GARNEAU-TSODIKOVA SYLVIE (US)
UNIV KENTUCKY RES FOUND (US)
US5334765A | 1994-08-02 | |||
US20210008032A1 | 2021-01-14 | |||
US20200385348A1 | 2020-12-10 |
GOVERDHAN, G. ; REDDY, A.R. ; SRINIVAS, K. ; HIMABINDU, V. ; REDDY, G.M.: "Identification, characterization and synthesis of impurities of zafirlukast", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, ELSEVIER B.V., AMSTERDAM, NL, vol. 49, no. 4, 1 May 2009 (2009-05-01), AMSTERDAM, NL , pages 895 - 900, XP026071217, ISSN: 0731-7085, DOI: 10.1016/j.jpba.2009.01.023
SUKNUNTHA KRAN, YUBOLPHAN RUEDEEMARS, KRUEAPRASERTKUL KANOKPAN, SRIHIRUN SIRADA, SIBMOOH NATHAWUT, VIVITHANAPORN PORNPUN: "Leukotriene Receptor Antagonists Inhibit Mitogenic Activity in Triple Negative Breast Cancer Cells", ASIAN PACIFIC JOURNAL OF CANCER PREVENTION : APJCP, WEST ASIA ORGANIZATION FOR CANCER PREVENTION, THAILAND, 28 March 2018 (2018-03-28), Thailand, pages 833 - 837, XP093143071, Retrieved from the Internet
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 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. 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: 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. 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. |
X = R 6 , O, S; Y = CH, N; R 13 = I, Br, Li, MgI, MgBr h. NaBH 4 , THF, i. PBr 3 , Et 2 O; j. n-BuLi, THF; k. n-BuLi, ZnBr 2 , Pd(PPh 3 ) 4 , THF; l. n-BuLi, Et 2 O; m. Zn, I 2 , S-Phos, Pd 2 dba 3 , 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 R 1 = 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 F 254 . 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 1 H NMR spectra at 500 or 400 MHz, respectively. A Varian 400 MHz spectrometer was used to record all 13 C 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 CH 2 Cl 2 (3×). The combined organic layers were washed with NaHCO 3 , H 2 O, and brine, dried over MgSO 4 , 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: 1 H NMR (500 MHz, CDCl 3 ) δ 8.58 (dd, J 1 = 2.2 Hz, J 2 = 0.5 Hz, 1H, aromatic), 8.10 (dd, J 1 = 9.1 Hz, J 2 = 2.3 Hz, 1H, aromatic), 7.34 (dt, J 1 = 9.1 Hz, J 2 = 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, NCH 2 CH 3 ), 1.49 (t, J = 7.4 Hz, 3H, NCH 2 CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) 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: 1 H NMR (500 MHz, CDCl 3 ) δ 8.57 (d, J = 2.3Hz, 1H, aromatic), 8.09 (dd, J 1 = 9.1 Hz, J 2 = 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, NCH 2 CH 2 CH 3 ), 1.88 (sextet, J = 7.4 Hz, 2H, NCH 2 CH 2 CH 3 ), 0.93 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); 13 C 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 CH 2 Cl 2 (3×). The combined organic layers were washed with NaHCO 3 , H 2 O, and brine, dried over MgSO 4 , 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: 1 H NMR (500 MHz, CDCl 3 ) δ 8.57 (d, J = 2.2 Hz, 1H, aromatic), 8.09 (dd, J 1 = 9.1 Hz, J 2 = 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, NCH 2 CH 2 CH 2 CH 3 ), 1.33 (sextet, J = 7.7 Hz, 2H, NCH 2 CH 2 CH 2 CH 3 ), 0.93 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); 13 C 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 (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.89) to yield compound SM5 (1.12 g, 28%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ,) 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, J 1 = 9.1 Hz, J 2 = 0.7 Hz, 1H, aromatic), 7.20 (d, J = 3.3 Hz, 1H, aromatic), 6.66 (dd, J 1 = 3.2 Hz, J 2 = 0.8 Hz, 1H, aromatic), 3.94 (d, J = 7.4 Hz, 2H, NCH 2 ), 2.18 (septet, J = 7.3 Hz, 1H, CH(CH3)2), 0.92 (d, J = 6.7 Hz, 6H, CH(CH3)2); 13 C 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 CH 2 Cl 2 (3×). The combined organic layers were washed with NaHCO 3 , H 2 O, and brine, dried over MgSO 4 , filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/3:1, Rf 0.58) to yield compound SM6 (3.10 g, 66%) as a tan solid: 1 H 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, J 2 = 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); 13 C 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 H 2 O and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO3, H 2 O, and brine, dried over MgSO 4 , 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: 1 H NMR (500 MHz, CDCl 3 ) δ 8.46 (dd, J 1 = 2.2 Hz, J 2 = 0.6 Hz, 1H, aromatic), 8.09 (dd, J 1 = 9.1 Hz, J 2 = 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, J 2 = 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, NCH 2 CH 3 ), 4.06 (s, 2H, CH 2 Ar), 3.87 (s, 3H, ArOCH 3 ), 3.85 (s, 3H, ArCO2CH3), 1.44 (t, J = 7.4 Hz, 3H, NCH2CH3); 13 C 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 NaHCO 3 , H 2 O, and brine, dried over MgSO 4 , 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: 1 H NMR (500 MHz, CDCl 3 ) δ 8.46 (dd, J 1 = 2.3 Hz, J 2 = 0.5 Hz, 1H, aromatic), 8.08 (dd, J 1 = 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, CH 2 Ar), 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); 13 C 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 (SiO 2 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): 1 H NMR (500 MHz, CDCl3) δ 8.45 (dd, J1 = 2.3 Hz, J2 = 0.5 Hz, 1H, aromatic), 8.08 (dd, J 1 = 9.1 Hz, J 2 = 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, NCH 2 CH 2 CH 2 CH 3 ), 4.05 (s, 2H, CH 2 Ar), 3.87 (s, 3H, ArOCH 3 ), 3.85 (s, 3H, ArCO 2 CH 3 ), 1.81-1.75 (m, 2H, NCH 2 CH 2 CH 2 CH 3 ), 1.34-1.27 (m, 2H, NCH 2 CH 2 CH 2 CH 3 ), 0.92 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); 13 C 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 NaHCO 3 , H 2 O, and brine, dried over MgSO 4 , filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.72) to yield compound SM12 (0.11 g, 36%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) 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, CH 2 Ar), 3.87 (d, J = 7.4 Hz, 2H, NCH 2 ), 3.87 (s, 3H, ArOCH 3 ),3.84 (s, 3H, ArCO 2 CH 3 ), 2.14 (septet, J = 7.0 Hz, 1H, CH(CH3)2), 0.90 (t, J = 6.7 Hz, 6H, CH(CH3)2); 13 C 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 H 2 O and extracted with CH 2 Cl 2 (3×). The combined organic layers were washed with NaHCO 3 , H 2 O, and brine, dried over MgSO 4 , 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: 1 H NMR (500 MHz, CDCl3) δ 8.47 (dd, J1 = 2.3 Hz, J2 = 0.5 Hz, 1H, aromatic), 8.05 (dd, J 1 = 9.1 Hz, J 2 = 2.2 Hz, 1H, aromatic), 7.68 (d, J = 2.4 Hz, 1H, aromatic), 7.35 (dd, J 1 = 8.6 Hz, J 2 = 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, ArCO 2 CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) 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: 1 H NMR (400 MHz, CDCl 3 ) δ 10.7 (very br s, 1H, CO 2 H), 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, NCH 3 ); 13 C NMR (100 MHz, CDCl 3 ) 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 CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to yield compound SM15 (0.17 g, 75%) as a yellow solid: 1 H 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, J 1 = 8.5 Hz, J 2 = 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); 13 C NMR (100 MHz, CDCl 3 ) 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 MgSO 4 , filtered, and concentrated to yield compound SM16 (0.17 g, 88%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 8.38 (d, J = 2.2 Hz, 1H, aromatic), 8.08 (dd, J 1 = 9.1 Hz, J 2 = 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, CH 2 Ar), 4.06 (t, J = 7.2 Hz, 2H, NCH 2 CH 2 CH 3 ), 4.05 (s, 3H, ArOCH3), 1.85 (sextet, J = 7.4 Hz, 2H, NCH2CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); 13 C 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 CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to yield compound SM17 (71 mg, 82%) as a yellow solid: 1 H 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, J 1 = 8.6 Hz, J 2 = 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, NCH 2 CH 2 CH 2 CH 3 ), 1.27-1.20 (m, 2H, NCH 2 CH 2 CH 2 CH 3 ), 0.86 (t, J = 7.5 Hz, 3H, NCH 2 CH 2 CH 2 CH 3 ); 13 C NMR (100 MHz, (CD 3 ) 2 SO) 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 CH 2 Cl 2 (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): 1 H NMR (500 MHz, (CD 3 ) 2 SO) δ 8.41 (d, J = 2.3 Hz, 1H, aromatic), 8.00 (dd, J 1 = 9.1 Hz, J 2 = 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, CH 2 Ar), 4.04 (d, J = 7.4 Hz, 2H, NCH 2 ), 3.77 (s, 3H, ArOCH 3 ), 2.10 (septet, J = 7.2 Hz, 1H, CH(CH3)2), 0.84 (d, J = 6.7 Hz, 6H, CH(CH3)2); 13 C 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 (2CH 3 ). [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 CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to yield compound SM19 (60 mg, 31%) as a yellow solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.33 (d, J = 2.1 Hz, 1H, aromatic), 7.94 (dd, J 1 = 9.2 Hz, J 2 = 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); 13 C 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 H 2 O and extracted with CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.17) to yield compound 27 (18 mg, 40%) as an orange solid: 1 H 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, J 1 = 9.1 Hz, J 2 = 2.2 Hz, 1H, aromatic), 7.89 (d, J = 2.5 Hz, 1H, aromatic), 7.56 (dd, J 1 = 8.6 Hz, J 2 = 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); 13 C 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 H 2 O and extracted with CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, Rf 0.25) to yield compound 28 (26 mg, 53%) as an orange solid: 1 H 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, J 1 = 9.1 Hz, J 2 = 2.3 Hz, 1H, aromatic), 7.89 (d, J = 2.5 Hz, 1H, aromatic), 7.69 (dd, J 1 = 7.9 Hz, J 2 = 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, J 1 = 8.5 Hz, J 2 = 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, NCH 3 ), 3.71 (s, 5H, CH2Ar, ArOCH3); 13 C 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 C 24 H 20 BrN 3 O 6 S 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: 1 H NMR (500 MHz, CDCl 3 ) δ 10.64 (s, 1H, NH), 8.33 (d, J = 2.8 Hz, 1H, aromatic), 8.08 (dd, J 1 = 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); 13 C 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. CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.41) to yield compound 30 (16 mg, 35%) as an yellow solid: 1 H 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, J 1 = 9.1 Hz, J 2 = 2.4 Hz, 1H, aromatic), 7.87 (d, J = 2.5 Hz, 1H, aromatic), 7.47 (dd, J 1 = 8.5 Hz, J 2 = 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, ArOCH 3 ); 13 C NMR (100 MHz, (CD 3 ) 2 SO) 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 (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.18) to yield compound 31 (12 mg, 26%) as an amber solid: 1 H 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, J 1 = 8.6 Hz, J 2 = 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, NCH 3 ), 3.73 (s, 5H, CH2Ar, ArOCH3); 13 C 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 C 24 H 19 F 2 N 3 O 6 S 515.49. organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.46) to yield compound 32 (50 mg, quant.) as a yellow solid: 1 H 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, J 1 = 9.2 Hz, J 2 = 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); 13 C 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 MgSO 4 , 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: 1 H NMR (500 MHz, (CD 3 ) 2 SO) 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, J 1 = 8.6 Hz, J 2 = 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, NCH 2 CH 3 ), 4.06 (s, 2H, CH2Ar), 3.80 (s, 3H, ArOCH3), 1.33 (t, J = 7.3 Hz, 3H, NCH2CH3); 13 C 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 (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.46) to yield compound 33 (39 mg, 91%) as a yellow solid: 1 H NMR (500 MHz, (CD 3 ) 2 SO) 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, NCH 2 CH 2 CH 3 ), 4.07 (s, 2H, CH 2 Ar), 3.78 (s, 3H, ArOCH3), 1.79 (sextet, J = 7.3 Hz, 2H, NCH2CH2CH3), 0.80 (t, J = 7.4 Hz, 3H, NCH 2 CH 2 CH 3 ); 13 C NMR (100 MHz, (CD 3 ) 2 SO) 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 MgSO 4 , filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, Rf 0.26) to yield compound 39 (22 mg, 49%) as an orange solid: 1 H 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, J 1 = 9.1 Hz, J 2 = 2.2 Hz, 1H, aromatic), 7.90 (d, J = 2.4 Hz, 1H, aromatic), 7.45 (dd, J 1 = 8.6 Hz, J 2 = 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, ArOCH 3 ), 1.83 (sextet, J = 7.3 Hz, 2H, NCH 2 CH 2 CH 3 ), 0.90 (t, J = 7.4 Hz, 3H, NCH2CH2CH3); 13 C 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 C 26 H 24 N 4 O 8 S 552.56. MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, R f 0.63) to yield compound 34 (24 mg, 56%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) 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, J 1 = 8.6 Hz, J 2 = 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, CH 2 Ar), 1.76 (p, J = 7.6 Hz, 2H, NCH 2 CH 2 CH 2 CH 3 ), 1.30 (sextet, J = 7.7 Hz, 2H, NCH2CH2CH2CH3), 0.91 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); 13 C 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 C 27 H 26 FN 3 O 6 S 539.58. q . The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO 2 gel, Hexanes:EtOAc/1:1, Rf 0.45) to yield compound 40 (28 mg, 62%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) 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, J 1 = 9.1 Hz, J 2 = 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, CH 2 Ar), 4.03 (s, 3H, ArOCH 3 ), 1.77 (p, J = 7.5 Hz, 2H, NCH 2 CH 2 CH 2 CH 3 ), 1.30 (sextet, J = 7.6 Hz, 2H, NCH2CH2CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3); 13 C NMR (100 MHz, CDCl 3 ) 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 MgSO 4 , 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: 1 H NMR (500 MHz, (CD3)2SO) δ 12.24 (s, 1H, NH), 8.41 (d, J = 7.7 Hz, 1H, aromatic), 7.98 (dd, J 1 = 9.1 Hz, J 2 = 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(CH 3 ) 2 ), 0.82 (d, J = 6.7 Hz, 6H, CH(CH 3 ) 2 ); 13 C 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 C 27 H 26 FN 3 O 6 S 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 MgSO 4 , 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: 1 H NMR (500 MHz, CD 3 OD) 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, J 1 = 8.7 Hz, J 2 = 1.8 Hz, 1H, aromatic), 7.23 (s, 1H, aromatic), 7.06 (d, J = 8.5 Hz, 1H, aromatic), 4.09 (s, 2H, CH 2 Ar), 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); 13 C 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 H 2 O and extracted with CH 2 Cl 2 (3×). The combined organic layers were washed with brine, dried over MgSO 4 , 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: 1 H 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, J 1 = 9.1 Hz, J 2 = 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, J 1 = 7.9 Hz, J 2 = 2.2 Hz, 2H, aromatic), 6.97 (s, 1H, aromatic), 6.96 (d, J = 8.7 Hz, 1H, aromatic), 5.27 (s, 2H, NCH 2 Ar), 4.05 (s, 2H, CH2Ar), 4.04 (s, 3H, ArOCH3); 13 C 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 C 30 H 24 N 4 O 8 S 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 IC 50 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 IC 50 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 (IC 50 = 30 mM) as a thiol isomerase inhibitor. An electron withdrawing group (R 1 = NO2) on the indole (ring A) resulted in increased thiol isomerase inhibition activity and yielded derivative compounds 22, 23, and 27 with moderate activity (IC 50 = 30 mM) and compound 28 (IC 50 = 40 mM), and the most active compound 21 (IC 50 ~10 mM). By performing a pairwise comparison to observe the trend of the substituents on the arylsulfonamide (Ar 2 ) was found to be similar for the nitro and naphthalene substituents and varying for the fluoro substituents for compounds 15-20 (R 1 = H) vs compounds 21-26 (R 1 = NO 2 ) where compounds 15-20 (3-F phenyl displayed better activity (>) than 2-F phenyl > 3-NO 2 phenyl ≈ 4-NO 2 phenyl ≈ 2-naphthyl > 4-F) and compounds 21-26 (2-F phenyl > 3-F phenyl ≈ 4-F phenyl > 3-NO 2 phenyl > 4-NO 2 phenyl ≈ 2-naphthyl). The most active compound from derivative compounds 1-26 was compound 21 Ar 2 = 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 IC 50 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 IC 50 ‘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.