Phenylthione-2,3-dihydro-1h-pyrrolizine derivatives and pharmaceutical compositions thereof useful as h2s-releasing ketorolac analogues

Abstract

The present application is directed to H2S-releasing ketorolac analogs of Formula I, and pharmaceutically acceptable salts, solvates and / or prodrugs thereof. The application also includes pharmaceutical compositions comprising these compounds and methods of treating diseases, disorders or conditions that benefit from treatment with ketorolac using these compounds.

Description

PHENYLTHIONE-2.3-DIHYDRO-1 H-PYRROLIZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONSTHEREOF USEFUL AS H2S-RELEASING KETOROLAC ANALOGUESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority from co-pending U.S. provisional patent application no. 63 / 586,926 filed on September 29, 2024, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present application relates to ketorolac analogue compounds that have been modified to include an H2S releasing moiety, compositions comprising such compounds and their use, for example, as therapeutics.BACKGROUND

[0003] Ketorolac, or 5-benzoyl-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat moderate to severe pain. Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2), thereby decreasing production of prostaglandins. Ketorolac was patented in 1976 and approved for medical use as a ketorolac tromethamine salt in 1989. It is now widely available as a generic medication.

[0004] Though ketorolac has a potent analgesic effect in humans, its use is limited by the potential for causing gastric damage (Denton C., September 2022, Monthly FAQs, University of Illinois at Chicago College of Pharmacy).

[0005] H2S has been shown to contribute to gastrointestinal mucosal defense and the protection against gastrointestinal ulcers. In the intestine, H2S modulates epithelial secretion and promotes resolution of colitis. H2S inhibits leukocyte adherence to the vascular endothelium and appears to play an important role in the regulation of systemic blood pressure. H2S has also been observed to exert anti-inflammatory and analgesic effects. (Wang, FASEB J. 2002, 16:1792-1798; Wang, Gastroenterology, 2005, 129:1210-1224). Subsequent evidence along the same lines has been provided in Li H et al. J. Virol. 2015; 89:5557-5568; Bazhanov N et al. Sci. Rep. 2017; 7:41029; Yang G. Am. J. Physiol. Cell Physiol. 2020; 318:C244-C249; Citi V. et al. Brit. J. Pharmacol. 2020; 177:4931-4941 ; and Kim JZJ Et al. 2020, Journal of Translational Medicine, volume 18, Article number: 257, among other sources. No data or working embodiments of ketorolac derivatized with an H2S releasing moiety have been published.

[0006] WIPO publication W02008009127A1 describes (H2S)-releasing moieties conjugated to various nonsteroidal anti-inflammatory drugs (NSAIDS).

[0007] There remains a need for further advances in pharmacology to reduce or eliminate gastric damage caused by ketorolac.SUMMARY

[0008] The present application discloses ketorolac analogues, modified to include an H2S releasing moiety, which provide improved anti-inflammatory properties and reduced gastric damage compared to administration of ketorolac.

[0009] Accordingly, the present application includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein:R1and R2are independently selected from H, halo and Ci ealkyl;Y is absent or Y is selected from O, NH and OCH2CH2O;X is selected from H, Ci-4alkyl, OR3, NR4R5and an H2S releasing moiety;R3, R4and R5are independently selected from H and Chalky I; and all available hydrogen atoms are optionally and independently replaced with halo or a a deuterium atom.

[0010] The present application also includes a pharmaceutical composition comprising a compound of the application (a compound of Formula I ora pharmaceutically acceptable salt, solvate and / or prodrug thereof as defined above), and a pharmaceutically acceptable carrier.

[0011] The present application also includes a method for treating diseases, disorders or conditions that benefit from treatment with ketorolac, the method comprisingadministering an effective amount of a compound of the application to a subject in need thereof.

[0012] In some embodiments, the disease, disorder or condition that benefits from treatment with ketorolac is an inflammatory condition and / or pain. In some embodiments, the pain is post-operative pain or visceral pain.

[0013] In some embodiments, the administration of the compound reduces gastric damage compared to administration of an equivalent dose of ketorolac.

[0014] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.DRAWINGS

[0015] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0016] Figure 1 shows the starting time of twisting in mice injected with acetic acid and treated with vehicle, ketorolac (10 mg / kg), flurbiprofen (20 mg / kg) and two exemplary compounds I-26 (at doses of 11 mg / kg, 22 mg / kg and 33 mg / kg) and I-2 (at doses of 16 mg / kg, 32 mg / kg and 48 mg / kg). Cut-off threshold for observation setup at 1800 sec (30 min). Mice dosed with vehicle do not show any twisting.

[0017] Figure 2 shows a) time-dependent number of twisting events at 5-15 min and 15-30 min and b) total number of twisting events at 5-30 min, in mice injected with acetic acid and treated with vehicle, ketorolac (10 mg / kg), flurbiprofen (20 mg / kg) and two exemplary compounds I-26 (at doses of 11 mg / kg, 22 mg / kg and 33 mg / kg) and I-2 (at doses of 16 mg / kg, 32 mg / kg and 48 mg / kg).

[0018] Figure 3 shows the results of the Writhing Test in mice injected with acetic acid and treated with vehicle, ketorolac (10 mg / kg), flurbiprofen (20 mg / kg) and two exemplary compounds I-26 (33 mg / kg) and I-2 (48 mg / kg) at 5-15 min and 15-30 min.

[0019] Figure 4 shows the total number of writhing movements in mice injected with acetic acid and treated with vehicle, ketorolac (10 mg / kg), flurbiprofen (20 mg / kg) and two exemplary compounds I-26 (33 mg / kg) and I-2 (48 mg / kg).

[0020] Figure 5 shows the results of the Thermal Hyperalgesia test in Sprague Dawley (SD) rat model post carrageenan injection treated with ketorolac (10 mg / kg), naproxen (20 mg / kg) and two exemplary compounds I-26 (at doses of 11 mg / kg, 32 mg / kg and 64 mg / kg) and I-2 (at doses of 16 mg / kg, 48 mg / kg and 96 mg / kg) carried out at 2, 4 and 6 hours. Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Triangles: Pre-treatment + I-26. Diamonds: Pre-treatment + I-2. Squares: Pre-treatment + benchmarks. Dotted lines (except benchmarks): low concentration. Dashed lines (except benchmark): mid concentration. Solid lines (except normal and vehicle groups): high concentration.

[0021] Figure 6 shows the results of the Thermal Hyperalgesia test in SD rat model post carrageenan injection carried out at 2, 4 and 6 hours and treated with a) I-26 and b) I-2 (exemplary compounds of the application). Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Triangles: Pre-treatment + I-26 / I-2. Dotted lines (except benchmarks): low concentration. Dashed lines (except benchmarks): mid concentration. Solid lines (except normal and vehicle groups): high concentration.

[0022] Figure 7 shows the results of the Thermal Hyperalgesia test in SD rat model post carrageenan injection carried out at 2, 4 and 6 hours and treated with ketorolac and naproxen. Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Squares: Pretreatment + benchmarks.

[0023] Figure 8 shows the results of the Thermal Hyperalgesia test in mice Paw Incision (PI) model treated with ketorolac (10 and 90 mg / kg), and two exemplary compounds I-26 (at doses of 11 mg / kg, 32 mg / kg and 64 mg / kg) and I-2 (at doses of 16 mg / kg, 48 mg / kg and 96 mg / kg) carried out at day 1 at 2, 4 and 6 hours. Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Triangles: Pre-treatment + I-26. Diamonds: Pre-treatment + I-2. Squares: Pre-treatment + benchmarks. Dotted lines: low concentration. Dashed lines: mid concentration. Solid lines (except normal and vehicle groups): high concentration.

[0024] Figure 9 shows the results of the Thermal Hyperalgesia test in mice Paw Incision (PI) model treated with ketorolac (10 and 90 mg / kg), and two exemplarycompounds I-26 (at doses of 11 mg / kg, 32 mg / kg and 64 mg / kg) and I-2 (at doses of 16 mg / kg, 48 mg / kg and 96 mg / kg) carried out at day 2 at 2, 4 and 6 hours. Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Triangles: Pre-treatment + I-26. Diamonds: Pre-treatment + I-2. Squares: Pre-treatment + benchmarks. Dotted lines: low concentration. Dashed lines: mid concentration. Solid lines (except normal and vehicle groups): high concentration.

[0025] Figure 10 shows the results of the Thermal Hyperalgesia test in mice Paw Incision (PI) model treated with a) exemplary compound I-26 (at doses of 11 mg / kg, 32 mg / kg and 64 mg / kg), b) exemplary compound I-2 (at doses of 16 mg / kg, 48 mg / kg and 96 mg / kg), and c) ketorolac (10 and 90 mg / kg), carried out at day 1 at 2, 4 and 6 hours. Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Triangles: Pre-treatment + l-26 / l-2 / benchmark. Dotted lines: low concentration. Dashed lines: mid concentration. Solid lines (except normal and vehicle groups): high concentration.

[0026] Figure 11 shows the results of the Thermal Hyperalgesia test in mice Paw Incision (PI) model treated with a) exemplary compound I-26 (at doses of 11 mg / kg, 32 mg / kg and 64 mg / kg), b) exemplary compound I-2 (at doses of 16 mg / kg, 48 mg / kg and 96 mg / kg), and c) ketorolac (10 and 90 mg / kg), carried out at day 2 at 2, 4 and 6 hours. Empty circles: no treatment. Full circles: Pre-treatment + vehicle. Triangles: Pre-treatment + l-26 / l-2 / benchmark. Dotted lines: low concentration. Dashed lines: mid concentration. Solid lines (except normal and vehicle groups): high concentration.

[0027] Figure 12 shows the gastric damage score measured in rats treated with vehicle, ketorolac (at a dose of 20 mg / kg) and five exemplary compounds of the application I-26 (at a dose of 21 mg / kg), 1-1 (at a dose of 38 mg / kg), I-2 (at a dose of 32 mg / kg), I-4 (at a dose of 36 mg / kg), and 1-13 (at a dose of 33 mg / kg). Dark bar: Gastric ulcer scores. Error bars: SEM. Grey bars and labels: percentage decrease of gastric damage score compared to Ketorolac.

[0028] Figure 13 shows the results of the thermodynamic solubility of the exemplary compounds a) I-26 and b) I-27 of the application. Highest concentration tested was 300 pM. Standard curve range from 500 pM to 4 pM. PBS / 3% DMSO, 25 °C. Quantification by UV chromatography. Full circles: standard curve. Empty circles: assay samples.

[0029] Figure 14 shows the results of the chemical stability of the exemplary compounds a) I-26 and b) I-27 of the application for a period of 3h. Assay concentration of 50 pM, in PBS / 1 % DMSO, at 25 °C. Quantification by UV chromatography. Full circles: samples in PBS / 1 % DMSO. Empty circles: samples in ACN.DETAILED DESCRIPTIONI. Definitions

[0030] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0031] The term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.

[0032] The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0033] The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0034] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0035] As used in this application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise.

[0036] In embodiments comprising an “additional” or “second” component, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0037] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or “one or more” of the listed items is used or present.

[0038] The term “compound(s) of the application” or “compound(s) of the present application”, and the like, as used herein refers to a compound of Formula I, or a salt, solvate and / or prodrug of Formula I.

[0039] The term “composition(s) of the application” or “composition(s) of the present application, and the like, as used herein refers to a composition comprising one or more compounds of the application and a carrier.

[0040] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art.

[0041] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0042] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0043] The term “inert organic solvent” as used herein refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically nonpolar and dissolve compounds that are non soluble in aqueous solutions.

[0044] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term C1-1 oal ky I means an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0045] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0046] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0047] The term “H2S releasing moiety” as used herein refers to any chemical moiety that comprises sulfur and is capable of releasing hydrogen sulfide. The chemical moiety may comprise a molecular group or be a single S atom.

[0048] The term “subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0049] The term “pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.

[0050] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0051] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0052] The term “solvate” as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0053] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0054] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations. Treating pain includes a decrease in pain and does not require complete alleviation of pain signs or symptoms, and does not require a cure. In various embodiments, reducing pain includes even a marginal decrease in pain. By way of example, the administration of one or more effective dosages of the compound of the application may be used to prevent, treat or relieve the symptoms of post-operative pain and / or inflammation incidental to surgery.

[0055] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the applicationthat is effective, at dosages and for periods of time necessary to achieve the desired result.

[0056] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell either in cell culture or in a subject.II. Compounds and Compositions of the Application

[0057] The present application includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein:R1and R2are independently selected from H, halo and Ci-ealkyl;Y is absent or Y is selected from O, NH and OCH2CH2O;X is selected from H, Ci-4alkyl, OR3, NR4R5and an H2S releasing moiety;R3, R4and R5are independently selected from H and Ci-4al kyl ; and all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom.

[0058] In some embodiments, Y is O. In some embodiments, Y is NH.

[0059] In some embodiments, Y is O and the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2and X are as defined for Formula I.

[0060] In some embodiments, the X is an H2S releasing moiety. In some embodiments, X is selected from X1 , X2 and X3:(X1), (X2) and (X3) wherein R6and R7are independently selected from H, halo, Ci-4alkyl and OCi-4alkyl; each Q is independently selected from CH and N; each Z1is independently selected from O and S;Z2is selected from O and S; each R8is independently selected from H, Ci-4alkyl and NHR10;R9is selected from H, OH, Ci-4alkyl, OCi-4alkyl and NHR11;R10and R11are independently selected from H and Ci-4alkyl; n and m are, independently, 1 or 2; and all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom.

[0061] In some embodiments, X is X1 .

[0062] In some embodiments, X is X1 ,, and the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R6, Y, Q, Z1and n are as defined for Formula I.

[0063] In some embodiments, X is X2,, and the compound ofFormula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R7, R8,Y and m are as defined for Formula I.

[0064] In some embodiments, X is X3,and the compound ofFormula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R9, Y and Z2are as defined for Formula I.

[0065] In some embodiments, X is X1 and n is 1. In some embodiments, X is X1 and n is 2.

[0066] In some embodiments, when X is X1 and n is 1 , X has the following formula:. In this embodiment, the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R6, Y, Q and Z1are as defined for Formula I.

[0067] In some embodiments, when X is X1 and n is 2, X has the following formula:. In this embodiment, each Z1 and Q can be the same or different. In some embodiments, each Z1 and Q are the same. In this embodiment, the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R6, Y, Q and Z1are as defined for Formula I.

[0068] In some embodiments, X is X2 and m is 1. In some embodiments, X is X2 and m is 2.

[0069] In some embodiments, when X is X2 and m is 1 , X has the following formula:. In this embodiment, the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R7, R8and Y are as defined for Formula I.

[0070] In some embodiments, when X is X2 and m is 2, X has the following formula:. In this embodiment, each R8can be the same or different. In some embodiments, each R8is the same. In this embodiment, the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, wherein R1, R2, R7, R8and Y are as defined for Formula I.

[0071] In some embodiments, Q is CH. In some embodiments, Q is N.

[0072] In some embodiments, Z1is O. In some embodiments, Z1is S.

[0073] In some embodiments, Z2is O.

[0074] In some embodiments, each R8is independently selected from H, Ci salkyl and NHR10, wherein all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom. In some embodiments, each R8is independently selected from H, CH3, NH2 and NHCH3. In some embodiments, R4is NH2. In some embodiments, when m is 2, each R8is different. In some embodiments, when m is 2, each R8is the same. In some embodiments, when m is 2, each R8is NH2.

[0075] In some embodiments, R9is selected from H, OH, Ci salkyl , OCi-salkyl and NHR11, wherein all available hydrogen atoms are optionally and independently replaced with halo or deuterium atom. In some embodiments, each R9is independently selected from H, OH, CH3, CD3, CF3, OCH3, OCD3, OCF3, NH2 and NHCH3. In some embodiments, each R9is independently selected from H, OH, CH3, OCH3, NH2 and NHCH3. In some embodiments, R9is OH..

[0076] In some embodiments, X is selected from the following groups:

[0077] In some embodiments, R6is selected from H, halo, Ci salkyl and OCi-3alkyl, wherein all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom. In some embodiments, R6is selected from H, F, CF3, CD3, CH3, OCH3, OCF3 and OCD3. In some embodiments, R6is selected from H, F, CH3 and OCH3.

[0078] In some embodiments, R7is selected from H, halo, Ci salkyl and OCi-salkyl, wherein all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom. In some embodiments, R7is selected from H, F, CF3, CD3, CH3, OCH3, OCF3 and OCD3. In some embodiments, R7is selected from H, F, CH3 and OCH3.

[0079] In some embodiments, R6is located ortho to the Y group of the compound of Formula I. In some embodiments, R6is located meta to the Y group of the compound of Formula I.

[0080] In some embodiments, R7is located ortho to the Y group of the compound of Formula I. In some embodiments, R7is located meta to the Y group of the compound of Formula I.

[0081] In some embodiments, Y is absent.

[0082] In some embodiments, when Y is absent, X is selected from H, Ci salkyl, OR3, and NR4R5. In some embodiments, X is selected from H, OH, CH3, CH2CH3, CD3, CF3, OCH3, OCD3, OCF3, NH2 and NHCH3. In some embodiments, X is selected from H, CH3, CH2CH3, OH, OCH3, NH2 and NHCH3. In some embodiments, X is OH.

[0083] In some embodiments, Y is absent, X is OH and the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0084] In some embodiments, the compound of Formula I is in a salt form. In some embodiments, the salt is tromethamine salt.

[0085] In some embodiments, R1and R2are independently selected from H, halo and Ci-4alkyl, wherein all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom. In some embodiments, R1is selected from H, Cl,F, Br, CHs, CF3and CDs. In some embodiments, R1is selected from H, Cl, F, Br and CHs. In some embodiments, R1is H. In some embodiments, R2is selected from H, Cl, F, Br, CHs, CFs and CDs. In some embodiments, R2is selected from H, Cl, F, Br and CHs. In some embodiments, R2is H. In some embodiments, R1and R2are both H.

[0086] In some embodiments, the compounds of Formula I are selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0087] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0088] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. In some embodiments, the mono- or di-acid salts are formed and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0089] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline,diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, abutyl amine, choline and salts with amino acids such as arginine, lysine and the like. Basic nitrogen containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts) and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0090] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the application and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the application. In addition, when a compound of the application contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds of the application may exist in zwitterionic form, having both anionic andcationic centers within the same compound and a net neutral charge. Such zwitterions are included within the application.

[0091] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0092] Prodrugs of the compounds of the present application include, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0093] It is understood and appreciated that in some embodiments, compounds of the present application may have at least one chiral center and therefore can exist as enantiomers and / or diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0094] The compounds of the present application may further exist in varying amorphous and polymorphic forms and it is contemplated that any amorphous forms, polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0095] The compounds of the application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0096] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologicallycompatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0097] A compound of the application is suitably used on their own but will generally be administered in the form of a composition in which the one or more compounds of the application (the active ingredient) is in association with an acceptable carrier.

[0098] The compounds of the application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. A compound of the application may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump ortransdermal administration and the pharmaceutical compositions formulated accordingly. Administration can be by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0099] Parenteral administration includes intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0100] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.

[0101] A compound of the application may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets,carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions can be formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0102] Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Such liquid preparations for oral administration may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethylalcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0103] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0104] A compound of the application may also be administered parenterally. Solutions of a compound of the application can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0105] The compounds of the application may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0106] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.

[0107] For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0108] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0109] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example:Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0110] Compounds of the application may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, compounds of the application may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0111] In an embodiment, compounds of the application may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers.

[0112] In some embodiments, depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the compounds of the application, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of one or more pharmaceutically acceptable carriers, all percentages by weight being based on the total composition.

[0113] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the compounds of the application are administered in a dose of about 0.01 mg / kg body weight to about 250 mg / kg body weight, about 0.1 mg / kg to about 230 mg / kg, about 1 mg / kg to about 210 mg / kg, about 30 mg / kg to about 200 mg / kg, about 50 mg / kg to about 180 mg / kg, about 60 mg / kg, to about 150 mg / kg, about 80 mg / kg to about 120 mg / kg once daily or twice daily.

[0114] In some embodiments, a compound of the application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides asingle unit dosage form comprising one or more compounds of the application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0115] In the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced.III. Methods and Uses of the Application

[0116] Exemplary compounds of the application were tested in standard animal models of inflammation, acute-surgically-induced pain and visceral pain. Exemplary compounds showed activity that was comparable to ketorolac and flurbiprofen (administered at their respective standard dosages). The exemplary compounds showed reduced incidence of gastric damage, as compared to ketorolac. Specifically, the exemplary compounds showed up to 99% reduction of gastric damage, as compared to ketorolac.

[0117] Accordingly, compounds of the application, may, for example, be useful for the treatment of various diseases, disorders or conditions that benefit from treatment with ketorolac. Compounds of the application are hhS-releasing derivatives of ketorolac which showed good activity in animal models of inflammation, acute-surgically-induced pain and visceral pain, and provided reduced gastric damage. The H2S releasing properties of the compounds of the application are expected to provide compounds with anti-inflammatory properties and reduced risk for causing gastric damage. Therefore, the compounds of the present application highly effective replacement of ketorolac with reduced gastric damage.

[0118] In some embodiments, the present application includes a use of a compound of the application as a medicament.

[0119] The present application also includes a method for treating diseases, disorders or conditions that benefit from treatment with ketorolac, the method comprising administering an effective amount of a compound of the application to a subject in need thereof. The present application further includes a use of a compound of the application for treating diseases, disorders or conditions that benefit from treatment with ketorolac, a use of a compound of the application for preparation of a medicament for treating diseases, disorders or conditions that benefit from treatment with ketorolac, as well as a compound of the application for use to treat diseases, disorders or conditions that benefit from treatment with ketorolac.

[0120] In some embodiments, the compound of the application is useful in the treatment of an inflammatory condition and / or pain in a patient. Therefore in some embodiments, the diseases, disorders or conditions that benefit from treatment with ketorolac are selected from one or more of inflammatory conditions and pain. Accordingly, the present application also includes a method of treating an inflammatory condition and / or pain comprising administering an effective amount of a compound of the application to a subject in need thereof.

[0121] The present application also includes a use of a compound of the application for treatment of an inflammatory condition and / or pain as well as a use of a compound of the application for the preparation of a medicament for treatment of an inflammatory condition and / or pain. The application further includes a compound of the application for use in treating an inflammatory condition and / or pain in a patient.

[0122] In some embodiments, the compound of the application can be used to treat moderate to severe pain, such as trauma-inflicted pain, post-operative pain, visceral pain, cancer pain and the like.

[0123] In some embodiments, administration of the compounds of the application reduces gastric damage compared to administration of an equivalent dose of ketorolac.

[0124] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0125] When used in combination with other agents or therapies, it is an embodiment that compounds of the application are administered contemporaneously with those agents or therapies. As used herein, “contemporaneous administration” of two substances or therapies to a subject means providing each of the two substances or therapies so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances or therapies in the presence of each other, and can include administering the two substances or therapies within a few hours of each other, or even administering one substance or therapy within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, the substances or therapies will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition in the case of administration of two substances. It is a further embodiment ofthe present application that a combination of agents or therapies is administered to a subject in a non-contemporaneous fashion.

[0126] Effective amounts may vary according to factors such as the disease state, age, sex and / or weight of the subject. The amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. The effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.

[0127] In the context of treating inflammatory condition and / or pain, an effective amount is an amount that, for example, reduces inflammation and / or pain, compared to inflammation and / or pain without administration of a compound of the application.

[0128] The dosage of a compound of the application can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of a compound of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600mg or about 650 mg of per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 10 mg / kg. For administration in suppository form, a representative amount is from about 0.1mg / kg to about 10 mg / kg. In some embodiments, of the application, compositions are formulated for oral administration and the compounds are suitably in the form of tablets or suppositories containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet. Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three, four, five or six daily doses.

[0129] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for rectal administration, in some embodiments, the compounds of the application are administered in a dose of about 0.01 mg / kg body weight to about 250 mg / kg body weight, about 0.1 mg / kg to about 230 mg / kg, about 1 mg / kg to about 210 mg / kg, about 30 mg / kg to about 200 mg / kg, about 50 mg / kg to about 180 mg / kg, about 60 mg / kg, to about 150 mg / kg, about 80 mg / kg to about 120 mg / kg and values therebetween in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three, four, five or six daily doses.

[0130] In some embodiments, a compound of the application is administered at least once a week. However, in another embodiment, a compounds is administered to the subject from about one time per two weeks, three weeks or one month. In another embodiment, a compound of the application is administered about one time per week to about once daily. In another embodiment, a compound of the application is administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of a compound of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject. In some embodiments a compound of the application is administered or used at an initial dose (loading dose) which is administered or used one or more times, followed by administration or use of one or more lower doses, in which the amounts are optionally tapered to lower and lower amounts.

[0131] All references to “a compound” above, also include embodiments where one or more compounds are administered or used.IV. Methods of Preparing the Compounds of the Application

[0132] In some embodiments, compounds of the application are prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of the application is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. In the Schemes below showing the preparation of compounds of the application, all variables are as defined in Formula I, unless otherwise stated.

[0133] In some embodiments, a compound of Formula I is prepared as shown in Scheme 1 , where R1and R2are as defined in Formula I.Scheme 1

[0134] Step a in Scheme 1 is an alkylation reaction (or alternatively another protecting group incorporation reaction) which is achieved using a variety of conditions known to those skilled in the art. In some embodiments, the alkylation reaction is achieved by using methanol and acid catalyst, such as sulfuric, hydrochloric or phosphoric acid.

[0100] Step b in Scheme 1 is a thiolation reaction which is achieved using a variety of thiolating conditions known to those skilled in the art, for example, using reagents phosphorus pentasulfide (P2S5), Lawesson's reagent (LR), elemental sulfur (Ss),hexamethyldisilathiane, a combination of P2S5 and hexamethyldisiloxane in a suitable solvent (for example, THF, MeCN, toluene or xylenes) with heating if required.

[0135] Step c in Scheme 1 is a hydrolysis which is achieved using a variety of conditions known to those skilled in the art, for example, by using a suitable base (for example lithium hydroxide, sodium hydroxide or potassium hydroxide) in a suitable solvent (for example water, THF, 1 ,4-dioxane, methanol, ethanol or mixtures thereof) with heating if required.

[0136] Step d in Scheme 1 is a coupling reacting which is achieved by using a common coupling reagent (for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), propylphosphonic anhydride (T3P) or 1,1'- carbonyldiimidazole (CDI)) prior to reaction with the corresponding nucleophile (X’, see for example, Schemes 2, 3, 4 and 5 below)) with a suitable non-nucleophilic base (for example triethylamine, N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP)) in an suitable polar aprotic solvent (for example dichloromethane (DCM), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), EtOAc or combination thereof) with heating if necessary.

[0137] In some embodiments, when X is group X2, and m is 2 the reagent used to incorporate X2 into the compounds of the application (i.e. X’) is prepared as shown in Scheme 2, where R7and R8are as defined in Formula I.Scheme 2

[0138] In step e of Scheme 2, the benzene-1 ,3-dicarboxylic acid is converted to an acyl halide (using for example thionyl chloride, oxalyl chloride, PCh or PCIs) with a suitable non-nucleophilic base (for example triethylamine, DIPEA or DMAP) in a suitable polar aprotic solvent (for example DCM, DMF, NMP, THF, 1 ,4-dioxane or a combination thereof), then group HO-R4is added in a suitable solvent (for example, DCM, MeOH, 1 ,4- dioxane, EtOAc or diethyl ether) with heating if required.

[0139] In step f of Scheme 2, thiolation reaction is achieved using a variety of thiolating conditions known to those skilled in the art, for example, using reagents phosphorus pentasulfide (P2S5), Lawesson's reagent (LR), elemental sulfur (S8), hexamethyldisilathiane, a combination of P2S5 and hexamethyldisiloxane in a suitable solvent (for example, THF, MeCN, toluene or xylenes) with heating if required.

[0140] In step g of Scheme 2, demethylation is achieved using a variety of conditions known to those skilled in the art, for example, by use of a suitable Lewis acid (for example BBrs and AICI3) in a suitable polar aprotic solvent (for example DCM, DMF, NMP, THF, 1 ,4-dioxane or a combination thereof), with heating if required.

[0141] In some embodiments, when X is group X1 , Z1 is S, Q is CH and n is 1 , the reagent used to incorporate X1 into the compounds of the application (i.e. X’) is prepared as shown in Scheme 3, where R6is as defined in Formula I.Scheme 3

[0142] In step h of Scheme 3, ethylpotassium malonate with a suitable non- nucleophilic base (for example triethylamine, DI PEA or DMAP) in a suitable polar aprotic solvent (for example DCM, CHCI3, DMF, NMP, THF or EtOAc) and catalyst such as MgCl2 are added to a mixture of compound h in a suitable solvent (for example DCM, CHCI3, DMF, NMP, THF or EtOAc) and a suitable coupling reagent (for example EDC, HOBt, HATU, T3P or CDI) to obtain compound j.

[0143] In step j of Scheme 3, a thiolation reaction may be achieved using a variety of thiolating conditions known to those skilled in the art, for example, using reagents phosphorus pentasulfide (P2S5), Lawesson's reagent (LR), elemental sulfur (Ss), hexamethyldisilathiane, a combination of P2S5 and hexamethyldisiloxane in a suitable solvent (for example, ethanol, THF, MeCN, toluene or xylenes) with heating if required.

[0144] In step k of Scheme 3, demethylation may be achieved using a variety of conditions known to those skilled in the art, for example, by use of a suitable Lewis acid (for example BBrs and AICI3) in a suitable polar aprotic solvent (for example DCM, DMF, NMP, THF, 1 ,4-dioxane or a combination thereof) and with an appropriate base (for example triethylamine, DIPEA, DMAP), with heating if required.

[0145] Alternatively, the group OCH3 on compound h can be OH. In this embodiment, group OH can be protected with any suitable protecting group in step j and deprotected after step k.

[0146] In some embodiments, when X is group X1 , Z1 is S, Q is CH and n is 1 , the reagent used to incorporate X1 into the compounds of the application (i.e. X’) is prepared as shown in Scheme 4, where R6is as defined in Formula I.Scheme 4

[0147] In Scheme 4, pre-melted sulfur is added to allyl-phenol and the mixture is heated to obtain compound X'.

[0148] In some embodiments, when X is group X2, R8is NH2 and n is 1 , the reagent used to incorporate X into the compounds of the application (i.e. X’) is prepared as shown in Scheme 5, where R7is as defined in Formula I.Scheme 5

[0149] In Scheme 5, thiolation reaction is achieved using a variety of thiolating conditions known to those skilled in the art, for example, using reagents phosphorus pentasulfide (P2S5), Lawesson's reagent (LR), elemental sulfur (Ss), hexamethyldisilathiane, a combination of P2S5 and hexamethyldisiloxane in a suitable solvent (for example, ethanol, THF, MeCN, toluene or xylenes) with heating if required.

[0150] In some embodiments, when Y is O and X is H, the compounds of Formula I are prepared as shown in Scheme 6, where R1and R2are as defined in Formula I.Scheme 6

[0151] In Scheme 6, thiolation reaction is achieved using a variety of thiolating conditions known to those skilled in the art, for example, phosphorus pentasulfide (P2S50), Lawesson's reagent (LR), Elemental sulfur (Ss), hexamethyldisilathiane, a combination of P2Ssand hexamethyldisiloxane in an appropriate solvent (for example, THF, acetonitrile, toluene, xylene, pyridine) with heating if required.

[0152] Salts of the compound of Formula I, or a pharmaceutically acceptable prodrug and / or solvate thereof, are generally formed by dissolving the neutral compound in an inert organic solvent and adding either the desired acid or base and isolating the resulting salt by either filtration or other known means.

[0153] The formation of solvates of the compound of Formula I, or a pharmaceutically acceptable salt and / or prodrug thereof, will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried orazeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0154] Prodrugs may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).

[0155] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent intoanother group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0156] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, and / or chromatography or other suitable method.

[0157] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0101] The following non-limiting examples are illustrative of the present application:EXAMPLESGeneral Methods

[0158] Unless otherwise noted, chemicals were purchased from Sigma-Aldrich Canada Ltd, Oakville, ON, Canada or Combi-Blocks, Inc., San Diego, CA, USA, or Ambeed, Inc., IL, USA, or Oakwood Products, Inc., SC, USA, or Enamine Ltd, USA. All solvents were HPLC grade and used as such or treated as specified for each case.

[0159] Flash column chromatography (FCC) was carried out using silica gel grade 60, mesh size 230-400 or C18 silica 100 A 30 pm. When required, flash chromatographic purifications were performed on Biotage Isolera Prime systems (wavelength 254 and 280 nm) using pre-packed Biotage® or Innoflash™ flash cartridges.

[0160] Nuclear magnetic resonance spectra were recorded on Bruker 400-MHz Avance spectrometer (400 MHz for1H and 100 MHz for13C). Chemical shifts (5) are reported in parts per million (ppm) after calibration to residual isotopic solvent or relative to tetramethylsilane. Coupling constants (J) are reported in Hz and reported to one decimal place. The splitting pattern for NMR spectra are denoted as follows: s (singlet), br (broad), d (doublet), t (triplet), m (multiplet), dd (doublet of doublet).

[0161] Mass spectrometry data were obtained on an Agilent 1100 series HPLC system equipped with an autosampler, binary pump, degasser, and a UV detector connected directly to a mass detector (Agilent 6110 Quadrupole LC / MS mass spectrometer) with an electrospray ionization (ESI) source. Chromatographic separations were carried out at room temperature using an Eclipse XDB-C18 column (5 pm particle size silica, 150 mm x 4.6 mm I.D.). The mobile phase consisted of a linear gradient of: H2O (0.1 % formic acid) -CH3CN (0.1 % formic acid) from 50 : 50 to 0 : 100 in 10 min and a flow rate of 1 .0 mL min-1. Data acquisition was carried out in positive or negative polarity mode, and data processing was carried out with Agilent Chemstation Software.Example 1A: 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (1-26)

[0162] To a stirred solution of ketorolac (5 g, 19.59 mmol) in methanol (50 mL) was added dropwise cone. H2SO4 (961 mg, 9.79 mmol, 0.522 mL). The resulting solution was refluxed for 2 h. The mixture was diluted with water and extracted with dichloromethane(DCM). The combined organic extract was washed with aq. NaHCOa, then with water and brine. The solution was dried over NaaSC , filtered, concentrated and further dried to give methyl 5-(benzoyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (4.97 g, 94% yield), which was used for the next step without further purification. ESI-MS [M+H]+: 270.

[0163] To a stirred suspension of methyl 5-(benzoyl)-2,3-dihydro-1 H-pyrrolizine-1- carboxylate (1.24 g, 4.61 mmol) in toluene (24 mL) under argon was added Lawesson's reagent (950 mg, 2.35 mmol). The mixture was stirred at 70 °C for 30 min and concentrated. The crude was diluted with EtOAc and washed with a mixture of brine:water (1 :1 ), and brine. The organic extract was dried over Na2SO4, concentrated and purified by flash column chromatography (EtOAc - hexane) to give methyl 5- (benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (1.1 g, 84% yield). ESIMS [M+H]+: 286.

[0164] To a solution of methyl 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylate (1.2 g, 4.21 mmol) in tetrahydrofuran (THF) (20 mL) was added NaOH 5M (4.2 mL). The reaction was stirred at 65°C for 3 h and then at room temperature overnight. The mixture was acifidied with 1 N HCI and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4 and concentrated in vacuo. The crude product was purified on C18 reverse phase chromatography (CH3CN-H2O). The fractions containing the desired product were concentrated and lyophilized to afford 5-(benzenecarbothioyl)- 2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (100 mg, 0.38 mmol, 9% yield).1H NMR (400 MHz, DMSO-cfe) 5 12.94 (s, 1 H), 7.56 - 7.46 (m, 3H), 7.41 (dd, J = 8.1 , 6.7 Hz, 2H), 6.62 (d, J = 4.2 Hz, 1 H), 6.23 (d, J = 4.2 Hz, 1 H), 4.62 - 4.51 (m, 1 H), 4.46 - 4.35 (m, 1 H), 4.13 (t, J = 7.7 Hz, 1 H), 2.80 - 2.70 (m, 2H). ESI-MS [M+H]+: 272.48.Example 1B: 5-(benzenecarbothioyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylate (1-1)

[0165] To a stirred solution of 5-(benzenecazrbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (250 mg, 0.92 mmol), 5-(4-oxidanylphenyl)dithiole-3-thione (208 mg, 0.92 mmol) and 4-dimethylaminopyridine (DMAP) (5.63 mg, 0.046 mmol) in DCM (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (194 mg, 1.01 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed with a mixture of brine / water / 1 N HCI (1 :1 :1), followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo, and purified by flash column chromatography (DCM - hexane) to give [4-(5- sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1- carboxylate (164 mg, 0.34 mmol, 37% yield).1H NMR (400 MHz, DMSO-cfe) 68.05 - 7.97 (m, 2H), 7.85 (s, 1 H), 7.58 - 7.48 (m, 3H), 7.47 - 7.38 (m, 4H), 6.68 (d, J = 4.2 Hz, 1 H),6.43 (d, J = 4.2 Hz, 1 H), 4.72 - 4.56 (m, 2H), 4.53 - 4.42 (m, 1 H), 3.00 - 2.91 (m, 2H).1H NMR (400 MHz, CDCI3) 5 7.76 - 7.69 (m, 2H), 7.67 - 7.62 (m, 2H), 7.51 - 7.44 (m, 1 H),7.44 - 7.35 (m, 3H), 7.32 - 7.25 (m, 2H), 6.74 (d, J = 4.2 Hz, 1 H), 6.31 (dd, J = 4.2, 0.8 Hz, 1 H), 4.85 - 4.74 (m, 1 H), 4.66 (m, 1 H), 4.36 (dd, J = 9.1 , 5.8 Hz, 1 H), 3.16 - 3.05 (m, 1 H), 3.02 - 2.89 (m, 1 H); ESI-MS [M+H]+: 480.Example 1C: (4-azanylcarbothioylphenyl) 5-(benzenecarbothioyl)-2,3-dihydro-1H- pyrrolizine-1 -carboxylate (1-2)

[0166] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (250 mg, 0.92 mmol), 4-hydroxythiobenzamide (140 mg, 0.92 mmol) and DMAP (6 mg, 0.046 mmol) in DCM (2 mL) was added EDC. HCI (265 mg, 1 .38 mmol). The mixture was stirred at room temperature for2 h, diluted with ethyl acetate and washed with a mixture of brine:water (1 :1), followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo then purified by flash column chromatography (EtOAc - DCM). The product containing fractions were concentrated in vacuo to give a dry foamy solid, which was stirred in hexanes for 2 h, then filtered and dried to get thedesired (4-azanylcarbothioylphenyl) 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylate (127 mg, 0.31 mmol, 33% yield) as a maroon powder.1H NMR (400 MHz, DMSO) 5 9.92 (s, 1 H), 9.55 (s, 1 H), 8.00 - 7.92 (m, 2H), 7.58 - 7.48 (m, 3H), 7.47 - 7.39 (m, 2H), 7.30 - 7.23 (m, 2H), 6.68 (d, J = 4.2 Hz, 1 H), 6.41 (d, J = 4.2 Hz, 1 H), 4.71 - 4.62 (m, 1 H), 4.60 (t, J = 7.6 Hz, 1 H), 4.53 - 4.42 (m, 1 H), 2.94 (q, J = 7.4 Hz, 1 H). ESIMS [M+H]+: 407.1.Example 1D: [4-(5-oxidanylidene-1 ,2,4-dithiazol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3- dihydro-1 H-pyrrolizine-1 -carboxylate (1-3)

[0167] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (250 mg, 0.92 mmol), 5-(4-oxidanylphenyl)-1 ,2,4-dithiazol-3-one (195 mg, 0.92 mmol) and DMAP (6 mg, 0.046 mmol) in DCM (2 mL) and THF (2 mL) at room temperature was added EDC (265 mg, 1 .38 mmol) and the mixture was stirred overnight. The mixture was diluted with ethyl acetate, washed with a mixture of brine:water (1 :1 ) and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and purified by flash column chromatography (EtOAc - hexanes) to give [4-(5-oxidanylidene- 1 ,2,4-dithiazol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 - carboxylate (35 mg, 0.075 mmol, 8% yield).1H NMR (400 MHz, CDCI3) 5 8.17 (d, J = 8.8 Hz, 2H), 7.66 - 7.59 (m, 2H), 7.50 - 7.41 (m, 1 H), 7.38 - 7.36 (m, 1 H), 7.34 - 7.30 (m, 2H), 6.72 (d, J = 4.2 Hz, 1 H), 6.29 (dd, J = 4.2, 0.8 Hz, 1 H), 4.83 - 4.72 (m, 1 H), 4.70 - 4.59 (m, 1 H), 4.34 (dd, J = 9.1 , 5.7 Hz, 1 H), 3.15 - 3.02 (m, 1 H), 2.99 - 2.89 (m, 1 H); ESIMS [M+H]+: 465.Example 1E: [4-(5-oxidanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro- 1 H-pyrrolizine-1 -carboxylate (1-4)

[0168] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (110 mg, 0.4 mmol), 5-(4-oxidanylphenyl)dithiol-3-one (85 mg, 0.4 mmol) and DMAP (2.5 mg, 0.02 mmol) in DCM (2 mL) and THF (2 mL) was added EDC.HCI (116 mg, 0.6 mmol) and the mixture was stirred vigorously overnight. The mixture was diluted with ethyl acetate, washed with brine:water (1 :1), followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and purified by flash column chromatography (EtOAc - hexanes) to give [4-(5-oxidanylidenedithiol-3- yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (78 mg, 41 % yield).1H NMR (400 MHz, CDCI3) 5 7.70 - 7.65 (m, 2H), 7.65 - 7.59 (m, 2H), 7.50 - 7.41 (m, 1 H), 7.41 - 7.32 (m, 2H), 7.27 (s, 1 H), 7.25 (s, 1 H), 6.82 (s, 1 H), 6.72 (d, J = 4.2 Hz, 1 H), 6.29 (dd, J = 4.2, 0.8 Hz, 1 H), 4.83 - 4.72 (m, 1 H), 4.68 - 4.58 (m, 1 H), 4.33 (d, J = 3.3 Hz, 1 H), 3.13 - 3.04 (m, 1 H), 2.98 - 2.88 (m, 1 H); ESI-MS [M+H]+: 463.9. Example 1F: [3,5-bis(azanylcarbothioyl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1H- pyrrolizine-1 -carboxylate (1-5)

[0169] To a stirred suspension of 5-methoxybenzene-1 ,3-dicarboxylic acid (4.21 g, 21.46 mmol) in DCM (30 mL) and DMF (2 drops) was added oxalyl chloride (8.17 g, 64.39 mmol, 5.62 mL) slowly. The mixture was stirred at room temperature overnight and concentrated in vacuo to give a sticky yellow solid. The residue was dissolved in DCM (15 mL) and added to a rapidly stirred mixture of ethyl acetate (50 mL) and NH4OH (40 mL) cooled in an ice bath. The mixture was diluted with hexane (50 mL) and filtered to collect the solid. The filter cake was stirred in water then filtered to collect the solid, which was further dried under high vacuum to give the desired 5-methoxybenzene-1 ,3- dicarboxamide (3.91 g, 94% yield).1H NMR (400 MHz, DMSO-cfe) 5 8.01 (br s, 2H), 7.96 (s, 1 H), 7.54 (d, J = 1.2 Hz, 2H), 7.45 (br s, 2H), 3.85 (s, 3H). ESI-MS [M+H]+195.2.

[0170] To a stirred suspension of 5-methoxybenzene-1 ,3-dicarboxamide (3.9 g, 20.08 mmol) in THF (40 mL) was added Lawesson's reagent (9.75 g, 24.10 mmol). After stirring at 65 °C for 2 h, the mixture was diluted with ethyl acetate, washed with brine:water:NaHCO3 (1 :1 :1), followed by waterbrine (1 :1) and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo then purified by flash column chromatography (EtOAc - hexanes). The product containing fractions were concentrated in vacuo then stirred in diethyl ether. The suspension was filtered to collect the desired 5- methoxybenzene-1 ,3-dicarbothioamide (4.2 g, 92% yield).1H NMR (400 MHz, DMSO-cfe) 5 9.96 (br s, 2H), 9.54 (br s, 2H), 7.94 (d, J = 1 .2 Hz, 1 H), 7.49 (d, J = 1 .2 Hz, 2H), 3.84 (s, 3H). ESI-MS [M+H]+227.2.

[0171] To a stirred suspension of 5-methoxybenzene-1 ,3-dicarbothioamide (1 g, 4.42 mmol) in DCM (5.00 mL) was added boron tribromide (1 M in DCM, 30.94 mL). The mixture was stirred at room temperature for 4 days, then at 40 °C for 3 days. The mixture was poured over ice, diluted with brine and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred in diethyl ether at room temperature and the suspension was filtered to give 5-oxidanylbenzene-1 ,3-dicarbothioamide (644 mg, 3.03 mmol, 69% yield) as a pale-yellow solid.1H NMR (400 MHz, DMSO-cfe) 59.96 (s, 1 H), 9.88 (br s, 2H), 9.44 (br s, 2H), 7.66 (t, J = 1.6 Hz, 1 H), 7.35 (d, J = 1.6 Hz, 2H). ESI-MS [M+H]+213.18.

[0172] To a stirred suspension of 5-(benzenecarbothioyl)-2,3-dihydro-1 H- pyrrolizine-1 -carboxylic acid (275 mg, 1.0 mmol), 5-oxidanylbenzene-1 ,3- dicarbothioamide (215 mg, 1.0 mmol) and DMAP (6 mg, 0.05 mmol) in THF (3 mL) andDCM (2 mL) was added EDC.HCI (210 mg, 1.11 mmol) and the mixture was stirred vigorously for 2 h. The mixture was diluted with ethyl acetate, washed with a mixture of aq. NaHCO3:water: brine (1 :1 :1), followed by brine:1 N HCI. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo then purified by flash column chromatography (EtOAc - DCM). The product containing fractions were concentrated in vacuo then triturated with Et20, filtered and dried to collect a dark red solid of [3,5- bis(azanylcarbothioyl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 - carboxylate (77 mg, 165 mmol, 17% yield).1H NMR (400 MHz, DMSO) 5 10.10 (s, 2H), 9.65 (s, 2H), 8.23 - 8.13 (m, 1 H), 7.81 (d, J = 1.7 Hz, 2H), 7.58 - 7.48 (m, 3H), 7.43 (m, 2H), 6.69 (d, J = 4.2 Hz, 1 H), 6.43 (d, J = 4.2 Hz, 1 H), 4.72 - 4.55 (m, 2H), 4.54 - 4.41 (m, 1 H), 3.01 - 2.89 (m, 2H). ESI-MS [M+H]+: 466.Example 1 G: [3-fluoranyl-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)- 2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (1-6)

[0173] A mixture of ethyl potassium malonate (3.04 g, 17.63 mmol), anhydrous MgCl2 (895 mg, 9.40 mmol) and triethylamine (1 .78 g, 17.63 mmol, 2.46 mL) in anhydrous THF (15 mL) was stirred at 65 °C for 6 h (mixture A). In a separate flask, a mixture of 2- fluoranyl-4-methoxy-benzoic acid (1 g, 5.88 mmol) and 1 ,1 '-carbonyldiimidazole (CDI) (1.14 g, 7.05 mmol) in anhydrous THF (7 mL) was heated at 60 °C for 30 min. This homogenous solution was added to mixture A and the resulting mixture was stirred at 65 °C overnight. The reaction was cooled to rt, acidified with 1 N HCI and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (EtOAc - hexane) to give ethyl 3-(2-fluoranyl-4-methoxy-phenyl)-3-oxidanylidene-propanoate (1.3 g, 92% yield) as a clear oil.ESI-MS [M+H]+: 241.

[0174] Into a mixture of phosphorus pentasulfide (330 mg, 0.75 mmol), hexamethyldisiloxane (608 mg, 3.75 mmol, 800 pL) and sulfur (43 mg, 1.25 mmol) in m- xylene (4 mL) was added dropwise a solution of ethyl 3-(2-fluoranyl-4-methoxy-phenyl)- 3-oxidanylidene-propanoate (300 mg, 1.25 mmol) in m-xylene (2 mL) at 135-140 °C. The mixture was heated at the same temperature for 2 h and cooled to rt. Brine was added and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated and purified by flash column chromatography to give 5-(2- fluoranyl-4-methoxy-phenyl)dithiole-3-thione(260 mg, 81 % yield) as a brown / red solid.1H NMR (400 MHz, DMSO-cfe) 5 7.94 (t, J = 9.0 Hz, 1 H), 7.68 (s, 1 H), 7.14 (dd, J = 13.9, 2.5 Hz, 1 H), 6.97 (dd, J = 8.8, 2.6 Hz, 1 H), 3.88 (s, 3H).19F NMR (376 MHz, DMSO-cfe) 5 - 106.65 (dd, J = 13.9, 9.1 Hz). ESI-MS [M+H]+: 259.

[0175] To a solution of 5-(2-fluoranyl-4-methoxy-phenyl)dithiole-3-thione (875 mg, 3.38 mmol) and DMAP (80 mg, 0.68 mmol) in anhydrous DCM (30 mL) at 0 °C was added dropwise boron tribromide (1 M in DCM, 16.9 ml). After stirring at rt for 14 h, solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic extract was washed with 1 N HCI, followed by water then brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (EtOAc - hexane) to give 5-(2-fluoro-4-hydroxyphenyl)-3H-1 ,2-dithiole-3-thione (441 mg, 53% yield).1H NMR (400 MHz, DMSO-d6): 5 11 .00 (s, 1 H), 7.83 (t, J = 9.0 Hz, m), 7.62 (1 H, s), 6.80 (m, 2H).

[0176] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (210 mg, 0.77 mmol), 5-(2-fluoro-4-hydroxyphenyl)-3H-1 ,2-dithiole-3- thione (190 mg, 0.77 mmol) and DMAP (10 mg, 0.077 mmol) in DCM (5 mL) was added EDC. HCI (225 mg, 1.16 mmol). The mixture was stirred at rt for 4 hr, concentrated and purified by flash column chromatography (EtOAc - hexane), followed by C18 reverse phase chromatography (CH3CN-H2O) to give [3-fluoranyl-4-(5-sulfanylidenedithiol-3- yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (196 mg, 0.39 mmol, 50% yield).1H NMR (400 MHz, CDCfe): 5 7.72 (t, J = 8.6 Hz, 1 H), 7.69 - 7.61 (m, 2H), 7.56 - 7.45 (m, 2H), 7.39 (dd, J = 8.3, 6.9 Hz, 2H), 7.18 - 7.07 (m, 2H), 6.75 (d,J = 4.2 Hz, 1 H), 6.30 (d, J = 4.2 Hz, 1 H), 4.83-4.76 (m, 1 H), 470-4.64 (m, 1 H), 4.35 (dd, J = 9.1 , 5.7 Hz, 1 H), 3.14-3.06 (m, 1 H), 3.01-2.92 (m, 1 H). ESI-MS [M+H]+: 498.2.Example 1H: [2-fluoranyl-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)- 2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (1-7)

[0177] A mixture of ethyl potassium malonate (9.1 g, 52.90 mmol), anhydrous MgCl2 (2.69 g, 28.21 mmol) and triethylamine (5.35 g, 52.9 mmol, 7.4 mL) in anhydrous THF (40 mL) was stirred at 65 °C for 6 h (mixture A). In a separate flask, a mixture of 3- fluoranyl-4-methoxy-benzoic acid (3 g, 17.63 mmol) and CDI (3.43 g, 21 .16 mmol) in THF, anhydrous (10 mL) was heated at 60 °C for 30 min. This homogenous solution was added to mixture A and the resulting mixture was stirred at 65 °C overnight. The reaction was cooled to rt, acidified with aq. 1 N HCI and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (EtOAc-hexane) to give ethyl 3-(3-fluoranyl-4-methoxy-phenyl)-3- oxidanylidene-propanoate (4.22, quantitative) as a clear oil. ESI-MS [M+H]+: 241.

[0178] Into a mixture of phosphorus pentasulfide (1.67 g, 3.75 mmol), hexamethyldisiloxane (3.0 g, 3.98 mL, 18.73 mmol) and sulfur (213 mg, 6.24 mmol) in m- xylene (4 mL) was added dropwise a solution of ethyl 3-(3-fluoranyl-4-methoxy-phenyl)- 3-oxidanylidene-propanoate (1.5 g, 6.24 mmol) in m-xylene (2 mL) at 135-140 °C. The mixture was heated at the same temperature for 2 h and cooled to rt. Brine was added and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated and purified by flash column chromatography to give 5-(2- fluoranyl-4-methoxy-phenyl)dithiole-3-thione (475 mg, 29 % yield) as a brown / red solid.1H NMR (400 MHz, DMSO-d6): 87.90-7.94 (1 H, d, J = 16 Hz), 7.85 (1 H, s), 7.75-7.80 (1 H, m), 7.32-7.36 (1 H, t, J = 8 Hz), 3.96 (3H, s). ESI-MS [M+H+: 259.

[0179] To a solution of 5-(3-fluoranyl-4-methoxy-phenyl)dithiole-3-thione (1.62 g, 6.26 mmol) and DMAP (150 mg, 1.25 mmol) in anhydrous DCM (100 mL) at 0 °C was added dropwise boron tribromide (1 M in DCM, 31.3 mL). After stirring at rt for 14 h, solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic extract was washed with aq. 1 N HCI, followed by water and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (EtOAc-hexane) to give 5-(3-fluoro-4-hydroxyphenyl)-3H-1 ,2-dithiole-3-thione (640 mg, 40% yield).1H NMR (400 MHz, DMSO-d6): 8 11.00 (1 H, s), 7.82-7.86 (1 H, d, J = 16 Hz), 7.80 (1 H, s), 7.65 (1 H, m), 7.10-7.14 (1 H, t, J = 8 Hz); ESI-MS [M+H]+: 245.

[0180] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (280 mg, 1.03 mmol), 5-(3-fluoranyl-4-oxidanyl-phenyl)dithiole-3-thione (250 mg, 1 .03 mmol) and DMAP (15 mg, 0.10 mmol) in DCM (5 mL) was added EDC. HCI (300 mg, 1.55 mmol). The mixture was stirred at rt for 2 h and concentrated. The crude was purified by Silica column chromatography (EtOAc-hexane), followed by C18 reverse phase chromatography (CH3CN-H2O) to give [2-fluoranyl-4-(5-sulfanylidenedithiol-3- yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (220 mg, 0.44 mmol, 42% yield).1H NMR (400 MHz, CDCI3) 5 7.66-7.63 (m, 2H), 7.57 - 7.43 (m, 3H), 7.43 - 7.34 (m, 3H), 7.38 - 7.30 (m, 1 H), 6.75 (d, J = 4.2 Hz, 1 H), 6.33 (d, J = 4.1 Hz, 1 H), 4.84-4.78 (m, 1 H), 4.72 - 4.61 (m, 1 H), 4.40 (dd, J = 9.1 , 6.0 Hz, 1 H), 3.17 - 3.05 (m, 1 H), 3.05 - 2.92 (m, 1 H). ESI-MS [M+H]+: 498.2.Example 11: [2-methyl-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3- dihydro-1 H-pyrrolizine-1 -carboxylate (1-8)

[0181] A mixture of ethyl potassium malonate (15.365 g, 90.269 mmol), anhydrous MgCl2 (5.730 g, 60.179 mmol) and triethylamine (12.582 mL, 90.269 mmol) in anhydrous THF (30.0 mL) was stirred at 65 °C for 6 h (mixture A). In a separate flask, a mixture of 4- methoxy-3-methylbenzoic acid (5.0 g, 30.090 mmol) and CDI (5.855 g, 36.108 mmol) in anhydrous THF (20.0 mL) was heated at 65 °C for 30 min. The homogenous solution was added to the above mixture A and the resulting reaction mixture was stirred at 65 °C under inert atmosphere. The reaction was cooled to rt, acidified with aq. 1 N HCI and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (EtOAc-hexane) to give ethyl 3-(4-methoxy-3- methylphenyl)-3-oxopropanoate (5.1 g, 72% yield) as pale-yellow liquid.1H NMR (400 MHz, DMSO-de) 5 7.84 (dd, J =8.4 Hz, 2.0 Hz, 1 H), 7.76 (d, J = 1.6 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 4.13-4.08 (m, 4H), 3.88 (s, 3H), 2.19 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).

[0182] A mixture of phosphorus pentasulfide (11 .289 g, 25.395 mmol), hexamethyl disiloxane (13.493 mL, 63.487 mmol) and sulphur (1 .356 g, 42.324 mmol) in o-xylene (40 mL) was heated at 140°C. To this mixture, a solution of ethyl 3-(4-methoxy-3- methylphenyl)-3-oxopropanoate (5.0 g, 21 .162 mmol) in o-xylene (10 mL) was added drop wise. The resulting reaction mixture was heated at the same temperature for 4 h and cooled to rt. Brine was added, and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (EtOAc - hexanes) to give 5-(4-methoxy-3-methylphenyl)-3H-1 ,2- dithiole-3-thione (3.35 g, 62% yield) as a pale-brown solid.1H NMR (400 MHz, DMSO- d6) 57.77-7.75 (m, 3H), 7.08 (d, J= 8.4 Hz, 1 H), 3.88 (s, 3H), 2.20 (s, 3H). ESI-MS [M+H]+: 255.

[0183] To a stirred solution of 5-(4-methoxy-3-methylphenyl)-3H-1 ,2-dithiole-3- thione (5.0 g, 19.65 mmol) and DMAP (480 mg, 3.93 mmol) in anhydrous DCM (150 mL) at 0 °C under inert atmosphere, boron tribromide (1 M in DCM, 98.3 mL, 98.278 mmol) was added drop wise and the resulting reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with aq. 1 N HCI, followed by water, and dried over anhydrous Na2SO4. The organic layer was concentrated and triturated with diethyl ether and n-pentane to afford 5-(4-hydroxy-3- methylphenyl)-3H-1 ,2-dithiole-3-thione (3.05 g, 65% yield) as a pale-brown solid.1H NMR(400 MHz, DMSO-de) 6 10.43 (s, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.68 (s, 1 H), 7.61 (dd, J =8.4 Hz, 2.4 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 2.17 (s, 3H); ESI-MS [M+H]+: 241.

[0184] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (340 mg, 1.25 mmol), 5-(3-methyl-4-oxidanyl-phenyl)dithiole-3-thione (300 mg, 1.25 mmol), and DMAP (8 mg, 0.062 mmol) in DCM (3 mL) and THF (3 mL), EDC.HCI (360 mg, 1.87 mmol) was added at room temperature. The mixture was stirred at room temperature overnight and concentrated and purified by flash column chromatography (DCM - hexane) to give [2-methyl-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (109 mg, 0.22 mmol, 18% yield).1H NMR (400 MHz, CDCh) 5 7.68 - 7.63 (m, 2H), 7.60 - 7.52 (m, 2H), 7.52 - 7.44 (m, 1 H), 7.44 - 7.34 (m, 3H), 7.19 (d, J = 8.3 Hz, 1 H), 6.75 (d, J = 4.2 Hz, 1 H), 6.32 (d, J = 4.2 Hz, 1 H), 4.84 - 4.78 (m, 1 H), 4.75 - 4.62 (m, 1 H), 4.38 (dd, J = 9.0, 5.5 Hz, 1 H), 3.15 - 3.07 (m, 1 H), 3.04 - 2.89 (m, 1 H), 2.25 (s, 3H); ESI-MS [M+H]+: 494.2.Example 1J: [3-methyl-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3- dihydro-1 H-pyrrolizine-1 -carboxylate (1-9)

[0185] A mixture of ethyl potassium malonate (41 g, 240.71 mmol), anhydrous MgCl2 (11 .46 g, 120.36 mmol) and triethylamine (34 mL, 240.72 mmol) in anhydrous THF (100 mL) was stirred at 60 °C for 6 h (mixture A). In another flask, a mixture of 4-methoxy- 2-methylbenzoic acid (10.0 g, 60.18 mmol) and CDI (14.64 g, 90.27 mmol) in anhydrous THF (50 mL) was heated at 60 °C for 30 min. The resulting homogenous solution was added to mixture A and was stirred at reflux temperature for 16 h. The reaction was cooled to room temperature, acidified with aq. 1 N HCI and extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated. The crude waspurified by Silica column chromatography (EtOAc - petroleum ether) to give ethyl 3-(4- methoxy-2-methylphenyl)-3-oxopropanoate (11.0 g, 77% yield) as pale-yellow oil.1H NMR (400 MHz, CDCI3) 5 7.70 (d, J = 9.6 Hz, 1 H), 6.77-6.72 (m, 2H), 4.24-4.17 (m, 2H), 3.93 (s, 2H), 3.84 (s, 3H), 2.57 (s, 3H), 1.30-1.23 (m, 3H).

[0186] A mixture of phosphorus pentasulfide (13.55 g, 30.47 mmol), hexamethyldisiloxane (16.19 mL, 76.18 mmol) and sulfur (1.63 g, 50.79 mmol) in o-xylene (40 mL) was heated at 140 °C. To this mixture, a solution of ethyl 3-(4-methoxy-2- methylphenyl)-3-oxopropanoate (6.0 g, 25.39 mmol) in o-xylene (20 mL) was added dropwise. The mixture was heated at the same temperature for 4 h. After cooling to room temperature, the mixture was diluted with brine and extracted with EtOAc. The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (EtOAc - petroleum ether) to afford 5-(4- methoxy-2-methylphenyl)-3H-1 ,2-dithiole-3-thione (5.0 g, 77% yield) as pale-brown gummy mass.1H NMR (400 MHz, DMSO-cfe) 5 7.52 (d, J = 8.4 Hz, 1 H), 7.38 (s, 1 H), 6.99 (d, J = 2.4 Hz, 1 H), 6.92 (dd, J =8.4 Hz, 2.4 Hz, 1 H), 3.81 (s, 3H), 2.39 (s, 3H); ESIMS [M+H]+: 255.

[0187] To a solution of 5-(4-methoxy-3-methylphenyl)-3H-1 ,2-dithiole-3-thione (5.0 g, 19.656 mmol) and DMAP (480 mg, 3.931 mmol) in anhydrous DCM (100 mL) at 0 °C, boron tribromide (1 M in DCM, 98.3 mL) was added dropwise and the resulting mixture was allowed to stir at ambient temperature for 16 h. The mixture was concentrated, and the residue was diluted with ethyl acetate and washed with aq. 1 N HCI, and water, dried over anhydrous Na2SO4 and concentrated. The crude was purified by trituration with diethyl ether (10 mL) and n-pentane (10 mL) to afford 5-(4-hydroxy-3-methylphenyl)-3H- 1 ,2-dithiole-3-thione (2.55 g, 54% yield) as brown solid.1H NMR (400 MHz, DMSO-de) 5 10.13 (s, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.34 (s, 1 H), 6.78 (d, J = 2.Q Hz, 1 H), 6.73 (dd, J =8.4 Hz, 2.4 Hz, 1 H), 2.34 (s, 3H); ESI-MS [M-Hp: 239.

[0188] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (500 mg, 1.84 mmol), 5-(2-methyl-4-oxidanyl-phenyl)dithiole-3-thione (445 mg, 1.84 mmol) and DMAP (10 mg, 0.092 mmol) in DCM (12 mL) was added EDC. HCI (525 mg, 2.76 mmol). The mixture was stirred at room temperature for 3 h and concentrated. The crude was purified by flash column chromatography (EtOAc - DCM) to give [3-methyl-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (715 mg, 1.45 mmol, 78% yield) as a maroon powder.1H NMR (400 MHz, CDCh) 5 7.65 - 7.60 (m, 2H), 7.49 - 7.41 (m, 2H), 7.36 (dd, J = 8.2, 6.8 Hz, 2H), 7.12 (s, 1 H), 7.10 - 7.04 (m, 2H), 6.72 (d, J = 4.2 Hz, 1 H), 6.29 (dd, J = 4.2, 0.8 Hz, 1 H), 4.81 - 4.74 (m, 1 H), 4.68 - 4.59 (m, 1 H), 4.32 (dd, J = 9.1 , 5.8 Hz, 1 H), 3.13 - 3.02 (m, 1 H), 2.98 - 2.87 (m, 1 H), 2.44 (s, 3H); ESI-MS [M+H]+: 494.2.Example 1K: [2-methoxy-4-(5-sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)- 2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (1-10)

[0189] To a stirred suspension of pre-melted elemental sulfur (15.59 g, 487.2 mmol) at 140 °C, 4-allyl-2-methoxyphenol (10.0 g, 60.9 mmol) was added and the resulting reaction mixture stirred at 220 °C for 4 h. The reaction mixture was cooled to room temperature, the residue was diluted with 10% MeOH in DCM (500 mL). The undissolved solid was filtered-off through celite, washed with 10% MeOH in DCM (200 mL). The collected filtrate was concentrated and purified by flash column chromatography (EtOAc - petroleum ether) to give 5-(3-methoxy-4-oxidanyl-phenyl)dithiole-3-thione (1.6 g, 10% yield) as brown solid.1H NMR (400 MHz, DMSO-d6) 6 10.12 (s, 1 H), 7.82 (s, 1 H), 7.41 (d, J = 2.4 Hz, 1 H), 7.38 (dd, J =8.4 Hz, 2.4 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 3.87 (s, 3H); ESI-MS [M-H]’: 255.

[0190] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (500 mg, 1.84 mmol), 5-(3-methoxy-4-oxidanyl-phenyl)dithiole-3-thione (470 mg, 1.84 mmol) and DMAP (10 mg, 0.092 mmol) in DCM (10 mL) was added EDC.HCI (530 mg, 2.76 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated, diluted with ethyl acetate and washed with brine:water (1 :1 ), and brine. The organic extract was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (EtOAc - DCM) to give [2-methoxy-4-(5- sulfanylidenedithiol-3-yl)phenyl] 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 - carboxylate (61 mg, 0.20 mmol, 6.4% yield) as a solid.1H NMR (400 MHz, CDCh) 5 7.68 - 7.58 (m, 2H), 7.48 - 7.42 (m, 1 H), 7.42 - 7.31 (m, 3H), 7.29 - 7.27 (m, 1 H), 7.18 - 7.16(m, 2H), 6.73 (d, J = 4.2 Hz, 1 H), 6.31 (d, J = 4.2 Hz, 1 H), 4.83 - 4.76 (m, 1 H), 4.66 - 4.59 (m, 1 H), 4.34 (dd, J = 9.1 , 6.1 Hz, 1 H), 3.88 (s, 3H), 3.13 - 3.03 (m, 1 H), 3.00 - 2.89 (m, 1 H); ESI-MS [M+H]+: 510.2.Example 1L: (4-azanylcarbothioyl-3-fluoranyl-phenyl) 5-(benzenecarbothioyl)-2,3- dihydro-1 H-pyrrolizine-1 -carboxylate (1-11)

[0191] To a stirred solution of phosphorus pentasulfide (64.85 g, 145.86 mmol) in ethanol (200 mL) at room temperature, 2-fluoro-4-hydroxybenzonitrile (10 g, 72.93 mmol) was added and the mixture was stirred at 75 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc - petroleum ether) to give 2-fluoro-4-hydroxybenzothioamide (3.12 g, 25% yield) as yellow solid.1H NMR (400 MHz, DMSO-de) 5 10.39 (s, 1 H), 9.87 (s, 1 H), 9.16 (s, 1 H), 7.65 (t, J = 8.8 Hz, 1 H), 6.64 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.56 (dd, J = 12.8, 2.4 Hz, 1 H). ESI-MS [M+H]+: 172.

[0192] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (500 mg, 1.84 mmol), 2-fluoranyl-4-oxidanyl-benzenecarbothioamide (315 mg, 1 .84 mmol) and DMAP (11 mg, 0.092 mmol) in DCM (5 mL) was added EDC.HCI (530 mg, 2.76 mmol). The mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with brine:water (1 :1 ), and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography (EtOAc - DCM) to give (4-azanylcarbothioyl-3-fluoranyl-phenyl) 5- (benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylate (217 mg, 0.51 mmol, 27% yield) as a dark red powder.1H NMR (400 MHz, CDCI3) 5 8.45 (t, J = 9.1 Hz, 1 H), 7.85 (s, 1 H), 7.71 (s, 1 H), 7.66 - 7.56 (m, 2H), 7.49 - 7.42 (m, 1 H), 7.36 (dd, J = 8.4, 6.9 Hz, 2H), 7.07 - 6.95 (m, 2H), 6.71 (d, J = 4.2 Hz, 1 H), 6.27 (d, J = 4.2 Hz, 1 H), 4.79 - 4.73 (m, 1 H), 4.68 - 4.58 (m, 1 H), 4.31 (dd, J = 9.1 , 5.8 Hz, 1 H), 3.12 - 3.00 (m, 1 H), 2.97 - 2.84 (m, 1 H);19F NMR (376 MHz, CDCI3) 5 -109.80 - -109.95 (m). ESI-MS [M-Hp: 423.2.Example 1M: [3-methoxy-4-(5-thioxodithiol-3-yl)phenyl] 5-(benzenecarbonothioyl)-2,3- dihydro-1 H-pyrrolizine-1 -carboxylate (1-12)

[0193] Sodium dihydrogen phosphate (102.513 g, 854.420 mmol) and sodium chlorite (61.82 g, 683.5 mmol) were added to a stirred solution of 4-hydroxy-2-methoxy- benzaldehyde (13 g, 85.4 mmol) in a mixture of DMSO (250 mL) and water (150 mL) at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was diluted with water (500 mL) and solid NaHCOa was added to adjust the pH to 8. The solution was washed with EtOAc. The pH of the aqueous layer was adjusted to 4 with aq. 1 N HCI and the mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 4-hydroxy-2-methoxybenzoic acid (11 .2 g, 78%) as palebrown solid.1H NMR (400 MHz, DMSO-d6) 5 12.02 (br s, 1 H), 10.18 (s, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 6.39 (dd, J =8.4 Hz, 2.0 Hz, 1 H), 3.76 (s, 3H). ESIMS [M+H]+: 169.

[0194] A mixture of ethyl potassium malonate (30.36 g, 178.414 mmol), anhydrous MgCL (9.51 g, 99.9 mmol) and triethylamine (24.87 mL, 24.87 mmol) in anhydrous THF (100 mL) was stirred at 60 °C for 6 h (mixture A). In a separate flask, a mixture of 4- hydroxy-2-methoxybenzoic acid (10.0 g, 59.47 mmol) and CDI (11.57 g, 71.37 mmol) in anhydrous THF (50 mL) was heated at 60 °C for 30 min. The obtained homogenous solution was added to mixture A and the resulting mixture was refluxed for 16 h underinert atmosphere. The reaction was cooled to rt, acidified with aq. 1 N HCI (8.0 ml) and extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated. The crude was dissolved in DCM (200 mL) and DMF (16 mL) and cooled to 0°C. Imidazole (8.1 g, 118.94 mmol) and DMAP (3.63 g, 29.73 mmol) were added followed by TBDMS-CI (13.44 g, 89.21 mmol). The mixture was allowed to stir at ambient temperature for 6 h. The reaction mixture was filtered through a celite and concentrated. The obtained residue was dissolved in water (200 mL) and extracted with EtOAc. The combined organic extract was dried over Na2SO4, filtered and concentrated to obtain ethyl 3-(4-((tert-butyldimethylsilyl)oxy)-2-methoxyphenyl)-3-oxopropanoate (20.1 g, crude) as a brownish oily mass. The crude product was used for the next step without further purification. ESI-MS [M+H]+: 354.

[0195] A mixture of phosphorus pentasulfide (18.9 g, 42.55 mmol), hexamethyldisiloxane (27.14 mL, 127.66 mmol) and sulfur (1 .364 g, 42.55 mmol) in o- xylene (200 mL) was heated at 140 °C. To this mixture, a solution of ethyl 3-(4-((tert- butyldimethylsilyl)oxy)-2-methoxyphenyl)-3-oxopropanoate (15.0 g, 42.55 mmol) in o- xylene (50 mL) was added dropwise. The mixture was heated at the same temperature for 6 h. The mixture was cooled to rt, diluted with brine and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered and concentrated to obtain 5-(4-((tert- butyldimethylsilyl)oxy)-2-methoxyphenyl)-3H-1 ,2-dithiole-3-thione (15.0 g, crude) as a pale-brown gummy mass. The crude product was used for the next step without further purification. ESI-MS [M+H]+: 371.

[0196] To a solution of 5-(4-((tert-butyldimethylsilyl)oxy)-2-methoxyphenyl)-3 / 7-1 ,2- dithiole-3-thione (10 g, 26.98 mmol) in THF (50 mL) at 0 °C, TBAF (tetra-n- butylammonium fluoride) (1 M in THF, 15.6 mL, 53.96 mmol) was added drop wise and the resulting reaction mixture was allowed to stir at ambient temperature for 16 h under inert atmosphere. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with a mixture of water / brine (1 :1 ), and brine. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography (EtOAc - petroleum ether) to afford 5-(4-hydroxy-2-methoxyphenyl)-3 / 7-1 ,2-dithiole-3-thione (610 mg, 9% yield) as a brown solid.1H NMR (400 MHz, DMSO-cfe) 5 10.66 (s, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.76 (s, 1 H), 6.61 (d, J = 2.0 Hz, 1 H), 6.57 (dd, J = 8.8 Hz, 2.0 Hz, 1 H), 3.94 (s, 3H); ESI-MS [M+H]+: 257.

[0197] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (250 mg, 0.92 mmol), 5-(4-hydroxy-2-methoxyphenyl)-3 / 7-1 ,2-dithiole- 3-thione (236 mg, 0.92 mmol) and DMAP (6 mg, 0.046 mmol) in DCM (10 mL) was added EDC.HCI (265 mg, 1.38 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate and washed with a mixture of brine:water (1 :1), and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography (EtOAc - DCM) to give [3-methoxy-4-(5-thioxodithiol-3-yl)phenyl] 5-(benzenecarbonothioyl)-2,3-dihydro- 1 H-pyrrolizine-1 -carboxylate (37 mg, 0.073 mmol, 8% yield) as a dark powder.1H NMR (400 MHz, CDCI3) 5 7.71 (d, J = 8.3 Hz, 1 H), 7.68 - 7.62 (m, 3H), 7.51 - 7.45 (m, 1 H), 7.39 (t, J = 7.6 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 4.2 Hz, 1 H), 6.32 (d, J = 4.1 Hz, 1 H), 4.84 - 4.78 (m, 1 H), 4.71 - 4.62 (m, 1 H), 4.35 (dd, J = 9.1 , 5.7 Hz, 1 H), 3.99 (s, 3H), 3.16 - 3.05 (m, 1 H), 3.01 - 2.90 (m, 1 H).Example 1N: (4-azanylcarbothioyl-3-methyl-phenyl) 5-(benzenecarbothioyl)-2,3-dihydro- 1 H-pyrrolizine-1 -carboxylate (1-13)

[0198] A mixture of phosphorus pentasulfide (132.92 g, 298.97 mmol) in EtOH (200 mL) was stirred at room temperature for 1 h. To this mixture, 4-methoxy-2- methylbenzonitrile (11.0 g, 74.74 mmol) was added portion wise at room temperature. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc - petroleum ether) to obtain 4-methoxy-2-methylbenzothioamide (11.2 g, 83% yield) asyellow liquid.1H NMR (400 MHz, DMSO-cfe) 6 9.83 (s, 1 H), 9.27 (s, 1 H), 7.21 (d, J= 9.2 Hz, 1 H), 6.751-6.727 (m, 3H), 3.74 (s, 3H), 2.32 (s, 3H). ESI-MS [M+H]+: 181.

[0199] To a stirred solution of 4-methoxy-2-methylbenzothioamide (11.2 g, 61.78 mmol) in DCM (110 mL) at 0 °C, boron tribromide (185 mL, 1 M in DCM) was added drop wise and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was poured in ice water (450 mL). The resulting suspension was filtered and washed with ice water. The resulting solid cake was dried at 50 °C under vacuum to obtain 4-hydroxy-2-methylbenzothioamide (3.037 g, 29% yield) as yellow solid.1H NMR (400 MHz, DMSO-cfe) 5 9.72 (s, 1 H), 9.53 (s, 1 H), 9.18 (s, 1 H), 7.13-7.11 (dd, J = 6 Hz, 2.8 Hz, 1 H), 7.56-7.54 (m, 2H), 2.26 (s, 3H). ESI-MS [M+H]+: 167.

[0200] To a stirred solution of 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine- 1 -carboxylic acid (500 mg, 1.84 mmol), 4-hydroxy-2-methylbenzothioamide (308 mg, 1.84 mmol) and DMAP (11 mg, 0.092 mmol) in DCM (12 mL) was added EDC.HCI (530 mg, 2.76 mmol). The mixture was stirred at room temperature for 3 h, diluted with EtOAc and washed with a mixture of brine:water (1 :1 ) and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography (EtOAc - DCM, followed by EtOAc -hexanes) to give (4- azanylcarbothioyl-3-methyl-phenyl) 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 - carboxylate (200 mg, 0.48 mmol, 26% yield) as a red powder.1H NMR (400 MHz, CDCh) 5 7.72 (s, 1 H), 7.67 - 7.61 (m, 2H), 7.49 - 7.43 (m, 2H), 7.42 - 7.34 (m, 2H), 7.02 - 6.86 (m, 3H), 6.74 (d, J = 4.2 Hz, 1 H), 6.30 (dd, J = 4.2, 0.7 Hz, 1 H), 4.82 - 4.76 (m, 1 H), 4.68 - 4.64 (m, 1 H), 4.32 (dd, J = 9.1 , 5.9 Hz, 1 H), 3.14 - 3.02 (m, 1 H), 2.97 - 2.88 (m, 1 H), 2.49 (s, 3H); ESI-MS [M+H]+: 421.2.Example 10: 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (1-26)

[0201] This represents another method of preparing the compound I-26. To a mixture of 5-benzoyl-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (500 mg, 1 .96 mmol) in anhydrous THF (10 mL) at rt was added Lawesson’s reagent (792 mg, 1.96 mmol). The mixture was stirred at rt for 1.5 h, concentrated and diluted with EtOAc. The organic extract was washed with HC1 1 N, dried over Na2SO4, filtered and concentrated. The crudewas purified by flash column chromatography (MeOH - DCM) to give 5- (benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (360 mg, 1.33 mmol, 68% yield) as a solid.

[0202] To a mixture of 5-benzoyl-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (250 mg, 0.98 mmol) in anhydrous THF (6 mL) at rtwas added phosphorous pentasulfide (218 mg, 0.49 mmol). The mixture was stirred at rt for 30 min, concentrated and diluted with EtOAc. The organic extract was washed with HCI 1 N, dried over Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography (MeOH - DCM) to give 5-(benzenecarbothioyl)-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid (200 mg, 0.74 mmol, 75% yield) as a solid.Example 2: Evaluation of Efficacy of Exemplary compounds on AcOH-induced Pain Model in CD-1 MiceStudy Conduct

[0203] This study was a non-GLP study. All the procedures related to animal handling, care, and the treatment in this study were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Pharmaron Inc. (Beijing, China) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0204] In addition, all portions of this study were performed at Pharmaron adhered to the study protocol provided or approved by the sponsor and applicable standard operating procedures (SOPs).Study Design

[0205] Total number of 100 CD-1 mice at the age of 5-7 weeks (males), supplied by Vital River Co., LTD were used. AcOH supplied from Shanghai Jiuwo Biotechnology Co. , LTD (batch or lot number: 20230602) was used. G1 -G9 vehicle for 5% DMSO / 47.5% PEG- 400 / 47.5% Tween 80 (10% in water) and G10 vehicle for saline were used. Exemplary compounds I-26 (MW: 271.33, FW: 271.33, stored at 2-8°C), I-2 (MW: 406.52, FW: 406.52, stored at 2-8°C) and comparative ketorolac (MW: 255.269, FW: 255.269, stored at 2-8°C) were supplied by Dalriadatx Drug Discovery Inc. (Mississauga, Canada). Flurbiprofen was supplied by Beijing Teide Pharmaceutical Co., LTD and stored at 2-8°C.DMSO was supplied by Solarbio, PEG400 and Tween 80 were supplied by Sigma, and saline was supplied by Shijiazhuang NO.4 Pharmaceutical Co., Ltd.Animal Maintenance

[0206] General procedures for animal care and housing were in accordance with the standard, Commission on Life Sciences, National Research Council, Standard operating procedures (SOPs) of Pharmaron, Inc. The animals were kept in laminar flow rooms at constant temperature and humidity with three animals in each cage. Animals were housed in metabolic cage and in an environmentally monitored, well-ventilated room maintained at a temperature of (23 ± 3°C) and a relative humidity of 40%-70%. Fluorescent lighting provided illumination approximately 12 hours per day. Animals had free access to irradiation sterilized dry granule food during the entire study period except for time periods specified by the protocol. Sterile drinking water in a bottle was available to animal ad libitum during the quarantine and study periods.Groups and Treatments

[0207] According to the body weight, animals were randomly assigned to respective groups using a computer-generated randomization procedure. The study groups and treatment per group are shown in Table 1 .Table 1 : Groups and Treatments-26 was dosed 1.5 h prior to AcOH injection, I-2 was dosed 2.5 h prior to AcOH injection, ketorolac and Vehicle were dosed 1 h prior to AcOH injection, Flurbiprofen was dosed 15 minutes prior to AcOH injection.FormulationTable 2: FormulationInduction Procedure

[0208] Preparation of 0.6% AcOH Solution:Induction reagent: AcOH (0.6%)Route: IPDosing volume: 10 mL / kg Frequency: Single doseFormulation: 500uL glacial acetic acid were taken and diluted with 4.5 mL saline to prepare a concentration of 10% glacial acetic acid. Then 1 mL from 10% glacial acetic acid was taken and diluted with 15.667 mL normal saline to get 0.6% glacial acetic acid with final concentration. Dosing Procedure

[0209] Fast: Mice were fasted for 16 hours prior to dose.Route: G1-G9: PO; G10: IVDose volume: 10 mL / kgFrequency: Single doseDosing Time: G3-5: 1 .5 h prior to AcOH injection; G6-8: 2.5 h prior to AcOH injection; G1-2, G9: 1 h prior to AcOH injection; G10: 15 minutes prior to AcOH injectionExperimental method and Measurement parametersBody Weight

[0210] Body weight of all animals was recorded prior to dose.Assay of AcOH-l nd uced Writhing

[0211] Glacial acetic acid (0.6%) was injected into the abdominal cavity of mice and deposited in the visceral and parietal peritoneum, causing a large area of deep inflammatory pain for a long time, resulting in the appearance of abdominal indentation, trunk and hind limbs distention, and hip elevation, which is called the writhe reaction. The number of writhing in mice was used as the index of pain response to evaluate the analgesic effect of the tested products. The frequency of body twisting reaction is higher within 30 minutes after injection. The time interval from 0.6% glacial acetic acid injection to the first body twisting reaction and the number of "body twisting reaction" in 5-15 minutes and 15-30 minutes was observed and recorded in this study.Statistical Analysis

[0212] One-way analysis of variance (ANOVA) following multiple comparisons testing was applied among the groups with software SPSS 16.0, and P < 0.05 was accepted as significant.Results

[0213] Exemplary compounds I-26 and I-2 at various dosages were tested using Writhing test by intraperitoneal injection of acetic acid to mice. Acetic acid induced rapid onset of visceral pain in animals as measured visually by writhing response.

[0214] As can be seen in Figures 1 to 4, the exemplary compounds I-26 at a dosage of 33 mg / kg and I-2 at a dosage of 48 mg / kg performed well in comparison to ketorolac and the positive control flurbiprofen, administered at their standard treatment dosages (10 mg / kg and 20 mg / kg respectively). No adverse clinical symptoms or significant results associated with weight were noted.

[0215] Example 3: Evaluation of Efficacy of Exemplary Compounds on Carrageenan-induced Hyperalgesia in the Sprague Dawley (SD) Rat Model.Study Conduct

[0216] This study was a non-GLP study. All procedures related to animal handling, care, and the treatment in this study were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Pharmaron following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0217] In addition, all portions of this study were performed at Pharmaron adhered to the study protocol provided or approved by the sponsor and applicable standard operating procedures (SOPs).Study DesignTotal number of 80 SD rats at the age of 6-8 weeks (males), supplied by SPF (Beijing) Laboratory Animal Technology Co. Ltd were used. Carrageenan supplied from Sigma- aldrich (batch or lot number: 001408463) was used and was stored at RT. 5% DMSO / 47.5% PEG- 400 / 47.5% Tween 80(10% in water) vehicle was used for test compounds and saline was used for positive control Naproxen. Exemplary compounds I- 26 (MW: 271.33, FW: 271.33, stored at RT), I-2 (MW: 406.5, FW: 406.5, stored at RT) and comparative ketorolac (MW: 255.3, FW: 255.3, stored at RT) were supplied by Dalriadatx. Naproxen was supplied by Pharmaron and stored at RT.Animal Maintenance

[0218] General procedures for animal care and housing were in accordance with the standard, Commission on Life Sciences, National Research Council, Standard operating procedures (SOPs) of Pharmaron, Inc. The animals were kept in laminar flow rooms at constant temperature and humidity with three animals in each cage. Animals were housed in metabolic cage and in an environmentally monitored, well-ventilated room maintained at a temperature of (22 ± 3°C) and a relative humidity of 40%-80%. Fluorescent lighting provided illumination approximately 12 hours per day. Animals had free access to irradiation sterilized dry granule food during the entire study period. Sterile drinking water in a bottle was available to animal ad libitum during the quarantine and study periods.Groups and Treatments

[0219] Based on the body weight, paw volume, Von Frey test and Thermal Hyperalgesia test prior to dosing, rats were randomly assigned to respective groups using a computer-generated randomization procedure (mean body weight for each sex was ± 20%). The study groups and number of animals per group are shown in Table 3.Table 3: Group and TreatmentsInduction Procedure

[0220] Preparation of 3% Carrageenan Solution: Induction reagent: Carrageenan (3%)Route: Left paw sub-planter injectionDosing volume: 100 pL / ratFrequency: Single dose on Day 1Formulation: 600 mg of carrageenan were weighed out and dissolved in 20 mL of normal saline, and then stirred 6 hours to reach a final concentration of 3%Carrageenan solution.Dosing Procedure

[0221] Fast: Rats were not fasted.Route: POVolume: 5 mL / kgFrequency: SingleDosing Time: Vehicle, 1-26, 1-2, ketorolac and Naproxen were dosed immediately after Carrageenan injection. Experimental method and Measurement parametersBody Weight

[0222] Body weight of all animals was recorded during the study.Clinical Observation

[0223] Detailed observations were conducted at least once prior to dosing and post-dose. The detailed observation items are listed in Table 4.Table 4: Clinical ObservationsPaw Volume

[0224] To measure the paw volume, the conductor gently held the body of the animal with one hand and place the hind paw into the plethysmometer (Ugo Basile, Italy) with the other hand. Liquid displacement by the paw was recorded and used to represent paw volume.

[0225] The Paw Volume test was performed 4 times during the study including baseline prior to Carrageenan injection, 2, 4, 6 hours post carrageenan injection.Von Frey Test

[0226] Mechanical allodynia of the left hind paw was measured during the course of study by determining withdrawal thresholds to an electronic Von Frey filament (Bioseb, France). The filament was applied perpendicularly to the plantar surface of the paw with increasing force. The force required to induce a reflex paw withdrawal calculated by taking the average of 2-3 repeated stimuli (in g), which induced a reflex paw withdrawal.

[0227] The Von Frey test was performed 4 times during the study including baseline prior to Carrageenan injection, 2, 4, 6 hours post carrageenan injection.Thermal Hyperalgesia Test (TH)

[0228] Thermal hyperalgesia of the left hind paw was measured by using a planter heat test, which measured the paw withdrawal latency in response to radiant heat test. The mean paw withdrawal latencies (in seconds) for ipsilateral hind paws were determined from an average of 2 separated measures (planter heat test).

[0229] The thermal hyperalgesia test was performed 4 times during the study including baseline prior to Carrageenan injection, 2, 4, 6 hours post carrageenan injection.Statistic Analysis

[0230] One-way analysis of variance (ANOVA) following multiple comparisons testing was applied among the groups with software SPSS 16.0, and P < 0.05 will be accepted as significant.Results

[0231] Efficacy of exemplary compounds on Carrageenan-induced hyperalgesia in the SD rat model was evaluated. As can be seen in Figures 5 to 7, the exemplary compounds I-26 at dosages of 11 , 32 and 64 mg / kg and I-2 at dosages of 16, 48 and 96mg / kg performed well in comparison to ketorolac and flurbiprofen, administered at their standard treatment dosages (10 mg / kg and 20 mg / kg respectively).Example 4: Evaluation of an Analgesic Effect of Exemplary Compounds in Mice Paw Incision ModelStudy Conduct

[0232] This study is a non-GLP study. All the procedures related to animal handling, care, and the treatment in this study were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Pharmaron following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0233] In addition, all portions of this study were performed at Pharmaron adhered to the study protocol provided or approved by the sponsor and applicable standard operating procedures (SOPs).Study Design

[0234] Total number of 72 C57BL / 6J mice at the age of 6-8 weeks (males), body weight 18-20 g, supplied by SPF (Beijing) Laboratory Animal Technology Co. Ltd were used. 5% DMSO / 47.5% PEG- 400 / 47.5% Tween 80(10% in water) vehicle was used. Exemplary compounds I-26 (MW: 271.33, FW: 271.33), I-2 (MW: 406.5, FW: 406.5) and comparative ketorolac (MW: 255.3, FW: 255.3) were supplied by Dalriadatx. Naproxen was supplied by Pharmaron and stored at RT.Animal Maintenance

[0235] General procedures for animal care and housing were in accordance with the standard, Commission on Life Sciences, National Research Council, Standard operating procedures (SOPs) of Pharmaron, Inc. The animals were kept in laminar flow rooms at constant temperature and humidity with three animals in each cage. Animals were housed in polycarbonate cage in an environmentally monitored, well-ventilated room maintained at a temperature of (22±3°C) and a relative humidity of 40%-80%. Fluorescent lighting provided illumination approximately 12 hours per day. Animals had free access to irradiation sterilized dry granule food during the entire study period except for time periods specified by the protocol. Sterile drinking water in a bottle was available to animal ad libitum during the quarantine and study periods.Groups and Treatments

[0236] Based on the body weight, baseline of Von Frey and Thermal hyperalgesia on Day 1 , animals were randomly assigned to respective groups using a computergenerated randomization procedure. The study groups and treatment per group are shown in Table 5.Table 5: Groups and Treatments for main study animalsDosing Procedure and Formulation

[0237] Route: PO Frequency: QD*2 (once daily for two days)Dosing Time:Day 1 : After 2 hours post paw incision surgery, mechanical and thermal pain baseline prior to dose was determined. Dosing was performed after animals were grouped based on their baseline assessment. Day 2: After mechanical and thermal pain baseline of day 2 was determined.

[0238] Formulation:Test compounds: 5% DMSO / 47.5% PEG- 400 / 47.5% Tween 80(10% in water)Positive control Naproxen: salineTable 6: FormulationExperimental Method and Measurement ParametersBody Weight

[0239] Body weights of all animals were recorded prior to dosing of the study.Paw Incision (PI)

[0240] Mice were anesthetized with isoflurane (2%) in oxygen. After iodophor disinfection, a longitudinal incision about 1 cm long was made on the left plantar of rats with a scalpel. The plantar muscles were clamped with tweezers and cut longitudinally on the left and right sides of the incision.Von Frey Test

[0241] Mice were acclimated to the apparatus for 10 min prior to testing. A series of standardized Von Frey fibers were used to stimulate the mouse hind paw with up-down paradigm in sequential order. A higher force filament was tested if the mouse had no withdrawal response, while lower force filament was used if there was a withdrawal response.

[0242] The Von Frey test was performed 8 times during the study including baseline prior PI operation, prior dosing and 2, 4, 6 hours post dosing.Thermal Hyperalgesia Test (TH)

[0243] Thermal hyperalgesia of the left hind paw was measured by using a planter heat test, which measured the paw withdrawal latency in response to radiant heat test. The mean paw withdrawal latencies (in seconds) for ipsilateral hind paws were determined from an average of 2 separated measures (planter heat test).

[0244] Thermal Hyperalgesia Test was performed 8 times during the study including baseline prior PI operation, prior dosing and 2, 4, 6 hours post dosing.Data Acquisition and Statistical Analysis

[0245] One-way analysis of variance (ANOVA) following multiple comparisons testing was applied among the groups with software SPSS 16.0, and P < 0.05 will be accepted as significant.

[0246] Analgesic effect of exemplary compounds of the application in mice Paw Incision model was evaluated. As can be seen in Figures 8 to 11 , the exemplary compounds I-26 at dosages of 11 , 32 and 64 mg / kg and I-2 at dosages of 16, 48 and 96 mg / kg performed well in comparison to ketorolac and flurbiprofen, administered at their standard treatment dosages (10 mg / kg and 20 mg / kg respectively).Example 3: Gastric Damage Assessment of Exemplary Compounds in RatsStudy Outline200 g female SD rats aged 6 weeks were used for this study. After 3-7 days acclimation, the rats were assigned into groups. 3 hours after dosing, the rats were euthanized and the gastric area was harvested for internal gastric damage macroscopic observation and gastric damage scoring.Table 3. Grouping and Dosing Regimen for gastric damage assessment for in-vivo studyExperiment outline.

[0247] On day -1 , the rats were randomly grouped according to their body weight.On day -1 , the rats were deprived of food but not water for around 20 hours in the metabolic cages.On day 0, rats were treated with or without compounds.3 hours after the orally administrated compounds, the rats were euthanized, and the stomach was longitudinally scissored for macroscopic assessment for gastric damage.Gastric damage scoring done following the publication (Wallace et. al. GASTROENTEROLOGY 2000;119:706-714) by sum of the length of gastric damage spots. Formulation of compounds

[0248] 0.5% methyl cellulose in water was used as the vehicle for all test compounds.Table 4: FormulationResults:

[0249] As can be seen in Figure 12, all exemplary compounds demonstrated very good response with significantly reduced gastric damage of up to 99.5% as compared to ketorolac.Example 4: Chemical Stability and Thermodynamic solubilityThermodynamic Solubility

[0250] Test articles in solid form were diluted in PBS to a final concentration of 50 mg / mL in triplicate. Samples were incubated for 1 h at 25 °C. Then, solutions were filtered through 0.4 pm PC membranes and the filtrate diluted for quantification using UV chromatography. AUC values were compared to a 4-points standard curve prepared from a separate solid sample, obtaining saturation concentration.Chemical stability

[0251] Test articles dissolved in DMSO were diluted to a final concentration of 50 pM and 1 % DMSO and either PBS (assay sample) or ACN (reference sample). Without further postprocessing, samples were injected at specific time points to quantify the amount of test article remaining. Values are referenced to time zero samples and percentage remaining calculated.ResultsTable 5: Thermodynamic Solubility

[0252] Two exemplary compounds I-26 and I-27 of the present application were evaluated for thermodynamic solubility and chemical stability. As can be seen in Figures 13-14 and Table 5, both exemplary compounds showed good thermodynamic solubility and chemical stability of more than 95% after 3 hours.Example 6: In-vitro Safety Models

[0253] Compounds were assessed in the Eurofins Safety Screen 44 panel (Eurofins Discovery Inc. California, U.S.). The Safety 44 is an early preclinical safety screen that identifies standard potential issues to be aware of the compounds are advanced through increasingly formal preclinical development.

[0254] Compounds were tested at 1 .0E-05 M. Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target. Compound enzyme inhibition effect was calculated as a % inhibition of control enzyme activity. Exemplary compound I-26 is very selective, hitting just 2 / 44 assays @ 10pM - both the specific targets of the compounds. Table 6 presents the results of the 2 target hits for exemplary compound I-26.Table 6: Compound 1-26

[0255] Exemplary compound I-2 is selective, hitting just 7 / 44 assays @ 10pM - 2 of which are the specific targets of the compounds. Table 7 presents the results of the 7 target hits for exemplary compound I-2.Table 7: Compound 1-2

[0256] Given no parent compound is seen in plasma, off-target safety is likely not a significant risk.Results.

[0257] In this study, no compound of the application signaled a safety concern when tested in the Eurofins Safety Screen 44.

Claims

CLAIMS:

1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein:R1and R2are independently selected from H, halo and Ci-ealkyl;Y is absent or Y is selected from O, NH and OCH2CH2O;X is selected from H, Ci-4alkyl, OR3, NR4R5and an H2S releasing moiety;R3, R4and R5are independently selected from H and Ci-4al kyl ; and all available hydrogen atoms are optionally and independently replaced with halo or deuterium atom.

2. The compound of claim 1 , wherein Y is O.

3. The compound of claim 1 or claim 2, wherein X is an H2S releasing moiety selected from X1 , X2 and X3:wherein R6and R7are independently selected from H, halo, Ci-4alkyl and OCi-4alkyl; each Q is independently selected from CH and N; each Z1is independently selected from O and S;Z2is selected from O and S;each R8is independently selected from H, Ci-4alkyl and NHR10;R9is selected from H, OH, Ci-4alkyl, OCi-4alkyl and NHR11;R10and R11are independently selected from H and Ci-4alkyl; n and m are, independently, 1 or 2; and all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom4. The compound of claim 3, wherein X is X1 and n is 1 , X has the following formula:xia5. The compound of claim 3, wherein X is X1 and n is 2, X has the following formula:

6. The compound of claim 3, wherein X is X2 and m is 1 , X has the following formula:

7. The compound of claim 3, wherein X is X2 and m is 2, X has the following formula:

8. The compound of claim 3, wherein X is X3, X has the following formula:

9. The compound of any one of claims 3 to 5, wherein Q is CH.

10. The compound of any one of claims 3 to 5, wherein Q is N.11 . The compound of any one of claims 3 to 5, wherein Z1is O.

12. The compound of any one of claims 3 to 5, wherein Z1is S.

13. The compound of claim 3, 6 or 7, wherein R8is NH2.

14. The compound of claim 3 or claim 8, wherein Z2is O.

15. The compound of claim 3 or 8, wherein R9is OH.

16. The compound of claim 3, wherein X is selected from the following groups:

17. The compound of claim 16, wherein R7is selected from H, halo, Ci-3alkyl and OCi- salkyl, wherein all available hydrogen atoms are optionally and independently replaced with halo or a deuterium atom.

18. The compound of claim 17, wherein R7is selected from H, F, CF3, CD3, CH3, OCH3, OCD3 and OCF3.

19. The compound of claim 1 , wherein Y is absent.

20. The compound of claim 19, wherein X is OH.

21. The compound of claim 20, wherein the compound of Formula I has the following structure:or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

22. The compound of claim 21 , wherein the compound of Formula I is in a salt form.

23. The compound of claim 22, wherein the salt is tromethamine salt.

24. The compound of any one of claims 1 to 23, wherein R1and R2are independently selected from H, halo and Ci-4alkyl, wherein all available hydrogen atoms are optionally and independently replaced with halo or deuterium atom.

25. The compound of claim 24, wherein R1is selected from H, Cl, F, Br, CH3, CF3 andCD3.

26. The compound of claim 25, wherein R1is H.

27. The compound of claim 24, wherein R2is selected from H, Cl, F, Br, CH3, CF3 and CD3.

28. The compound of claim 27, wherein R2is H.

29. The compound of claim 1 , wherein the compound of Formula I is selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

30. A pharmaceutical composition comprising a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier. 31 . A method for treating diseases, disorders or conditions that benefit from treatment with ketorolac, the method comprising administering an effective amount of a compound of any one of claims 1 to 29 to a subject in need thereof.

32. The method of claim 31 , wherein the disease, disorder or condition that benefits from treatment with ketorolac is an inflammatory condition and / or pain.

33. The method of claim 32, wherein the pain is post-operative pain or visceral pain.

34. The method of any one of claims 31 to 33, wherein the subject is a mammal.

35. The method of any one of claims 31 to 34, wherein the administration of the compound reduces gastric damage compared to administration of an equivalent dose of ketorolac.

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