WO2024039822A1

WO2024039822A1 - Thiol isomerases inhibitors; preparation thereof; and methods of use thereof

Info

Publication number: WO2024039822A1
Application number: PCT/US2023/030535
Authority: WO
Inventors: Daniel Kennedy; Sylvie Garneau-Tsodikova
Original assignee: University of Kentucky Research Foundation; Western New England University
Current assignee: University of Kentucky Research Foundation; Western New England University
Priority date: 2022-08-19
Filing date: 2023-08-18
Publication date: 2024-02-22
Anticipated expiration: 2025-02-19
Also published as: CN120187701A; EP4573078A1

Abstract

Disclosed are novel thiol isomerase inhibitors and their use in the prevention or treatment of the development or progression of a disease or condition involving one or more of the extracellular thiol isomerases. Further disclosed a method for preventing or treating thrombosis, a thrombotic disease, platelet aggregation, fibrin generation, an infectious disease, a viral disease, an immune disorder, inflammation, a neurologic disease, a neurodegenerative disorder, a cancer or a combination thereof in a patient, comprising: administering to the patient in need thereof a therapeutically effective amount of a compound.

Description

THIOL ISOMERASES INHIBITORS; PREPARATION THEREOF; AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This Application claims the benefit of U.S. Provisional Application No. 63/399,516, filed August 19, 2022, and U.S. Provisional Application No. 63/454,974, filed March 28, 2023, each of which is incorporated by reference in its entirety for all purposes. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with government support under R21 CA231000 and F31DE029661 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. BACKGROUND: [0003] Thiol isomerases are members of a large family of disulfide oxidoreductases, which catalyze the posttranslational disulfide exchange necessary for the proper folding of newly synthesized proteins. Approximately twenty members of a large family of thiol isomerase/disulfide oxidoreductases exist in humans with a domain composition of thiol isomerases is a-b-b’-a’. These thiol isomerases are generally capable of oxidation reduction and isomerization reactions and are often found in the endoplasmic reticulum where they catalyze the proper folding of newly translated proteins. [0004] Additionally, some thiol isomerases such as protein disulfide isomerase (PDI), ERp5, ERp57, ERp72 and thioredoxin (TRX) have recently been discovered to perform extracellular functions. These five thiol isomerases, henceforth referred to as extracellular thiol isomerases, are secreted by cells such as platelets and reattach to the plasma membrane, where they function as extracellular oxidoreductases. Extracellular thiol isomerases have also been identified on the surface of endothelial cells and to play a role in the activation of thrombus formation and fibrin formation, as well as in platelet aggregation, granule secretion, fibrinogen binding, and calcium mobilization. Of these enzymes, the role of PDI in thrombus formation is the most-well studied and understood, while ERp5, ERp57 and ERp72 are also known to be required. [0005] PDI family members are upregulated in many distinct cancer types, including ovarian, prostate, lung, melanoma, lymphoma and glioma, while inhibition of PDI is cytotoxic in ovarian cancer cell lines. These enzymes are thought to have polyfunctional involvement in the oncogenesis of cancer, where they play roles in the oncogene activation, avoidance of apoptosis, secretion of major histocompatibility complex class I-related A protein (MICA), and the resistance to chemotherapeutic agents. [0006] Patients with cancer have a significantly greater risk of developing arterial thrombosis and venous thromboembolism, and the risk is substantially higher in patients receiving systemic chemotherapy. The mortality risk of a cancer patient who suffers a thromboembolism is doubled, with thrombosis being the second leading cause of death for cancer patients. The annual death rates due to arterial thrombosis or venous thrombosis in cancer patients are ~3-fold and 50-fold higher than the general population, respectively, and they can account for up to 14% of cancer mortality. [0007] Thromboembolic events frequently complicate the treatment of cancer and, while venous events are more common, arterial events are also more prevalent in patients with malignancy than in the rest of the population. However, there is a significant variation in risk among individuals, depending on the type of cancer, chemotherapy regimen, and other clinical risk factors such as stage of cancer, use of catheters, or other interventions, like surgery. When deciding whether a patient will be placed on prophylactic anticoagulation, the risk of the patient developing a thrombotic event needs to be weighed against the risks of taking the anticoagulant medication. A significant amount of time and resources is devoted to developing risk models and scores, such as the Khorana Score, to try and predict the patients who are at the highest risk for a thromboembolic event. Unfortunately, recent studies have found that these risk models are generally poor predictors of the risk of venous thromboembolism (VTE). Moreover, even if the risk scores could be properly predicted and applied to patients for a VTE, using low molecular weight heparin or similar anticoagulation treatments would not be indicated for arterial thrombosis and its sequelae such as myocardial infarctions and strokes. [0008] There remains a need in the art for novel compounds and methods for the treatment of cancer, thrombosis, thromobotic disease, and the treatment or prevention of cancer-induced thrombosis. SUMMARY: [0009] In an embodiment, a method of treating cancer or treating or preventing cancer-induced thrombosis, comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), or a pharmaceutically acceptable salt thereof:

R¹ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein R⁹ is hydrogen, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, or aryl; Q¹ each and Q² independently is a bond, O, or NR¹⁰, and R¹⁰ is hydrogen, C1-C8 alkyl, C₁-C₆ haloalkyl, or C₁-C₈ alkyl-OH; R² is hydrogen, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C₃-C₇ cycloalkyl, (C₃- C7 cycloalkyl)C0-C6 alkyl, C1-C4 alkanoyl, or unsubstituted or substituted aryl; X is O, S, or N; Y is N or CH; R⁶ is hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl when X is N, and R⁶ is absent when X is S or O; R⁷ is hydrogen, NO₂, cyano, halogen, NH₂, COOH, hydroxyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; Ar² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl substituted with R⁸ wherein R⁸ is NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di- C₁-C₈ alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; R⁴ is hydrogen, NO₂, cyano, halogen, NH₂, COOH, hydroxyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; and R⁵ is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl, with the following provisos a) and b): a) when

hydrogen, and Ar² is phenyl or phenyl substituted with R⁸, then R¹, R², and R⁸ do not meet the following six conditions for a compound of Formula (III):

NO₂, NH₂, mono-C₁-C₈ alkylamino, or di-C₁-C₈ alkylamino; R² is hydrogen or C₁-C₈ alkyl; R⁴ is hydrogen or C₁-C₈ alkyl; and R⁵ is hydrogen; then Ar² is not unsubstituted phenyl or phenyl substituted at the 2 position with C1- C8 alkyl. [0010] In another embodiment, a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof:

wherein R¹ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein R⁹ is hydrogen, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, or aryl; Q¹ each and Q² independently is a bond, O, or NR¹⁰, and R¹⁰ is hydrogen, C1-C8 alkyl, C₁-C₆ haloalkyl, or C₁-C₈ alkyl-OH; R² is hydrogen, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, C3-C7 cycloalkyl, (C3- C7 cycloalkyl)C0-C6 alkyl, C1-C4 alkanoyl, or unsubstituted or substituted aryl; X is O, S, or N; Y is N or CH; R⁶ is hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl when X is N, and R⁶ is absent when X is S or O; R⁷ is hydrogen, NO₂, cyano, halogen, NH₂, COOH, hydroxyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; Ar² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; R⁴ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; and R⁵ is hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, or C₁-C₄ alkanoyl with the following provisos a) and b): a) when

hydrogen, and Ar² is phenyl or phenyl substituted with R⁸, then R¹, R², and R⁸ do not meet the following six conditions for a compound of Formula (III): R¹ R² R⁸ gen, NO2, NH2, mono-C1-C8 alkylamino, or di-C1-C8 alkylamino; R² is hydrogen or C1-C8 alkyl; R⁴ is hydrogen or C1-C8 alkyl; and R⁵ is hydrogen; then Ar² is not unsubstituted phenyl or phenyl substituted at the 2 position with C₁- C8 alkyl. [0011] In yet another embodiment, a pharmaceutical composition comprises a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0012] The above described and other features are exemplified by the following figures and detailed description. [0013] In general, the disclosure may alternately comprise, consist of, or consist essentially of, any appropriate components herein disclosed. The disclosure may additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any components, materials, ingredients, adjuvants or species used in the prior art compositions or that are otherwise not necessary to the achievement of the function and/or objectives of the present disclosure. DRAWINGS: [0014] Referring now to the figures, which are exemplary embodiments and not to be considered limiting: FIG. 1A and FIG. 1B: The inhibition of thiol isomerase activity with ZAF (FIG. 1A) and MON (FIG. 1B) in an enzymatic thiol isomerase activity assay. [0015] FIG. 2A and FIG. 2B: Evaluation of cytotoxicity for analogues 21, 27, 28, ZAF, and MON against BEAS-2B cell line (FIG. 2A); and HEK-293 cell line (FIG. 2B, legend is the same as found in FIG. 2A). Controls included treatment with Triton-X® (TX, 1% v/v, positive control) and 1% DMSO (negative control). In instances where >100% cell survival was observed, the data as 100% cell survival (normalized data) was displayed. Experiments were performed in quadruplicate. [0016] FIG. 3A and FIG. 3B: The inhibition of mammalian cell growth with ZAF and compound 21. Cells were seeded and treated with drug 24 h later. After an additional 24 h of incubation, cell viability was determined using Prestoblue. The figures presents a summary of at least 3 independent experiments per cell line. Cell lines used include HEK-293 non-cancer cells (not shown); OVCAR-8 and HCT116. Comparison of ZAF (circles) and compound 21 (inverted triangles) in a 3-day growth inhibition against OVCAR-8 (FIG. 3A) and HCT116 cancer cells (FIG. 3B). [0017] FIG. 4A and FIG. 4B: Washed human platelets were incubated with compound 21 five minutes prior to stimulation with collagen and measured by an optical aggregometer. [0018] FIG. 5: ZAF inhibits cancer cell-induced activation of the coagulation cascade. ZAF has inhibitory effects on Factor Xa generation even at low concentrations on HCT116 cells. [0019] FIG. 6: Insulin turbidity assay, compound 32 inhibits PDI, ERp5, ERp57, and ERp72 similarly to zafirlukast. [0020] FIG. 7A-7D: Cellular thiol isomerase activity is inhibited by zafirlukast. (FIG. 7A) Cellular thiol isomerase activity is inhibited by zafirlukast treatment in a concentration dependent manner as measured by di‐eosin‐GSSG fluorescence (n=4) Data is presented as mean ±SD. One‐way ANOVA and a post‐hoc Dunnett’s test where *p=0.0217 for 3 μM zafirlukast, **p=0.0020 for 10 μM zafirlukast and ****p<0.0001 for 30 μM 14 zafirlukast compared to the control. (FIG. 7B) Levels of PDI, ERp5, ERp57, and ERp72 remain similar with increasing concentrations of zafirlukast in OVCAR8 cells (n=3). Data is presented as mean ±SD. A student’s t‐test was used for comparison to control. No significant changes were present. Cellular thiol isomerase activity is also inhibited by (FIG. 7C) montelukast (n=3) and (FIG. 7D) compound 32 analogue (n=4). Data is presented as mean ±SD. One‐way ANOVA and a post‐hoc Dunnett’s test where *p=0.0219 for 10 μM montelukast, **p=0.0018 for 30 μM montelukast and ***p=0.0002 for 100 μM montelukast compared to the control, while *p=0.0383 for 1 μM compound 32, **p=0.0017 for 3 μM compound 32, ***p= 0.0004 for 10 μM compound 32and ****p<0.0001 for 30 μM compound 32 compared to the control. [0021] FIG. 8A and FIG. 8B: Zafirlukast, montelukast, and compound 32 selectively cause cancer cell cytotoxicity. (FIG. 8A) Zafirlukast is about 5x more cytotoxic than montelukast and 1.5x more cytotoxic than the compound 32 (n=3). (FIG. 8B) Comparison of the relative potency of each compound in the experiments from FIG. 6, FIG. 7, and FIG. 8A. DETAILED DESCRIPTION: [0022] Disclosed herein are novel thiol isomerase inhibitors and their therapeutic use in the prevention or treatment of the development or progression of a disease or condition involving one or more of the extracellular thiol isomerases, including protein disulfide isomerase (PDI), thioredoxin, ERp5, ERp57, ERp72, or a combination thereof. These compounds find potential use in the prevention and/or treatment of a cancer, thrombosis (arterial, venous), a thrombotic disease, or a combination thereof. [0023] One promising mechanism to combat cancer-induced thrombosis is to utilize compounds that can inhibit thiol isomerases, which include protein disulfide isomerase (PDI) and the closely related enzymes, ERp5, ERp57, and ERp72. These enzymes have extracellular activity with important roles in both arterial and venous thrombosis as well as in a variety of cancers. PDI, ERp5, ERp57, and ERp72 are secreted by platelets; they attach to the plasma membrane, where they function as extracellular oxidoreductases. They are required for thrombus formation and fibrin formation as well as for platelet aggregation, dense granule secretion, fibrinogen binding, and calcium mobilization. The ability to inhibit both arterial and venous thrombosis is unprecedented amongst potential and current antithrombotic agents. Thiol isomerases are also upregulated in many distinct cancer types, including ovarian, prostate, lung, melanoma, lymphoma, and glioma, and increased levels of thiol isomerases have been positively correlated with increased oncogenic transformation, gene transcription, metastasis, and even promoting resistance to chemotherapy and radiation. Similar to their role in platelets, thiol isomerases can also be secreted from tumor cells and perform functions on the cell surface. Thiol isomerase inhibition is cytotoxic to multiple tumor types. For example, inhibiting thiol isomerases significantly suppresses ovarian tumor growth in xenograft mice without causing toxicity to normal tissues. [0024] Because of the potential dual utility of thiol isomerase inhibitors as anticancer and antithrombotic agents, thiol isomerases hold significant promise as targets in the prevention of cancer-associated thrombosis. Interestingly, despite their similarity, thiol isomerases are non-redundant in arterial and venous thrombosis formation in that the inhibition of one thiol isomerase will block thrombosis, and they have distinct roles in cancer growth and progression. An inhibitor of any one of thiol isomerases or a pan-thiol isomerase inhibitor would be valuable. FDA-approved medications zafirlukast (ZAF) and the related montelukast (MON) have been identified as promising broad-spectrum thiol isomerase inhibitors and their potential for the prevention and treatment of cancer-induced thrombosis have been confirmed, verifying the antineoplastic, antiplatelet, and anticoagulation functions of both compounds. [0025] The use of the compounds described herein can overcome the two major weaknesses of current prophylactic anticoagulation treatment. Data shows that ZAF was able to inhibit both arterial and venous thrombosis, unlike any clinically used antithrombotic agent. Also, while both arterial and venous thrombosis were affected, hemostasis was not, so that there was no increase in bleeding risk. Additionally, thiol isomerase inhibition-induced cytotoxicity to select cancer cell lines and in a xenograft model of ovarian cancer. Together, these data suggest that thiol isomerase inhibitors could significantly improve therapeutic outcomes of cancer-associated thrombosis by targeting both major types of thrombosis without effecting bleeding times, diminishing the risks of current prophylactic treatment and at the same time they could constitute a part of the chemotherapeutic regimen as antineoplastic agents. [0026] Disclosed herein are zafirlukast derivative compounds of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof:

R¹ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein R⁹ is hydrogen, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, or aryl; Q¹ each and Q² independently is a bond, O, or NR¹⁰, and R¹⁰ is hydrogen, C1-C8 alkyl, C₁-C₆ haloalkyl, or C₁-C₈ alkyl-OH; specifically R¹ is an electron withdrawing group; more specifically R¹ is NO₂, cyano, C₁-C₆ haloalkyl, CF₃, or C₂-C₆ alkanoyl; R² is hydrogen, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C₃-C₇ cycloalkyl, (C₃- C7 cycloalkyl)C0-C6 alkyl, C1-C4 alkanoyl, or unsubstituted or substituted aryl; specifically R² is hydrogen, C1-C6 alkyl, C1-C8 alkyl-OH, or unsubstituted or substituted phenyl; X is O, S, or N; Y is N or CH; R⁶ is hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl when X is N, and R⁶ is absent when X is S or O; R⁷ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; Ar² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; specifically Ar² is phenyl or naphthalene unsubstituted or substituted with R⁸ wherein R⁸ is NO₂, cyano, halogen, NH₂, COOH, hydroxyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; more specifically Ar² is phenyl or 2-naphthalene; R⁴ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; specifically R⁴ is C₁-C₆ alkyl or C1-C6 alkoxy; more specifically R⁴ is C1-C2 alkyl or C1-C2 alkoxy; and R⁵ is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl; specifically R⁵ is hydrogen. with the following provisos a) and b): [0027] In an embodiment, a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, as reported herein with the provisos that a) when

hydrogen, and Ar² is phenyl or phenyl substituted with R⁸, then R¹, R², and R⁸ do not meet the following six conditions for a compound of Formula (III): gen, NO2, NH2, mono-C1-C8 alkylamino, or di-C₁-C₈ alkylamino; R² is hydrogen or C₁-C₈ alkyl; R⁴ is hydrogen or C₁-C₈ alkyl; and R⁵ is hydrogen; then Ar² is not unsubstituted phenyl or phenyl substituted at the 2 position with C1- C8 alkyl. As understood herein, the compounds excluded from Formula (III) according to proviso b) are also excluded within the scope of Formula (I) and (II). [0028] A compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein Ar¹, Ar², R⁴, and R⁵ and are as previously defined. [0030] A compound of Formula (III), or a pharmaceutically acceptable salt thereof,

wherein Ar¹, Ar², R⁴, and R⁵ and are as previously defined. [0031] In an embodiment, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein

wherein R¹ and R² are as previously defined. [0032] In an embodiment, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R⁴ is C1-C8 alkoxy, including branched alkoxy; more specifically wherein R⁴ is C1-C4 alkoxy. [0033] In an embodiment, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein

wherein R¹ and R² are as previously defined and R⁴ is C₁-C₈ alkoxy, including branched alkoxy. [0034] In an embodiment, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein Ar² is phenyl substituted with R⁸ at the 2 position. Within this embodiment, R⁸ is halogen, specifically F. [0035] In an embodiment, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein

wherein R¹ and R² are as previously defined and Ar² is phenyl substituted with R⁸ at the 2 position; specifically, R⁸ is halogen, specifically F. In a further embodiment, R⁴ is C₁-C₈ alkoxy, including branched alkoxy. [0036] In an embodiment, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein

wherein R¹ is hydrogen, methyl, ethyl, methoxy, NH2, NO2, -CH2OH, or -Q¹(C=O)Q²R⁹ wherein R⁹ is hydrogen, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, or aryl and Q¹ and Q² are NH; and R² is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, -CH₂OH, - CH2NH2, or phenyl; R⁴ is C1-C4 alkoxy; R⁵ is hydrogen; and Ar² is phenyl substituted with R⁸ at the 2 position; specifically, R⁸ is halogen, specifically F. [0037] Also included in this disclosure are compounds of Formula (I) as set out in Table 1 in a non-salt form (e.g. free base form), or as a pharmaceutically acceptable salt thereof. [0038] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. Unless clearly contraindicated by the context each compound name includes the free acid or free base form of the compound as well hydrates of the compound and all pharmaceutically acceptable salts of the compound. [0039] The term “Formula (I)”, “Formula (II)”, and “Formula (III)”, as used herein, encompasses all compounds that satisfy Formula (I), (II), and (III) including any enantiomers, racemates and stereoisomers as well as all pharmaceutically acceptable salts, solvates, and hydrates of such compounds. [0040] In certain situations, the compounds of Formula (I), (II), and (III) may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates or racemic intermediates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column. [0041] Where a compound exists in various tautomeric forms, the compound is not limited to any one of the specific tautomers, but rather includes all tautomeric forms. [0042] All isotopes of atoms occurring in the present compounds are contemplated. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C. [0043] Certain compounds are described herein using a general formula that includes variables, e.g. R¹-R⁹, Y, Z, etc. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, if a group is said to be substituted, e.g., with 0-2 R¹, then the group may be substituted with up to two R¹ groups and R¹ at each occurrence is selected independently from the definition of R¹. Also, combinations of substituents and/or variables are permissible only if such combinations result in a stable compound. [0044] The term “active agent”, as used herein, means a compound (including a compound of Formula (I), (II), and (III)), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient. The indirect physiological effect may occur via a metabolite or other indirect mechanism. When the active agent is a compound, then salts, solvates (including hydrates) of the free compound, crystalline forms, non-crystalline forms, and any polymorphs of the compound are included. All forms are contemplated herein regardless of the methods used to obtain them. [0045] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(CH₂)C₃-C₈ cycloalkyl is attached through carbon of the methylene (CH2) group. [0046] “Alkanoyl” is an alkyl group as defined herein, covalently bound to the group it substitutes by a keto (-(C=O)-) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2alkanoyl group is an acetyl group having the formula CH3(C=O)-. A C₄alkanoyl group or greater can include a cycloalkyl group (e.g. cyclopropane group) as well as linear or branched groups. [0047] The term “alkyl”, as used herein, means a branched or straight chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms. The term C₁-C₆ alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. C1-C6 alkyl, C1-C4 alkyl, and C₁-C₂ alkyl. When C₀-C_n alkyl is used herein in conjunction with another group, for example, (cycloalkyl)C0-C4 alkyl, the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t- butyl, n-pentyl, and sec-pentyl. [0048] The term “cycloalkyl”, as used herein, indicates a saturated hydrocarbon ring group, having only carbon ring atoms and having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane. [0049] The term “heterocycloalkyl”, as used herein, indicates a saturated cyclic group containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Heterocycloalkyl groups have from 3 to about 8 ring atoms, and more typically have from 5 to 7 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups. A nitrogen in a heterocycloalkyl group may optionally be quaternized. [0050] The term “alkenyl”, as used herein, means straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur in any stable point along the chain. Alkenyl groups described herein typically have from 2 to about 12 carbon atoms. Exemplary alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, e.g. C₂-C₈, C₂-C₆, and C₂-C₄ alkenyl groups. Examples of alkenyl groups include ethenyl, propenyl, and butenyl groups. [0051] The term “cycloalkenyl”, as used herein, means a saturated hydrocarbon ring group, comprising one or more unsaturated carbon-carbon bonds, which may occur in any stable point of the ring, and having the specified number of carbon atoms. Monocyclic cycloalkenyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 7 (3, 4, 5, 6, or 7) carbon ring atoms. Cycloalkenyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkenyl group, which is attached as a spiro group. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl as well as bridged or caged saturated ring groups such as norbornene. [0052] The term “heterocycloalkenyl”, as used herein, refers to a 3- to 10- membered, including 4- to 8-membered, non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S. [0053] The terms “(cycloalkyl)C0-Cn alkyl”, as used herein, means a substituent in which the cycloalkyl and alkyl are as defined herein, and the point of attachment of the (cycloalkyl)alkyl group to the molecule it substitutes is either a single covalent bond, (C₀alkyl) or on the alkyl group. (Cycloalkyl)alkyl encompasses, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, and cyclohexylmethyl. [0054] The term “(heterocycloalkyl)C0-Cn alkyl”, as used herein, means a substituent in which the heterocycloalkyl and alkyl are as defined herein, and the point of attachment of the (heterocycloalkyl)alkyl group to the molecule it substitutes is either a single covalent bond, (C0alkyl) or on the alkyl group. (Heterocycloalkyl)alkyl encompasses, but is not limited to, morpholinylmethyl, piperazinylmethyl, piperidinylmethyl, and pyrrolidinylmethyl groups. [0055] The term “(heterocycloalkenyl)C0-C6 alkyl”, as used herein, means a substituent in which the heterocycloalkenyl and alkyl are as defined herein, and the point of attachment of the (heterocycloalkenyl)alkyl group to the molecule it substitutes is either a single covalent bond, (C0alkyl) or on the alkyl group. [0056] The term “aryl”, as used herein, means aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Bicyclic aryl groups may be further substituted with carbon or non-carbon atoms or groups. Bicyclic aryl groups may contain two fused aromatic rings (naphthyl) or an aromatic ring fused to a 5- to 7-membered non-aromatic cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, for example, a 3,4- methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and bi-phenyl. [0057] The term “mono- or bicyclic heteroaryl”, as used herein, indicates a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4, or specifically from 1 to 3, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, theses heteroatoms are not adjacent to one another. Specifically, the total number of S and O atoms in the heteroaryl group is not more than 2, more specifically the total number of S and O atoms in the heteroaryl group is not more than 1. A nitrogen atom in a heteroaryl group may optionally be quaternized. When indicated, such heteroaryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a [1,3]dioxolo[4,5-c]pyridyl group. In certain embodiments 5- to 6-membered heteroaryl groups are used. Examples of heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8- tetrahydroisoquinoline. [0058] “Haloalkyl” includes both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. [0059] “Alkoxy” is an alkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical). [0060] “Haloalkoxy” is a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical). [0061] “Halo” or “halogen” is any of fluoro, chloro, bromo, and iodo. [0062] “Mono- and/ or di-alkylamino” is a secondary or tertiary alkyl amino group, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino. [0063] The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When the substituent is oxo (i.e., =O) then 2 hydrogens on the atom are replaced. When an oxo group substitutes aromatic moieties, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent. [0064] Unless otherwise specified substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion, or when arylalkyl is listed as a possible substituent the point attachment to the core structure is the alkyl portion. [0065] Suitable groups that may be present on a “substituted” or “optionally substituted” position include, but are not limited to, halogen; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group such as acyl or the like); carboxamido; alkyl groups (including cycloalkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylsulfenyl groups including those having one or more sulfenyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those having one or more sulfinyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulfonyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; aminoalkyl groups including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms; aryl having 6 or more carbons and one or more rings, (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted aromatic); arylalkyl having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, with benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. [0066] The term “pharmaceutically acceptable salt”, as used herein, includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. [0067] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH₂)_n-COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). [0068] Also provided are pharmaceutical compositions comprising a compound of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions may contain the compound of Formulas(I)-(III) as the only active agent or may contain a combination with an additional pharmaceutically active agent including an additional extracellular thiol isomerase inhibitor or an active agent from a different pharmaceutical class, including an anti-thrombotic agent, and anti-coagulant agent, an anti-inflammatory agent, an anti-viral agent, a chemotherapeutic or an anti-cancer agent, etc., or a combination thereof. [0069] As used herein, “extracellular thiol isomerase inhibitor compound” is an inhibitor of one or more of the extracellular thiol isomerases. Exemplary extracellular thiol isomerase inhibitor compounds include a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, zafirlukast, montelukast, quercetin, PACMA-31, curcumin, rutin, isoquercetin, CCF642, and a combination thereof. [0070] The compound may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage form containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, can be subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. [0071] The term “dosage form”, as used herein, means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like. An exemplary dosage form is a solid oral dosage form. [0072] The term “pharmaceutical compositions”, as used herein, are compositions comprising at least one active agent, such as a compound or salt of Formula (I), (II), or (III) and at least one other substance, such as a carrier. Pharmaceutical compositions meet the U.S. FDA’s GMP (good manufacturing practice) standards for human or non-human drugs. The pharmaceutical compositions can be formulated into a dosage form. [0073] The term “carrier”, as used herein, applied to pharmaceutical compositions refers to a diluent, excipient, or vehicle with which an active compound is provided. [0074] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the active compound. [0075] Classes of carriers include, for example, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional additional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of Formula (I), (II), (III), etc. [0076] The pharmaceutical compositions can be formulated for oral administration. These compositions contain between 0.1 and 99 weight percent (“wt.%”) of the active compound of Formula (I), (II), (III) or pharmaceutically acceptable salt thereof, specifically at least about 5 wt.%. In some embodiments, the composition contains from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the active compound. [0077] The term “therapeutically effective amount” of a pharmaceutical composition, as used herein, means an amount effective, when administered to a patient, to provide a therapeutic benefit such as a prevention or an amelioration of symptoms, e.g., to treat a patient suffering from a disease or condition influenced by the activity of one or more of the extracellular thiol isomerases. A therapeutically effective amount may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the compound to elicit a desired response in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects. [0078] A therapeutically effective amount may range from about 0.001 µg/kg/day to about 500 mg/kg/day, preferably 0.01 µg/kg/day and 100 mg/kg/day of the compound of Formula (I), (II), (III) or pharmaceutically acceptable salt thereof. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a patient, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the patient, and other diseases present. Moreover, treatment of a patient with a therapeutically effective amount of an inhibitor compound can include a single treatment or, can include a series of treatments. It will also be appreciated that the effective dosage of an inhibitor compound used for treatment may increase or decrease over the course of a particular treatment. [0079] The compound of Formula (I), (II), (III) or pharmaceutically acceptable salt thereof can be administered once, twice, or three times a day to the patient in need thereof. Within this embodiment, the administration can be made orally. [0080] When administered orally, the total daily dose of the compound of Formula (I), (II), (III) or pharmaceutically acceptable salt thereof, can be about 0.1 to about 200 mg, specifically about 1 to about 175 mg, more specifically about 20 to about 150 mg, and still more specifically about 60 to about 125 mg administered once, twice, or three times a day orally. [0081] The pharmaceutical composition can be formulated in a package comprising the pharmaceutical composition in a container and further comprising instructions for using the composition in the prevention and treatment of a disease or disorder mediated by the one or more thiol isomerases of the extracellular thiol isomerases. [0082] Also provided are methods for therapeutic treatment using the compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof. In an embodiment, a method of treating or preventing cancer-induced thrombosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, optionally as a pharmaceutical composition comprising the compound. [0083] In an embodiment, a method of inhibiting one or more of the extracellular thiol isomerases in a patient in need thereof for the treatment or prevention of a disease or condition influenced by the activity of one or more of the extracellular thiol isomerases, or for inhibiting a process influenced by the activity of one or more of the extracellular thiol isomerases, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III) or pharmaceutically acceptable salt thereof or composition comprising the compound. In certain embodiments, the disease or condition is thrombosis, cancer-induced thrombosis, a thrombotic disease, an infectious disease including human immunodeficiency virus (HIV), a cancer, inflammation, or a combination thereof, as described herein. Extracellular thiol isomerases [0084] As used herein, “extracellular thiol isomerase” includes at least protein disulfide isomerase (PDI), thioredoxin (TRX), and the following endoplasmic reticulum resident proteins: ERp5, ERp57, and ERp72. [0085] PDI is a 508 amino acid protein that has an important role in platelet activation. The release of PDI from activated platelets was demonstrated nearly two decades ago and confirmed in many subsequent studies and it is also released by endothelial cells. Antibodies directed at PDI and micromolar concentrations of the antibiotic bacitracin inhibit platelet aggregation, adhesion, and secretion. Inhibition of PDI has been shown to inhibit cancer cell growth and induce tumor necrosis in an ovarian cancer model. [0086] ERp5 is a 440 amino acid protein that contains two thioredoxin (CGHC containing motifs) domains and shares a 47% sequence identify with PDI. Blocking cell- surface ERp5 results in decreased platelet aggregation, fibrinogen binding, and alpha-granule secretion. In addition to its role in hemostasis, high levels of ERp5 expression have been shown to correlate with preventing an efficient antitumor response in Hodgkin lymphomas and have been proposed as a biomarker for prostate and breast cancer progression. [0087] ERp57 is a thiol isomerase consisting of 505 amino acids and it plays important roles in regulating initial platelet activation and also supporting arterial thrombus formation, affecting platelet aggregation, dense granule secretion, fibrinogen binding, calcium mobilization and thrombus formation under arterial blood flow conditions. In addition to its role in thrombus formation, ERp57 has also been shown to be required for proper folding of influenza hemaagglutinin and implicated in disease progression of Alzheimer’s disease and cancer metastasis. [0088] ERp72 is a 645 amino acid soluble ER protein which shares 37% sequence homology with PDI. ERp72 has three catalytic CGHC domains compared to the two found in PDI, ERp5 and ERp57. The percent increase of ERp72 recruited to the surface of platelets after activation is higher than that of PDI, ERp5 and ERp57, suggesting it performs an important albeit currently unknown role in platelet activation. The effect of ERp72 inhibition on thrombus formation is similarly unknown. In addition to its relocation to the activated platelet surface, ERp72 has been implicated in the infectious process of polyomavirus and also in the redox signaling of NADPH oxidase (Nox) 1. [0089] Four thiol isomerases, PDI, ERp5, ERp57, and ERp72, have been demonstrated to be important for thrombosis associated with cancer. These four enzymes are non-redundant, i.e., inhibition of only one of them blocks thrombosis. Therefore, one or a combination of two or more of these enzymes are attractive targets for antithrombosis drug development. Furthermore, some cancers are dependent on these enzymes, which would make inhibitors of these enzymes have anticancer activities in these settings. [0090] Zafirlukast and montelukast are inhibitors of the four thiol isomerases PDI, ERp5, ERp57, and ERp72 and are able to inhibit both venous and arterial thrombosis without enhancing bleeding risk, and cancer cell and tumor growth. Certain zafirlukast derivatives described herein demonstrate improved activity when compared to zafirlukast. [0091] In an embodiment, the target for inhibition is one or more thiol isomerases of the extracellular thiol isomerases, including protein disulfide isomerase (PDI), thioredoxin (TRX), ERp5, ERp57, and ERp72. In an embodiment, the target for inhibition is PDI. In an embodiment, the target for inhibition is thioredoxin (TRX). In an embodiment, the target for inhibition is ERp5. In an embodiment, the target for inhibition is ERp57. In an embodiment, the target for inhibition is ERp72. [0092] The term “patient”, as used herein, is a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments the patient is a human patient. [0093] The term “providing”, as used herein, means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing. [0094] The term “providing a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, with an additional pharmaceutically active agent”, as used herein, means the compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, and the additional pharmaceutically active agent are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, and the additional pharmaceutically active agent are within the blood stream of a patient. The compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, and the additional pharmaceutically active agent not be prescribed for a patient by the same medical care worker. The additional pharmaceutically active agent need not require a prescription. Administration of the compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, or the additional pharmaceutically active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories or topical contact. [0095] The term “providing an extracellular thiol isomerase inhibitor compound or pharmaceutically acceptable salt thereof with at least one additional therapeutic agent”, as used herein, means an extracellular thiol isomerase inhibitor compound or pharmaceutically acceptable salt thereof and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the extracellular thiol isomerase inhibitor compound or pharmaceutically acceptable salt thereof and the at least one additional active agent are within the blood stream of a patient. The extracellular thiol isomerase inhibitor compound or pharmaceutically acceptable salt thereof and the additional active agent need not be prescribed for a patient by the same medical care worker. The additional active agent or agents need not require a prescription. Administration of the extracellular thiol isomerase inhibitor compound or pharmaceutically acceptable salt thereof or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories or topical contact. [0096] The term “treatment”, as used herein, includes providing an extracellular thiol isomerase inhibitor compound, a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt thereof, either as the only active agent or together with at least one additional active agent sufficient to: (a) prevent a disease or condition or a symptom of a disease or condition from occurring in a patient who may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition, i.e. arresting its development; and (c) relieving the disease or condition, i.e., causing regression of the disease or condition. “Treating” and “treatment” also means providing a therapeutically effective amount of an extracellular thiol isomerase inhibitor compound or pharmaceutically acceptable salt thereof, as the only active agent or together with at least one additional active agent to a patient suffering from a disease or condition influenced by the activity of one or more extracellular thiol isomerases. “A disease or condition influenced by the activity of one or more extracellular thiol isomerases” means the one or more extracellular thiol isomerase is implicated in the disease or condition. [0097] The extracellular thiol isomerase inhibitor compound or pharmaceutical compositions/combinations disclosed herein are useful for treating patients. The extracellular thiol isomerase inhibitor compound or pharmaceutical compositions/combinations are useful for treating or preventing diseases and disorders where the activity of one or more extracellular thiol isomerases are involved. In certain embodiments the patient is afflicted with thrombosis or is at a risk of developing a thrombosis. In certain embodiments the patient is afflicted with cancer. In certain embodiments the patient is at risk of, or afflicted with, cancer-induced thrombosis. In certain embodiments the disease is hematological cancer, HPV associated cancer, ovarian cancer, prostate cancer, gastric cancer, breast cancer, or colorectal cancer. In other embodiments the patient to be treated is afflicted with an inflammatory disorder, an infectious disease, an immune disorder, or a neurologic disease. Anti-thrombotic [0098] Extracellular thiol isomerases are involved the regulation of hemostasis and thrombosis, as the inhibition of one or more extracellular thiol isomerases will block platelet aggregation, granule secretion, adhesion, thrombus formation and fibrin generation. Antithrombotics can be used therapeutically for prevention (primary prevention, secondary prevention) or treatment of a dangerous blood clot (acute thrombosis). [0099] Inhibiting the activity of PDI, ERp5 or ERp57 blocks thrombus formation following laser-induced injury of blood vessels in a murine model of thrombosis. [0100] Furthermore, since inhibiting the activity of thiol isomerases effects both platelet accumulation and fibrin formation, these therapeutics would be an improvement over currently available therapies that only target either arterial clots (heart attacks and strokes largely triggered by inappropriate activation of platelets) or venous clots (deep-vein thrombosis and pulmonary embolism largely caused by inappropriate activation of the coagulation system). Data suggests that each thiol isomerase has unique substrate specificities and mechanisms of action suggesting each could be an independent target. [0101] The thrombotic disease or condition to be prevented or treated by the extracellular thiol isomerase inhibitor compound can be acute myocardial infarction, stable angina, unstable angina, acute occlusion following coronary angioplasty and/or stent placement, a transient ischemic attack, cerebrovascular disease, stroke, peripheral vascular disease, placental insufficiency, atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a combination thereof. [0102] Platelet responses in the presence of zafirlukast, (0.1µM –10µM) were tested in a range of platelet functional assays including aggregation, granule secretion and spreading studies. Zafirlukast was found to inhibit platelet aggregation, dense and α-granule secretion, platelet spreading upon collagen and thrombus formation under flow. These data suggest that zafirlukast and other broad spectrum inhibitors of thiol isomerases of the protein disulfide isomerase subfamily can be used as an anti-thrombotic drug. [0103] In an embodiment, the disease or condition influenced by the activity of one or more extracellular thiol isomerases is arterial thrombosis, venous thrombosis, a thrombotic disease such as acute myocardial infarction, stable angina, unstable angina, acute occlusion following coronary angioplasty and/or stent placement, a transient ischemic attack, cerebrovascular disease, stroke, peripheral vascular disease, placental insufficiency, atrial fibrillation, deep vein thrombosis, and pulmonary embolism, or a combination thereof; and wherein the extracellular thiol isomerase inhibitor compound is a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof. Anti-Cancer [0104] PDI inhibition is a viable target for cancer therapy. See, Xu et al. “Protein disulfide isomerase: a promising target for cancer therapy” Drug Discovery Today, Vol. 19, No. 3, March 2014. [0105] There is further evidence for tumor metastasis role for ERp5. See Gumireddy et al. “In vivo selection for metastasis promoting genes in the mouse” PNAS (2007) 104, 6696-6701. [0106] ERp57 is expressed from the PDIA3 gene in humans. It consists of 505 amino acids and it is upregulated in breast, lung, uterine, stomach and hepatic cancer, as well as melanoma in comparison to normal tissues. The expression levels of ERp57 have been positively correlated with the transforming abilities of the oncogenic sarcoma virus in NIH3T3 cells, suggesting that ERp57 is involved in oncogenic transformation. Unlike the other PDI family members, ERp57 has the ability to interact with nuclear DNA and activate gene expression as ERp57 interacts with DNA molecules through its catalytically active a’ domain. ERp57 is also a component of the STAT3-transcriptional complex and the ERp57- STAT3 modulates the cell signaling and proliferation regulated by STAT3. ERp57 also regulates gene expression through the mTOR pathway, which is another important regulator of cell proliferation and survival. ERp57 has also been implicated in binding at least three proteins involved with DNA repair, including Ref-1/APE, which itself has the ability to activate additional transcription factors. In addition to gene regulation functions, increased ERp57 expression is correlated to a resistance to treatment with paclitaxel in ovarian cancer and radioresistance in laryngeal cancer, promotes the metastasis of breast cancer into bone, and is involved in the deregulation of EGFR signaling in a breast cancer cell line, preventing its downstream activation of target molecules such as STAT3, Akt and PLCγ. As ERp57 plays a role in thrombus formation it is a potential target in the prevention of cancer- associated thrombosis, a major cause of morbidity and mortality in cancer patients. [0107] The cancer to be treated can be ovarian, prostate, lung, melanoma, lymphoma, glioma, breast, colon, colorectal, hematological, laryngeal, melanoma, or neuroblastoma. [0108] The compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof can be used alone or optionally in combination with another anti-cancer or chemotherapeutic agent. [0109] In an embodiment, the cancer is treated with a combination of the compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent such as carboplatin or cisplatin. [0110] This invention is further illustrated by the following examples that should not be construed as limiting. EXAMPLES: Example 1. Representative schemes for the synthesis of compounds [0111] Zafirlukast (ZAF) derivatives were prepared having Scaffolds I (indole), IIa, and IIb (Table 1). Scaffold I where the organization of the substituents on the benzoyl group (ring B) was kept the same as that found in the parent ZAF, and scaffolds IIa and IIb where the organization of the substituents on ring B was different than that found in ZAF. The use of three different ZAF scaffolds offered an ideal opportunity for initial SAR studies. Scheme I.

X = R⁶, O, S; Y = CH, N; R¹¹ = I, Br, Li; R¹² = MgI, MgBr a. NIS, TFA, THF; b. NIH, CH₂Cl₂; c. NBS, Al₂O₃, Et₃N, THF, hexanes; d. NBS, DMF; e. n- BuLi, THF, hexanes; f. I2, hexanes, Et2O, H2O; g. Mg, I2, THF.

X = R⁶, O, S; Y = CH, N; R¹³ = I, Br, Li, MgI, MgBr h. NaBH₄, THF, i. PBr₃, Et₂O; j. n-BuLi, THF; k. n-BuLi, ZnBr₂, Pd(PPh₃)₄, THF; l. n-BuLi, Et₂O; m. Zn, I₂, S-Phos, Pd₂dba₃, DMF; n. Zn, P(Ph)₃, Pd(OAc)₂, TMSCl, 1,2- dibromoethane, THF, o. Zn, Cl2Pd(PPh3)2, DMA, benzene; p. THF; q. KOH, MeOH/THF/H2O; r. arylsulfonamide, EDC•HCl, DMAP, CH2Cl2. [0112] Scheme I is a general three-step linear synthesis that will be used to make the indole derivatives proposed (alternative synthetic routes or additional steps may be used for the preparation of some of the proposed derivatives). This representative synthetic route shows: (a) a condensation reaction between substituted indoles and methyl-5-formyl-2- methoxy benzoate using triethylsilane, which is a source of anhydride, trifluoroacetic acid, and dichloromethane, (b) hydrolysis of the ester to a carboxylic acid using sodium hydroxide, methanol, tetrahydrofuran, and water, followed by (c) amide coupling using an arylsulfonamide, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, which is the reducing agent, 4-dimethylaminopyridine, and dichloromethane. [0113] Scheme II. is a general synthesis that will be used to make additional heteroaryl and heterocycles derivatives (containing N, O, or S) beyond the indole ring. For Scheme II. the step that will differ from that of Scheme I. is the first step with the condensation reaction (labeled as step (a) in Scheme II.), while steps (q) and (r) will remain the same as steps (b) and (c) for Scheme I. in terms of the hydrolysis of the ester to the carboxylic acid and amide coupling as the final two steps of the synthesis. For Scheme II., 5- and 6-membered heterocyclic rings will first undergo iodination, bromination, or undergo the addition of lithium at the C-2 position for 5-membered rings and the C-3 position for 6- membered. rings (using one of the steps a-f). These compounds will either be taken directly to the next step (with R₁ = iodine, bromine, or lithium) or they will undergo step (g) to synthesize a Grignard reagent to further push the reaction forward (with R1 = magnesium iodide or magnesium bromide). This synthesis is a convergent synthesis where methyl-5- formyl-2-methoxybenzoate undergoes a reduction (h) of the aldehyde to a primary alcohol, followed by (i) bromination, the addition of the heterocycle with R1 = iodine, bromine, lithium, magnesium iodide, or magnesium bromide (using one of the steps j-p) to yield the ester which undergoes the same hydrolysis of the ester to the carboxylic acid (step b from Scheme I.), and the final step as the amide coupling (step c from Scheme I.). These steps may allow for the 5- and 6-membered heterocycles to be more reactive in order to push the reactions to go to completion to move forward in making the final compounds. [0114] Representative compounds of Formula (I), (II), or (III) are described in Table 1.

Table 1.

Compounds 1-5 Compounds 6-35, 38-42 Compounds 36-37

* insulin-based turbidometric assay; “ND” = >100 µM. [0115] Materials and instrumentation. All chemicals were purchased from Oakwood Chemical (San Diego, CA), Combi-Blocks (San Diego, CA), TCI America (Portland, OR), Sigma Aldrich (St. Louis, MO), Synthonix (Wake Forest, NC), Matrix Scientific (Columbia, SC), Ricca Chemical Company (Arlington, TX), Acros Organics (Geel, Belgium), Beantown Chemical (Hudson, NH), Chem-Impex (Wood Dale, IL), Alfa Aesar (Ward Hill, MA), and used without further purification. All chemical reactions were monitored by thin layer chromatography (TLC) using glass plates coated with Merk silica gel 60 F₂₅₄. UV light was used to visualize the chromatographic bands on the TLC plates. Silica gel column chromatography with SiliaFlash® F60 (40-63 ^M, SiliCycle, Québec, Canada) was used to purify compounds. Varian 500 (VNMRS500) or 400 (MR400) MHz spectrometers were used to record ¹H NMR spectra at 500 or 400 MHz, respectively. A Varian 400 MHz spectrometer was used to record all ¹³C NMR spectra at 100 MHz. All NMR spectra chemical shifts (δ) are given in parts per million (ppm). All coupling constants (J) are given in Hertz (Hz), and the abbreviations used for signal shape are singlet (s), doublet (d), triplet (t), multiplet (m), doublet of doublets (dd), doublet of triplets (dt), and triplet of doublets (td). High-resolution mass spectrometry (HRMS) was performed on an AB SCIEX TripleTOFTM5600 mass spectrometer. [0116] Synthesis of compound SM2. A solution of 5- nitroindole (3.0 g, 18.5 mmol) in anhydrous DMF (15 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil, 1.48 g, 37.0 mmol).

The reaction mixture was allowed to stir at room temperature for 1 h. The mixture was cooled to 0 °C, iodoethane (2.98 mL, 37.0 mmol) was then slowly added, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by pouring onto ice and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with NaHCO₃, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/3:1, Rf 0.46) to yield compound SM2 (1.70 g, 48%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.58 (dd, J₁ = 2.2 Hz, J₂ = 0.5 Hz, 1H, aromatic), 8.10 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.34 (dt, J₁ = 9.1 Hz, J₂ = 0.7 Hz, 1H, aromatic), 7.25 (d, J = 3.3 Hz, 1H, aromatic), 6.66 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H, aromatic), 4.21 (q, J = 7.4 Hz, 2H, NCH₂CH₃), 1.49 (t, J = 7.4 Hz, 3H, NCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 138.7, 131.9, 130.4, 128.0, 118.5, 117.3, 109.3, 104.2, 41.7, 15.6. [0117] Synthesis of compound SM3 . A solution of 5- nitroindole (3.0 g, 18.5 mmol) in anhydrous DMF (15 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil, 1.48 g, 37.0 mmol). The

reaction mixture was allowed to stir at room temperature for 1 h. The mixture was cooled to 0 °C, 1-iodopropane (3.59 mL, 37.0 mmol) was then slowly added, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by pouring onto ice and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO3, H2O, and brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, R_f 0.81) to yield compound SM3 (2.71 g, 72%) as a brown liquid: ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J = 2.3Hz, 1H, aromatic), 8.09 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.33 (dd, J1 = 9.1 Hz, J2 = 0.7 Hz, 1H, aromatic), 7.23 (d, J = 3.2 Hz, 1H, aromatic), 6.66 (dt, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H, aromatic), 4.12 (t, J = 7.1 Hz, 2H, NCH₂CH₂CH₃), 1.88 (sextet, J = 7.4 Hz, 2H, NCH₂CH₂CH₃), 0.93 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 141.6, 139.0, 131.2, 127.8, 118.4, 117.2, 109.4, 104.0, 48.7, 23.7, 11.6. [0118] Synthesis of compound SM4 KCH-3-26 (SGT1631). A solution of 5-nitroindole (3.0 g, 18.5 mmol) in anhydrous DMF (15 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil, 1.48 g, 37.0 mmol). The reaction mixture was allowed to stir at room temperature for 1

h. The mixture was cooled to 0 °C, 1-iodobutane (4.20 mL, 37.0 mmol) was then slowly added, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by pouring onto ice and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with NaHCO₃, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/3:1, Rf 0.53) to yield compound SM4 (1.54 g, 38%) as a brown liquid: ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J = 2.2 Hz, 1H, aromatic), 8.09 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.33 (d, J = 9.1 Hz, 1H, aromatic), 7.23 (d, J = 3.3 Hz, 1H, aromatic), 6.65 (dd, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H, aromatic), 4.15 (t, J = 7.2 Hz, 2H, NCH2CH2CH2CH3), 1.82 (p, J = 7.7 Hz, 2H, NCH₂CH₂CH₂CH₃), 1.33 (sextet, J = 7.7 Hz, 2H, NCH₂CH₂CH₂CH₃), 0.93 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 141.7, 139.0, 131.2, 127.9, 118.5, 117.3, 109.4, 104.0, 46.8, 32.5, 20.3, 13.8. [0119] Synthesis of compound SM5 . A solution of 5-nitroindole (3.0 g, 18.5 mmol) in anhydrous DMF (15 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil, 1.48 g, 37.0 mmol). The reaction

mixture was allowed to stir at room temperature for 1 h. The mixture was cooled to 0 °C, 1-iodo-2-methylpropane (4.25 mL, 37.0 mmol) was then slowly added, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by pouring onto ice and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO3, H2O, and brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.89) to yield compound SM5 (1.12 g, 28%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃,) δ 8.57 (d, J = 2.3 Hz, 1H, aromatic), 8.09 (dd, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H, aromatic), 7.32 (dt, J₁ = 9.1 Hz, J₂ = 0.7 Hz, 1H, aromatic), 7.20 (d, J = 3.3 Hz, 1H, aromatic), 6.66 (dd, J₁ = 3.2 Hz, J₂ = 0.8 Hz, 1H, aromatic), 3.94 (d, J = 7.4 Hz, 2H, NCH₂), 2.18 (septet, J = 7.3 Hz, 1H, CH(CH3)2), 0.92 (d, J = 6.7 Hz, 6H, CH(CH3)2); ¹³C NMR (100 MHz, CDCl3) δ 141.6, 139.3, 131.7, 127.8, 118.4, 117.3, 109.6, 103.9, 54.7, 29.9, 20.4 (2CH3). [0120] Synthesis of compound SM6 . A solution of 5-nitroindole (3.0 g, 18.5 mmol) in anhydrous DMF (15 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil, 1.11 g, 27.8 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The mixture was

cooled to 0 °C, benzyl bromide (3.30 mL, 27.8 mmol) was then slowly added, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by pouring onto ice and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with NaHCO₃, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/3:1, Rf 0.58) to yield compound SM6 (3.10 g, 66%) as a tan solid: ¹H NMR (500 MHz, CDCl3) δ 8.59 (dd, J1 = 2.3 Hz, J2 = 0.6 Hz, 1H, aromatic ), 8.06 (dd, J1 = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.33-7.27 (m, 4H, aromatic), 7.26 (d, J = 3.3 Hz, 1H, aromatic), 7.09-7.18 (m, 2H, aromatic), 6.72 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H, aromatic), 5.35 (s, 2H, NCH2); ¹³C NMR (100 MHz, CDCl3) δ 142.0, 139.2, 136.4, 131.7, 129.2 (2CH), 128.3, 128.1, 127.0 (2CH), 118.4, 117.6, 109.8, 104.6, 50.8.

. was was allowed to warm to room temperature overnight. The reaction was quenched with H₂O and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO3, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.60) to yield compound SM9 (0.24 g, 63%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.46 (dd, J₁ = 2.2 Hz, J₂ = 0.6 Hz, 1H, aromatic), 8.09 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.69 (d, J = 2.5 Hz, 1H, aromatic), 7.35 (dd, J1 = 8.6 Hz, J2 = 2.4 Hz, 1H, aromatic), 7.30 (dd, J1 = 9.2 Hz, J₂ = 0.7 Hz, 1H, aromatic), 6.91 (d, J = 8.7 Hz, 1H, aromatic), 6.90 (s, 1H, aromatic), 4.14 (q, J = 7.4 Hz, 2H, NCH₂CH₃), 4.06 (s, 2H, CH₂Ar), 3.87 (s, 3H, ArOCH₃), 3.85 (s, 3H, ArCO2CH3), 1.44 (t, J = 7.4 Hz, 3H, NCH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 167.0, 157.9, 141.4, 139.2, 133.8, 132.1, 131.9, 128.6, 127.3, 120.3, 117.7, 117.6, 116.8, 112.5, 109.3, 56.4, 52.3, 41.6, 30.4, 15.6.

was allowed to warm to room temperature overnight. The reaction was quenched with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO₃, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.73) to yield compound SM10 (0.24 g, 63%) as a dark yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.46 (dd, J₁ = 2.3 Hz, J₂ = 0.5 Hz, 1H, aromatic), 8.08 (dd, J₁ = 9.1 Hz, J2 = 2.2 Hz, 1H, aromatic), 7.68 (d, J = 2.5 Hz, 1H, aromatic), 7.34 (dd, J1 = 8.6 Hz, J2 = 2.5 Hz, 1H, aromatic), 7.29 (d, J = 9.1 Hz, 1H, aromatic), 6.91 (d, J = 8.6 Hz, 1H, aromatic), 6.88 (app. t, J = 1.1 Hz, 1H, aromatic), 4.06 (s, 2H, CH₂Ar), 4.04 (t, J = 7.2 Hz, 2H, NCH2CH2CH3), 3.87 (s, 3H, ArOCH3), 3.85 (s, 3H, ArCO2CH3), 1.83 (sextet, J = 7.4 Hz, 3H, NCH2CH2CH3), 0.90 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 166.9, 157.9, 141.3, 139.6, 133.7, 132.1, 131.9, 129.4, 127.2, 120.2, 117.54, 117.46, 116.8, 112.5, 109.5, 56.3, 52.2, 48.5, 30.3, 23.8, 11.6.

temperature overnight. The reaction was quenched with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO3, H2O, and brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.60) to yield compound SM11 (0.10 g, 8%) as a yellow liquid (which contained some methyl-5-formyl-2-methoxybenzoate that was removed in the next synthetic step): ¹H NMR (500 MHz, CDCl3) δ 8.45 (dd, J1 = 2.3 Hz, J2 = 0.5 Hz, 1H, aromatic), 8.08 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.68 (d, J = 2.4 Hz, 1H, aromatic), 7.34 (dd, J1 = 8.6 Hz, J2 = 2.5 Hz, 1H, aromatic), 7.29 (d, J = 9.1 Hz, 1H, aromatic), 6.90 (d, J = 8.6 Hz, 1H, aromatic), 6.88 (app. t, J = 1.1 Hz, 1H, aromatic), 4.07 (t, J = 7.3 Hz, 2H, NCH₂CH₂CH₂CH₃), 4.05 (s, 2H, CH₂Ar), 3.87 (s, 3H, ArOCH₃), 3.85 (s, 3H, ArCO₂CH₃), 1.81-1.75 (m, 2H, NCH₂CH₂CH₂CH₃), 1.34-1.27 (m, 2H, NCH₂CH₂CH₂CH₃), 0.92 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 166.2, 156.5, 140.2, 134.8, 133.3, 132.5, 130.4, 126.4, 119.8, 116.54, 116.47, 116.0, 113.2, 112.7, 110.4, 55.8, 51.8, 31.9, 29.0, 19.4, 13.5. stirred at 0 C for 10 min and was allowed to warm to room temperature overnight. The reaction was quenched with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO₃, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.72) to yield compound SM12 (0.11 g, 36%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, J = 2.2 Hz, 1H, aromatic), 8.08 (dd, J1 = 9.1 Hz, J2 = 2.2 Hz, 1H, aromatic), 7.68 (d, J = 2.5 Hz, 1H, aromatic), 7.34 (dd, J1 = 8.6 Hz, J2 = 2.5 Hz, 1H, aromatic), 7.28 (d, J = 9.1 Hz, 1H, aromatic), 6.90 (d, J = 8.6 Hz, 1H, aromatic), 6.87 (app. t, J = 1.1 Hz, 1H, aromatic), 4.06 (s, 2H, CH₂Ar), 3.87 (d, J = 7.4 Hz, 2H, NCH₂), 3.87 (s, 3H, ArOCH₃),3.84 (s, 3H, ArCO₂CH₃), 2.14 (septet, J = 7.0 Hz, 1H, CH(CH3)2), 0.90 (t, J = 6.7 Hz, 6H, CH(CH3)2); ¹³C NMR (100 MHz, CDCl3) δ 166.9, 157.9, 141.3, 139.9, 133.7, 132.1, 131.9, 129.9, 127.1, 120.2, 117.6, 117.4, 116.8, 112.5, 109.7, 56.3, 54.5, 52.2, 30.3, 29.9, 20.4.

overnight. The reaction was quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with NaHCO₃, H₂O, and brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.59) to yield compound SM13 (0.23 g, 20%) as a yellow solid: ¹H NMR (500 MHz, CDCl3) δ 8.47 (dd, J1 = 2.3 Hz, J2 = 0.5 Hz, 1H, aromatic), 8.05 (dd, J₁ = 9.1 Hz, J₂ = 2.2 Hz, 1H, aromatic), 7.68 (d, J = 2.4 Hz, 1H, aromatic), 7.35 (dd, J₁ = 8.6 Hz, J₂ = 2.5 Hz, 1H, aromatic), 7.32-7.27 (m, 3H, aromatic), 7.08-7.05 (m, 2H, aromatic), 6.95 (app. t, J = 1.1 Hz, 1H, aromatic), 6.90 (d, J = 8.6 Hz, 1H, aromatic), 5.28 (s, 2H, NCH2Ar), 4.07 (s, 2H, CH2Ar), 3.87 (s, 3H, ArOCH3), 3.85 (s, 3H, ArCO₂CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 166.9, 157.9, 141.6, 139.8, 136.5, 133.7, 131.93, 131.87, 129.8, 129.2, 128.3, 127.5, 126.9, 120.3, 118.0, 117.9, 116.8, 112.5, 109.9, 56.3, 52.2, 50.7, 30.4.

[0126] Synthesis of compoundM14 A solution of methyl 2-methoxy-5-((1-methyl-5- nitro-1H-indol-3-yl)methyl)benzoate (112 mg, 0.32 mmol) in MeOH/THF/H2O (3 mL/1 mL/0.6 mL) was treated with KOH pellets (124 mg, 2.21 mmol), and the mixture was refluxed at 65° C. for 2 h. After completion of the reaction, the organic solvents were removed in vacuo. The resulting mixture was acidified to pH 1 with 1 N aqueous HCl. The precipitate was filtered and eluted with H2O to afford compound 20 (94 mg, 87%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 10.7 (very br s, 1H, CO₂H), 8.38 (d, J=2.0 Hz, 1H, aromatic), 8.10 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H, aromatic), 8.04 (d, J=2.4 Hz, 1H, aromatic), 7.49 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H, aromatic), 7.28 (d, J=9.2 Hz, 1H, aromatic), 7.00 (d, J=8.0 Hz, 1H, aromatic), 6.94 (s, 1H, aromatic), 4.09 (s, 2H, CH2Ar), 4.05 (s, 3H, ArOCH3), 3.79 (s, 3H, NCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 156.5, 141.2, 140.0, 135.0, 134.4, 133.6, 130.3, 126.8, 117.6, 117.5, 116.5, 116.4, 111.9, 109.2, 56.8, 33.2, 30.1; m/z calcd for C18H16N2O5340.1; found 323.1 [M−OH]⁺.

were removed in vacuo after the reaction was complete. The resulting mixture was acidified to pH 1 with 1 N aqueous HCl and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated to yield compound SM15 (0.17 g, 75%) as a yellow solid: ¹H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 2.2 Hz, 1H, aromatic), 8.09 (dd, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H, aromatic), 8.06 (d, J = 2.5 Hz, 1H, aromatic), 7.49 (dd, J₁ = 8.5 Hz, J₂ = 2.5 Hz, 1H, aromatic), 7.30 (d, J = 9.2 Hz, 1H, aromatic), 7.00 (d, J = 8.2 Hz, 1H, aromatic), 6.99 (s, 1H, aromatic), 4.15 (q, J = 7.4 Hz, 2H, NCH2CH3), 4.10 (s, 2H, CH2Ar), 4.05 (s, 3H, ArOCH3), 1.46 (t, J = 7.3 Hz, 3H, NCH2CH3); ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 156.8, 135.3, 134.7, 133.9, 128.7, 127.1, 117.8, 117.6, 116.9, 116.7, 112.1, 109.4, 57.0, 41.6, 30.5, 15.6.

resulting mixture was acidified to pH 1 with 1 N aqueous HCl and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated to yield compound SM16 (0.17 g, 88%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J = 2.2 Hz, 1H, aromatic), 8.08 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 8.06 (d, J = 2.5 Hz, 1H, aromatic), 7.48 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H, aromatic), 7.30 (d, J = 9.2 Hz, 1H, aromatic), 6.99 (d, J = 8.6 Hz, 1H, aromatic), 6.97 (app. t, J = 1.0 Hz, 1H, aromatic), 4.10 (s, 2H, CH₂Ar), 4.06 (t, J = 7.2 Hz, 2H, NCH₂CH₂CH₃), 4.05 (s, 3H, ArOCH3), 1.85 (sextet, J = 7.4 Hz, 2H, NCH2CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 165.5, 156.8, 141.3, 139.7, 135.2, 134.6, 133.8, 129.5, 127.0, 117.8, 117.6, 116.68, 116.66, 112.1, 109.6, 57.0, 48.6, 30.4, 23.8, 11.7.

was aqueous and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated to yield compound SM17 (71 mg, 82%) as a yellow solid: ¹H NMR (500 MHz, CD3OD) δ 8.30 (dd, J1 = 2.3 Hz, J2 = 0.6 Hz, 1H, aromatic), 7.97 (dd, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H, aromatic), 7.66 (d, J = 2.4 Hz, 1H, aromatic), 7.42 (d, J = 9.1 Hz, 1H, aromatic), 7.39 (dd, J₁ = 8.6 Hz, J₂ = 2.5 Hz, 1H, aromatic), 7.17 (app. t, J = 1.0 Hz, 1H, aromatic), 6.99 (d, J = 8.6 Hz, 1H, aromatic), 4.13 (t, J = 7.1 Hz, 2H, NCH2CH2CH2CH3), 4.04 (s, 2H, CH2Ar), 3.91 (s, 1H, OH), 3.81 (s, 3H, ArOCH3), 1.76-1.70 (m, 2H, NCH₂CH₂CH₂CH₃), 1.27-1.20 (m, 2H, NCH₂CH₂CH₂CH₃), 0.86 (t, J = 7.5 Hz, 3H, NCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz, (CD₃)₂SO) δ 156.4, 140.2, 139.1, 132.8, 132.6, 132.5, 130.4, 126.4, 121.0, 116.6, 116.5, 116.0, 113.0, 112.5, 110.4, 55.8, 45.5, 31.9, 29.1, 19.4, 13.5.

resulting mixture was acidified to pH 1 with 1 N aqueous HCl and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to yield compound SM18 (81 mg, 84%) as a yellow solid (which contained some methyl-5-formyl-2-methoxybenzoate that was removed in the next synthetic step): ¹H NMR (500 MHz, (CD₃)₂SO) δ 8.41 (d, J = 2.3 Hz, 1H, aromatic), 8.00 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.68 (d, J = 9.2 Hz, 1H, aromatic), 7.54 (d, J = 2.5 Hz, 1H, aromatic), 7.47 (s, 1H, aromatic), 7.42 (dd, J1 = 8.6 Hz, J2 = 2.4 Hz, 1H, aromatic), 7.05 (d, J = 8.6 Hz, 1H, aromatic), 4.10 (s, 2H, CH₂Ar), 4.04 (d, J = 7.4 Hz, 2H, NCH₂), 3.77 (s, 3H, ArOCH₃), 2.10 (septet, J = 7.2 Hz, 1H, CH(CH3)2), 0.84 (d, J = 6.7 Hz, 6H, CH(CH3)2); ¹³C NMR (100 MHz, (CD3)2SO) δ 166.4, 162.6, 140.2, 134.3, 132.8, 132.54, 132.45, 130.9, 128.7, 121.8, 121.0, 116.5, 116.0, 113.0, 112.5, 110.7, 56.4, 55.8, 29.3, 19.7 (2CH₃). [0131] Synthesis of compound SM19. A solution of compound SM13 (0.20 g, 0.46 mmol) in MeOH:THF:H2O/10:2:2 (14 mL total) was stirred and treated with KOH pellets (0.18 g, 3.25 mmol). The resulting mixture was refluxed at 65 °C for 2 h. The organic solvents were removed in vacuo after the reaction was complete. The resulting mixture was acidified to pH 1 with 1 N aqueous HCl and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated to yield compound SM19 (60 mg, 31%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.33 (d, J = 2.1 Hz, 1H, aromatic), 7.94 (dd, J₁ = 9.2 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.64 (d, J = 2.5 Hz, 1H, aromatic), 7.39 (dd, J1 = 8.5 Hz, J2 = 2.6 Hz, 1H, aromatic), 7.37 (d, J = 9.1 Hz, 1H, aromatic), 7.24-7.20 (m, 3H, aromatic), 7.20-7.15 (m, 1H, aromatic), 7.09-7.07 (m, 2H, aromatic), 6.99 (d, J = 8.6 Hz, 1H, aromatic), 5.35 (s, 2H, NCH2Ar), 4.06 (s, 2H, CH2Ar), 3.90 (s, 1H, OH), 3.80 (s, 3H, ArOCH3); ¹³C NMR (100 MHz, CDCl3) δ 165.5, 156.8, 141.6, 139.9, 136.4, 135.2, 134.5, 133.8, 130.0, 129.3, 128.3, 127.3, 126.9, 118.0, 117.8, 117.2, 116.7, 112.1, 110.0, 57.0, 50.7, 30.4.

quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.17) to yield compound 27 (18 mg, 40%) as an orange solid: ¹H NMR (500 MHz, CDCl3) δ 10.66 (s, 1H, NH), 8.29 (dd, J1 = 7.9 Hz, J2 = 1.7 Hz, 1H, aromatic), 8.20 (d, J = 2.2 Hz, 1H, aromatic), 8.09 (dd, J₁ = 9.1 Hz, J₂ = 2.2 Hz, 1H, aromatic), 7.89 (d, J = 2.5 Hz, 1H, aromatic), 7.56 (dd, J₁ = 8.6 Hz, J₂ = 2.5 Hz, 1H, aromatic), 7.53-7.42 (m, 3H, aromatic), 7.29 (d, J = 9.1 Hz, 1H, aromatic), 7.03 (d, J = 8.6 Hz, 1H, aromatic), 6.55 (s, 1H, aromatic), 4.08 (s, 3H, NCH3), 3.71 (s, 5H, CH2Ar, ArOCH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 155.5, 140.3, 139.8, 135.9, 135.2, 133.1, 132.3, 131.8 (2CH), 131.7, 130.8, 128.9, 127.61, 127.59, 125.8 (2CH), 119.8, 116.7, 116.3, 112.3, 110.5, 56.0, 36.6, 32.9; m/z calcd for C24H20ClN3O6S 513.95.

quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, Rf 0.25) to yield compound 28 (26 mg, 53%) as an orange solid: ¹H NMR (500 MHz, CDCl3) δ 10.72 (s, 1H, NH), 8.33 (dd, J1 = 7.9 Hz, J2 = 1.7 Hz, 1H, aromatic), 8.20 (d, J = 2.2 Hz, 1H, aromatic), 8.10 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.89 (d, J = 2.5 Hz, 1H, aromatic), 7.69 (dd, J₁ = 7.9 Hz, J₂ = 1.3 Hz, 1H, aromatic), 7.56 (dd, J1 = 8.6 Hz, J2 = 2.6 Hz, 1H, aromatic), 7.49 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H, aromatic), 7.42 (qd, J₁ = 8.5 Hz, J₂ = 1.8 Hz, 1H, aromatic), 7.29 (d, J = 9.1 Hz, 1H, aromatic), 7.03 (d, J = 8.6 Hz, 1H, aromatic), 6.55 (s, 1H, aromatic), 4.08 (s, 3H, NCH₃), 3.71 (s, 5H, CH2Ar, ArOCH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 155.6, 140.3, 139.8, 136.0, 135.2, 132.6, 131.9 (2CH), 129.1, 128.1, 125.8 (2CH), 119.8, 119.2 (2C), 116.7, 116.3, 112.4, 110.5 (2CH), 109.6, 56.1, 36.6, 32.9; m/z calcd for C₂₄H₂₀BrN₃O₆S 558.40.

. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, R_f 0.29) to yield compound 29 (11 mg, 25%) as an yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 10.64 (s, 1H, NH), 8.33 (d, J = 2.8 Hz, 1H, aromatic), 8.08 (dd, J₁ = 9.3 Hz, J2 = 2.4 Hz, 1H, aromatic), 7.90 (d, J = 2.4 Hz, 1H, aromatic), 7.56-7.51 (m, 1H, aromatic), 7.48 (dd, J1 = 8.6 Hz, J2 = 2.6 Hz, 1H, aromatic), 7.26 (d, J = 9.2 Hz, 1H, aromatic), 7.01 (t, J = 8.7 Hz, 2H, aromatic), 6.84 (d, J = 8.6 Hz, 1H, aromatic), 6.88 (s, 1H, aromatic), 4.05 (s, 3H, NCH3), 4.03 (s, 2H, CH2Ar), 3.76 (s, 3H, ArOCH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 164.1, 157.9, 148.8 (2C), 140.2, 139.6, 131.4, 129.2, 129.13 (2CH), 129.10, 129.06, 126.3, 126.0, 117.5, 116.6, 116.5, 115.9 (2CH), 112.2, 110.4, 55.9, 43.5, 32.8; m/z calcd for C24H19F2N3O6S 515.49.

CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.41) to yield compound 30 (16 mg, 35%) as an yellow solid: ¹H NMR (500 MHz, CDCl3) δ 10.57 (s, 1H, NH), 8.33 (d, J = 2.2 Hz, 1H, aromatic), 8.18-8.14 (m, 1H, aromatic), 8.08 (dd, J₁ = 9.1 Hz, J₂ = 2.4 Hz, 1H, aromatic), 7.87 (d, J = 2.5 Hz, 1H, aromatic), 7.47 (dd, J₁ = 8.5 Hz, J₂ = 2.1 Hz, 1H, aromatic), 7.26 (d, J = 9.1 Hz, 1H, aromatic), 7.05-7.01 (m, 1H, aromatic), 6.97 (d, J = 8.6 Hz, 1H, aromatic), 6.92-6.88 (m, 1H, aromatic), 6.87 (s, 1H, aromatic), 4.05 (s, 3H, NCH3), 4.03 (s, 2H, CH2Ar), 3.76 (s, 3H, ArOCH₃); ¹³C NMR (100 MHz, (CD₃)₂SO) δ 155.3, 140.2, 139.6 (2C), 133.6, 133.5, 132.9, 131.4, 129.1, 126.3, 116.5, 116.4, 115.9, 112.3, 112.2, 110.4 (2CH), 106.2, 105.94, 105.91, 105.7, 55.9, 32.8, 28.9; m/z calcd for C24H19F2N3O6S 515.49. and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.18) to yield compound 31 (12 mg, 26%) as an amber solid: ¹H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H, NH), 8.19 (d, J = 2.0 Hz, 1H, aromatic), 8.10 (dd, J1 = 9.1 Hz, J2 = 2.2 Hz, 1H, aromatic), 7.99-7.94 (m, 2H, aromatic), 7.92-7.89 (m, 1H, aromatic), 7.54 (dd, J₁ = 8.6 Hz, J₂ = 2.5 Hz, 1H, aromatic), 7.31 (d, J = 9.1 Hz, 2H, aromatic), 7.00 (d, J = 8.7 Hz, 1H, aromatic), 6.58 (s, 1H, aromatic), 4.06 (s, 3H, NCH₃), 3.73 (s, 5H, CH2Ar, ArOCH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 172.0, 164.1, 154.9 (2C), 140.2, 139.8, 134.6, 131.8, 131.7, 131.5, 128.3, 128.2, 125.9, 120.4 (2CH), 117.5, 116.8, 116.62, 116.58, 116.4, 110.5, 55.5, 37.1, 32.9; m/z calcd for C₂₄H₁₉F₂N₃O₆S 515.49.

organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.46) to yield compound 32 (50 mg, quant.) as a yellow solid: ¹H NMR (500 MHz, (CD3)2SO) δ 12.25 (s, 1H, NH), 8.43 (dd, J1 = 2.4 Hz, J2 = 0.5 Hz, 1H, aromatic), 8.00 (dd, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H, aromatic), 7.95 (t, J = 7.7 Hz, 1H, aromatic), 7.81-7.75 (m, 1H, aromatic), 7.65 (dd, J₁ = 9.2 Hz, J₂ = 0.5 Hz, 1H, aromatic), 7.49 (s, 1H, aromatic), 7.47-7.43 (m, 1H, aromatic), 7.30 (d, J = 2.3 Hz, 1H, aromatic), 7.06 (d, J = 8.6 Hz, 1H, aromatic), 4.24 (q, J = 7.3 Hz, 2H, NCH2CH3), 4.07 (s, 2H, CH2Ar), 3.78 (s, 3H, ArOCH3), 1.35 (t, J = 7.3 Hz, 3H, NCH2CH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 164.0, 157.0, 155.3, 140.2, 138.7, 132.9, 131.2, 129.8, 129.1, 126.4, 124.7, 117.5, 117.2, 117.0, 116.6, 116.4, 116.0, 112.2, 110.3, 109.6, 55.9, 40.7, 29.0, 15.4; m/z calcd for C25H22FN3O6S 511.52.

extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.27) to yield compound 38 (37 mg, 82%) as an orange solid: ¹H NMR (500 MHz, (CD₃)₂SO) δ 12.19 (s, 1H, NH), 8.45 (d, J = 8.9 Hz, 2H, aromatic), 8.40 (d, J = 2.3 Hz, 1H, aromatic), 8.20 (d, J = 9.0 Hz, 2H, aromatic), 7.99 (dd, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H, aromatic), 7.64 (d, J = 9.1 Hz, 1H, aromatic), 7.48 (s, 1H, aromatic), 7.46 (dd, J₁ = 8.6 Hz, J₂ = 2.4 Hz, 1H, aromatic), 7.33 (d, J = 2.3 Hz, 1H, aromatic), 7.06 (d, J = 8.6 Hz, 1H, aromatic), 4.23 (q, J = 7.3 Hz, 2H, NCH₂CH₃), 4.06 (s, 2H, CH2Ar), 3.80 (s, 3H, ArOCH3), 1.33 (t, J = 7.3 Hz, 3H, NCH2CH3); ¹³C NMR (100 MHz, (CD3)2SO) δ 165.1, 155.5, 150.3, 144.6, 140.2, 138.6, 133.5, 133.0, 129.8, 129.4, 129.3, 126.4, 124.4, 121.6, 116.5, 116.4, 115.9, 112.3, 110.3, 56.0, 40.7, 28.9, 15.3; m/z calcd for C25H22N4O8S 538.53. organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.46) to yield compound 33 (39 mg, 91%) as a yellow solid: ¹H NMR (500 MHz, (CD₃)₂SO) δ 12.25 (s, 1H, NH), 8.42 (d, J = 2.3 Hz, 1H, aromatic), 7.99 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H, aromatic), 7.95 (t, J = 7.3 Hz, 1H, aromatic), 7.81-7.74 (m, 1H, aromatic), 7.66 (d, J = 9.2 Hz, 1H, aromatic), 7.47 (s, 1H, aromatic), 7.44 (m, 3H, aromatic), 7.29 (d, J = 2.3 Hz, 1H, aromatic), 7.05 (d, J = 8.6 Hz, 1H, aromatic), 4.17 (t, J = 7.0 Hz, 2H, NCH₂CH₂CH₃), 4.07 (s, 2H, CH₂Ar), 3.78 (s, 3H, ArOCH3), 1.79 (sextet, J = 7.3 Hz, 2H, NCH2CH2CH3), 0.80 (t, J = 7.4 Hz, 3H, NCH₂CH₂CH₃); ¹³C NMR (100 MHz, (CD₃)₂SO) δ 159.5, 157.0, 155.3, 140.2, 139.1, 136.5, 133.1, 132.9, 131.2, 130.4, 129.1, 126.3, 124.8, 124.7, 117.2, 117.0, 116.44, 116.37, 115.9, 112.2, 110.4, 59.7, 55.9, 47.3, 28.9, 23.1, 11.0; m/z calcd for C26H24FN3O6S 525.55.

. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, Rf 0.26) to yield compound 39 (22 mg, 49%) as an orange solid: ¹H NMR (500 MHz, CDCl3) δ 10.49 (s, 1H, NH), 8.35 (d, J = 9.1 Hz, 2H, aromatic), 8.32 (d, J = 8.8 Hz, 2H, aromatic), 8.30 (d, J = 2.3 Hz, 1H, aromatic), 8.06 (dd, J₁ = 9.1 Hz, J₂ = 2.2 Hz, 1H, aromatic), 7.90 (d, J = 2.4 Hz, 1H, aromatic), 7.45 (dd, J₁ = 8.6 Hz, J₂ = 2.5 Hz, 1H, aromatic), 7.28 (d, J = 9.1 Hz, 1H, aromatic), 6.95 (d, J = 8.6 Hz, 1H, aromatic), 6.93 (s, 1H, aromatic), 4.03 (t, J = 7.2 Hz, 2H, NCH2CH2CH3), 4.04 (s, 2H, CH2Ar), 4.02 (s, 3H, ArOCH₃), 1.83 (sextet, J = 7.3 Hz, 2H, NCH₂CH₂CH₃), 0.90 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 162.6, 156.7, 150.9, 144.6, 141.3, 139.6, 135.8, 134.4, 132.7, 130.3, 129.5, 127.0, 124.2, 118.3, 117.6, 116.6, 116.5, 112.3, 109.6, 56.9, 48.6, 30.3, 23.8, 11.7; m/z calcd for C₂₆H₂₄N₄O₈S 552.56.

MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, R_f 0.63) to yield compound 34 (24 mg, 56%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 10.57 (s, 1H, NH), 8.33 (d, J = 2.3 Hz, 1H, aromatic), 8.14 (td, J1 = 7.6 Hz, J2 = 1.8 Hz, 1H, aromatic), 8.06 (dd, J1 = 9.1 Hz, J2 = 2.2 Hz, 1H, aromatic), 7.88 (d, J = 2.5 Hz, 1H, aromatic), 7.61-7.57 (m, 1H, aromatic), 7.44 (dd, J₁ = 8.6 Hz, J₂ = 2.6 Hz, 1H, aromatic), 7.33-7.30 (m, 1H, aromatic), 7.27 (d, J = 9.1 Hz, 1H, aromatic), 7.17-7.13 (m, 1H, aromatic), 6.96 (d, J = 8.6 Hz, 1H, aromatic), 6.89 (s, 1H, aromatic), 4.05 (t, J = 7.3 Hz, 2H, NCH2CH2CH2CH3), 4.05 (s, 3H, ArOCH3), 4.02 (s, 2H, CH₂Ar), 1.76 (p, J = 7.6 Hz, 2H, NCH₂CH₂CH₂CH₃), 1.30 (sextet, J = 7.7 Hz, 2H, NCH2CH2CH2CH3), 0.91 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 162.7, 156.7, 141.3, 139.6, 136.4, 136.3, 135.5, 134.2, 132.6, 132.3, 129.4, 127.0, 124.7, 124.6, 118.8, 117.6, 117.3, 117.1, 116.6, 112.3, 109.5, 56.9, 46.7, 32.5, 30.3, 20.3, 13.8; m/z calcd for C₂₇H₂₆FN₃O₆S 539.58. q . The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO₂ gel, Hexanes:EtOAc/1:1, Rf 0.45) to yield compound 40 (28 mg, 62%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 10.49 (s, 1H, NH), 8.35 (d, J = 9.0 Hz, 2H, aromatic), 8.32 (d, J = 9.1 Hz, 2H, aromatic), 8.29 (d, J = 2.3 Hz, 1H, aromatic), 8.05 (dd, J₁ = 9.1 Hz, J₂ = 2.2 Hz, 1H, aromatic), 7.90 (d, J = 2.5 Hz, 1H, aromatic), 7.45 (dd, J1 = 8.6 Hz, J2 = 2.5 Hz, 1H, aromatic), 7.28 (d, J = 9.1 Hz, 1H, aromatic), 6.95 (d, J = 8.6 Hz, 1H, aromatic), 6.92 (s, 1H, aromatic), 4.06 (t, J = 7.2 Hz, 1H, aromatic), 4.04 (s, 2H, CH₂Ar), 4.03 (s, 3H, ArOCH₃), 1.77 (p, J = 7.5 Hz, 2H, NCH₂CH₂CH₂CH₃), 1.30 (sextet, J = 7.6 Hz, 2H, NCH2CH2CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 156.7, 150.9, 144.6, 141.3, 139.6, 135.8, 134.4, 132.6, 130.3, 129.4, 126.9, 124.2, 118.3, 117.6, 116.6, 116.5, 112.3, 109.6, 56.9, 46.7, 32.5, 30.3, 20.3, 13.8; m/z calcd for C27H26N4O8S 566.59.

organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.29) to yield compound 35 (22 mg, 52%) as a yellow solid: ¹H NMR (500 MHz, (CD3)2SO) δ 12.24 (s, 1H, NH), 8.41 (d, J = 7.7 Hz, 1H, aromatic), 7.98 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.95 (t, J = 7.7 Hz, 1H, aromatic), 7.82-7.75 (m, 1H, aromatic), 7.67 (d, J = 9.1 Hz, 1H, aromatic), 7.45 (s, 1H, aromatic), 7.44 (m, 3H, aromatic), 7.28 (d, J = 2.3 Hz, 1H, aromatic), 7.06 (d, J = 8.6 Hz, 1H, aromatic), 4.07 (s, 2H, CH2Ar), 4.03 (d, J = 7.3 Hz, 2H, NCH2), 3.78 (s, 3H, ArOCH3), 2.09 (septet, J = 7.2 Hz, 1H, CH(CH₃)₂), 0.82 (d, J = 6.7 Hz, 6H, CH(CH₃)₂); ¹³C NMR (100 MHz, (CD3)2SO) δ 164.2, 159.6, 155.3, 140.2, 139.4, 136.6, 133.0, 131.2, 130.9, 129.1, 126.3, 124.8, 117.4, 117.3, 117.1, 116.5, 116.3, 115.9, 115.3, 112.2, 110.7, 55.9, 52.9, 29.2, 28.9, 19.7; m/z calcd for C₂₇H₂₆FN₃O₆S 539.58.

room temperature overnight. The reaction was quenched with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.41) to yield compound 41 (5 mg, 12%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.40 (d, J = 8.9 Hz, 2H, aromatic), 8.31 (d, J = 2.2 Hz, 1H, aromatic), 8.27 (d, J = 9.0 Hz, 2H, aromatic), 8.02 (dd, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H, aromatic), 7.49 (d, J = 9.2 Hz, 1H, aromatic), 7.48 (d, J = 2.2 Hz, 1H, aromatic), 7.45 (dd, J₁ = 8.7 Hz, J₂ = 1.8 Hz, 1H, aromatic), 7.23 (s, 1H, aromatic), 7.06 (d, J = 8.5 Hz, 1H, aromatic), 4.09 (s, 2H, CH₂Ar), 3.99 (d, J = 7.4 Hz, 2H, NCH2), 3.91 (s, 3H, ArOCH3), 2.15 (septet, J = 7.3 Hz, 1H, CH(CH3)2), 0.89 (d, J = 6.7 Hz, 6H, CH(CH3)2); ¹³C NMR (100 MHz, (CD3)2SO) δ 165.1, 155.5, 150.2, 144.6, 140.1, 139.4, 133.4, 133.0, 130.9, 129.32, 129.26, 126.2, 124.4, 121.6, 116.4, 116.2, 115.9, 112.2, 110.6, 56.0, 52.9, 29.2, 28.8, 19.7; m/z calcd for C27H26N4O8S 566.59.

quenched with H₂O and extracted with CH₂Cl₂ (3×). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/1:1, Rf 0.42) to yield compound 42 (29 mg, 66%) as a yellow solid: ¹H NMR (500 MHz, CDCl3) δ 10.49 (s, 1H, NH), 8.35 (d, J = 9.1 Hz, 2H, aromatic), 8.32 (d, J = 9.1 Hz, 2H, aromatic), 8.31 (d, J = 2.3 Hz, 1H, aromatic), 8.02 (dd, J₁ = 9.1 Hz, J₂ = 2.3 Hz, 1H, aromatic), 7.90 (d, J = 2.4 Hz, 1H, aromatic), 7.46 (dd, J1 = 8.6 Hz, J2 = 2.5 Hz, 1H, aromatic), 7.32-7.27 (m, 3H, aromatic), 7.23 (d, J = 9.5 Hz, 1H, aromatic), 7.05 (dd, J₁ = 7.9 Hz, J₂ = 2.2 Hz, 2H, aromatic), 6.97 (s, 1H, aromatic), 6.96 (d, J = 8.7 Hz, 1H, aromatic), 5.27 (s, 2H, NCH₂Ar), 4.05 (s, 2H, CH2Ar), 4.04 (s, 3H, ArOCH3); ¹³C NMR (100 MHz, CDCl3) δ 162.6, 156.7, 150.8, 144.6, 141.6, 139.8, 136.3, 135.8, 134.2, 132.6, 130.3, 129.9, 129.2, 128.3, 127.2, 126.9, 124.2, 118.3, 117.9, 117.0, 116.6, 112.3, 110.0, 56.9, 50.7, 30.3; m/z calcd for C₃₀H₂₄N₄O₈S 600.6. Example 2. Determination of the potency of ZAF derivatives for inhibition of PDI, ERp5, ERp57, and ERp72 [0146] Two methods are used to determine the potency of ZAF derivatives for inhibition of PDI, ERp5, ERp57, and ERp72. The first assay is the insulin turbidity assay used to measure the thiol isomerase inhibitory activity of the analogues. 30 µL of a cocktail consisting of 1.75 mg/mL insulin and an optimized concentration (0.5 µg/well of PDI, ERp57, and ERp72; 1 µg of ERp5) in 100 mM K2PO4, 0.2 mM EDTA, pH 7.2 will be added to a 384-well clear bottom plate. The reaction will be initiated by the addition of 0.3 mM DTT. Absorbance at 650 nm will be measured every minute. Wells containing no thiol isomerase, wells containing no inhibitors, and wells containing ZAF or MON will serve as controls. The IC50 of each compound will be determined by running 6-point dose curves with a minimum of three independent replicates. This insulin inhibition assay has a high-nM IC₅₀ sensitivity limit. The second assay is a highly sensitive continuous assay, where the fluorescence of di-(O-aminobenzoyl) glutathione disulfide (diabz-GSSG) is enhanced upon its reduction catalyzed by the above glutathione isomerase enzymes for very potent compounds. The substrate diabz-GSSG is straightforward to prepare, by a reaction of isatoic anhydride and oxidized glutathione in an aqueous buffer, followed by Sephadex G-10 purification. Fluorescence of the substrate is self-quenched in the oxidized S-S form and is greatly (~20-fold) enhanced upon enzymatic reduction. The substrate (15 mM) will be preincubated with 50 mM DTT (where diabz-GSSH is resistant to reduction), followed by the addition of one of the four enzymes (5 nM-500 nM, where low-nM concentrations will be used for inhibitors with respective potencies) in 0.1 potassium phosphate buffer pH 7.0, and the fluorescence (ex/em = 312 nm/415 nm) time course will be monitored. Time courses will be collected in triplicate for each inhibitor concentration. Initial velocities will then be used for the steady-state analysis of inhibitor potency. The mode of inhibition will be determined by performing above measurements at different substrate concentrations. The calibration will be performed by measuring the signal change by fully reducing the substrate with 10 mM DTT. [0147] ZAF and MON inhibit thiol isomerases. The potency of ZAF and MON in the insulin turbidity assay for PDI, ERp5, ERp57, and ERp72 was determined. The reduction of insulin catalyzed by thiol isomerases in the presence of dithiothreitol (DTT) results in aggregation of insulin chains. The turbidity of insulin aggregation is monitored by measuring light absorbance at 650 nm. The insulin-based turbidometric assay was adapted to a 384-well format. ZAF inhibited PDI, ERp5, ERp57, and ERp72 with IC₅₀ values of 10-30 µM (FIG. 1A); data for MON is shown in FIG. 1B. [0148] The derivative compounds were tested for activity as inhibitors of PDI and ERp57. Derivatives 1-5, compounds belonging to Scaffold I, which all lacked the cyclopentyl carbamate group at the C-5 position of the indole (ring A) of ZAF, in general, displayed poor activity when tested for activity as inhibitors of PDI and ERp57. Compounds belonging to Scaffold IIa displayed similar or increased activity as inhibitors when compared to the parent ZAF. These data suggest that the cyclopentyl carbamate of ZAF is not required for activity as thiol isomerase inhibitors and the substituents on ring B were kept constant with the 2-methoxy-5-indoyl organization, as Scaffold IIa yielded the most active compound 21. When tested for inhibitory activity against thiol isomerases, derivative compounds 6-11 displayed no activity. Additionally, derivative compounds 12-14 were found to be inactive. Slight increase in activity was seen with derivative compounds 15-20 that contain N-methyl on indole (ring A) with derivative compound 16 displaying moderate activity (IC₅₀ = 30 mM) as a thiol isomerase inhibitor. An electron withdrawing group (R¹ = NO2) on the indole (ring A) resulted in increased thiol isomerase inhibition activity and yielded derivative compounds 22, 23, and 27 with moderate activity (IC₅₀ = 30 mM) and compound 28 (IC₅₀ = 40 mM), and the most active compound 21 (IC₅₀ ~10 mM). By performing a pairwise comparison to observe the trend of the substituents on the arylsulfonamide (Ar²) was found to be similar for the nitro and naphthalene substituents and varying for the fluoro substituents for compounds 15-20 (R¹ = H) vs compounds 21-26 (R¹ = NO₂) where compounds 15-20 (3-F phenyl displayed better activity (>) than 2-F phenyl > 3-NO₂ phenyl ≈ 4-NO₂ phenyl ≈ 2-naphthyl > 4-F) and compounds 21-26 (2-F phenyl > 3-F phenyl ≈ 4-F phenyl > 3-NO₂ phenyl > 4-NO₂ phenyl ≈ 2-naphthyl). The most active compound from derivative compounds 1-26 was compound 21 Ar² = 2-F phenyl. To investigate the importance of the N-methyl indole (ring A) on the most active compound 21, compounds 32-35 were synthesized with varying chain lengths that led to compounds with a slight decrease in activity (IC50 = 50 to >100 mM). Additionally, the importance of the 2-F phenyl for the arylsulfonamide of compound 21 was investigated by the synthesis of compounds 27-31 that contained other halogens and di-fluoro groups, which led to compounds with a slight decrease in activity compared to the lead compound 21. Example 3. Toxicity Studies [0149] The cytotoxic effect of ZAF, montelukast (MON), and compounds 21, 27, and 28 against two mammalian cell lines: BEAS-2B and HEK-293 were conducted. The two cell lines were plated in 96-well plates at 10,000 cells/well. After 24 h of incubation, the cells were treated with 1% Triton-X® (positive control), 1% DMSO (negative control), and treatments of ZAF, MON, compounds 21, 27, and 28 at concentrations of 0 to 62.6 mg/mL. After 12 h of incubation, 10 µL of resazurin was added to each well and the plate was read on a SpectraMax M5 plate reader at a fluorescence excitation at 560 nm and emission at 590 nm. None of the compounds were found to display toxicity against any of the mammalian cell lines tested (FIG. 2). Example 4. Zafirlukast and Compound 21 Inhibit Cancer Cell Growth [0150] ZAF and compound 21 inhibit cancer cell growth. ZAF and compound 21 were tested to assess the viability of HCT116 colon cancer cells and OVCAR-8 ovarian cancer cells. HEK-293 embryonic kidney cells were used as a non-cancer cell control. For ZAF, the IC₅₀ values were in the 3-10 µM range. In FIG. 3, cellular growth inhibition by Compound 21 (inverted triangles) was measured using the standard 3-day growth inhibition assay and compared to ZAF (circles). Compound 21 was 3- to 8-fold more potent than ZAF. The inhibition of mammalian cell growth with ZAF and compound 21. Cells were seeded and treated with drug 24 h later. After an additional 24 h of incubation, cell viability was determined using Prestoblue. The FIG. 3 presents a summary of at least 3 independent experiments per cell line. Cell lines used include HEK-293 non-cancer cells (not shown); OVCAR-8 and HCT116. Comparison of ZAF (circles) and compound 21 (inverted triangles) in a 3-day growth inhibition against OVCAR-8 (FIG. 3A) and HCT116 cancer cells (FIG. 3B). Example 5. Platelet Aggregation and Fibrin Inhibition [0151] ZAF and MON inhibit platelet aggregation and fibrin formation. Compound 21 (FIG. 4A, FIG. 4B) inhibits platelet aggregation. Platelet aggregation was measured in washed platelet suspensions in the presence of either DMSO, ZAF (0.1-40 µM), or compound 21 (0.6-30 µM) and stimulated for 180 seconds with collagen, decreasing platelet aggregation in a dose dependent manner, with a potency of compound 21 > ZAF > MON. [0152] Thiol isomerase inhibition also impaired integrin αIIbβ3 activation and conformational change leading to fibrinogen ligation. The effects of ZAF on platelet surface fibrinogen binding were measured using flow cytometry where ZAF pre-treatment (10 µM) significantly reduced fibrinogen binding to platelets and therefore integrin activation by 50% (2043 ± 165 AU. A higher concentration of 20 µM ZAF inhibited fibrinogen binding further causing 61% inhibition (1633 ± 162 AU). Example 6. ZAF inhibits cancer cell generated Factor Xa [0153] The ability of ZAF to prevent activation of the clotting cascade was made by measuring its ability to inhibit the generation of Factor Xa by HCT116 cells. Cells were plated in 12-well dishes at 50,000 cells/well. After 24 h of growth, they were treated with ZAF, washed twice with Tris-buffered saline (TBS) and read kinetically in a SpectraMax for 60 min with TBS containing 5 nmol/L of FVIIa, 150 nmol/L of FX, and 5 mmol/L of CaCl2. Fluorescence was measured with excitation and emission wavelengths of 352 nm and 450 nm, respectively. We found that in the presence of ZAF, Factor Xa generation was inhibited in a dose-dependent manner (FIG. 5). Example 7. ZAF inhibits platelet aggregation and thrombus formation in mice [0154] Mouse platelet aggregation (in animal) and thrombus formation are inhibited by ZAF. Thiol isomerases inhibition prevents thrombus formation inside of a live mouse after laser injury, as measured by intravital microscopy (See Holbrook et al. “Zafirlukast is a broad-spectrum thiol isomerase inhibitor that inhibits thrombosis without altering bleeding times” Br. J. Pharmacol. 2021;178:550–563). It has been previously demonstrated that thiol isomerase inhibition diminishes fibrin formation using the same model, and it has been shown that thiol isomerase inhibition diminishes tumor growth and progression without causing damage to normal tissues. Importantly, thiol isomerase inhibition does not increase bleeding times (Holbrook et al.), which is a major side effect associated with current antithrombotic therapies. Example 8. Compound 21 Assessment of platelet aggregation and thrombus formation in mice [0155] In order to assess the ability of compound 21 to inhibit arterial thrombus formation, intravital microscopy using laser injury will be performed. Male C57BL/6J mice aged 4-5 weeks will be anaesthetized with a weight range of 19-25 g by intraperitoneal injection of ketamine (125 mg/kg), xylazine (12.5 mg/kg), and atropine (0.25 mg/kg). Platelets will be labelled by intravenous infusion of DyLight 649-conjugated anti-GPIb platelet labelling antibody (0.2 µg/g of body weight). After the exposure of the testicular cremaster muscle, the vehicle of DMSO (0.1% v/v) or zafirlukast derivative will be infused intravenously and following a 5-min incubation period, the arteriole wall injury will be induced by laser ablation (Micropoint, Andor Technology, Belfast, UK). Then thrombus formation will be observed using an Olympus BX microscope (Olympus, Essex, UK) and a Hamamatsu (Hamamatsu Photonics, Hertfordshine, UK) CCD camera, with the data analyzed using Slidebook Software 5.0 (Intelligent Imaging Innovations, Denver, USA). Mice will be killed using Schedule 1 approved methods at the end of the experiment. All animal experiments will be blinded for both the experimental treatment and the analysis. Animal experiments have previously been approved by the University of Reading Local Ethical Review Panel and authorized by the UK Home Office. Animal studies are reported in compliance with the ARRIVE guidelines and with the recommendations made by the British Journal of Pharmacology. Example 9. Ex-vivo Thrombus Formation [0156] Zafirlukast was found to inhibit thrombus formation under arterial flow conditions in an in vitro thrombus formation model using whole human blood (US20210008032A1). The active thiol isomerase inhibitor analogues described herein, e.g. compound 21, would be expected to also inhibit thrombus formation in vitro. Example 10. Compound 32 [0157] Compound 32 is an analogue of zafirlukast where it has been modified to significantly decrease or abolish its affinity for the leukotriene receptor 1 (LTR1) receptor while retaining its potency as a thiol isomerase inhibitor. Compound 32 maintained a similar potency (~1.5‐fold less) to that of zafirlukast at inhibiting thiol isomerases in the insulin turbidity assay (Figure 6). [0158] The thiol isomerase activity of OVCAR8 cells is also inhibited by zafirlukast treatment. The cleavage of the fluorescent di‐eosin thiol isomerase substrate was inhibited after treatment with zafirlukast in a concentration‐dependent manner. Treatment of OVCAR8 cells with 3, 10, or 30 μM of zafirlukast for 10 minutes significantly inhibited PDI activity, by 18%, 24%, and 45%, respectively (Figure 7A). To confirm that the addition of zafirlukast did not alter thiol isomerase expression, thiol isomerases levels were measured following 1 hour of treatment with 10 µM and 30 µM zafirlukast in OVCAR8 cells. No significant change in expression was observed (Figure 7B), confirming that the observed change in activity was due to enzymatic inhibition and not a decrease in enzyme levels. The cellular thiol isomerase activity of OVCAR8 cells also significantly decreased upon treatment with montelukast and Compound 32, with montelukast being somewhat less effective (reduction by 20%, 30%, and 40%, at 10, 30, and 100 μM, respectively) than zafirlukast (Figure 7C). In contrast, the compound 32 was more potent than zafirlukast, significantly inhibiting activity by 25%, 39%, 29%, and 44% at 1, 3, 10, and 30 μM, respectively (Figure 7D). [0159] As inhibitors of thiol isomerase activity have been shown to have antineoplastic activity, the effect of these drugs on cancer cell viability was evaluated. Zafirlukast inhibited OVCAR8 cancer cell viability with an IC50 of 12 μM, while montelukast and compound 32 inhibited cell viability about 5‐ and ~1.5‐fold less potently (with IC₅₀‘s of 60 and 20 μM, respectively) (Figure 8A). It is notable that relative potencies of zafirlukast, compound 32, and montelukast remained consistent across the assays (cell‐free and a cellular activity assay as well as between a cellular activity assay and a viability assay), with compound 32 having a similar potency to that of zafirlukast and montelukast being ~5‐fold less potent in each assay (Figure 8B). Insulin‐based Turbidimetric Assay [0160] An insulin‐based turbidimetric assay was utilized to determine the selectivity of zafirlukast and montelukast for thiol isomerases PDI, ERp57, ERp72, and ERp5. These drugs were diluted in a 6‐12 point dose curve in a 384‐well plate, and a final concentration of 10 µg/mL thiol isomerase (30 µg/mL for ERp5 only), 125 µM insulin, 2 mM EDTA, and 100 mM potassium phosphate buffer were added for a total volume of 30 µL per well. The turbidity of insulin aggregation was measured every minute for 75 minutes after initiating the reaction with 0.3 mM DTT using a SpectraMax M3 plate reader (Molecular Devices, Sunnyvale, CA). PrestoBlue Assay [0161] The indicated cell lines were plated at 5,000 cells per well in a 96‐well plate and allowed to grow for 24 hours. The cells were then treated with either a drug or a vehicle control for an additional 2‐24 hours prior to the addition of PrestoBlue reagent (Invitrogen, Waltham, MA) for 10‐20 minutes at 37°C. Cell viability was determined by measuring the fluorescent signal at an excitation wavelength of 560 nm and emission wavelength of 590 nm. The signal was normalized to a percentage of the control. Di‐eosin‐GSSG Disulfide Reductase Assay [0162] OVCAR8 cells were plated at 10,000 cells per well, allowed to grow overnight, then treated with 0‐100 μM of zafirlukast, montelukast, or compound 32 for 10 minutes. Samples were then subjected to 150 nM of the di‐eosin‐GSSG probe in the presence of 5 μM of DTT and potassium phosphate buffer 1 (containing 100 mM potassium phosphate (pH 7.4) and 2 mM EDTA). Increase in fluorescence was monitored every 30 seconds for 30 minutes by excitation at 520 nm and emission at 550 nm. Generated data were then normalized to the control for each sample, with raw data representing relative fluorescent units (RFU)/minute. [0163] With blood samples, the assay was performed as previously described (Raturi, A., and Mutus, B. (2007) Characterization of redox state and reductase activity of 24 protein disulfide isomerase under different redox environments using a sensitive 25 fluorescent assay. Free Radic Biol Med 43, 62-70) with a modification to use plasma at a 1:1 dilution with potassium phosphate buffer (containing 100 mM potassium phosphate (pH 7.4) and 2 mM EDTA). Samples were then subjected to 150 nM of the di‐eosin‐GSSG probe in the presence of 5 μM DTT. Increase in fluorescence was monitored for 30 minutes by excitation at 520 nm and emission at 550 nm. Generated data from day 28 were then normalized to day 0 control for each sample, with raw data representing relative fluorescent units (RFU)/minute (n=3 for each patient sample). [0164] The statistical analysis was performed using GraphPad Prism (Version 9.4.0, San Diego, CA). Data were presented as the mean ± SD. For di‐eosin‐GSSG assays a one way ANOVA with a post‐hoc Dunnett’s test was used for statistical analysis between test groups and the control. *P < 0.05, **P < 0.01, ***P < 0.001, or ****P < 0.0001 was considered to be statistically significant. [0165] Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. [0166] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The endpoints of all ranges directed to the same characteristic or component are independently combinable and inclusive of the recited endpoint. The suffix “(s)” as used herein is intended to include both the singular and the plural of the term that it modifies, thereby including one or more of that term (e.g., the carrier(s) includes one or more carriers). The term “or” means “and/or” unless clearly indicated otherwise by context. The term “combination” is inclusive of blends, mixtures, and the like. [0167] Reference throughout the specification to “an embodiment”, “another embodiment”, “some embodiments”, and so forth, means that a particular element (e.g., feature, structure, step, or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various embodiments. [0168] In general, the compositions, methods, and articles can alternatively comprise, consist of, or consist essentially of, any ingredients, steps, or components herein disclosed. The compositions, methods, and articles can additionally, or alternatively, be formulated, conducted, or manufactured so as to be devoid, or substantially free, of any ingredients, steps, or components not necessary to the achievement of the function or objectives of the present claims. [0169] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not. [0170] “About” or “approximately” as used herein is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (e.g., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations. [0171] While the invention has been described in detail in connection with only a limited number of embodiments, it should be readily understood that the invention is not limited to such disclosed embodiments. Rather, the invention can be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not heretofore described, but which are commensurate with the spirit and scope of the invention. Additionally, while various embodiments of the invention have been described, it is to be understood that aspects of the invention can include only some of the described embodiments. Accordingly, the invention is not to be seen as limited by the foregoing description, but is only limited by the scope of the appended claims. [0172] All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. However, if a term in the present application contradicts or conflicts with a term in the incorporated reference, the term from the present application takes precedence over the conflicting term from the incorporated reference.

Claims

CLAIMS: 1. A method of treating cancer or treating or preventing cancer-induced thrombosis, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), or a pharmaceutically acceptable salt thereof:

R¹ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein R⁹ is hydrogen, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, or aryl; Q¹ each and Q² independently is a bond, O, or NR¹⁰, and R¹⁰ is hydrogen, C1-C8 alkyl, C₁-C₆ haloalkyl, or C₁-C₈ alkyl-OH; R² is hydrogen, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C₃-C₇ cycloalkyl, (C₃- C7 cycloalkyl)C0-C6 alkyl, C1-C4 alkanoyl, or unsubstituted or substituted aryl; X is O, S, or N; Y is N or CH; R⁶ is hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl when X is N, and R⁶ is absent when X is S or O; R⁷ is hydrogen, NO₂, cyano, halogen, NH₂, COOH, hydroxyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; Ar² is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl substituted with R⁸ wherein R⁸ is NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C₁-C₆ haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di- C₁-C₈ alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; R⁴ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined; and R⁵ is hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, or C₁-C₄ alkanoyl, with the following provisos a) and b): a) when

NO2, NH2, mono-C1-C8 alkylamino, or di-C1-C8 alkylamino; R² is hydrogen or C1-C8 alkyl; R⁴ is hydrogen or C1-C8 alkyl; and R⁵ is hydrogen; then Ar² is not unsubstituted phenyl or phenyl substituted at the 2 position with C₁- C8 alkyl. 2. The method of claim 1, wherein

3. The method of any one of claims 1-2, wherein R¹ is an electron withdrawing group; or R¹ is NO₂, cyano, C₁-C₆ haloalkyl, CF₃, or C₂-C₆ alkanoyl.

4. The method of any one of claims 1-3, wherein R² is hydrogen, C₁-C₆ alkyl, C₁-C₈ alkyl-OH, or unsubstituted or substituted phenyl. 5. The method of claim 1, wherein Ar¹ is

, X is O, S, or N; Y is N or CH; and R⁶ is hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl when X is N, and R⁶ is absent when X is S or O. The method of claim 1, wherein Ar is

and R⁷ is hydrogen, NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C₁-C₈ alkyl-OH, C₁-C₈ alkyl-NH₂, C₁-C₈ alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C2-C6 alkenyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined. 7. The method of any one of claims 1-6, wherein Ar² is unsubstituted phenyl or naphthalene or R⁸ substituted phenyl or naphthalene. 8. The method of any one of claims 1-6, wherein Ar² is phenyl substituted with halogen or 2-naphthalene. 9. The method of any one of claims 1-8, wherein R⁴ is C₁-C₆ alkyl or C₁-C₆ alkoxy. 10. The method of any one of claims 1-8, wherein R⁴ is C1-C2 alkyl or C1-C2 alkoxy. 11. The method of any one of claims 1-10, wherein R⁵ is hydrogen. 12. The method of any one of claims 1-11, wherein the cancer is breast, colon, colorectal, glioma, hematological, laryngeal, lung, lymphoma, melanoma, neuroblastoma, ovarian, prostate, or a combination thereof.

13. The method of any one of claims 1-11, wherein the cancer-induced thrombosis is arterial, venous, or a combination thereof. 14. The method of any one of claims 1-13, further comprising providing the patient with an additional pharmaceutically active agent. 15. The method of claim 14, wherein the additional pharmaceutically active agent is an anti-thrombotic, an anti-coagulant, a chemotherapeutic, an anti-viral, or an anti- inflammatory. 16. A method for preventing or treating thrombosis, a thrombotic disease, platelet aggregation, fibrin generation, an infectious disease, a viral disease, an immune disorder, inflammation, a neurologic disease, a neurodegenerative disorder, or a combination thereof in a patient, comprising: administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof. 17. The method of claim 16, wherein the thrombosis is arterial thrombosis or venous thrombosis and wherein the thrombotic disease is acute myocardial infarction, stable angina, unstable angina, acute occlusion following coronary angioplasty and/or stent placement, a transient ischemic attack, cerebrovascular disease, stroke, peripheral vascular disease, placental insufficiency, atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a combination thereof. 18. A compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof:

hydrogen, and Ar² is phenyl or phenyl substituted with R⁸, then R¹, R², and R⁸ do not meet the following six conditions for a compound of Formula (III): R¹ R² R⁸ gen, NO2, NH2, mono-C1-C8 alkylamino, or di-C1-C8 alkylamino; R² is hydrogen or C1-C8 alkyl; R⁴ is hydrogen or C1-C8 alkyl; and R⁵ is hydrogen; then Ar² is not unsubstituted phenyl or phenyl substituted at the 2 position with C₁- C8 alkyl. 19. The compound of claim 18, wherein

20. The compound of claim 18 or 19, wherein R¹ is an electron withdrawing group; or R¹ is NO₂, cyano, C₁-C₆ haloalkyl, CF₃, or C₂-C₆ alkanoyl. 21. The compound of any one of claims 18-20, wherein R² is hydrogen, C1-C6 alkyl, C₁-C₈ alkyl-OH, or unsubstituted or substituted phenyl. 22. The compound of claim 18, wherein Ar¹ is

, X is O, S, or N; Y is N or CH; and R⁶ is hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C0-C6 alkyl, or C1-C4 alkanoyl when X is N, and R⁶ is absent when X is S or O. 23. The compound of claim 18, wherein Ar¹ is

and R⁷ is hydrogen, NO₂, cyano, halogen, NH₂, COOH, hydroxyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C1-C8 alkylamino, di-C1-C8 alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₀-C₆ alkyl, C₂-C₆ alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined. 24. The compound of any one of claims 18-23, wherein Ar² is phenyl or naphthalene unsubstituted or substituted with R⁸ wherein R⁸ is NO2, cyano, halogen, NH2, COOH, hydroxyl, C1-C8 alkyl, C1-C6 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-NH2, C1-C8 alkoxy, mono-C₁-C₈ alkylamino, di-C₁-C₈ alkylamino, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C0-C6 alkyl, C2-C6 alkanoyl, or -Q¹(C=O)Q²R⁹ wherein Q¹, Q², and R⁹ are as previously defined 25. The compound of any one of claims 18-23, wherein Ar² is phenyl substituted with halogen or 2-naphthalene. 26. The compound of any one of claims 18-25, wherein R⁴ is C₁-C₆ alkyl or C₁-C₆ alkoxy. 27. The compound of any one of claims 18-25, wherein R⁴ is C₁-C₂ alkyl or C₁-C₂ alkoxy. 28. The compound of any one of claims 18-27, wherein R⁵ is hydrogen. 29. A pharmaceutical composition, comprising the compound of any one of claims 18-28 and a pharmaceutically acceptable excipient. 30. The pharmaceutical composition of claim 29, formulated for administration orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, or rectally. 31. The pharmaceutical composition of claim 29, formulated as a tablet or capsule.