen exchange in the lungs (pulmonary function), but OI also incorporates airway pressure (and thus lung compliance) into its measurement. Therefore, changes in PEEP delivery without inherent changes in pulmonary function do not alter OI (unlike the PaO2 / FiO2 ratio, which can be adjusted by changing PEEP). OI can be interpreted as follows: 0–25 = favorable outcome; 25–40 = chance of death >40%; and >40 = consider extracorporeal membrane oxygenation.

[0055] The Tie-2 activators described herein can reduce OI in a subject. The change in OI can be determined from baseline compared to 6, 24, 36, 48, 72 hours, or 7 days after administration of a treatment described herein. In some embodiments, the change in OI is about 1 to about 5, about 1 to about 10, or about 1 to about 20. In some embodiments, the change in OI is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, or more than 50.

[0056] The Acute Lung Injury Score (LIS), or Murray score, is an assessment of ALI severity. The LIS is a composite 4-point scoring system that includes the PaO2 / FiO2 ratio, PEEP, lung compliance, and the degree of infiltration (alveolar consolidation) determined by the subject's chest radiograph. The scoring system ranges from 0 to 4, with 4 indicating the greatest degree of lung injury. The total LIS is obtained by dividing the sum by the number of components used: chest radiograph, hypoxemia, PEEP, and respiratory system compliance. Table 1 shows the LIS components and corresponding scores. The LIS can be interpreted as follows: 0 = no lung injury; 1–2.5 = mild to moderate lung injury; and >2.5 = severe lung injury. Respiratory system compliance is an assessment of the lung's ability to stretch and expand. This index, also known as lung compliance, includes the total compliance of both lungs and measures the change in lung volume per unit increase in transpulmonary pressure (if sufficient time is allowed for the system to reach equilibrium). Lung compliance can be calculated by the change in lung volume / change in transpulmonary pressure. The change in LIS can be evaluated over 7 days or on the last day of positive pressure ventilation before the 7th day after administration of the treatment described herein. In some embodiments, the change in LIS is 1, 2, 3 or 4. [Table 1]

[0057] Pulmonary dead space fraction (the ratio of dead space to tidal volume [V]) is a risk factor for ARDS mortality. D / V T] ) is the portion of the tidal volume that does not participate in gas exchange and therefore consists of exhaled gases that do not contain carbon dioxide. PeCO2 is the partial pressure of mean exhaled CO2. Dead space fraction is calculated as (PaCO2-PeCO2) / PaCO2. Changes in lung dead space fraction can be assessed, for example, on days 1, 2, 3, 4, 5, 6, or 7 after treatment.

[0058] Radiographic Assessment of Pulmonary Edema (RALE) assesses the degree and density of alveolar opacities on chest radiographs to estimate the extent of pulmonary edema in ARDS. To calculate the RALE score, each radiographic quadrant is scored for the degree of consolidation (0-4) and the density of the opacities (1-3). The products of the consolidation and density scores for each of the four quadrants are summed. RALE scores range from 0 (best) to 48 (worst). RALE scores can be measured on days 1, 2, 3, 4, 5, 6, or 7 after treatment.

[0059] The resolution of ARDS symptoms can be further evaluated by the improvement of pulmonary function, for example, a reduction in the need for assisted ventilation. Quantification of the duration of ventilator weaning can be evaluated, for example, over 7 days, 14 days, or 28 days. In some embodiments, quantification of the duration of ventilator weaning can be evaluated for more than 28 days. The duration of assisted ventilation can also be evaluated over 7, 14, or 28 days. In some embodiments, the duration of assisted ventilation can be evaluated for more than 28 days. For example, the percentage of subjects who achieve pressure support ventilation for 2 hours can be evaluated over 28 days. For example, the PEEP of assisted ventilation is 5 cmH2O for 2 hours.

[0060] The incidence of infection can be assessed over 7, 14, 21, or 28 days. Non-limiting examples of infections include superficial incision / wound infections, deep incision infections, organ / space infections, and ventilator-associated pneumonia.

[0061] The Sequential Organ Failure Assessment (SOFA) is a mortality prediction score based on the degree of dysfunction of six organ systems: respiratory, cardiovascular, hepatic, coagulation, renal, and neurological, each ranging from 0 to 4. The SOFA score is the sum of six scores ranging from 0 (best) to 24 (worst). The SOFA score can be assessed over a seven-day period following treatment. For example, the SOFA score can be assessed on days 3 and 7.

[0062] COVID-19 ordinal scales can be used to assess COVID-19 disease severity. For example, the COVID-19 ordinal scale published by the World Health Organization in February 2020 is summarized in Table 2. Virological evidence of infection can be obtained from nasopharyngeal or respiratory samples, blood, urine, or feces. Scores can also be based on additional factors, such as admission to a critical care unit; need for supplemental oxygen, mechanical ventilation / oxygenation, extracorporeal membrane oxygenation (ECMO), or extracorporeal life support (ECLS); need for intravenous vasoactive medications; need for renal replacement therapy (RRT); death in the critical care unit, death in the hospital, and vital status at day 28 (death); non-hospitalized days, non-ICU; and biological and immunological markers of disease. [Table 2]

[0063] The occurrence of thromboembolic events can be assessed over a 60-day period. Thromboembolic events can be measured by ultrasound of the deep venous system or CT angiography of the chest.

[0064] Further evaluation includes determining the level of a biomarker in the subject's plasma after administering the treatment described herein to the subject. Non-limiting examples of plasma biomarkers include Ang-2, Ang-1, VEGF, receptor for advanced glycation end products (RAGE), IL-6, IL-8, soluble TNF-1 (sTNF-1), plasma protein C, lipoxin A4, resolvin D1, keratinocyte growth factor (KGF), soluble Tie2, c-reactive protein (CRP), and D-dimer. For example, changes in plasma biomarker levels can be determined from baseline compared to 6, 24, 36, 48, 72 hours, and 7 days. In some embodiments, changes in plasma biomarker levels can be determined from baseline compared to 7 days after treatment.

[0065] In some embodiments, the change in the level of the biomarker is from about 0.1 ng / mL to about 5 ng / mL, from about 0.1 ng / mL to about 10 ng / mL, from about 0.1 ng / mL to about 20 ng / mL, from about 0.1 ng / mL to about 30 ng / mL, or from about 0.1 ng / mL to about 50 ng / mL. In some embodiments, the change in the level of the biomarker is about 0.1 ng / mL, about 0.2 ng / mL, about 0.3 ng / mL, about 0.4 ng / mL, about 0.5 ng / mL, about 0.6 ng / mL, about 0.7 ng / mL, about 0.8 ng / mL, about 0.9 ng / mL, about 1 ng / mL, about 1.1 ng / mL, about 1.2 ng / mL, about 1.3 ng / mL, about 1.4 ng / mL, about 1.5 ng / mL, about 1.6 ng / mL, about 1.7 ng / mL, about 1.8 ng / mL, about 1.9 ng / mL, about 2 ng / mL, about 2.1 ng / mL, about 2.2 ng / mL, about 2.3 ng / mL, about 2.4 ng / mL, about 2.5 ng / mL, about 2.6 ng / mL, about 2.7 ng / mL, about 2.8 ng / mL, about 2.9 ng / mL, about 3.0 ng / mL, about 3.1 ng / mL, about 3.2 ng / mL, about 3.4 ng / mL, about 3.5 ng / mL, about 3.6 ng / mL, about 3.7 ng / mL, about 3.8 ng / mL, about 3.9 ng / mL, about 4.0 ng / mL, about 4.1 ng / mL, about 4.2 ng / mL, about 4.3 ng / mL, about 4.4 ng / mL, about 4.5 ng / mL, about 4.6 ng / mL, about 4.7 ng / mL, about 4.8 ng / mL, about 4.9 ng / mL, about 5.0 ng / mL, about 5.1 ng / mL, about mL, about 2.9 ng / mL, about 3 ng / mL, about 3.1 ng / mL, about 3.2 ng / mL, about 3.3 ng / mL, about 3.4 ng / mL, about 3.5 ng / mL, about 3.6 ng / mL, about 3.7 ng / mL, about 3.8 ng / mL, about 3.9 ng / mL, about 4 ng / mL, about 4.1 ng / mL, about 4.2 ng / mL, about 4.3 ng / mL, about 4.4 ng / mL, about 4.5 ng / mL, about 4.6 ng / mL, about 4.7 ng / mL, about 4.8 ng / mL, about 4.9 ng / mL, about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, or about 50 ng / mL.In some embodiments, the change in the level of the biomarker is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94% %,approximately 50%,approximately 51%,approximately 52%,approximately 53%,approximately 54%,approximately 55%,approximately 56%,approximately 57%,approximately 58%,approximately 59%,approximately 60%,approximately 61%,approximately 62%,approximately 63%,approximately 64%,approximately 65%,approximately 66%,approximately 67%,approximately 68%,approximately 69%,approximately 70%,approximately 71%,approximately 72%,approximately 73%,approximately 74%,approximately 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0066] The change in plasma Ang-2 / Ang-1 ratio can be determined from baseline compared to 6, 24, 36, 48, 72 hours, or 7 days after administration of a treatment described herein. In some embodiments, the change in plasma Ang-2 / Ang-1 ratio is about 1 to about 10, about 1 to about 20, about 1 to about 30, about 1 to about 40, about 1 to about 50, or about 1 to about 100. In some embodiments, the change in plasma Ang-2 / Ang-1 ratio is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100.

[0067] Microalbuminuria can be an indicator of increased vascular permeability, for example, caused by sepsis, ARDS, and systemic inflammatory response due to renal injury.Therefore, respiratory function can be evaluated by the change in the level of urinary microalbumin in a subject after administering the treatment described herein to the subject.For example, the change in the level of urinary microalbumin can be determined from baseline compared with 24, 36, 48, 72 hours or 7 days after administration.

[0068] Protein concentration in alveolar edema fluid can be an indicator of lung injury progression. Higher total protein concentrations in bronchoalveolar lavage (BAL) are associated with higher mortality rates in ARDS patients. Therefore, respiratory function can also be assessed by changes in total protein levels, for example, in mini-bronchoalveolar lavage (mBAL) obtained from a subject after administration of the treatments described herein. For example, changes in protein concentration in BAL can be determined from baseline compared to 24, 36, 48, 72 hours, or 7 days after administration.

[0069] ARDS and respiratory failure models Treatment of ARDS, lung injury, and respiratory failure can be evaluated by measuring the effect of the compounds disclosed herein on pulmonary vascular leakage using in vitro or in vivo models.For example, inflammatory pulmonary vascular leakage can be induced in cultured endothelial cells by gram-negative endotoxin, lipopolysaccharide (LPS).The reduction of LPS-induced vascular leakage can be evaluated using the compounds described herein.

[0070] Treatment efficacy was also assessed in an inducible endothelial cell knockout mouse model of VE-PTP (Cdh5-Cre ERT2 :PTPR-β lox / loxVascular leakage in mouse models can be assessed using a VEGF-mediated inflammatory response (iECKO-VE-PTP). Vascular leakage in mouse models can be induced by inflammatory permeability triggers such as histamine and VEGF. Additional non-limiting examples of disease models include LPS-induced lung and kidney injury, polymicrobial septic shock induced by cecal ligation and puncture (CLP), IL-8-induced leukocyte-endothelial cell migration, and IL-2-induced cytokine storm. High doses of IL-2 can increase Ang-2 levels. IL-2-induced vascular leak syndrome manifests as hypotension and can lead to shock and death.

[0071] Tie-2 activator The compounds disclosed herein can be effective as Tie-2 activators. The compounds can enhance its activity, for example, by binding to or inhibiting HPTPβ. Such compounds can bind to HPTPβ by mimicking the binding mechanism of a natural substrate, such as a phosphorylated compound. Some compounds can be phosphate mimetics or bioisosteres, such as sulfamic acid. The compounds can also be derived from amino acid building blocks or contain amino acid backbones for efficient and economical synthesis.

[0072] In some embodiments, the compounds disclosed herein are compounds of the formula [ka] or a pharmaceutically acceptable salt, tautomer or zwitterion thereof, wherein: 1 is a substituted or unsubstituted aryl group; aryl 2is a substituted or unsubstituted aryl group; X is an alkylene, alkenylene, alkynylene, ether bond, amine bond, amide bond, ester bond, thioether bond, carbamate bond, carbonate bond, sulfone bond (any of which may be substituted or unsubstituted) or a chemical bond; Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSOR g or NHCOR g (any of which may be substituted or unsubstituted) or [ka] wherein L is alkylene, alkenylene, or alkynylene, any of which may be substituted or unsubstituted, or together with the nitrogen atom to which L is attached, forms an amide bond, a carbamate bond, or a sulfonamide bond, or a chemical bond, or R a , R b , R c and R d together with either of the groups to form a substituted or unsubstituted ring; R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted, or L, R b , R c and R d together with either of the groups to form a substituted or unsubstituted ring; R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted, or L, R a , R c and R d together with either of the groups to form a substituted or unsubstituted ring; R cis H or substituted or unsubstituted alkyl, or L, R a , R b and R d together with either of the groups to form a substituted or unsubstituted ring; R d is H or substituted or unsubstituted alkyl, or L, R a , R b and R c together with either of the groups to form a substituted or unsubstituted ring; R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted.

[0073] In some embodiments, aryl 1 is a substituted or unsubstituted phenyl, and aryl 2 is a substituted or unsubstituted heteroaryl and X is alkylene. In some embodiments, aryl 1 is a substituted phenyl, and aryl 2 is substituted heteroaryl and X is methylene.

[0074] In some embodiments, a compound is a compound of the formula [ka] [ka] wherein aryl 1 is a para-substituted phenyl, and 2 is a substituted heteroaryl; X is methylene; L is alkylene, alkenylene, or alkynylene (any of which may be substituted or unsubstituted), or together with the nitrogen atom to which L is attached, forms an amide bond, a carbamate bond, or a sulfonamide bond, or is a chemical bond; R ais H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; R c is H or substituted or unsubstituted alkyl; R d is H or substituted or unsubstituted alkyl.

[0075] In some embodiments, aryl 1 is para-substituted phenyl; aryl 2 is a substituted thiazole moiety; X is methylene; L, together with the nitrogen atom to which it is attached, forms a carbamate bond; R a is a substituted or unsubstituted alkyl; R b is a substituted or unsubstituted arylalkyl; R c is H;R d is H.

[0076] In some embodiments, aryl 2 teeth, [ka] where R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; R fis H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl (any of which may be substituted or unsubstituted).

[0077] In some embodiments, R e is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; R f is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted. In some embodiments, R e is H, OH, F, Cl, Br, I, an alkyl or alkoxy group (any of which may be substituted or unsubstituted), and R f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which may be substituted or unsubstituted. In some embodiments, aryl 1 is 4-phenylsulfamic acid; R a is a substituted or unsubstituted alkyl; R b is a substituted or unsubstituted arylalkyl; R e is H;R f is heteroaryl. In some embodiments, aryl 1 is 4-phenylsulfamic acid; R a is a substituted or unsubstituted alkyl; R b is a substituted or unsubstituted arylalkyl; R e is H;Rf is alkyl.

[0078] In some embodiments, aryl 2 teeth, [ka] where R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; R f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted. In some embodiments, R e is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; R f is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted. In some embodiments, R e is H, OH, F, Cl, Br, I, an alkyl or alkoxy group, any of which may be substituted or unsubstituted; R fis alkyl, aryl, heterocyclyl, or heteroaryl, any of which may be substituted or unsubstituted. In some embodiments, aryl 1 is 4-phenylsulfamic acid; R a is a substituted or unsubstituted alkyl; R b is a substituted or unsubstituted arylalkyl; R e is H;R f is heteroaryl.

[0079] In some embodiments, the substituted phenyl group is [ka] where R ph1 , R ph2 , R ph3 , R ph4 and R ph5 are each independently H, OH, F, Cl, Br, I, CN, sulfamic acid, tosylate, mesylate, triflate, besylate, alkyl, alkenyl, alkynyl, alkoxy, sulfhydryl, nitro, azide, sulfoxide, sulfone, sulfonamide, ether, carboxylic acid, carboxaldehyde, ester, amine, amide, carbonate, carbamate, thioether, thioester, thioacid, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0080] Illustrative compounds include: [ka] [ka] [ka]

[0081] Optional substituents for chemical groups Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, haloalkyl groups, alkenyl groups, haloalkenyl groups, alkynyl groups, haloalkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.

[0082] Non-limiting examples of alkyl and alkylene groups include linear, branched, and cyclic alkyl and alkylene groups. Alkyl groups include, for example, substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49or C 50 It can be a group.

[0083] Non-limiting examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0084] Branched alkyl groups include any straight chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.

[0085] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused bicycles, bridged bicycles, and spiro bicycles, as well as higher fused, bridged, and spiro systems. Cyclic alkyl groups can be substituted with any number of linear, branched, or cyclic alkyl groups.

[0086] Non-limiting examples of alkenyl and alkenylene groups include straight-chain, branched, and cyclic alkenyl groups. The olefin(s) of the alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. The alkenyl or alkenylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C109, C111, C112, C113, C114, C115, C116, C117, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 It can be a group.

[0087] Non-limiting examples of alkynyl or alkynylene groups include straight-chain, branched, and cyclic alkynyl groups. The triple bond of the alkynyl or alkynylene group can be internal or terminal. The alkynyl or alkynylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C99, C101, C102, C103, C104 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 It can be a group.

[0088] A haloalkyl group can be any alkyl group substituted with any number of halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms. A haloalkenyl group can be any alkenyl group substituted with any number of halogen atoms. A haloalkynyl group can be any alkynyl group substituted with any number of halogen atoms.

[0089] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0090] The aryl group can be heterocyclic or non-heterocyclic. The aryl group can be monocyclic or polycyclic. The aryl group can be substituted with any number of substituents described herein, such as hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.

[0091] An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.

[0092] An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.

[0093] An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy.

[0094] Heterocycles can be any ring containing non-carbon ring atoms, such as N, O, S, P, Si, B, or any other heteroatom. Heterocycles can be substituted with any number of substituents, such as alkyl groups and halogen atoms. Heterocycles can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0095] Acyl groups can be, for example, carbonyl groups substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or heterocycles. Non-limiting examples of acyls include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.

[0096] An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or ester group includes an acyloxy group. A non-limiting example of an acyloxy or ester group is acetate.

[0097] A carbamate group can be an oxygen atom substituted with a carbamoyl group, where the nitrogen atom of the carbamoyl group is unsubstituted or mono- or di-substituted with one or more hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl groups. When the nitrogen atom is di-substituted, the two substituents together with the nitrogen atom can form a heterocyclic ring.

[0098] In some embodiments, the activator of Tie-2 is MAN-01.

[0099] Pharmaceutically acceptable salts The methods disclosed herein provide for the use of pharmaceutically acceptable salts of any of the compounds described herein. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to a compound to form an acid addition salt can be an organic acid or an inorganic acid. The base added to a compound to form a base addition salt can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

[0100] Metal salts can be formed by the addition of an inorganic base to a compound disclosed herein. The inorganic base consists of a metal cation paired with a basic counterion, such as hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0101] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0102] Ammonium salts can be generated by the addition of ammonia or an organic amine to the compounds disclosed herein. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, piprazole, imidazole, or pyrazine.

[0103] In some embodiments, the ammonium salt is a triethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a piperazole salt, an imidazole salt, or a pyrazine salt.

[0104] Acid addition salts can be formed by adding an acid to a compound disclosed herein. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0105] In some embodiments, the salt is hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate salt, saccarate salt, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0106] The compounds herein include salts of acidic groups, e.g., [ka] [ka] It could be.

[0107] The compounds herein include salts of basic groups formed from strong acids, e.g., [ka] It could be.

[0108] The compounds herein may be in zwitterionic form, e.g., [ka] It can also exist as formulation

[0109] The pharmaceutical compositions of the present disclosure can provide a therapeutically effective amount of an activator of Tie-2.

[0110] The disclosed formulations can include one or more pharmaceutically acceptable agents that, alone or in combination, solubilize the compounds herein or pharmaceutically acceptable salts thereof.

[0111] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is present in the formulation at a concentration of about 0.1 mg / mL to about 100 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 5 mg / mL to about 10 mg / mL, about 10 mg / mL to about 15 mg / mL, about 15 mg / mL to about 20 mg / mL, about 20 mg / mL to about 25 mg / mL, about 25 mg / mL to about 30 mg / mL, about 30 mg / mL to about 35 mg / mL, about 35 mg / mL to about 40 mg / mL, It is present at about 40 mg / mL to about 45 mg / mL, about 45 mg / mL to about 50 mg / mL, about 50 mg / mL to about 55 mg / mL, about 55 mg / mL to about 60 mg / mL, about 60 mg / mL to about 65 mg / mL, about 65 mg / mL to about 70 mg / mL, about 70 mg / mL to about 75 mg / mL, about 75 mg / mL to about 80 mg / mL, about 80 mg / mL to about 85 mg / mL, about 85 mg / mL to about 90 mg / mL, about 90 mg / mL to about 95 mg / mL, and about 95 mg / mL to about 100 mg / mL.

[0112] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a concentration of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL, about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL 4mg / mL, about 25mg / mL, about 26mg / mL, about 27mg / mL, about 28mg / mL, about 29mg / mL, about 30mg / mL, about 31mg / mL, about 32mg / mL, about 33mg / mL, about 34mg / mL, about 35mg / mL, about 36mg / mL, about 3 7mg / mL, approximately 38mg / mL, approximately 39mg / mL, approximately 40mg / mL, approximately 41mg / mL, approximately 42mg / mL, approximately 43mg / mL, approximately 44mg / mL, approximately 45mg / mL, approximately 46mg / mL, approximately 47mg / mL, approximately 48mg / mL, approximately 49mg / mL, approximately 50 mg / mL, approximately 51 mg / mL, approximately 52 mg / mL, approximately 53 mg / mL, approximately 54 mg / mL, approximately 55 mg / mL, approximately 56 mg / mL, approximately 57 mg / mL, approximately 58 mg / mL, approximately 59 mg / mL, approximately 60 mg / mL, approximately 61 mg / mL, approximately 62 mg / mL, approximately 63 mg / mL, approximately 64 mg / mL, approximately 65 mg / mL, approximately 66 mg / mL, approximately 67 mg / mL, approximately 68 mg / mL, approximately 69 mg / mL, approximately 70 mg / mL, approximately 71 mg / mL, approximately 72 mg / mL, approximately 73 mg / mL, approximately 74 mg / mL, approximately 75 mg / mL, approximately 76 m

[0049] The compound is present in the formulation in an amount of about 77 mg / mL, about 78 mg / mL, about 79 mg / mL, about 80 mg / mL, about 81 mg / mL, about 82 mg / mL, about 83 mg / mL, about 84 mg / mL, about 85 mg / mL, about 86 mg / mL, about 87 mg / mL, about 88 mg / mL, about 89 mg / mL, about 90 mg / mL, about 91 mg / mL, about 92 mg / mL, about 93 mg / mL, about 94 mg / mL, about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, or about 100 mg / mL.

[0113] The formulations disclosed herein may be made more soluble by the addition of certain additives or agents. Improved solubility of the formulation may be increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 450%, or about 500%.

[0114] The formulations disclosed herein may be stable for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. The formulations disclosed herein may be stable at, for example, about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 60°C, about 70°C, or about 80°C.

[0115] alcohol Non-limiting examples of solubilizers include organic solvents.Non-limiting examples of organic solvents include alcohols, such as C1-C4 linear alkyl, C3-C4 branched alkyl, ethanol, ethylene glycol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol, sorbitol, xylitol; substituted or unsubstituted aryl and benzyl alcohol.

[0116] cyclodextrin Non-limiting examples of cyclodextrins include α-cyclodextrin, β-cyclodextrin, methyl β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin sodium salt, hydroxyethyl-β-cyclodextrin (HE-β-CD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMβCD), 2-hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin (HPγCD). Cyclodextrins can have large cyclic structures with channels running through the center of the structure. The interior of the cyclodextrin can be hydrophobic and interact favorably with hydrophobic molecules. The exterior of the cyclodextrin can be highly hydrophilic due to several hydroxyl groups exposed to the bulk solvent. By entrapment of hydrophobic molecules, such as the compounds disclosed herein, within the channels of cyclodextrins, complexes stabilized by non-covalent hydrophobic interactions can be formed that can be soluble in water and carry the entrapped hydrophobic molecule into the bulk solvent.

[0117] Formulations of the present disclosure may include randomly methylated β-cyclodextrin (RAMEB or RMCD). Formulations of the present disclosure may include RAMEBs that contain at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 methyl groups.

[0118] The disclosed solubilization system includes 2-hydroxypropyl-beta-cyclodextrin (HPβ-CD). 2-Hydroxypropyl-β-cyclodextrin [CAS No. 128446-35-5] is commercially available under the trademark Cavitron. 2-Hydroxypropyl-β-cyclodextrin, also listed as hydroxypropyl-β-cyclodextrin or HPβCD, has the following formula: [ka] [ka] It can be represented by either

[0119] Cavitron™ has an average molecular weight of approximately 1396 Da and an average degree of substitution of about 0.5 to about 1.3 units of 2-hydroxypropyl per ring glucose unit.

[0120] The disclosed solubilization system includes 2-hydroxypropyl-γ-cyclodextrin (HPγCD). 2-hydroxypropyl-γ-cyclodextrin [CAS No. 128446-34-4], also known as hydroxypropyl-γ-cyclodextrin, or HPGCD, has the following formula: [ka] It can be expressed as:

[0121] In one embodiment, a formulation disclosed herein can include a ratio of about 20 parts compound herein or a pharmaceutically acceptable salt thereof to about 1 part solubilizing system (about 20:about 1), to about 1 part compound herein or a pharmaceutically acceptable salt thereof to about 20 parts solubilizing system (about 1:about 20). For example, a formulation containing about 100 mg of a compound herein or a pharmaceutically acceptable salt thereof can include about 5 mg to about 2000 mg of a solubilizing agent, e.g., a cyclodextrin. In another embodiment, the ratio can be based on the number or moles of compound compared to the number or moles of solubilizing system.

[0122] The following are non-limiting examples of ratios of a compound herein to a solubilizing agent, such as a cyclodextrin: Alternatively, the following examples describe ratios of a solubilizing agent, such as a cyclodextrin, to a compound herein. The ratios are about 20:about 1, about 19.9:about 1, about 19.8:about 1, about 19.7:about 1, about 19.6:about 1, about 19.5:about 1, about 19.4:about 1, about 19.3:about 1, about 19.2:about 1, about 19.1:about 1, about 19:about 1, about 18.9:about 1, about 18.8:about 1, about 18.7:about 1, about 18.6:about 1, about 18.5:about 1, about 18.4:about 1, about 18.3:about 1, about 18.2:about 1, about 18.1:about 1, about 18:about 1, about 17.9:about 1, about 17.8:about 1, about 17.7:about 1, about 17.6:about 1, about 17.5:approx. 1, approximately 17.4:approx. 1, approximately 17.3:approx. 1, approximately 17.2:approx. 1, approximately 17.1:approx. 1, approximately 17:approx. 1, approximately 16.9:approx. 1, approximately 16.8:approx. 1, approximately 16.7:approx. 1, approximately 16.6:approx. 1, approximately 16.5:approx. 1, approximately 16.4:approx. 1, approximately 16.3:approx. 1, approximately 16.2:approx. 1, approximately 16.1:approx. 1, approximately 16:approx. 1, approximately 15.9:approx. 1, approximately 15.8:approx. 1, approximately 15.7:approx. 1, approximately 15.6:approx. 1, approximately 15.5:approx. 1, approximately 15.4:approx. 1, approximately 15.3:approx. 1, approximately 15.2:approx. 1, approximately 15.1:approx. 1, approximately 15:approx. 1 , about 14.9: about 1, about 14.8: about 1, about 14.7: about 1, about 14.6: about 1, about 14.5: about 1, about 14.4: about 1, about 14.3: about 1, about 14.2: about 1, about 14.1: about 1, about 14: about 1, about 13.9: about 1, about 13.8: about 1, about 13.7: about 1, about 13.6: about 1, about 13.5: about 1, about 13.4: about 1, about 13.3: about 1, about 13.2: about 1, about 13.1: about 1, about 13: about 1, about 12.9: about 1, about 12.8: about 1, about 12.7: about 1, about 12.6: about 1, about 12.5: about 1, about 12. 4: approx. 1, approx. 12.3: approx. 1, approx. 12.2: approx. 1, approx. 12.1: approx. 1, approx. 12: approx. 1, approx. 11.9: approx. 1, approx. 11.8: approx. 1, approx. 11.7: approx. 1, approx. 11.6: approx. 1, approx. 11.5: approx. 1, approx. 11.4: approx. 1, approx. 11.3: approx. 1, approx. 11.2: approx. 1, approx. 11.1: approx. 1, approx. 11: approx. 1, approx. 10.9: approx. 1, approx. 10.8: approx. 1, approx. 10.7: approx. 1, approx. 10.6: approx. 1, approx. 10.5: approx. 1, approx. 10.4: approx. 1, approx. 10.3: approx. 1, approx. 10.2: approx. 1, approx. 10.1: approx. 1, approx. 10: approx. 1, approx. 9.9: approx. 1, approx. 9.8:approx. 1, approximately 9.7:approx. 1, approximately 9.6:approx. 1, approximately 9.5:approx. 1, approximately 9.4:approx. 1, approximately 9.3:approx. 1, approximately 9.2:approx. 1, approximately 9.1:approx. 1, approximately 9:approx. 1, approximately 8.9:approx. 1, approximately 8.8:approx. 1, approximately 8.7:approx. 1, approximately 8.6:approx. 1, approximately 8.5:approx. 1, approximately 8.4:approx. 1, approximately 8.3:approx. 1, approximately 8.2:approx. 1, approximately 8.1:approx. 1, approximately 8:approx. 1, approximately 7.9:approx. 1, approximately 7.8:approx. 1, approximately 7.7:approx. 1, approximately 7.6: about 1, about 7.5: about 1, about 7.4: about 1, about 7.3: about 1, about 7.2: about 1, about 7.1: about 1, about 7: about 1, about 6.9: about 1, about 6.8: about 1, about 6.7: about 1, about 6.6: about 1, about 6.5: about 1, about 6.4: about 1, about 6.3: about 1, about 6.2: about 1, about 6.1: about 1, about 6: about 1, about 5.9: about 1, about 5.8: about 1, about 5.7: about 1, about 5.6: about 1, about 5.5: about 1, about 5.4: about 1, Approximately 5.3: approximately 1, approximately 5.2: approximately 1, approximately 5.1: approximately 1, approximately 5: approximately 1, approximately 4.9: approximately 1, approximately 4.8: approximately 1, approximately 4.7: approximately 1, approximately 4.6: approximately 1, approximately 4.5: approximately 1, approximately 4.4: approximately 1, approximately 4.3: approximately 1, approximately 4.2: approximately 1, approximately 4.1: approximately 1, approximately 4: approximately 1, approximately 3.9: approximately 1, approximately 3.8: approximately 1, approximately 3.7: approximately 1, approximately 3.6: approximately 1, approximately 3.5: approximately 1, approximately 3.4: approximately 1, approximately 3.3: approximately 1, approximately 3.2: approximately 1, approximately 3. The ratio can be 1:about 1, about 3:about 1, about 2.9:about 1, about 2.8:about 1, about 2.7:about 1, about 2.6:about 1, about 2.5:about 1, about 2.4:about 1, about 2.3:about 1, about 2.2:about 1, about 2.1:about 1, about 2:about 1, about 1.9:about 1, about 1.8:about 1, about 1.7:about 1, about 1.6:about 1, about 1.5:about 1, about 1.4:about 1, about 1.3:about 1, about 1.2:about 1, about 1.1:about 1, or about 1:about 1.

[0123] Polyvinylpyrrolidon Another non-limiting example of a solubilizing agent is a compound of the formula: [ka] where the subscript n is from about 40 to about 200. The PVP can have an average molecular weight of from about 5500 to about 28,000 g / mol. One non-limiting example is PVP-10, which has an average molecular weight of approximately 10,000 g / mol.

[0124] Polyakylene oxides and their ethers Other non-limiting examples of solubilizing agents include polymers of polyalkylene oxides and alcohols or polyols. The polymers may be mixed or contain a single monomer repeat subunit. For example, polyethylene glycols (PEGs) having an average molecular weight of about 200 to about 20,000, such as PEG200, PEG400, PEG600, PEG1000, PEG1450, PEG1500, PEG4000, PEG4600, and PEG8000. In some embodiments, the composition includes one or more polyethylene glycols selected from PEG400, PEG1000, PEG1450, PEG4600, and PEG8000.

[0125] Other polyalkylene oxides include those of the formula: HO[CH(CH3)CH2O] x H where the subscript x represents the average number of propyleneoxy units in the polymer. The subscript x can be expressed as an integer or a fraction. For example, polypropylene glycol (PEG8000) with an average molecular weight of 8,000 g / mol has the formula: HO[CH(CH3)CH2O] 138 H or HO[CH(CH3)CH2O] 137.6 H or the polypropylene glycol may be represented by the common shorthand notation: PEG8000.

[0126] Another example of a polypropylene glycol may have an average molecular weight of about 1,200 g / mol to about 20,000 g / mol, ie, a polypropylene glycol having an average molecular weight of about 8,000 g / mol, such as PEG8000.

[0127] Another solubilizer is Polysorbate 80 (Tween® 80), which is an oleic acid ester of sorbitol and its anhydrides copolymerized with approximately 20 moles of ethylene oxide per mole of sorbitol and sorbitol anhydrides. Polysorbate 80 is composed of sorbitan mono-9-octadecanoate poly(oxy-1,2-ethanediyl) derivatives.

[0128] Solubilizers include those of the formula: HO(CH2CH2) y1 (CH2CH2CH2O) y2 (CH2CH2O) y3 OH Also included are poloxamers having the subscript y, which are nonionic block copolymers composed of a polypropyleneoxy unit adjacent to two polyethyleneoxy units. 1 , y 2 and y 3 has a value such that the poloxamer has an average molecular weight of about 1000 g / mol to about 20,000 g / mol.

[0129] excipients Pharmaceutical compositions of the compounds disclosed herein can be any combination of the pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. The pharmaceutical composition can be administered in a therapeutically effective amount as a pharmaceutical composition by various forms and routes, including, for example, intravenous, intravitreal, intranasal, inhalation, nasal inhalation, oral inhalation, intratracheal, intrapulmonary, transmucosal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, aural, nasal, and topical administration.

[0130] Pharmaceutical compositions can be administered locally or systemically, for example, by directly injecting the compound into an organ, as needed, as a depot or sustained-release formulation.Pharmaceutical compositions can be provided in the form of a rapid-release formulation, a sustained-release formulation, or an intermediate-release formulation.Rapid-release formulations can provide immediate release.Sustained-release formulations can provide controlled release or sustained delayed release.

[0131] For oral administration, pharmaceutical compositions can be easily formulated by combining active compounds with pharmaceutically acceptable carriers or excipients.By using such carriers, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc. can be formulated for oral ingestion by subjects.

[0132] The pharmaceutical preparation for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture as needed, and processing the resulting granular mixture, and then adding suitable auxiliary agents if desired, to obtain tablets or dragee cores.The cores can be provided with suitable coatings.For this purpose, concentrated sugar solution can be used, and the sugar solution can contain excipients such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixtures.For example, dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of dosages of active compounds.

[0133] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the capsules include hard gelatin capsules containing one or more of pharmaceutical gelatin, bovine gelatin, and vegetable gelatin. Gelatin may be treated with alkali. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, or a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers may be added. All formulations for oral administration are provided in dosages suitable for such administration.

[0134] For buccal or sublingual administration, the compositions may be in the form of a tablet, lozenge, or gel.

[0135] Parenteral injections can be formulated for bolus injection or continuous infusion. The pharmaceutical compositions can be in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, such as suspending, stabilizing, or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Suspensions of the active compound can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspensions can also contain suitable stabilizers or agents that increase the solubility of the compound, thereby allowing for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0136] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0137] Formulations suitable for transdermal administration of active compounds can use transdermal delivery devices and patches, which can be lipophilic emulsions or buffered aqueous solutions dissolved or dispersed in polymers or adhesives. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical compounds. Transdermal delivery can be achieved using iontophoresis patches. Furthermore, transdermal patches can provide controlled delivery. The absorption rate can be slowed by using a rate-limiting membrane or by trapping the compound within a polymer matrix or gel. Conversely, absorption can be enhanced by using an absorption enhancer. The absorption enhancer or carrier can include an absorbable pharmaceutically acceptable solvent that aids in passage through the skin. For example, a transdermal device can be in the form of a bandage containing a backing material, a reservoir containing the compound and carrier, a rate-limiting barrier that delivers the compound to the subject's skin at a controlled, predetermined rate over an extended period of time, and an adhesive to secure the device to the skin or eye.

[0138] For administration by inhalation, the active compound may be in the form of an aerosol, vapor, mist, or powder. Inhalation may occur via nasal delivery, oral delivery, or both. The pharmaceutical composition is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack, nebulizer, or atomizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, difluoroethane, carbon dioxide, nitrogen, oxygen, or other suitable gas. The nebulizer can be a jet nebulizer, ultrasonic nebulizer, or vibrating mesh nebulizer. Jet nebulizers are powered by compressed air. Ultrasonic nebulizers use a piezoelectric transducer to generate droplets from an open liquid reservoir. Vibrating mesh nebulizers use a vibrating perforated membrane (mesh) powered by a circular piezoelectric element. The membrane's holes have a wide cross-sectional diameter on the liquid supply side and a narrow cross-sectional diameter on the droplet exit side.

[0139] In the case of pressurized aerosols, dosage units can be determined by providing a valve that delivers a metered dose, for example, using a metered-dose inhaler (MDI). Capsules and cartridges, for example, made of gelatin, for use in inhalers or insufflators can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch. Powder aerosols can be administered by dry powder inhalers (DPIs). Aerosols can also be administered by a face mask interface. This may be the preferred delivery route for pediatric patients under the age of 5. The selection of an appropriate inhalation device depends on preferences such as the nature of the active compound and its formulation, the intended delivery site, and pulmonary pathophysiology.

[0140] Nasal administration or intranasal administration involves insufflation of compound through the nose, including nasal drops and nasal sprays.This administration route can produce local and / or systemic effects.Inhaler or insufflation device can be used to deliver the compounds described herein from the nose to the lungs.

[0141] The compounds can also be formulated as rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases, such as cocoa butter or other glycerides, and synthetic polymers, such as polyvinylpyrrolidone and PEG. In compositions in the form of suppositories, low-melting waxes, such as mixtures of fatty acid glycerides or cocoa butter, can be used.

[0142] When carrying out the treatment or use method provided herein, a therapeutically effective amount of the compound described herein is administered as a pharmaceutical composition to a subject with a disease or condition to be treated.In some embodiments, the subject is a mammal, for example, a human.The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0143] Pharmaceutical compositions can be formulated with one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active compounds into pharmaceutically usable preparations.Preparation can be modified according to the selected route of administration.The pharmaceutical compositions comprising the compounds described herein can be prepared by, for example, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing process.

[0144] Pharmaceutical compositions can include at least one pharmaceutically acceptable carrier, diluent, or excipient, and the compounds described herein in the form of a free base or a pharmaceutically acceptable salt. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs) and active metabolites of these compounds that have the same type of activity.

[0145] The method for preparing a composition containing the compound described herein includes formulating the compound with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein.Semi-solid compositions include, for example, gels, suspensions, and creams.The composition may exist as a liquid solution or suspension, a solid form suitable for dissolution or suspension in liquid before use, or an emulsion.These compositions may also contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives.

[0146] Non-limiting examples of dosage forms suitable for use in the methods disclosed herein include feeds, foods, pellets, lozenges, liquids, elixirs, aerosols, inhalants, sprays, powders, tablets, pills, capsules, gels, geltabs, nanosuspensions, nanoparticles, microgels, suppositories, lozenges, aqueous or oily suspensions, ointments, patches, lotions, dentifrices, emulsions, creams, drops, dispersible powders or granules, emulsions in hard or soft gel capsules, syrups, phytoceuticals, dietary supplements, and any combination thereof.

[0147] Non-limiting examples of pharmaceutically acceptable excipients suitable for use in the methods disclosed herein include granulating agents, binders, lubricants, disintegrants, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, antioxidants, gums, coating agents, colorants, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifiers, antimicrobial agents, plant cellulosic materials, and spheronizing agents, and any combination thereof.

[0148] The composition of the compound disclosed herein can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compound to act quickly. Non-limiting examples of immediate release formulations include easily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation in which the drug release rate and drug release profile are adapted to meet physiological and chronotherapeutic needs, or are formulated to release the drug at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed-release granules, hydrogels (e.g., synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fiber), matrix-based formulations (e.g., formulations containing polymeric materials in which at least one active ingredient is dispersed), granules in a matrix, polymer mixtures, and granular agglomerates.

[0149] The disclosed compositions may optionally contain about 0.001% to about 0.005% (weight / volume) of a pharmaceutically acceptable preservative. One non-limiting example of a suitable preservative is benzyl alcohol.

[0150] In some cases, controlled release formulations are delayed release formulations.Delayed release formulations can be formulated to delay the action of compound for a long period of time.Delayed release formulations can be formulated to delay the release of effective dose of one or more compounds for, for example, about 4, about 8, about 12, about 16 or about 24 hours.

[0151] Controlled release formulation can be sustained release type.Sustained release type can be formulated to maintain the effect of compound for a long time.Sustained release type can be formulated to provide effective dose of any compound described herein for about 4, about 8, about 12, about 16 or about 24 hours (for example, provide physiologically effective blood profile).

[0152] Non-limiting examples of pharmaceutically acceptable excipients are found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0153] The methods disclosed herein include, for example, administering a Tie-2 activator, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[0154] The Tie-2 activators disclosed herein or their pharmaceutically acceptable salts can be conveniently formulated into pharmaceutical compositions consisting of one or more pharmaceutically acceptable carriers.For example, see Remington's Pharmaceutical Sciences, latest edition, EW Martin Mack Pub. Co., Easton, PA (incorporated herein by reference), which discloses representative carriers and conventional methods for preparing pharmaceutical compositions that can be used in conjunction with the preparation of the compounds described herein.Such pharmaceuticals can be standard carriers for administering compositions to humans and non-humans, including solutions such as sterile water, saline, and physiological pH buffers.Other compositions can be administered according to standard procedures.For example, pharmaceutical compositions can also contain one or more additional active ingredients, such as antibacterial agents, anti-inflammatory agents, and anesthetics.

[0155] Non-limiting examples of pharmaceutically acceptable carriers include saline, Ringer's solution, and dextrose solution. The pH of the above solutions can be from about 5 to about 8, and can be from about 7 to about 7.5. Further carriers include sustained-release preparations, such as semipermeable matrices of solid hydrophobic polymers containing the Tie-2 activator or a pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, such as films, liposomes, microparticles, and microcapsules.

[0156] The methods disclosed herein involve administering a Tie-2 activator or a pharmaceutically acceptable salt thereof as part of a pharmaceutical composition. In various embodiments, the compositions of the compounds disclosed herein can include a liquid containing the active agent in the form of a solution, a suspension, or both. The liquid composition can include a gel. In one embodiment, the liquid composition is aqueous. Alternatively, the composition can be in the form of an ointment. In another embodiment, the composition is an in-situ gellable aqueous composition. In some embodiments, the composition is an in-situ gellable aqueous solution.

[0157] In addition to the compounds disclosed herein, pharmaceutical preparations may contain additional carriers, thickeners, diluents, buffers, preservatives and surfactants. Pharmaceutical preparations may also contain one or more additional active ingredients, such as antibacterial agents, anti-inflammatory agents, anesthetics, etc.

[0158] Excipients may serve a role as simple and straightforward as an inert filler, or as used herein, excipients may be part of a pH stabilizing system or coating that ensures safe delivery of the ingredients to the stomach.

[0159] The Tie-2 activator or a pharmaceutically acceptable salt thereof may also be present as a liquid, emulsion, or suspension for delivery of the active therapeutic agent in the form of an aerosol to a body cavity, such as the nose, throat, or bronchial passages. The ratio of the Tie-2 activator or a pharmaceutically acceptable salt thereof to other ingredients in these preparations may be varied as required by the dosage form.

[0160] Depending on the intended mode of administration, pharmaceutical compositions administered as part of the methods disclosed herein may be in solid, semi-solid, or liquid form, e.g., tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or other unit dosage forms suitable for single administration of precise dosages. The compositions may comprise an effective amount of a Tie-2 activator or a pharmaceutically acceptable salt thereof, as described above, together with a pharmaceutically acceptable carrier, and may further include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and the like.

[0161] For solid compositions, non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. In one embodiment, a composition containing a Tie-2 activator or a pharmaceutically acceptable salt thereof in an amount of approximately 4 mg per 0.1 mL of liquid is prepared. The liquid phase comprises sterile water and an appropriate amount of a saccharide or polysaccharide.

[0162] Pharmaceutical Compositions Pharmaceutical compositions containing the compounds described herein can be administered for preventive or therapeutic treatment. The compositions can contain any number of active agents. In therapeutic applications, the compositions can be administered to a subject already suffering from a disease or condition in an amount sufficient to cure the disease or condition, or to at least partially halt the symptoms of the disease or condition, or to cure, cure, improve, reduce, reduce, or ameliorate the disease or condition. The compounds can also be administered to reduce or decrease the likelihood of developing, contracting, or worsening the condition. The amount effective for this use can vary based on the severity and course of the disease or condition, previous treatment, the subject's health, weight, response to the drug, and the judgment of the treating physician.

[0163] Multiple therapeutic agents can be administered in any order or simultaneously.If administered simultaneously, the multiple therapeutic agents can be provided in a single integrated form or in multiple forms, for example, as multiple separate pills or injections.The compounds can be packaged together or separately in a single package or multiple packages.One or all of the therapeutic agents can be administered in multiple doses.If not administered simultaneously, the timing between multiple doses can vary.

[0164] The compounds and compositions of the present disclosure can be assembled as a kit. In some embodiments, the present disclosure provides a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and written instructions for using the kit in the treatment of the conditions described herein. In some embodiments, the present disclosure provides a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, an antibody, and written instructions for using the kit in the treatment of the conditions described herein.

[0165] Administration and Dosage The compound disclosed herein can be administered via subcutaneous or intravenous injection.The volume of injection can be about 0.1mL, about 0.2mL, about 0.3mL, about 0.4mL, about 0.5mL, about 0.6mL, about 0.7mL, about 0.8mL, about 0.9mL, about 1mL, about 1.1mL, about 1.2mL, about 1.3mL, about 1.4mL, about 1.5mL, about 1.6mL, about 1.7mL, about 1.8mL, about 1.9mL, about 2mL, about 2.1mL, about 2.2mL, about 2.3mL, about 2.4mL, about 2.5mL, about 2.6mL, about 2.7mL, about 2.8mL, about 2.9mL or about 3mL. The individual doses administered to a subject may be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 7 It can be 1 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0166] The pharmaceutical compositions described herein can be in unit dosage form suitable for single administration of precise dosage.In unit dosage form, the preparation is divided into unit doses containing appropriate amounts of one or more compounds.The unit dosage form can be in the form of a package containing discrete amounts of preparation.Non-limiting examples are packaged injections, vials or ampoules.Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.Multiple-dose reclosable containers can also be used, for example, with or without preservatives.Preparations for parenteral injection can be provided in unit dosage form, for example, as ampoules or in multi-dose containers containing preservatives.

[0167] The Tie-2 activators described herein may be administered in an amount of about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, or about 65 mg to about 70 mg. , about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, or about 250 mg to about 300 mg.

[0168] The Tie-2 activators described herein may be present in the compositions in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 300 mg.

[0169] The Tie-2 activators described herein may be administered in an amount of about 0.5 μg, about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 150 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about It may be present in the composition in an amount of 400 μg, about 450 μg, about 500 μg, about 550 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 950 μg, about 1 mg, about 1.1 mg, about 1.2 mg, 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, or about 2 mg.

[0170] The Tie-2 activators described herein can be administered to a subject in an amount of about 0.1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 500 mg / kg, about 0.1 mg / kg to about 300 mg / kg, about 1 mg / kg to about 300 mg / kg, or about 0.1 mg / kg to about 30 mg / kg. In some embodiments, the Tie-2 activator is administered at about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, The compound is administered to a subject in an amount of about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 120 mg / kg, about 150 mg / kg, about 160 mg / kg, about 180 mg / kg, about 200 mg / kg, about 240 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 360 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, or about 600 mg / kg.

[0171] The compounds described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering a composition containing the compound can vary.For example, the compounds can be used as prophylactic agents and can be continuously administered to subjects with a condition or tendency to a disease to reduce or decrease the likelihood of the disease or condition occurring.The compounds and compositions can be administered to subjects while symptoms occur or as soon as possible after the onset of symptoms.Administration of the compound can begin within the first 48 hours, the first 24 hours, the first 6 hours, or the first 3 hours of the onset of symptoms.The initial administration can be via any practical route, for example, by any route described herein, using any formulation described herein.

[0172] The compound may be administered as soon as possible after the onset of a disease or condition is detected or suspected, and for the length of time necessary to treat the disease, for example, from about 1 month to about 3 months. In some embodiments, the length of time the compound may be administered is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, or about 9 months. The treatment period may be about 1 month, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, about 21 years, about 22 years, about 23 years, about 24 years, or about 25 years. The length of treatment may vary from subject to subject.

[0173] Dosage schedules for administering the compounds described herein include, but are not limited to, once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly, twice weekly, three times weekly, once monthly, twice monthly, and once every other month.

[0174] Treatment of a subject with a Tie-2 activator Disclosed herein are methods for treating subjects suffering from, for example, ARDS, lung injury, respiratory failure, and lung inflammation with a Tie-2 activator or an HPTPβ inhibitor. The subject can be a human. Treatment can include treating a human in a clinical trial. Treatment can include administering to the subject a pharmaceutical composition comprising one or more Tie-2 activators described throughout this disclosure. Treatment can include administering to the subject a therapy that promotes phosphorylation of the Tie-2 molecule.

[0175] In some embodiments, the methods disclosed herein provide Tie-2 activators for use in treating an indication disclosed herein. In some embodiments, the methods disclosed herein provide Tie-2 activators for use in the manufacture of a medicament for treating an indication disclosed herein. In some embodiments, the methods disclosed herein provide Tie-2 activators for use alone as a component of a mixture or in combination with one or more therapeutic agents. For example, the Tie-2 activators of the present disclosure can be co-formulated or co-administered with an antibody, e.g., an anti-VEGF agent. The anti-VEGF agent can be a compound, an antibody, or an antibody fragment, variant, or derivative thereof. Non-limiting examples of anti-VEGF agents include bevacizumab (Avastin®), ranibizumab (Lucentis®), and aflibercept (Eylea®). In some embodiments, the Tie-2 activators of the present disclosure can be co-formulated or co-administered with a non-inflammatory agent, e.g., a VEGF modulator. Non-limiting examples of VEGF modulating agents include, for example, dexamethasone, fluocinolone, and triamcinolone. In some embodiments, the compounds described herein can be used before, during, or after treatment with an anti-VEGF or VEGF modulating agent.

[0176] Non-limiting examples of subjects to which the therapeutic agent may be administered include: subjects can be humans, non-human primates (e.g., chimpanzees and other ape and monkey species); farm animals (e.g., cows, horses, sheep, goats, and pigs); domestic animals (e.g., rabbits, dogs, and cats); and laboratory animals (including rats, mice, and guinea pigs). Subjects can be of any age. Subjects can be, for example, elderly, adults, adolescents, pre-adolescents, children, infants, babies, and newborns.

[0177] Combination therapy The Tie-2 activators described herein can be co-formulated or co-administered with one or more additional therapies or therapeutic agents for treating lung injury, ARDS, or COVID-19. For example, the combination therapy can include a Tie-2 activator that stabilizes the endothelium in combination with an agent that inhibits viral replication, such as an anti-inflammatory agent, an anti-cytokine agent, an angiotensin-converting enzyme (ACE) inhibitor, or a statin.

[0178] The combination can be administered sequentially, simultaneously, in a single dosage form, or in separate dosage forms. Non-limiting examples of additional treatments include supplemental oxygen (e.g., mechanical ventilation), extracorporeal membrane oxygenation (ECMO). Non-limiting examples of additional therapeutic agents include Ang-1 activators, Ang-1 agonists, Ang-1 peptide agonists, Ang-1 mimetics, Ang-1 antibodies, Ang-1 antibody agonists, Ang-2 inhibitors, Ang-2 antagonists, Ang-2 mimetics, Ang-2 antibodies, Ang-2 peptide antagonists, Ang-2 antibody antagonists, anti-inflammatory agents, anti-cytokine agents, immunomodulatory agents, interleukin antagonists, ACE inhibitors, statins, steroids, corticosteroids, IL-6 inhibitors, IL-2 inhibitors, JAK inhibitors, antibiotics, antivirals, antiparasitics, diuretics, bronchodilators, prostaglandin agonists, prostaglandin analogs, epoprostenol, alprostadil, vasodilators, and vasoconstrictors. In some embodiments, the additional therapeutic agent is remdesivir, hydroxychloroquine, chloroquine, azithromycin, tocilizumab, acalabrutinib, tofacitinib, ruxolitinib, baricitinib, anakinra, mavrilimumab, sarilumab, lopinavir, ritonavir, iopinavir, interferon-beta, oseltamivir, favipiravir, umifenovir, galidesivir, colchicine, ivermectin, or ascorbic acid.

[0179] In some embodiments, the additional therapeutic agent is convalescent plasma, hyperimmune globulin, human immunoglobulin against COVID-19 (COVID19-HIG), or a SARS-CoV-2-specific monoclonal antibody. Convalescent plasma is plasma obtained from patients who have recovered from COVID-19. Antibody-containing plasma from recovered patients can be administered intravenously to patients suffering from COVID-19. Donor antibodies can help reduce the severity of the disease, for example, by recognizing viral particles.

[0180] In some embodiments, the Tie-2 activators described herein can be administered in combination with remdesivir. Remdesivir is an RNA polymerase inhibitor that inhibits viral RNA synthesis. Remdesivir has been used to treat Ebola virus disease. Remdesivir has demonstrated activity against SARS-CoV, MERS-CoV, and SARS-CoV-2 in cell culture and animal models. Remdesivir can shorten the time to recovery in subjects with COVID-19 by reducing the amount of coronavirus in the body.

[0181] Remdesivir may be an effective treatment for COVID-19, for example, under emergency or investigational use. Remdesivir can be used to treat adults and children with suspected or laboratory-confirmed COVID-19 and severe disease, defined as SpO2 ≤ 94% in room air, who require supplemental oxygen, mechanical ventilation, or ECMO. Remdesivir can be administered to patients in a hospital setting via intravenous infusion by a healthcare provider. Remdesivir can be administered intravenously (intravenously or IV) once daily for up to 10 days.

[0182] Non-limiting side effects of remdesivir treatment include: Infusion-related reactions. Infusion-related reactions occurred during remdesivir infusion or around the time remdesivir was administered. Signs and symptoms of infusion-related reactions may include hypotension, nausea, vomiting, sweating, and shivering. Increased liver enzyme levels. Elevated liver enzyme levels have been observed in people receiving remdesivir, which may be a sign of liver inflammation or cell damage. Blood tests can be performed by a healthcare provider to check liver enzyme levels before administering remdesivir and daily while receiving remdesivir. · Brief pain, bleeding, skin bruising, tingling, swelling, and possible infection at the injection site.

[0183] Remdesivir for Injection (100 mg) is a sterile, preservative-free, lyophilized solid that is reconstituted with 19 mL of sterile water for injection and diluted in 0.9% saline prior to intravenous administration. After reconstitution, a single-dose clear glass vial contains a 5 mg / mL concentrated remdesivir solution with sufficient volume to allow withdrawal of 20 mL. Remdesivir Injection (5 mg / mL) is a sterile, preservative-free, clear solution that is diluted in 0.9% saline prior to intravenous administration.

[0184] Remdesivir for injection (100 mg vials) should be stored below 30°C until use. Remdesivir injection (5 mg / mL vials) should be stored at refrigerated temperatures (2°C to 8°C) until use. After dilution with 0.9% saline, the solution can be stored at room temperature (20°C to 25°C) for up to 4 hours or refrigerated (2°C to 8°C) for 24 hours.

[0185] In some embodiments, the Tie-2 activator is an Ang-1 activator, an Ang-1 mimetic, an Ang-1 antibody, or an Ang-1 polypeptide. In some embodiments, the Tie-2 activator is MAN-01.

[0186] Pharmacodynamic and pharmacokinetic parameters Pharmacokinetic and pharmacodynamic data can be obtained by various experimental techniques. The appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition may vary due to variations in the metabolism of Tie-2 activators in different subjects. Pharmacokinetic and pharmacodynamic profiles can be based on determining the mean parameters of a group of subjects. The group of subjects can include any reasonable number of subjects suitable for determining a representative mean value, such as 5, 10, 15, 20, 25, 30, 35, or more subjects. The mean value is determined by calculating the average of all subject measurements for each measured parameter.

[0187] Treatment can be used to inhibit a particular biological or biochemical function at lower dosages. The dose can be adjusted to achieve a desired pharmacokinetic or pharmacodynamic profile, e.g., a desired or effective hematological profile, as described herein. The 50% inhibitory concentration (IC 50 IC is a measure of a substance's effectiveness in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a particular drug or compound is required to half-inhibit a given biological process, such as the activity of HPTPβ. Combination drug treatments have a lower IC compared to monotherapy. 50 The value may be indicated.

[0188] The outcome of treating a human subject with a therapy can be measured by calculating pharmacodynamic and pharmacokinetic parameters. Non-limiting examples of pharmacodynamic and pharmacokinetic parameters that can be used to determine the effectiveness of treating a subject with a therapy of the present disclosure include: a) the amount of drug administered, which can be expressed as dose D; b) the dosing interval, which can be expressed as τ; c) the volume of distribution V d (where V d = D / C0); d) the apparent volume of distribution of the drug, which can be expressed as the concentration C0 or C ssThe amount of drug in a given volume of tissue (C or C) can be expressed as ss =D / V d );e) Drug half-life t 1 / 2 (where t 1 / 2 =ln(2) / k e ;f) the rate at which the drug is eliminated from the body, k e (where k e =ln(2) / t 1 / 2 =CL / V d );g)Formula K in the injection rate required to balance in =C ss CL);h) The integral of the concentration-time curve after administration of a single dose, which is AUC 0-∞

number

number

number

number

number

[0189] The pharmacokinetic parameter can be any parameter suitable for describing the tissue concentration profile of the treatment of the present disclosure. For example, the pharmacokinetic profile can be, for example, about 0 minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, about 75 minutes, about 76 minutes, about 77 minutes, about 78 minutes, about 79 minutes , approximately 31 minutes, approximately 32 minutes, approximately 33 minutes, approximately 34 minutes, approximately 35 minutes, approximately 36 minutes, approximately 37 minutes, approximately 38 minutes, approximately 39 minutes, approximately 40 minutes, approximately 41 minutes, approximately 42 minutes, approximately 43 minutes, approximately 44 minutes, approximately 45 minutes, approximately 46 minutes, approximately 47 minutes, approximately 48 minutes, approximately 49 minutes, approximately 50 minutes, approximately 51 minutes, approximately 52 minutes, approximately 53 minutes, approximately 54 minutes, approximately 55 minutes, approximately 56 minutes, approximately 57 minutes, approximately 58 minutes, approximately 59 minutes, approximately 60 minutes, approximately 1 hour, approximately 0.5 hours Hours, approx. 1.5 hours, approx. 2 hours, approx. 2.5 hours, approx. 3 hours, approx. 3.5 hours, approx. 4 hours, approx. 4.5 hours, approx. 5 hours, approx. 5.5 hours, approx. 6 hours, approx. 6.5 hours, approx. 7 hours, approx. 7.5 hours, approx. 8 hours, approx. 8.5 hours, approx. 9 hours, approx. 9.5 hours, approx. 10 hours, approx. 10.5 hours, approx. 11 hours, approx. 11.5 hours, approx. 12 hours, approx. 12.5 hours, approx. 13 hours, approx. 13.5 hours, approx. 14 hours The antibody can be obtained at about 14.5 hours, about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours, about 18 hours, about 18.5 hours, about 19 hours, about 19.5 hours, about 20 hours, about 20.5 hours, about 21 hours, about 21.5 hours, about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours, or about 24 hours post-dosing.

[0190] The pharmacokinetic parameters can be any parameters suitable for describing small molecule activators of Tie-2. maxis, for example, about 1 ng / mL or more; about 2 ng / mL or more; about 3 ng / mL or more; about 4 ng / mL or more; about 5 ng / mL or more; about 6 ng / mL or more; about 7 ng / mL or more; about 8 ng / mL or more; about 9 ng / mL or more; about 10 ng / mL or more; about 15 ng / mL or more; about 20 ng / mL or more; about 25 ng / mL or more; about 50 ng / mL or more; about 75 ng / mL or more; about 100 ng / mL or more; about 200 ng / mL or more; about 300 ng / mL or more or greater than about 1000 ng / mL; or greater than about 1250 ng / mL; or greater than about 1500 ng / mL; or greater than about 1750 ng / mL; or greater than about 2000 ng / mL; or any other C suitable for describing the pharmacokinetic profile of an activator of Tie-2 described herein. max C maxFor example, about 1 ng / mL to about 5,000 ng / mL; about 1 ng / mL to about 4,500 ng / mL; about 1 ng / mL to about 4,000 ng / mL; about 1 ng / mL to about 3,500 ng / mL; about 1 ng / mL to about 3,000 ng / mL; about 1 ng / mL to about 2,500 ng / mL; about 1 ng / mL to about 2,000 ng / mL; about 1 ng / mL to about 1,500 ng / mL; about 1 ng / mL to about 1,000 ng / mL; about 1 ng / mL to about 900 ng / mL; about 1 ng / mL to about 800 ng / mL; about 1 ng / mL to about 700 ng / mL; about 1 ng / mL to about 600ng / mL; about 1ng / mL to about 500ng / mL; about 1ng / mL to about 450ng / mL; about 1ng / mL to about 400ng / mL; about 1ng / mL to about 350ng / mL; about 1ng / mL to about 300ng / mL; about 1ng / mL to about 250ng / mL; about 1ng / mL ~200ng / mL;1ng / mL~150ng / mL;1ng / mL~125ng / mL;1ng / mL~100ng / mL;1ng / mL~90ng / mL;1ng / mL~80ng / mL;1ng / mL~70ng / mL;1ng / mL~approx. 60ng / mL; about 1ng / mL to about 50ng / mL; about 1ng / mL to about 40ng / mL; about 1ng / mL to about 30ng / mL; about 1ng / mL to about 20ng / mL; about 1ng / mL to about 10ng / mL; about 1ng / mL to about 5ng / mL; about 10ng / mL to about 4,000 ng / mL; about 10ng / mL to about 3,000ng / mL; about 10ng / mL to about 2,000ng / mL; about 10ng / mL to about 1,500ng / mL; about 10ng / mL to about 1,000ng / mL; about 10ng / mL to about 900ng / mL; about 10ng / mL to about 800ng / mL mL; about 10ng / mL to about 700ng / mL; about 10ng / mL to about 600ng / mL; about 10ng / mL to about 500ng / mL; about 10ng / mL to about 400ng / mL; about 10ng / mL to about 300ng / mL; about 10ng / mL to about 200ng / mL; about 10ng / mL ~100ng / mL;10ng / mL~50ng / mL;25ng / mL~500ng / mL;25ng / mL~100ng / mL;50ng / mL~500ng / mL;50ng / mL~100ng / mL;100ng / mL~500ng / mL;It may be about 100 ng / mL to about 400 ng / mL; about 100 ng / mL to about 300 ng / mL; or about 100 ng / mL to about 200 ng / mL.

[0191] The Tie-2 activators described herein max is, for example, about 0.1 hours, about 0.2 hours, about 0.3 hours, about 0.4 hours, about 0.5 hours or less, about 1 hour or less, about 1.5 hours or less, about 2 hours or less, about 2.5 hours or less, about 3 hours or less, about 3.5 hours or less, about 4 hours or less, about 4.5 hours or less, about 5 hours or less, or any other T suitable for describing the pharmacokinetic profile of the Tie-2 activators described herein. max It can be. T maxis, for example, about 0.1 hours to about 24 hours; about 0.1 hours to about 0.5 hours; about 0.5 hours to about 1 hour; about 1 hour to about 1.5 hours; about 1.5 hours to about 2 hours; about 2 hours to about 2.5 hours; about 2.5 hours to about 3 hours; about 3 hours to about 3.5 hours; about 3.5 hours to about 4 hours; about 4 hours to about 4.5 hours; about 4.5 hours to about 5 hours; about 5 hours to about 5.5 hours; about 5.5 hours to about 6 hours; Approximately 6 hours to 6.5 hours; Approximately 6.5 hours to 7 hours; Approximately 7 hours to 7.5 hours; Approximately 7.5 hours to 8 hours; Approximately 8 hours to 8.5 hours; Approximately 8.5 hours to 9 hours; Approximately 9 hours to 9.5 hours; Approximately 9.5 hours to 10 hours; Approximately 10 hours to 10.5 hours; Approximately 10.5 hours to 11 hours; Approximately 11 hours to 11.5 hours; Approximately 11.5 hours to 12 hours; Approximately 12 hours to 12.5 hours ;Approx. 12.5 hours to 13 hours;Approx. 13 hours to 13.5 hours;Approx. 13.5 hours to 14 hours;Approx. 14 hours to 14.5 hours;Approx. 14.5 hours to 15 hours;Approx. 15 hours to 15.5 hours;Approx. 15.5 hours to 16 hours;Approx. 16 hours to 16.5 hours;Approx. 16.5 hours to 17 hours;Approx. 17 hours to 17.5 hours;Approx. 17.5 hours to 18 hours;Approx. 18 hours to 18. 5 hours; about 18.5 hours to about 19 hours; about 19 hours to about 19.5 hours; about 19.5 hours to about 20 hours; about 20 hours to about 20.5 hours; about 20.5 hours to about 21 hours; about 21 hours to about 21.5 hours; about 21.5 hours to about 22 hours; about 22 hours to about 22.5 hours; about 22.5 hours to about 23 hours; about 23 hours to about 23.5 hours; or about 23.5 hours to about 24 hours.

[0192] AUC of the Tie-2 activators described herein (0-inf) or AUC (last)is, for example, about 1 ng·hr / mL or more, about 5 ng·hr / mL or more, about 10 ng·hr / mL or more, about 20 ng·hr / mL or more, about 30 ng·hr / mL or more, about 40 ng·hr / mL or more, about 50 ng·hr / mL or more, about 100 ng·hr / mL or more, about 150 ng·hr / mL or more, about 200 ng·hr / mL or more, about 250 ng·hr / mL or more, about 300 ng·hr / mL or more, about 350 ng·hr / mL or more, about 400 ng·hr / mL or more, about 450 ng·hr / mL or more, about 500 ng·hr / mL or more, about 600 ng·hr / mL or more, about 700 ng·hr / mL or more, about 800 ng·hr / mL or more, about 900 ng·hr / mL or more , about 1000 ng·hr / mL or more, about 1250 ng·hr / mL or more, about 1500 ng·hr / mL or more, about 1750 ng·hr / mL or more, about 2000 ng·hr / mL or more, about 2500 ng·hr / mL or more, about 3000 ng·hr / mL or more, about 3500 ng·hr / mL or more, about 4000 ng·hr / mL or more, about 5000 ng·hr / mL or more, about 6000 ng·hr / mL or more, about 7000 ng·hr / mL or more, about 8000 ng·hr / mL or more, about 9000 ng·hr / mL or more, about 10,000 ng·hr / mL or more, or any other AUC suitable to describe the pharmacokinetic profile of the activators of Tie-2 described herein. (0-inf) The AUC of Tie-2 activators (0-inf)is, for example, about 1ng·hr / mL to about 10,000ng·hr / mL; about 1ng·hr / mL to about 10ng·hr / mL; about 10ng·hr / mL to about 25ng·hr / mL; about 25ng·hr / mL to about 50ng·hr / mL; about 50ng·hr / mL to about 100ng·hr / mL; about 100ng·hr / mL to about 200ng·hr / mL; about 200ng·hr / mL to about 300ng·hr / mL; about 300ng·hr / mL to about 400ng·hr / mL; about 400ng·hr / mL to about 500ng·hr / mL; about 500ng·hr / mL mL ~ about 600ng hr / mL; about 600ng hr / mL about 700ng hr / mL; about 700ng hr / mL about 800ng hr / mL; about 800ng hr / mL about 900ng hr / mL; about 900ng hr / mL about 1,000ng hr / mL; Approximately 1,000ng·hr / mL ~ Approx. 1,250ng · hr / mL; Approx. 1,250ng · hr / mL ~ Approx. 1,500ng · hr / mL; Approx. 1,500ng · hr / mL ~ Approx. 1,750ng · hr / mL; Approx. 1,750ng · hr / mL ~ Approx. 2,000ng · hr / mL; Approx. 2 ,000ng·hr / mL~about 2,500ng·hr / mL;about 2,500ng·hr / mL~about 3,000ng·hr / mL;about 3,000ng·hr / mL~about 3,500ng·hr / mL;about 3,500ng·hr / mL~about 4,000ng·hr / mL;about 4, 000ng·hr / mL~Approx. 4,500ng·hr / mL;Approx. 4,500ng·hr / mL~Approx. 5,000ng·hr / mL;Approx. 5,000ng·hr / mL~Approx. 5,500ng·hr / mL;Approx. 5,500ng·hr / mL~Approx. 6,000ng·hr / mL;Approx. 6,00 It may be 0 ng·hr / mL to about 6,500 ng·hr / mL; about 6,500 ng·hr / mL to about 7,000 ng·hr / mL; about 7,000 ng·hr / mL to about 7,500 ng·hr / mL; about 7,500 ng·hr / mL to about 8,000 ng·hr / mL; about 8,000 ng·hr / mL to about 8,500 ng·hr / mL; about 8,500 ng·hr / mL to about 9,000 ng·hr / mL; about 9,000 ng·hr / mL to about 9,500 ng·hr / mL; or about 9,500 ng·hr / mL to about 10,000 ng·hr / mL. [Example]

[0193] Example 1. Compounds with inhibitory activity against HPTPβ. HPTPβ IC of exemplary compounds 50 Non-limiting examples of activity (μM) are listed in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] [Table 3-22] [Table 3-23] [Table 3-24] [Table 3-25] [Table 3-26]

[0194] Example 2 VE-PTP is induced in stressed endothelium of the ARDS lung microvasculature. VE-PTP is induced in stressed endothelium, a key pathology in ARDS. Therefore, ARDS lung microvasculature is a promising target for HPTPβ / VE-PTP inhibitors. Figure 3 demonstrates the pathophysiological relevance of Tie-2 and VE-PTP in ARDS. Panel A of Figure 3 shows RNA expression data for VE-PTP from humans; each line represents a cell type or tissue, and the degree of bias to the right represents the expression level. VE-PTP is most highly expressed in the lung, even in the absence of stress. Panel B of Figure 3 shows immunoblots and corresponding protein expression levels of VE-PTP (upper panel) or Tie2 (lower panel) immunoprecipitated from whole lung lysates of Akita / Ren diabetic hypertensive mice compared with control mice. VE-PTP conditional knockout restored Tie2 activation in Akita / Ren mice (last lane in the lower left panel). Panel C of Figure 3 shows a Western blot analysis of lysates from cultured endothelial cells demonstrating that VE-PTP is induced by hypoxia, a canonical stressor for the endothelium. This analysis demonstrates that VE-PTP is induced by hypoxia (a canonical stressor for the endothelium associated with COVID-19 and ARDS). HPTPβ / VE-PTP inhibition can restore Tie-2 activation and stabilize the stressed vasculature.

[0195] Example 3 Targeted Protection from Ligand-Independent Tie-2 Activation and Pulmonary Vascular Leak by HPTPβ Inhibitors Pulmonary vascular leakage was assessed using Compound 1, an HPTPβ inhibitor described herein. When applied to cultured endothelial cells, Compound 1 achieved ligand-independent Tie-2 activation, activating Tie-2 even when Ang-1 failed to do so during endothelial cell hypoxia (Figure 4, panel A).

[0196] The effects of Compound 1 were also evaluated in a mouse model of inflammatory pulmonary vascular leakage. Mice treated with control siRNA or Tie-2 siRNA were analyzed for pulmonary vascular leakage induced by the gram-negative endotoxin, lipopolysaccharide (LPS) (Figure 4, Panel B). LPS increased pulmonary vascular leakage in both groups of mice. However, Compound 1 only counteracted LPS-induced vascular leakage when Tie-2 was not artificially inhibited. These results demonstrated that Compound 1 acts in a Tie-2-dependent manner to reduce inflammatory pulmonary vascular leakage.

[0197] The effect of Compound 1 on VE-PTP was also evaluated in vivo in VE-PTP inducible endothelial cell knockout mice (Cdh5-Cre ERT2 :PTPR-β lox / lox , hereafter referred to as "iECKO-VE-PTP"). lox / lox Compared to control mice, iECKO-VE-PTP mice exhibited less vascular leakage in response to histamine and VEGF, two unrelated inflammatory permeability triggers. Furthermore, while compound 1 reduced inflammatory vascular leakage in control mice, mice lacking endothelial VE-PTP did not exhibit further reduction in leakage with compound 1 treatment (Figure 4, Panel C). Together, these results demonstrate that (a) compound 1 is a potent activator of Tie-2 in stressed endothelium and (b) compound 1 reduces inflammatory vascular leakage in vivo by specifically acting through VE-PTP to enhance Tie-2 signaling.

[0198] Panel A of Figure 4 shows Western blot analysis of cultured endothelial cell lysates demonstrating Tie-2 activation (p-Tyr) by Compound 1 in the absence of Ang-1 and Ang-2 ligands, as well as enhancement of Ang-1- and Ang-2-induced Tie-2. Thus, Compound 1 achieved ligand-independent Tie-2 activation and counteracted mammalian vascular leakage in a highly targeted manner. Panel B of Figure 4 shows that Tie-2 expression is required for Compound 1 to counteract LPS-induced pulmonary vascular leakage, as demonstrated by siRNA versus Tie-2. Panel C of Figure 4 shows that conditional deletion of VE-PTP (Ptprb) demonstrates the requirement for Compound 1 (Cpd1) to counteract vascular leakage in mice induced by VEGF or histamine.

[0199] Compound 1 also reduced LPS-mediated vascular leakage and leukocyte migration (neutrophils and lymphocytes) in the lungs, two key components of COVID-19 pulmonary pathology that contribute to respiratory failure. Compound 1 also reduced pulmonary toxicity and improved survival in a mouse model of IL2-induced cytokine storm, which is thought to be related to poor outcomes in COVID-19. Furthermore, compound 1-mediated VE-PTP inhibition improved outcomes in models of diabetic nephropathy, LPS-induced acute kidney injury, and cerebral ischemia, demonstrating the potential benefit of restoring Tie-2 activation in critical extrapulmonary vascular beds. Compound 1 also enhanced the Tie-2 agonist properties of both Ang-1 and Ang-2, restoring Tie-2 activation and angiopoietin responsiveness in hypoxic endothelial cells. These results suggest the benefit of Tie-2 activation in COVID-19 patients with respiratory failure.

[0200] Example 4 Effect of Compound 1 on Sepsis in Vivo The cecal ligation and puncture (CLP) model of sepsis involves laparotomy under general anesthesia, followed by ligation of a portion of the cecum in conjunction with creation of a cecocolectomy by needle puncture, as shown in Figure 5. This model results in 1) surgical trauma to the tissue, 2) ischemic tissue from the ligated cecum, and 3) polymicrobial sepsis from fecal shedding after needle puncture.

[0201] In sepsis, elevated Ang-2 levels correlate with vascular leakage and mortality. Compound 1 (Cpd 1) was used to evaluate its effects on sepsis in vivo. Male Sprague-Dawley rats were fasted for 16 hours before cecal ligation. The cecum was surgically exposed and then ligated below the ileocecal valve. The excised cecum was punctured twice with a 16-gauge needle. Fecal material was removed by squeezing before the animals were sutured and resuscitated with fluids. After 24 hours, the necrotic cecum was removed, the abdominal cavity was lavaged, and the animals were sutured again. Drug treatment was then administered subcutaneously twice daily (BID) on days 1–5 (n=16 / group). Body weight and mortality were monitored for 10 days. The broad-spectrum antibiotic imipenem (IM) was used as a positive control. Animals were divided into four groups: vehicle control, Cpd 1 (10 mg / kg), Cpd 1 (10 mg / kg) + IM (20 mg / kg), and IM (20 mg / kg). The resulting survival rates are shown in Figure 6. Vehicle-treated controls showed 50% survival (8 / 16), compared with the Cpd 1 group, which had 100% survival (16 / 16; p=0.001), and the Cpd 1 + IM group, which had 94% survival (15 / 16; p=0.007). The 81% survival in the IM-treated group reached statistical significance (13 / 16; p=0.06) compared with vehicle controls. Survival results were analyzed by the Kaplan-Meier method and compared by the log-rank test. The results indicate that HPTPβ inhibition may be an effective treatment for polymicrobial septic shock.

[0202] Example 5 Evaluation of Subcutaneous Formulations of Compound 1 in Humans Clinical Pharmacokinetics A phase 1 study was conducted to evaluate the pharmacokinetic (PK) effects of repeated 28-day SC doses of Compound 1 in subjects with diabetic macular edema (DME). Four dose cohorts received Compound 1 BID at 5, 15, 22.5, and 30 mg, respectively. Plasma samples were collected over 4 hours after the morning dose on days 1 and 14. The resulting mean plasma concentration-time profiles are shown in Figure 7. For all profiles shown in the figure, samples were collected only after the morning dose of the BID regimen. The mean (SD) PK parameters of Compound 1 after the morning dose on day 14 are summarized in Table 3. PK samples for the 22.5 mg dose group were collected only after the day 14 dose.

[0203] Absorption of Compound 1 after SC injection in humans was rapid, with a mean T max The plasma concentration-time profile showed a rapid T max After that, it declines rapidly and has a relatively short T 1 / 2 The AUC was approximately 1 hour. 0-inf increased dose-proportionally with increasing doses of Compound 1. Urinary excretion of Compound 1 was approximately 9-13% of the dose for all dose groups. These results support a dose-related increase in plasma exposure in subjects with DME. [Table 3-27]

[0204] Clinical efficacy Inhibition of VE-PTP can activate Tie-2 regardless of extracellular levels of Ang-1 (agonist) or Ang-2 (antagonist) and therefore represents an efficient pharmacological approach to restore Tie-2 activation in patients suffering from ARDS. After SC injection, Compound 1 is rapidly absorbed into the circulation, where it has direct access to the damaged endothelium. In a Phase 1b study, BID administration to patients with DME demonstrated similar PK profiles between days 1 and 14 (Figure 7 and Table 3), with no evidence of dose-proportional increases in plasma concentrations or accumulation.

[0205] SC administration of Compound 1 resulted in a transient, dose-dependent reduction in blood pressure. Panel A of Figure 8 shows the transient, dose-dependent reduction in blood pressure in a Phase 1b study. This result corresponded to a plasma concentration profile consistent with eNOS activation downstream of Tie-2. The blood pressure reduction at the 15 mg dose in the Phase 1 study was replicated in a Phase 2 study (Panel B of Figure 8) and a Phase 2b study (data not shown). In the Phase 2 study, as shown in Panel C of Figure 8, a greater reduction in systolic blood pressure was observed in patients with a baseline systolic BP ≥ 140 mmHg (left panel) compared with patients with a baseline systolic BP < 140 mmHg (right panel). The study groups were as follows: Compound 1 alone at 15 mg BID; Compound 1 + ranibizumab (RBZ) at 15 mg BID; and placebo + ranibizumab (RBZ). The magnitude of blood pressure reduction with Compound 1 depended on baseline blood pressure in each of the three studies. This relationship is shown in Figure 8, Panel C, where the majority of the reduction in blood pressure occurred in patients with a baseline systolic pressure of 140 mmHg or greater. Smaller changes in blood pressure were observed in patients with a baseline systolic pressure less than 140 mmHg. This reduction in blood pressure is consistent with improved endothelial function in these hypertensive patients with diabetes. Improved endothelial function may be beneficial in patients with ARDS and COVID-19.

[0206] In a phase 2 study in patients with DME, 15 mg of SC Compound 1 administered twice daily in combination with monthly intravitreal injections of standard-of-care ranibizumab (Lucentis®) resulted in highly statistically significant reductions in retinal thickness compared with ranibizumab alone. Patients with DME were treated with three monthly intravitreal injections of ranibizumab, Compound 1 (15 mg SC twice daily), or Compound 1 (15 mg SC twice daily) plus monthly intravitreal injections of ranibizumab. Figure 9 shows the effect of Compound 1 alone and in combination with ranibizumab (RBZ) on reducing central retinal subfield thickness (CST) in patients with DME. 15 mg of SC Compound 1 administered twice daily demonstrated an additive effect on ranibizumab for CST reduction. The combination of daily SC Compound 1 administered twice daily plus monthly intravitreal ranibizumab significantly reduced macular edema more than ranibizumab alone.

[0207] In patients with evidence of diabetic nephropathy (i.e., urinary albumin / creatinine ratio [UACR] ≥ 30 mg / g), compound 1 reduced UACR by approximately 20% compared with increases in patients treated with ranibizumab alone. Results indicate potential beneficial effects on renal function. In a subsequent Phase 2b study in patients with nonproliferative diabetic retinopathy, SC compound 1, 15 mg once or twice daily for 48 weeks, resulted in a dose-dependent reduction in UACR in patients with significant baseline albuminuria (UACR > 30 mg / g) of up to 20% with BID administration compared with increases in placebo-treated patients (Figure 10). The 20% reduction in UACR observed in Phase 2 and Phase 2b studies is consistent with other interventions providing long-term renal protection and reducing progression to end-stage renal disease. Thus, evidence of target engagement as demonstrated by blood pressure effects and evidence of vascular stabilizing efficacy as suggested by beneficial effects in the diabetic retina and kidney supports the 15 mg dose of Compound 1 for the treatment of ARDS or COVID-19.

[0208] Figure 10 shows the effect of Compound 1 on UACR, a marker of renal glomerular hyperpermeability. Compound 1 administered once daily (QD) or twice daily (BID) reduced urinary protein leakage in diabetic patients (LOCF = imputation at last observed value). Patients in a Phase 2b study were equally randomized to SC placebo or Compound 1, 15 mg, once or twice daily. UACR was measured at baseline and every 3 months, including at the end of 48 weeks of the study. Patients with a baseline UACR ≥ 30 mg / mL were included in the analysis.

[0209] Example 6 Clinical trial of SQ Compound 1 for prevention of pulmonary function deterioration in acute noncardiogenic hypoxemic respiratory failure A multicenter, placebo-controlled, double-blind, randomized clinical trial was conducted to evaluate the potential for hypoxemia progression in patients undergoing mechanical ventilation for acute noncardiogenic hypoxemic respiratory failure who do not meet the criteria for moderate-to-severe ARDS. The patient population was adults undergoing invasive mechanical ventilation with acute noncardiogenic hypoxemic respiratory failure, defined as a PaO2 / FiO2 (P:F) ratio of less than 300 mmHg, who did not meet the Berlin criteria for moderate-to-severe ARDS. This population included patients with noncardiogenic hypoxemic respiratory failure without ARDS (i.e., patients with acute hypoxemic respiratory failure without bilateral pulmonary infiltrates) and patients with mild ARDS according to the Berlin criteria. Patients with hypoxemia due to cardiogenic pulmonary edema or fluid overload were excluded. Patients with moderate-to-severe ARDS (i.e., P:F ratio less than 200 mmHg with bilateral pulmonary infiltrates) were excluded because these patients have already progressed to a pathophysiological state of severe pulmonary vascular leak (prevention is no longer possible). Patients will be enrolled within 24 hours of meeting the inclusion criteria. The eligibility criteria are listed below.

[0210] Inclusion Criteria: 1. Age 18 or older 2. Invasive mechanical ventilation, defined as positive pressure ventilation via endotracheal tube or tracheostomy 3. Respiratory failure not adequately explained by heart failure or fluid overload; objective evaluation (e.g., echocardiography) to rule out hydrostatic edema is required if none of the following ARDS risk factors have occurred in the past 7 days: pneumonia, aspiration of gastric contents, inhalation injury, drowning, non-pulmonary sepsis, trauma, pancreatitis, burns, non-cardiogenic shock, drug overdose, and multiple blood product transfusions. 4. A PaO2 / FiO2 ratio of ≤300 mmHg with PEEP ≥ 5 cmH2O must be confirmed within 4 hours of starting study medication.

[0211] Exclusion criteria: 1. Lack of informed consent for clinical trial participation 2. Unable to start study medication within 24 hours of meeting the inclusion criteria 3. Pregnant 4. Breastfeeding 5. Prisoner 6. Patients meet the Berlin criteria for moderate-to-severe ARDS, including bilateral pulmonary infiltrates and a PaO2 / FiO2 ratio of less than 200 mmHg. 7. Norepinephrine infusion ≥ 10 μg / min (or equivalent dose of an alternative vasoconstrictor) 8. Lung transplant recipients 9. Cystic fibrosis 10. WHO class III or IV pulmonary hypertension 11. Currently undergoing in vitro treatment 12. Chronic respiratory failure, defined as home oxygen use or outpatient PaCO2 > 60mmHg 13. Chronic invasive mechanical ventilation before hospitalization 14. Severe chronic liver disease defined as a Child-Pugh score ≥ 12 15. Decision to withhold life-sustaining treatment (a decision to withhold CPR only in the case of cardiac arrest does not meet this exclusion criterion) 16. Critically ill patients who, in the opinion of the treating clinical team, are not expected to survive for 24 hours 17. Clinicians are unwilling to utilize low tidal volumes of approximately 6 mL / kg ideal body weight. 18. Enrollment in another IND-supported study within the past 30 days 19. Previous allergic reaction to Compound 1 20. Previous enrollment in this study

[0212] Figure 11 shows the spectrum of disease from least severe to most severe acute noncardiogenic hypoxemic respiratory failure: acute hypoxemic respiratory failure without ARDS, mild ARDS, moderate ARDS, and severe ARDS. This pathophysiological progression of lung injury is based on the PaO2 / FiO2 ratio (P:F ratio) and the presence of bilateral pulmonary infiltrates (B1I infiltrates) as determined by chest X-ray (CXR). The study described in Example 6 includes patients early in the pathophysiological progression, including those with hypoxemia without bilateral pulmonary infiltrates and those with mild ARDS. The study described in Example 7 includes patients with more advanced ARDS pathophysiology, including those with moderate and severe ARDS.

[0213] Non-limiting examples of strategies for defining the patient population at risk for moderate-to-severe ARDS include the Lung Injury Prediction Score (LIPS) and ICU admission with conditions that predispose to lung injury. In this study, eligible patients have acute noncardiogenic hypoxemic respiratory failure on mechanical ventilation. The goal of increasing the severity of illness required for study entry compared with prior prevention trials may be to increase the risk of worsening lung function in patients in the placebo group (prognostic enrichment).

[0214] Dosing schedule: Dosing is 15 mg or 30 mg of Compound 1 administered SC three times daily (TID), every 8 hours (q8h) for 3 days (72 hours) or 7 days.

[0215] The safety of SQ Compound 1 will be evaluated in a target population, i.e., patients undergoing mechanical ventilation for acute noncardiogenic hypoxemic respiratory failure who do not meet the criteria for moderate-to-severe ARDS. These patients are at high risk for severe pulmonary vascular leakage and fulminant ARDS, but have not yet progressed to the most advanced stage of the disease. This study will evaluate whether early use of Compound 1 in these patients reduces the likelihood of more severe lung injury through reduced Tie-2 receptor activation and resulting pulmonary vascular leakage.

[0216] The efficacy of SQ Compound 1 will be evaluated based on improvement in oxygenation and prevention of moderate-to-severe ARDS in this target population. The primary outcome is change in oxygenation index, an established measure of lung function in mechanically ventilated patients with respiratory failure. Thus, the results of this trial can determine the extent to which Tie-2 activation can stabilize or even improve oxygenation in patients with acute hypoxemic respiratory failure who are at high risk for developing moderate-to-severe ARDS. This trial can also examine whether Tie-2 activation by Compound 1 in patients early in the pathophysiological progression from hypoxia to fulminant ARDS can reduce the likelihood of the most severe form of lung injury (Figure 11). Phase 2 trials can also define the safety of the SQ formulation in this vulnerable population. This SQ program may lead to the development of a portable, easily administered formulation for use in high-volume exposures in the field and other resource-limited settings.

[0217] Patients randomized to the intervention arm will receive 15 mg of the compound by SC injection every 8 hours for 72 hours (9 doses). Patients randomized to the control arm will receive a matching placebo by SC injection every 8 hours for 72 hours (9 doses). Vital signs and clinical status will be closely monitored in the ICU setting for all enrolled patients during the treatment phase of the study. Blood pressure will be recorded hourly. If a patient exhibits worsening hypotension after study drug administration (a decrease in systolic blood pressure of more than 10 mmHg or an increase in norepinephrine infusion of more than 5 μg / min), subsequent doses will be withheld.

[0218] Plasma and urine samples from living and hospitalized enrolled patients will be collected at the following time points: baseline, 24 hours, 48 ​​hours, 72 hours, and 7 days. Samples will be stored at the enrollment site and then shipped to a central laboratory for measurement of Ang-2, Ang-1, IL-6, IL-8, and TNFα.

[0219] Study Procedure: After written informed consent for study participation, patients will be randomized to Compound 1 or matching placebo in a 1:1 ratio. Randomization will be completed using the REDCap electronic randomization tool and will be performed in permuted blocks of 2 and 4 stratified by enrollment site. Study group assignment will be blinded to patients, clinicians, and investigators. Study pharmacists at each site will be unblinded. Data for calculating oxygenation index, PaO2 / FiO2 ratio, acute lung injury score, and SOFA score will be collected at baseline (between randomization and the start of study drug administration), 24 hours, 48 ​​hours, 72 hours, and 7 days. The first dose of study medication (Compound 1 vs. placebo) will be administered as soon as possible after randomization and must begin within 24 hours of the patient first meeting the inclusion criteria. Patients will be evaluated daily for adverse events through discharge. Patients will be contacted on day 28 (either in person if still in the hospital or by phone if discharged). During the 28-day assessment, investigators will collect data on vital status, return visits, and recurrence of invasive mechanical ventilation.

[0220] The study will evaluate intermittent SC administration of Compound 1 compared with placebo in adults at risk for moderate-to-severe ARDS for improvement in lung function as measured by change in oxygenation index during the first 72 hours of treatment. The study design is a multicenter, two-arm, parallel-group, blinded RCT with a 1:1 allocation to receive Compound 1, 15 mg subcutaneously every 8 hours for 72 hours, or a matching placebo.

[0221] Primary Outcome: The primary outcome is the change in oxygenation index between baseline and 72 hours. Figure 12 shows exemplary oxygenation index data 72 hours after randomization from three ARDS network trials (ALTA, EDEN, OMEGA) involving patients with PaO2 / FiO2 ratios less than 300 mmHg. These data demonstrate that in the absence of effective treatment of pulmonary vascular leak, oxygenation index improved from baseline on days 1 and 2 but remained impaired through day 3.

[0222] Clinical developments during the course of ARDS treatment that could obscure the association between the intervention and the primary outcome (oxygenation index during 72 hours of drug delivery) include: death within 72 hours (competing risk of death); liberation from mechanical ventilation within 72 hours (competing risk of extubation); prone ventilation as a treatment for ARDS; extracorporeal membrane oxygenation (ECMO) as a treatment for ARDS; and epoprostenol as a treatment for ARDS. Each of these occurrences is prospectively tracked and addressed as follows: Patients who die before 72 hours can be assigned the worst (highest) oxygenation index they progressed to; and patients liberated from invasive mechanical ventilation before 72 hours can be assigned the best (lowest) oxygenation index. Because the study protocol includes criteria for the use of proning, ECMO, and epoprostenol, these treatments are used in a standardized manner in both the intervention and control arms. Sensitive analyses include patients who do not receive proning, ECMO, or epoprostenol treatment during the 72-hour intervention period.

[0223] Secondary outcomes included: (1) development of moderate-to-severe ARDS according to the Berlin criteria within 7 days; (2) change in oxygenation index between baseline and 7 days; (3) change in PaO2 / FiO2 ratio between baseline and 72 hours and between baseline and 7 days; (4) change in acute lung injury score between baseline and 72 hours and between baseline and 7 days; (5) change in SOFA score between baseline and 72 hours and between baseline and 7 days; and (6) up to day 28. (7) ICU-free days up to day 28; (8) mortality within 72 hours, 7 days, and 28 days; (9) freedom from mechanical ventilation within 72 hours, 7 days, and 28 days; (10) change in plasma Ang-2 concentration between baseline and 72 hours and between baseline and 7 days; (11) change in plasma Ang-2 / Ang-1 ratio between baseline and 72 hours and between baseline and 7 days; (12) change in plasma concentrations of markers of systemic inflammation, including IL-6, IL-8, and TNFα.

[0224] Blood pressure regulation will be evaluated in study participants. Previous safety data with SQ Compound 1 demonstrate the drug's rapid absorption and circulating C max The study demonstrated a mild and transient decrease in systolic blood pressure of approximately 5 mmHg associated with Tie-2 activation. This pharmacological effect of Compound 1 may indicate eNOS activation downstream of Tie-2. This study can be used to determine whether the antihypertensive effect is attenuated or well tolerated in patients with respiratory failure and even improves pulmonary function by attenuating hypoxia-induced pulmonary vasoconstriction. SC intermittent administration may facilitate use in forward positions in military settings and in a broader patient population outside the ICU in both military and civilian hospitals.

[0225] Post-hoc stratification analyses using Ang-2 and Ang-1 biomarkers will be performed to inform enrichment and monitoring for future trials. Samples can be collected for pharmacokinetics, pharmacodynamics, and further exploratory studies.

[0226] Statistical plan and data analysis The primary objective of this study is to determine whether compound 1 can safely reduce the likelihood of lung function deterioration in patients at risk for moderate to severe ARDS. The change in oxygenation index between baseline (pretreatment) and the end of the 72-hour treatment period (ΔOI) is the primary outcome measure, serving as a sensitive indicator of lung injury progression. The incidence of moderate to severe ARDS and mortality can be quantified to facilitate the design of subsequent phase 3 trials.

[0227] The initial analysis will characterize participants stratified by treatment group. Characteristics will include demographics, medical history, and clinical and laboratory data. Continuous data will be described using mean and standard deviation or median and range, as appropriate. Categorical data will be described using frequencies and percentages. Descriptive statistics will then be provided to document adherence to the treatment protocol and the ability to follow participants for primary and secondary endpoints. Safety will be assessed by recording relevant adverse events. Percentages will be presented with 95% confidence intervals.

[0228] Example 7 Testing of IV Compound 1 for the Treatment of Moderate to Severe ARDS An IV formulation of Compound 1 will be developed and used to conduct human studies of safety, tolerability, and pharmacokinetics. An IV Compound 1 formulation suitable for clinical trials will be used to establish pharmacokinetics and maximum tolerated dose in healthy volunteers and to examine safety and tolerability.

[0229] Dosing schedule: Dosing is 15 mg of Compound 1 IV three times daily (TID) every 8 hours for 3 days (72 hours).

[0230] The safety of IV Compound 1 will be evaluated in the target population, e.g., patients with moderate to severe ARDS. The efficacy of IV Compound 1 will be evaluated based on improved oxygenation levels in this target population. Post-hoc stratified analyses using Ang-2 and Ang-1 biomarkers can be performed to inform enrichment and monitoring for future trials. Samples can be collected for pharmacokinetics, pharmacodynamics, and further exploratory studies.

[0231] Subsequently, a multicenter, placebo-controlled, double-blind, randomized clinical trial will be initiated to evaluate treatment for moderate to severe ARDS as defined by the Berlin criteria. This patient population may be more unstable than patients with acute respiratory failure without moderate to severe ARDS. In this setting, IV infusion may allow greater flexibility and control in administration at rates that may help optimize safety in this population.

[0232] A prototype formulation for IV administration was developed and a preliminary non-GLP nonclinical dose-ranging study, including pharmacokinetic (PK) evaluation, was conducted. Initial PK analysis demonstrated an ideal PK profile for IV administration, with plasma concentrations during the 2-hour infusion rapidly reaching steady state after initiation and rapidly declining after cessation. This profile is consistent with the rapid clearance of Compound 1 observed in previous nonclinical PK studies using IV and SC injections. This PK profile for IV infusion may allow for rapid adjustment of exposure up or down in critically ill and hemodynamically unstable patients in an ICU setting. Furthermore, the initial nonclinical dose-ranging study indicates that exposures exceeding 10-fold the intended clinical exposure may be well tolerated in the proposed pivotal nonclinical safety study.

[0233] Listed below are in vitro, PK, and toxicology studies related to the 3-day IV infusion administration of Compound 1 in a human clinical trial, administered as a 1-2 hour IV infusion TID for 3 days: Compound 1 is formulated into a 10% HPβCD formulation at a dose of ≦30 mg / kg / dose BID (60 mg / kg / day). In vitro assessment of blood hemolysis, aggregation, and platelet activation. A non-GLP 7-day TID IV infusion dose-ranging study in rats or dogs to characterize the PK and tolerability of Compound 1 in the HPβCD formulation administered by IV infusion (2 hours) TID over a range of doses up to the maximum tolerated daily dose (60 mg / kg / day) observed in a previous IV infusion tolerability study. A rat or dog GLP 14-day TID IV infusion toxicity study was conducted to characterize the toxicity and toxicokinetics of Compound 1 in a 10% HPβCD vehicle formulation. Vehicle and Compound 1 formulations were administered by IV infusion (2 hours) TID at a Compound 1 dose informed by a non-GLP 7-day tolerability study. The systemic safety of Compound 1 in a 10% HPβCD formulation administered by SC injection is outlined in Example 6. Thus, single-species toxicity studies can bridge the safety of different administration routes and rigorously evaluate the effects of IV infusion exposure on previously identified target organs and local injection sites.

[0234] Initial safety testing Study Design: A single-center, double-blind, placebo-controlled, three-cohort, ascending-dose study in healthy volunteers will be conducted to determine the safety, tolerability, and PK of up to three single ascending doses of Compound 1 delivered as a single 2-hour continuous infusion.

[0235] Population: Healthy volunteers

[0236] Key inclusion criteria: The study included a 2 ~32.0kg / m 2 Healthy, non-smoking, male and female subjects aged 18-55 years (inclusive) with a body mass index (BMI) between 0.01 and 0.05 (inclusive) may be enrolled. All subjects may be required to sign an informed consent form.

[0237] Important exclusion criteria: pregnant women, subjects who refuse to use necessary contraceptive methods for the specified time frame, subjects with a history of symptomatic orthostatic hypotension, vasovagal syndrome, syncope or near-syncope within 1 year prior to screening, and subjects with a diastolic blood pressure <60mmHg or systolic blood pressure <105mmHg at screening.

[0238] Intervention group: Three single ascending doses of Compound 1 delivered by IV infusion over 2 hours. Groups may consist of eight healthy volunteers randomized 3:1 to Compound 1 or placebo. Suggested doses are 15 mg, 30 mg, and 45 mg. However, these doses may be modified based on tolerability / safety or PK in nonclinical studies or tolerability or PK in previous dose cohorts.

[0239] Test Procedure: The key test procedures are outlined in the following steps: 1. Enroll subjects using protocol-defined inclusion / exclusion criteria, including medical and medication history, vital signs, and laboratory analyses to assess health status. 2. Subjects resided within the clinical facility from the evening before dose administration until completion of final study procedures (at least 24 hours total). 3. Administration of IV infusion doses according to the randomization schedule. 4. Collection of PK samples at specific times during and after dose administration. 5. Collection of safety parameters including vital signs, laboratory samples, and AE monitoring. 6. Subject discharge after completion of all study procedures.

[0240] Primary outcome: Safety, including adverse events, vital signs, and laboratory assessments.

[0241] Secondary outcomes include pharmacokinetic parameters of Compound 1 determined from individual subject plasma concentration-time profiles. Key parameters are described in the analysis plan below.

[0242] Summary: A 60-patient randomized controlled trial will be developed to evaluate the safety and efficacy of Compound 1 administered by IV infusion to adults with moderate to severe ARDS to improve lung function. This treatment trial complements the prevention trial outlined in Example 6 by extending the trial data to an IV formulation of Compound 1 and a more severely affected patient population with established moderate to severe ARDS. As described in Example 6, SC Compound 1 can be evaluated for preventing severe lung injury in patients at high risk for decompensation of pulmonary function. Additionally, the IV formulation of Compound 1 will be evaluated for the treatment of established moderate to severe ARDS.

[0243] Dosage Form: As in Example 6, the active dosage form is Compound 1 solubilized at 20 mg / mL in 10% HPβCD and presented as a lyophilized product in a vial. The product is aseptically reconstituted on-site with a sterile solution containing 5% dextrose (D5 or equivalent) to a Compound 1 concentration of 20 mg / mL for IV infusion. The dosage form allows for dose escalation (e.g., 10 mg, 30 mg, and 45 mg) based on the amount of reconstituted 20 mg / mL formulation material injected. The placebo dosage form is a vial containing a lyophilized aliquot of 10% HPβCD equal to the amount of lyophilized active product. The placebo is aseptically reconstituted on-site with a sterile solution containing 5% dextrose (D5 or equivalent) to the original 10% HPβCD concentration for IV infusion.

[0244] Rationale for IV Administration: The rationale for IV infusion in this treatment trial includes maintaining consistent serum levels in patients who are potentially most vulnerable to toxicity at high serum levels and loss of efficacy at lower serum levels.

[0245] Study Design: A multicenter, two-arm, parallel-group, blinded RCT with a 1:1 allocation of Compound 1 or placebo (9 doses) administered by IV infusion every 8 hours for 72 hours.

[0246] Population: Adults receiving invasive mechanical ventilation with moderate to severe ARDS according to the Berlin criteria. Patients can be enrolled within 48 hours of meeting the criteria for moderate to severe ARDS. Eligibility criteria are listed below.

[0247] Inclusion Criteria: 1. Age 18 or older 2. Invasive mechanical ventilation, defined as positive pressure ventilation via endotracheal tube or tracheostomy 3. Bilateral pulmonary opacities on chest radiograph or computed tomography not adequately explained by pleural effusion, lobar / pulmonary collapse, or nodules 4. Respiratory failure not adequately explained by heart failure or fluid overload; objective evaluation (e.g., echocardiography) to rule out hydrostatic edema is required if none of the following ARDS risk factors have occurred in the past 7 days: pneumonia, aspiration of gastric contents, inhalation injury, drowning, non-pulmonary sepsis, trauma, pancreatitis, burns, non-cardiogenic shock, drug overdose, and multiple blood product transfusions. 5. PaO2 / FiO2 ratio ≤ 200 mmHg with PEEP ≥ 5 cmH2O. A PaO2 / FiO2 ratio ≤ 200 mmHg must be confirmed within 4 hours of initiating study medication.

[0248] Exclusion criteria: 1. Lack of informed consent for clinical trial participation 2. Unable to start study medication within 48 hours of meeting the inclusion criteria 3. Pregnant 4. Breastfeeding 5. Prisoner 6. Norepinephrine infusion ≥ 50 μg / min (or equivalent dose of an alternative vasoconstrictor) 7. Lung transplant recipients 8. Cystic fibrosis 9. WHO class III or IV pulmonary hypertension 10. Currently undergoing in vitro treatment 11. Chronic respiratory failure, defined as PaCO2 > 60mmHg on home oxygen or outpatient visit 12. Pre-hospital chronic invasive mechanical ventilation 13. Severe chronic liver disease defined as a Child-Pugh score ≥ 12 14. Decision to withhold life-sustaining treatment (decision to withhold CPR only in the case of cardiac arrest does not meet this exclusion criterion) 15. Critically ill patients who, in the opinion of the treating clinical team, are not expected to survive for 24 hours 16. Clinicians are unwilling to utilize low tidal volumes of approximately 6 mL / kg ideal body weight. 17. Enrollment in another IND-supported study within the past 30 days 18. Previous allergic reaction to Compound 1 19. Previous enrollment in this study or any previous Compound 1 prevention study

[0249] Intervention Group: Patients randomized to the intervention arm will receive Compound 1 via IV infusion for 72 hours. Dosing will be determined from the results described in Example 6. Dosing will occur every 8 hours (9 doses over 72 hours). Patients randomized to the control arm will receive a placebo solution (plasmalyte-A) via IV infusion. Vital signs and clinical status will be closely monitored in an ICU environment during the procedure. Blood pressure will be recorded every hour. If patients exhibit worsening hypotension after study drug administration (a decrease in systolic blood pressure of more than 10 mmHg or an increase in norepinephrine infusion of more than 5 μg / min), subsequent doses may be withheld.

[0250] Biological sample collection: Plasma and urine samples will be collected from living and hospitalized patients at the following time points: baseline, 24 hours, 48 ​​hours, 72 hours, and 7 days. Samples will be stored at the enrollment site and then shipped to a central laboratory for measurement of Ang-1, Ang-2, IL-6, IL-8, TNFα, soluble Tie2, CRP, and D-dimer.

[0251] Study Procedures: After written informed consent for study participation, patients will be randomized 1:1 to IV Compound 1 or matching placebo. Randomization will be completed using the REDCap electronic randomization tool and will be performed in permuted blocks of 2 and 4 stratified by enrollment site. Study group assignment will be blinded to patients, clinicians, and investigators. A study pharmacist at each site will be able to unblind. Data for calculating oxygenation index, PaO2 / FiO2 ratio, acute lung injury score, and SOFA score will be collected at baseline (between randomization and the start of study drug administration), 24 hours, 48 ​​hours, 72 hours, and 7 days. Administration of the first dose of study medication (Compound 1 vs. placebo) should begin as soon as possible after randomization, within 48 hours after the patient first meets inclusion criteria, and within 4 hours of confirming a PaO2 / FiO2 ratio of <200 mmHg. Patients will be evaluated daily for adverse events through discharge. Patients will be contacted on day 28 (either in person if still in the hospital or by phone if discharged). During the 28-day assessment, investigators will collect data on vital status, return visits, and recurrence of invasive mechanical ventilation.

[0252] Outcomes: Similar to the prevention study described in Example 6, the primary outcome of this treatment study is the change in oxygenation index between baseline and 72 hours. Secondary outcomes included: (1) change in oxygenation index between baseline and 7 days; (2) change in PaO2 / FiO2 ratio between baseline and 72 hours and between baseline and 7 days; (3) change in acute lung injury score between baseline and 72 hours and between baseline and 7 days; (4) change in SOFA score between baseline and 72 hours and between baseline and 7 days; (5) duration of ventilator freedom through day 28; (6) number of ICU-free days through day 28; (7) mortality within 72 hours, 7 days, and 28 days; (8) freedom from mechanical ventilation within 72 hours, 7 days, and 28 days; (9) change in plasma Ang-2 concentration between baseline and 72 hours and between baseline and 7 days; (10) change in plasma Ang-2 / Ang-1 ratio between baseline and 72 hours and between baseline and 7 days; and (11) change in plasma concentrations of markers of systemic inflammation, including IL-6, IL-8, and TNFα.

[0253] Analytical approach: The interaction between biomarker levels and treatment (predictive enrichment), change in biomarkers over time (response to treatment), and the relationship between initial and final biomarker levels (prognostic accuracy) are each modeled. Each biomarker domain—Ang-1, Ang-2, and the Ang-2 / Ang-1 ratio—is measured individually as part of a more complex mathematical model that adjusts for factors including demographics, comorbidities, disease type, and severity. Multimarker models are examined to determine whether the model retains enrichment, response to treatment, or prognostic potential.

[0254] Further biosample analyses will be performed (a) to compare angiopoietin measurements with cytokines associated with ARDS pathogenesis: TNFα, IL-1, and IL-6; (b) to compare angiopoietin measurements with a larger set of endothelial markers also associated with critical illness: soluble ectodomain of E-selectin (sE-selectin), sVCAM-1, and sVE-cadherin, which are associated with vascular manifestations of critical illness; (c) to apply SomaScan proteomics to identify novel protein signatures associated with Compound 1 responsiveness (a technology successfully deployed in the ICU by our team); and (d) to perform pharmacokinetic analyses of SQ and IV Compound 1 in target populations.

[0255] Analysis plan Tables, lists, and descriptive statistics will be used to evaluate safety data, including clinical chemistry / hematology and adverse events. Using PK concentration-time data, PK parameters can be determined using non-compartmental methods and can be listed for individual subjects. Actual dosing and sampling times can be used for all calculations. Reasons for excluding any samples from the analysis can be provided. Individual subject and mean concentration-time data can be tabulated and presented graphically. The following PK parameters can be determined and summarized for each treatment using descriptive statistics: C max -Concentration at end of infusion AUC last - Area under the curve from time 0 to the last quantifiable concentration AUC inf - Area under the curve from time 0 to infinity CL-Clearance ·V d -Volume of distribution

[0256] Dose-proportionality analysis can be addressed in terms of point estimates of statistical model parameters (slope) and CIs. The power model has the following general formula: y=β0×doseβ1 where y is the dependent variable, e.g., AUC and Cmax The exponents in the model can be estimated by regressing the natural log-transformed PK parameters against the natural log-transformed dose. logy=logβ+β1log(dose)

[0257] Furthermore, the relationship between changes in hemodynamic variables (BP and HR) and exposure parameters can be investigated using appropriate analyses.

[0258] Analysis plan for the treatment study: The purpose of this study is to determine whether Compound 1 can improve lung function in patients with moderate to severe ARDS. As in the prevention study (Example 6), the primary outcome measure is the change in oxygenation index (ΔOI) between baseline and 72 hours. This measure is a sensitive indicator of improvement in lung function in this treatment study (Example 7). Analysis can then proceed as described above, starting with descriptive statistics, followed by safety characterization, and finally analysis of the primary physiological endpoint (oxygenation index).

[0259] Example 8 Testing of SQ Compound 1 for the Treatment of Moderate to Severe COVID-19 A phase 2, randomized, double-blind, placebo-controlled, multicenter study can be conducted to evaluate the safety and efficacy of Compound 1 at doses of 15 mg or 30 mg three times daily (q8 h) for up to 7 days in hospitalized subjects with moderate to severe COVID-19. This study can examine the effects of Compound 1 on biomarkers of inflammation and coagulation disorders (e.g., CRP and D-dimer) in the plasma of subjects with moderate to severe COVID-19. This study can also examine the effects of Compound 1 on biomarkers of vascular leakage and inflammation (e.g., Ang-2, IL-6, IL-8, TNFα, and HMGB-1) in the plasma of subjects with moderate to severe COVID-19.

[0260] Primary efficacy outcomes at day 7 or earlier discharge may include: 1. Mean change from baseline and proportion of subjects with a clinical status ≥ 7 at day 7 on a COVID-19 ordinal scale consisting of the following categories: 1 is asymptomatic, 2 is "symptomatic; independent" 3 is "symptomatic; needs assistance" 4 is "hospitalized; no oxygen treatment" 5 is "Hospitalization; oxygen via mask or nasal cannula" 6 is "non-invasive ventilation or high-flow oxygen" 7 is "intubation and mechanical ventilation, SpO2:FiO2 ratio ≥ 200" 8 is "mechanical ventilation, SpO2:FiO2 ratio < 200 or vasopressors" 9 is "mechanical ventilation, SpO2:FiO2 ratio < 200 and vasopressors, dialysis or ECMO" 10 is "death." 2. Days of survival and ventilator weaning; and 3. Change from baseline in SpO2:FiO2 ratio on days 3 and 7.

[0261] Secondary outcomes may include: 1. Survival and ventilator weaning (or discharge) at 28 days 2. Mortality rate 3. Length of hospital stay 4. Percentage of subjects discharged without transition to mechanical ventilation before day 7 5. Changes in clinical status on the COVID-19 ordinal scale up to day 7 (or hospital discharge) 6. Number of subjects in each category on the COVID-19 ranking scale at day 7 7. Mean change from baseline in clinical status on the COVID-19 ordinal scale at day 7 8. Proportion of subjects with an improvement of ≥2 categories on the COVID-19 ordinal scale at Day 7 9. Proportion of subjects with a worsening of ≥2 categories on the COVID-19 ordinal scale at Day 7 10. Number of subjects with any serious adverse events 11. Number of subjects with any treatment-emergent adverse event 12. Changes from baseline in CRP and D-dimer

[0262] Exploratory endpoints include changes from baseline in systemic biomarkers of vascular leakage and inflammation (Ang-1, Ang-2, IL-6, IL-8, TNFα, and HMGB-1).

[0263] The study population will be subjects aged at least 18-75 years with documented COVID-19 infection who are hospitalized and receiving standard of care for SARS-CoV-2. Eligible subjects must require supplemental oxygen at screening; subjects requiring mechanical ventilation at screening will not be eligible.

[0264] This study will evaluate the safety and efficacy of subcutaneous Compound 1 administered at either 15 mg or 30 mg three times daily (TID; q8) for up to 7 days in subjects with moderate to severe COVID-19 receiving standard of care. At screening, subjects must require supplemental oxygen. Subjects requiring mechanical ventilation at screening are ineligible. After consent for study participation is obtained and eligibility is determined, subjects will be randomized in a 1:1:1 ratio to one of three treatment arms (15 mg TID Compound 1, 30 mg TID Compound 1, or placebo TID) according to a computer-generated randomization list, stratified by center. Treatment group assignment will be blinded to patients, clinicians, and investigators. Subjects will receive Compound 1 administered intraperitoneally TID for 7 days or until hospital discharge (or death), whichever occurs first. In addition to routine clinical monitoring and laboratory evaluations that are part of standard treatment, the following may be performed: supine BP and HR may be assessed at 30 and 90 minutes before and after the first dose of study drug on Day 1; data on the subject's oxygen support requirements and adverse events may be collected through Day 7; clinical status may be assessed daily through Day 28 (or discharge); blood sampling for biomarkers related to coagulation, inflammation, and vascular leakage (CRP and D-dimer are required; biomarkers as needed include Ang-1, Ang-2, IL-6, IL-8, and TNFα) may be performed on Days 1, 3, and 7, and once on Day ≥ 14 for subjects who remain hospitalized. For these subjects, blood sampling for biomarkers may be performed on Day 28 or the day of discharge, whichever occurs first. The safety review team may conduct a masked review of available safety data after the first 15 subjects have completed treatment (Day 7), and then in 25% increments of subjects who have completed treatment (Day 7). The study design is summarized in Figure 13.

[0265] Approximately 180 subjects may be randomized (60 per treatment group) from approximately 10 sites across the U.S. Participation may last approximately 29 days: screening (up to approximately day 1), treatment period (7 days), and post-treatment observation on day 28.

[0266] Inclusion Criteria: 1. Must be capable of understanding and providing informed consent 2. Men and non-pregnant women aged 18–75 years (inclusive) 3. Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any specimen and documented by either: a positive PCR in a specimen collected less than 72 hours before randomization; or a positive PCR in a specimen collected more than 72 hours before randomization with documented inability to obtain a repeat specimen (e.g., lack of testing supplies, limited testing capacity, results taking more than 24 hours, etc.) AND progressive illness suggestive of ongoing SARS-CoV-2 infection. 4.Currently hospitalized and receiving standard of care (SOC) for COVID-19 5. Requires supplemental oxygen 6. SpO2:FiO2 ratio greater than 100 and less than 300 D-dimer greater than 7,500 ng / mL

[0267] Exclusion criteria: 1. Unable to start study medication within 12 hours of meeting the inclusion criteria 2. Women of childbearing potential who are unable or unwilling to use birth control until day 28 or who are unable or unwilling to abstain from breastfeeding 3. Systolic blood pressure less than 100 mmHg 4. Mechanically ventilated or receiving ECMO 5. Shock or needing vasopressor support 6. Receiving inhaled nitric oxide or epoprostenol or similar intervention 7. Alanine transaminase (ALT) or aspartate transaminase (AST) >3 times the upper limit of normal 8. Estimated glomerular filtration rate (eGFR) less than 30 mL / min or receiving hemodialysis or hemofiltration 9. Critically ill patients who, in the opinion of the treating clinical team, are not expected to survive for 24 hours 10. Any serious medical condition (e.g., active malignancy during chemotherapy, post-organ transplant, end-stage congestive heart failure) or unlikely to respond to treatment 11. Decisions to withhold life-sustaining treatment (e.g., decisions to withhold CPR only in the case of cardiac arrest do not meet this exclusion criterion) 12. Concurrent treatment with other agents with actual or potential direct-acting antiviral activity against SARS-CoV-2 is prohibited within 24 hours prior to study drug administration. 13. Participation in another research study during this study until the final visit (Day 28) 14. Previous enrollment in this study

[0268] Regarding the primary outcome:

[0269] Clinical status on day 7 · Change from baseline: 60 subjects per group provides 80% power to demonstrate superiority of active over placebo, assuming a true mean difference of 1.4, an SD of 3.0, and a two-sided α = 0.10. Proportion of subjects with clinical status ≥ 7 (intubated): 60 subjects per group provides 80% power to demonstrate the superiority of active over placebo in the proportion of intubated subjects, assuming true rates of 0.098 and 0.30 for active and placebo, respectively, and a two-sided α = 0.05.

[0270] Days Survival and Ventilator Weaning: 60 subjects per group provides 80% power to demonstrate superiority of active over placebo in mean days ventilator weaning and survival, assuming a true mean difference of 1.2 days, an SD of 2.25, and a two-sided α=0.05.

[0271] SpO2:FiO2 ratio: 60 subjects per group provides 80% power to demonstrate superiority of active over placebo in mean CFB P / F ratio, assuming a true mean difference of 41.3, an SD of 80, and a two-sided α=0.05.

[0272] Test Drug: Ready-to-Administer Sterile Solution of Compound 1 for Subcutaneous Injection: 20 mg / mL sterile solution provided ready to administer - delivers 15 mg of Compound 1 in a 0.75 mL dose 40 mg / mL sterile solution provided ready to administer - delivers 30 mg of Compound 1 in a 0.75 mL dose

[0273] Placebo of a ready-to-administer sterile solution of Compound 1 for subcutaneous injection: Compound 1 placebo (sterile saline) will be procured locally for immediate administration. A 0.75 mL dose of placebo solution will be administered. Blood volume collected: 4 x 6 mL biomarker samples collected at screening / days 1, 3, and 7, and once post-procedure for subjects remaining hospitalized after day 14. Total blood volume collected as specified per protocol, including biomarkers as needed: up to 24 mL per subject.

[0274] Table 4 summarizes the protocol-specific alternative schedules of assessments. [Table 4]

[0275] Example 9 Pharmaceutical Formulations of Compound 1 Compound 1, as a sodium salt, can be formulated in a hydroxypropyl betadex (hydroxypropyl-β-cyclodextrin; HPβCD) solution. The solubility of Compound 1 in water is approximately 15 mg / mL. A solution of 10% HPβCD can improve the solubility of Compound 1 to approximately 48 mg / mL. A concentration of 20 mg / mL of Compound 1 in 10% HPβCD can maintain a stable formulation.

[0276] Pharmaceutical compositions of Compound 1 are formulated and lyophilized as described below. Compositions can be prepared using 20 mg / mL of Compound 1 in a vehicle containing 10.0% w / v (100 mg / mL) HPβCD. Once in solution, aliquots are placed in 20 mL vials and lyophilized. The lyophilized Compound 1 + HPβCD is reconstituted using commercially available sterile fluids (i.e., sterile D5 5% dextrose in sterile water for injection) to adjust tonicity. A volume of diluent is added to obtain a 20 mg / mL solution of Compound 1. The vials are fitted with rubber septum-design caps and crimp seals, allowing for aseptic reconstitution and subsequent preparation and administration of SC or IV infusion doses using a readily available 1 mL sterile staked-needle syringe fitted with a 27-gauge to 29-gauge 1 / 2-inch (13 mm) needle or standard injection equipment. The volume of 20 mg / mL Compound 1 removed from the vial determines the dose administered. The placebo is an equivalent volume of 10% HPβCD (matching the active vial fill volume), which is lyophilized and sealed in the same manner. Reconstitution and dosing are performed as specified for the active substance.

[0277] The formulation is Compound 1 at 20 mg / mL in a vehicle containing 10.0% w / v (100 mg / mL) HPβCD and 2.5% w / v (25 mg / mL) dextrose in sterile water for injection adjusted to pH 5-8.5 with hydrochloric acid or sodium hydroxide.

[0278] The dosing solution will be supplied in 0.75 mL doses as a pre-filled syringe containing the following primary packaging elements: Syringe: 1 mL long, colorless, Type 1 borosilicate glass syringe fitted with a 27-gauge 1 / 2-inch (13 mm) needle; Plunger: Gray FluroTec® plunger that fits the syringe; and Plunger Rod: Polypropylene plunger rod that fits plungers and syringes.

[0279] Example 10 Combination of Tie-2 Activators with Remdesivir for the Treatment of COVID-19 The Tie-2 activators described herein can be used in combination with remdesivir for the treatment of COVID-19, ARDS, or other respiratory failure conditions. For example, Compound 1 and remdesivir can be co-formulated and administered simultaneously to a subject with COVID-19 as a single IV infusion. In some embodiments, Compound 1 and remdesivir can be administered sequentially in separate dosage forms. Compound 1 can be formulated with, for example, HPβCD, as described herein. Remdesivir can be formulated with sulfo-butyl ether cyclodextrin. Embodiment

[0280] Embodiment 1. A method of treating a pulmonary condition in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a Tie-2 activator, said administration increasing an oxygenation index of said subject by about 1 to about 20 compared to the absence of administration.

[0281] Embodiment 2. The method of embodiment 1, wherein said administering increases the oxygenation index of said subject by about 1 to about 10.

[0282] Embodiment 3. The method of embodiment 1, wherein said administering increases the oxygenation index of said subject by about 1 to about 20 within 72 hours after administration.

[0283] Embodiment 4. The method of embodiment 1, wherein said administering increases the oxygenation index of said subject by about 1 to about 20 within 48 hours after administration.

[0284] Embodiment 5. The method of embodiment 1, wherein said administering increases the oxygenation index of said subject by about 1 to about 20 within 24 hours after administration.

[0285] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the administration reduces the mean airway pressure required to be applied to the subject by a ventilator by about 1 cmH2O to about 30 cmH2O compared to not administering.

[0286] Embodiment 7. The method of any one of embodiments 1 to 5, wherein the administration reduces the mean airway pressure required to be applied to the subject by a ventilator by about 1 cmH2O to about 30 cmH2O within 72 hours after administration.

[0287] Embodiment 8. The method of any one of embodiments 1 to 5, wherein the administration reduces the mean airway pressure required to be applied to the subject by a ventilator by about 1 cmH2O to about 30 cmH2O within 48 hours after administration.

[0288] Embodiment 9. The method of any one of embodiments 1 to 5, wherein the administration reduces the mean airway pressure required to be applied to the subject by a ventilator by about 1 cmH2O to about 30 cmH2O within 24 hours after administration.

[0289] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the administration increases the PaO2 / FiO2 ratio in the subject by about 1 to about 100 compared to the absence of administration.

[0290] Embodiment 11. The method of any one of embodiments 1 to 9, wherein said administering increases the subject's PaO2 / FiO2 ratio by about 1 to about 100 within 72 hours after administration.

[0291] Embodiment 12. The method of any one of embodiments 1 to 9, wherein the administration increases the subject's PaO2 / FiO2 ratio by about 1 to about 100 within 48 hours after administration.

[0292] Embodiment 13. The method of any one of embodiments 1 to 9, wherein the administration increases the subject's PaO2 / FiO2 ratio by about 1 to about 100 within 24 hours after administration.

[0293] Embodiment 14 The method of any one of embodiments 1 to 13, wherein the administration reduces the subject's acute lung injury score by 1 to 4 compared to no administration.

[0294] Embodiment 15. The method of any one of embodiments 1 to 13, wherein the administration reduces the subject's acute lung injury score by 1 to 4 within 72 hours of administration.

[0295] Embodiment 16 The method of any one of embodiments 1 to 13, wherein the administration reduces the subject's acute lung injury score by 1 to 4 within 48 hours of administration.

[0296] Embodiment 17 The method of any one of embodiments 1 to 13, wherein the administration reduces the subject's acute lung injury score by 1 to 4 within 24 hours of administration.

[0297] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 compared to no administration.

[0298] Embodiment 19. The method of any one of embodiments 1 to 17, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 within 72 hours after administration.

[0299] Embodiment 20 The method of any one of embodiments 1 to 17, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 within 48 hours after administration.

[0300] Embodiment 21 The method of any one of embodiments 1 to 17, wherein the administration modulates the Sequential Organ Failure Assessment (SOFA) score in the subject by 1 to 24 within 24 hours after administration.

[0301] Embodiment 22 The method of any one of embodiments 1 to 21, wherein the administering modulates a change in the level of plasma Ang-2 concentration in the subject after administration.

[0302] Embodiment 23 The method of any one of embodiments 1 to 22, wherein the administering modulates a change in the level of plasma Ang-2 / Ang-1 ratio in the subject after administration.

[0303] Embodiment 24 The method of any one of embodiments 1 to 23, wherein the administration modulates a change in the level of plasma IL-6 concentration in the subject after administration.

[0304] Embodiment 25 The method of any one of embodiments 1 to 24, wherein the administration modulates a change in the level of plasma IL-8 concentration in the subject after administration.

[0305] Embodiment 26 The method of any one of embodiments 1 to 25, wherein the administering modulates a change in the level of plasma TNFα concentration in the subject after administration.

[0306] Embodiment 27 The method of any one of embodiments 1 to 26, wherein the administration modulates a change in the level of plasma D-dimer concentration in the subject after administration.

[0307] Embodiment 28 The method of any one of embodiments 1 to 27, wherein the administering modulates a change in the level of plasma CRP concentration in the subject after administration.

[0308] Embodiment 29 The method of any one of embodiments 1 to 28, wherein the administration reduces systemic inflammation in the subject after administration.

[0309] Embodiment 30 The method of any one of embodiments 1 to 29, wherein the administering activates endothelial nitric oxide synthase (eNOS) in the subject after administration.

[0310] Embodiment 31 The method of any one of embodiments 1 to 30, wherein the administration increases the production of nitric oxide (NO) in the subject after administration.

[0311] Embodiment 32 The method of any one of embodiments 1 to 31, wherein the Tie-2 activator is administered to the subject in a unit dosage form.

[0312] Embodiment 33 The method of embodiment 32, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

[0313] Embodiment 34 The method of embodiment 33, wherein the pharmaceutically acceptable excipient is a cyclodextrin.

[0314] Embodiment 35 The method of embodiment 33, wherein the pharmaceutically acceptable excipient is HPβCD.

[0315] Embodiment 36 The method of embodiment 33, wherein the pharmaceutically acceptable excipient is D-mannitol.

[0316] Embodiment 37 The method of embodiment 33, wherein the pharmaceutically acceptable excipient is dextrose.

[0317] Embodiment 38 The method of embodiment 32, wherein the unit dosage form further comprises HPβCD in an amount of about 10% by weight of the unit dosage form.

[0318] Embodiment 39 The method of embodiment 32, wherein the unit dosage form further comprises D-mannitol in an amount of about 4.5% by weight of the unit dosage form.

[0319] Embodiment 40 The method of embodiment 32, wherein the unit dosage form further comprises dextrose in an amount of about 5% by weight of the unit dosage form.

[0320] Embodiment 41 The method of any one of embodiments 1 to 40, wherein the administration is by continuous infusion for 1 hour.

[0321] Embodiment 42 The method of any one of embodiments 1 to 40, wherein the administration is by continuous infusion for 2 hours.

[0322] Embodiment 43 The method of any one of embodiments 1 to 40, wherein the administration is by continuous infusion for 2 to 2.5 hours.

[0323] Embodiment 44 The method of any one of embodiments 1 to 43, wherein the administration is twice daily.

[0324] Embodiment 45 The method of any one of embodiments 1 to 43, wherein the administration is three times daily.

[0325] Embodiment 46 The method of any one of embodiments 1 to 43, wherein the administration is three times daily for seven days.

[0326] Embodiment 47 The method of any one of embodiments 1 to 43, wherein the administration is every 8 hours for 72 hours.

[0327] Embodiment 48. The method of any one of embodiments 1 to 47, wherein the therapeutically effective amount is from about 0.1 mg / kg to about 30 mg / kg of the subject per dose.

[0328] Embodiment 49. The method of any one of embodiments 1 to 47, wherein the therapeutically effective amount is from about 0.1 mg per kg to about 20 mg per kg of the subject per dose.

[0329] Embodiment 50 The method of any one of embodiments 1 to 49, wherein the therapeutically effective amount is about 750 ng·hr / mL / day.

[0330] Embodiment 51 The method of any one of embodiments 1 to 50, wherein the therapeutically effective amount is about 510.2 ng·hr / mL / day.

[0331] Embodiment 52 The method of any one of embodiments 1 to 51, wherein the therapeutically effective amount of the Tie-2 activator is about 10 mg.

[0332] Embodiment 53 The method of any one of embodiments 1 to 51, wherein the therapeutically effective amount of the Tie-2 activator is about 15 mg.

[0333] Embodiment 54 The method of any one of embodiments 1 to 51, wherein the therapeutically effective amount of the Tie-2 activator is about 30 mg.

[0334] Embodiment 55 The method of any one of embodiments 1 to 51, wherein the therapeutically effective amount of the Tie-2 activator is about 45 mg.

[0335] Embodiment 56 The method of any one of embodiments 1 to 55, wherein the Tie-2 activator is administered in a formulation having a concentration of about 20 mg / mL.

[0336] Embodiment 57 The method of any one of embodiments 1 to 56, wherein the administration is subcutaneous.

[0337] Embodiment 58 The method of any one of embodiments 1 to 56, wherein the administration is intravenous.

[0338] Embodiment 59 The method of any one of embodiments 1 to 56, wherein the administration is by bolus intravenous injection.

[0339] Embodiment 60 The method of any one of embodiments 1 to 56, wherein the administration is by continuous intravenous infusion.

[0340] Embodiment 61 The method of any one of embodiments 1 to 60, wherein the pulmonary condition is acute lung injury.

[0341] Embodiment 62 The method of any one of embodiments 1 to 60, wherein the pulmonary condition is acute hypoxemic respiratory failure.

[0342] Embodiment 63 The method of any one of embodiments 1 to 60, wherein the pulmonary condition is acute respiratory distress syndrome (ARDS).

[0343] Embodiment 64 The method of embodiment 63, wherein the ARDS is mild ARDS.

[0344] Embodiment 65 The method of embodiment 63, wherein the ARDS is moderate ARDS.

[0345] Embodiment 66 The method of embodiment 63, wherein the ARDS is severe ARDS.

[0346] Embodiment 67. The method of any one of embodiments 1 to 66, wherein the pulmonary condition is COVID-19.

[0347] Embodiment 68 The method of any one of embodiments 1 to 67, wherein the subject has a PaO2 / FiO2 ratio of less than about 300 as determined from the subject's arterial blood.

[0348] Embodiment 69. The method of any one of embodiments 1 to 67, wherein the subject has a PaO2 / FiO2 ratio of about 200 to about 300 as determined from the subject's arterial blood.

[0349] Embodiment 70. The method of any one of embodiments 1 to 67, wherein the subject has a PaO2 / FiO2 ratio of about 100 to about 200 as determined from the subject's arterial blood.

[0350] Embodiment 71 The method of any one of embodiments 1 to 67, wherein the subject has a PaO2 / FiO2 ratio of less than about 100 as determined from the subject's arterial blood.

[0351] Embodiment 72 The method of any one of embodiments 1 to 71, wherein the subject has bilateral pulmonary infiltrates as determined by chest x-ray.

[0352] Embodiment 73 The method of any one of embodiments 1 to 71, wherein the subject does not have bilateral pulmonary infiltrates as determined by chest x-ray.

[0353] Embodiment 74 The method of any one of embodiments 1 to 73, wherein the subject has a viral infection.

[0354] Embodiment 75 The method of embodiment 72, wherein the viral infection is a coronavirus infection.

[0355] Embodiment 76 The method of embodiment 72, wherein the viral infection is SARS-CoV-2.

[0356] Embodiment 77 The method of any one of embodiments 1 to 76, wherein the subject has hypertension.

[0357] Embodiment 78 The method of any one of embodiments 1 to 77, wherein the subject has pulmonary hypertension.

[0358] Embodiment 79 The method of any one of embodiments 1 to 78, wherein the subject is a human.

[0359] Embodiment 80. The Tie-2 activator is a compound of the formula [ka] or a pharmaceutically acceptable salt thereof, wherein: - Aryl 1 is a substituted or unsubstituted aryl group; - Aryl 2 is a substituted or unsubstituted aryl group; - X is an alkylene, alkenylene, alkynylene, ether bond, amine bond, amide bond, ester bond, thioether bond, carbamate bond, carbonate bond, ureido bond, sulfone bond, or chemical bond, wherein any of the alkylene, alkenylene, alkynylene, ether bond, amine bond, amide bond, ester bond, thioether bond, carbamate bond, carbonate bond, or sulfone bond is substituted or unsubstituted; - Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSOR g or NHCOR g (any of which may be substituted or unsubstituted), or [ka] where: -L 2 is alkylene, alkenylene, or alkynylene, any of which may be substituted or unsubstituted, or L 2 forms an amide bond, a carbamate bond, or a sulfonamide bond together with the nitrogen atom to which R is attached, or is a chemical bond, or a , R b , R c and R d - R ais H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; or L 2 , R b , R c and R d together with either of the following to form a substituted or unsubstituted ring; -R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; or L 2 , R a , R c and R d together with either of the following to form a substituted or unsubstituted ring; -R c is H or substituted or unsubstituted alkyl, or L 2 , R a , R b and R d together with either of the following to form a substituted or unsubstituted ring; -R d is H or substituted or unsubstituted alkyl, or L 2 , R a , R b and R c together with either of the following to form a substituted or unsubstituted ring; -R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; 80. The method of any one of embodiments 1 to 79, wherein the compound is a compound or a pharmaceutically acceptable salt thereof.

[0360] Embodiment 81. - Aryl 1is substituted or unsubstituted phenyl; - Aryl 2 is substituted or unsubstituted heteroaryl; X is alkylene; The method of embodiment 80.

[0361] Embodiment 82. - aryl 1 is a substituted phenyl; -aryl 2 is a substituted heteroaryl; The method of embodiment 80 or 81, wherein -X is methylene.

[0362] Embodiment 83. The compound that activates Tie-2 has the formula: [ka] is a compound of formula -aryl 1 is a para-substituted phenyl; -aryl 2 is a substituted heteroaryl; -X is methylene, -L 2 is alkylene, alkenylene, or alkynylene, any of which may be substituted or unsubstituted, or L 2 forms an amide bond, a carbamate bond, or a sulfonamide bond together with the nitrogen atom to which it is attached, or is a chemical bond, -R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; -R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; -R c is H or substituted or unsubstituted alkyl, -R d The method of any one of embodiments 80 to 82, wherein is H or substituted or unsubstituted alkyl.

[0363] Embodiment 84. - aryl 1 is a para-substituted phenyl; -aryl 2 is a substituted thiazole moiety, -X is methylene; -L 2 But, L 2 forms a carbamate bond with the nitrogen atom to which it is bonded, -R a is substituted or unsubstituted alkyl; -R b is a substituted or unsubstituted arylalkyl; -R c is H, -R d 84. The method of any one of embodiments 81 to 83, wherein

[0364] Embodiment 85. Aryl 2 but, [ka] wherein: -R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, any of which may be substituted or unsubstituted; -R fis H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, any of which may be substituted or unsubstituted; The method of embodiment 84.

[0365] Embodiment 86.-R e is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; -R f 86. The method of embodiment 85, wherein is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted.

[0366] Embodiment 87.-R e is H, OH, F, Cl, Br, I, an alkyl or alkoxy group, any of which may be substituted or unsubstituted; -R f 86. The method of embodiment 85, wherein is alkyl, aryl, heterocyclyl, or heteroaryl, any of which may be substituted or unsubstituted.

[0367] Embodiment 88. - aryl 1 is 4-phenylsulfamic acid, -R a is substituted or unsubstituted alkyl; -R b is a substituted or unsubstituted arylalkyl; -Re is H, -R f 86. The method of embodiment 85, wherein is heteroaryl.

[0368] Embodiment 89. The compound is: [ka] 81. The method of embodiment 80, wherein

[0369] Embodiment 90. The compound is: [ka] 81. The method of embodiment 80, wherein

[0370] Embodiment 91. - aryl 1 is 4-phenylsulfamic acid, -R a is substituted or unsubstituted alkyl; -R b is a substituted or unsubstituted arylalkyl; -R e is H, -R f 86. The method of embodiment 85, wherein is alkyl.

[0371] Embodiment 92. The compound is: [ka] 81. The method of embodiment 80, wherein

[0372] Embodiment 93. The compound is: [ka] 81. The method of embodiment 80, wherein

[0373] 94. Aryl 2 but, [ka] wherein: -R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, any of which may be substituted or unsubstituted; -R f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, alkoxy group, ether group, carboxylic acid group, carboxaldehyde group, ester group, amine group, amide group, carbonate group, carbamate group, thioether group, thioester group, thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, any of which may be substituted or unsubstituted; The method of embodiment 84.

[0374] Embodiment 95.-R e is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted; -R f 95. The method of embodiment 94, wherein is H, OH, F, Cl, Br, I, alkyl, alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which may be substituted or unsubstituted.

[0375] Embodiment 96.-R eis H, OH, F, Cl, Br, I, an alkyl or alkoxy group, any of which may be substituted or unsubstituted; -R f 95. The method of embodiment 94, wherein is alkyl, aryl, heterocyclyl, or heteroaryl, any of which may be substituted or unsubstituted.

[0376] Embodiment 97. - aryl 1 is 4-phenylsulfamic acid, -R a is substituted or unsubstituted alkyl; -R b is a substituted or unsubstituted arylalkyl; -R e is H, -R f 95. The method of embodiment 94, wherein is heteroaryl.

[0377] Embodiment 98. The compound is: [ka] 81. The method of embodiment 80, wherein

[0378] Embodiment 99. The compound is: [ka] 81. The method of embodiment 80, wherein

[0379] Embodiment 100. -aryl 1 is 4-phenylsulfamic acid, -R a is substituted or unsubstituted alkyl; -R b is a substituted or unsubstituted arylalkyl; -R e is H, -R f95. The method of embodiment 94, wherein is alkyl.

[0380] Embodiment 101. The compound is: [ka] 81. The method of embodiment 80, wherein

[0381] Embodiment 102. The compound is: [ka] 81. The method of embodiment 80, wherein

[0382] Embodiment 103. A method of treating acute respiratory distress syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein said administration increases the oxygenation index of the subject by about 1 to about 20 within 7 days of administration compared to no administration, wherein said therapeutically effective amount is about 0.1 mg to about 30 mg per kg of the subject per dose, and wherein said therapeutically effective amount is about 10 mg to about 40 mg per kg of the subject, and wherein said Tie-2 activator is present in said unit dosage form at a concentration of about 20 mg / mL, and wherein said subject is infected with SARS-CoV-2, and wherein said administration treats acute respiratory distress syndrome in said subject.

[0383] Embodiment 104. A method of treating COVID-19 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein said administration increases the oxygenation index of the subject by about 1 to about 20 within 7 days after administration compared to no administration, wherein said therapeutically effective amount is about 0.1 mg to about 30 mg per kg of the subject per dose, and wherein said therapeutically effective amount is about 10 mg to about 40 mg per kg of the subject, and wherein said Tie-2 activator is present in said unit dosage form at a concentration of about 20 mg / mL, and wherein said subject is infected with SARS-CoV-2, and wherein said administration treats acute respiratory distress syndrome in said subject.

[0384] Embodiment 105. A method of treating acute respiratory distress syndrome in a subject having COVID-19, the method comprising administering to the subject a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein said administration increases the subject's oxygenation index by about 1 to about 20 within 7 days after administration compared to no administration, wherein said therapeutically effective amount is about 0.1 mg to about 30 mg per kg of said subject per dose, and said therapeutically effective amount is about 10 mg to about 40 mg per kg of said subject, wherein said Tie-2 activator is present in said unit dosage form at a concentration of about 20 mg / mL, wherein said subject is infected with SARS-CoV-2, and wherein said administration treats acute respiratory distress syndrome in said subject.

[0385] Embodiment 106 The method of any one of embodiments 103 to 105, wherein the administration is subcutaneous.

[0386] Embodiment 107 The method of any one of embodiments 103 to 105, wherein the administration is intravenous.

[0387] Embodiment 108 The method of any one of embodiments 103 to 105, wherein the administration is by inhalation.

[0388] Embodiment 109. The Tie-2 activator is: [ka] ;or 109. The method of any one of embodiments 103 to 108, wherein the compound is a pharmaceutically acceptable salt thereof.

[0389] Embodiment 110. The Tie-2 activator is: [ka] ;or 109. The method of any one of embodiments 103 to 108, wherein the compound is a pharmaceutically acceptable salt thereof.

[0390] Embodiment 111. The Tie-2 activator is: [ka] ;or 109. The method of any one of embodiments 103 to 108, wherein the compound is a pharmaceutically acceptable salt thereof.

[0391] Embodiment 112 The Tie-2 activator is: [ka] ;or 109. The method of any one of embodiments 103 to 108, wherein the compound is a pharmaceutically acceptable salt thereof.

Claims

1. 1. A composition for treating a pulmonary condition selected from the group consisting of acute lung injury, acute hypoxemic respiratory failure, acute respiratory distress syndrome, and COVID-19 in a subject in need of such treatment, the composition comprising a Tie-2 activator, wherein the composition is administered to the subject in a therapeutically effective amount of the Tie-2 activator, the Tie-2 activator having the following formula: 【Chemistry 31】 or a pharmaceutically acceptable salt, tautomer, or zwitterion thereof, wherein the subject has hypertension, and wherein the administration increases the oxygenation index of the subject by about 1 to about 20 compared to the case without administration.

2. 10. The composition of claim 1, wherein said administering increases said subject's oxygenation index by about 1 to about 20 within 72 hours after administration.

3. the administration reduces the mean airway pressure required to be applied to the subject by a ventilator by about 1 cmH compared to when the administration is not performed ２ O ~ approx. 30cmH ２ 10. The composition of claim 1, wherein the composition reduces O.

4. the administration reduces PaO in the subject compared to not administering ２ / FiO ２ The composition of claim 1, wherein the ratio is increased by about 1 to about 100.

5. 2. The composition of claim 1, wherein said administration reduces the subject's acute lung injury score by 1 to 4 compared to when said composition is not administered.

6. 10. The composition of claim 1, wherein said administration modulates the Sequential Organ Failure Assessment (SOFA) score in said subject by 1 to 24 compared to no administration.

7. 2. The composition of claim 1, wherein said administration modulates a change in the level of a plasma concentration in said subject after administration, wherein said plasma concentration is selected from the group consisting of plasma Ang-2 concentration, plasma Ang-2 / Ang-1 ratio, plasma IL-6 concentration, plasma IL-8 concentration, plasma TNFα concentration, plasma D-dimer concentration, and plasma CRP concentration.

8. 10. The composition of claim 1, wherein the composition is administered to the subject in a unit dosage form containing a pharmaceutically acceptable excipient.

9. 10. The composition of claim 1, wherein the administration is a continuous infusion, and the continuous infusion lasts from about 1 hour to about 2.5 hours.

10. 10. The composition of claim 1, wherein the administration is selected from the group consisting of subcutaneous administration, intravenous administration, bolus intravenous injection, and continuous intravenous infusion.

11. 10. The composition of claim 1, wherein the pulmonary condition is selected from the group consisting of acute respiratory distress syndrome (ARDS) and COVID-19.

12. 1. A composition for treating acute respiratory distress syndrome in a subject in need thereof, comprising a Tie-2 activator, wherein the Tie-2 activator has the following formula: 【Chemistry 32】 wherein the composition is administered to the subject in a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein the administration increases the oxygenation index of the subject by about 1 to about 20 within seven days of administration compared to no administration, the therapeutically effective amount being about 10 mg to about 40 mg, the subject is infected with SARS-CoV-2, and the administration treats acute respiratory distress syndrome in the subject, and the subject has high blood pressure.

13. 1. A composition for treating COVID-19 in a subject in need thereof, comprising a Tie-2 activator, wherein the Tie-2 activator has the following formula: 【Transformation 33】 wherein the composition is administered to the subject in a therapeutically effective amount of a Tie-2 activator in a unit dosage form, wherein the administration increases the oxygenation index of the subject by about 1 to about 20 within seven days of administration compared to no administration, the therapeutically effective amount being about 10 mg to about 40 mg, the subject is infected with SARS-CoV-2, and the administration treats acute respiratory distress syndrome in the subject, and the subject has high blood pressure.

14. 13. The composition of claim 12, wherein the administration is subcutaneous, intravenous, or inhaled.

15. 14. The composition of claim 13, wherein the administration is subcutaneous, intravenous, or inhaled.

Images