WO2021217053A1

WO2021217053A1 - Plasma kallikrein inhibitors for the treatment of ards and related conditions

Info

Publication number: WO2021217053A1
Application number: PCT/US2021/028924
Authority: WO
Inventors: Brian Roberts; Jeff BREIT
Original assignee: Rezolute, Inc.
Priority date: 2020-04-24
Filing date: 2021-04-23
Publication date: 2021-10-28

Abstract

Provided herein are methods of treating an acute respiratory syndrome, non-cardiogenic pulmonary edema, viral infections, coronavirus disease 2019 (COVID-19), and/or systemic inflammatory response syndrome (SIRS) in the subject in need thereof by administering an effective amount of a compound of Formula I, a compound of Formula II, or prodrugs thereof.

Description

PLASMA KALLIKREIN INHIBITORS FOR THE TREATMENT OF ARDS AND RELATED CONDITIONS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/015,062 filed April 24, 2020, which is incorporated herein by reference in its entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] NOT APPLICABLE REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK [0003] NOT APPLICABLE BACKGROUND [0004] Acute respiratory syndromes, such as acute respiratory distress syndrome (ARDS), are lung ailments charaterized by widespread inflammation in the lungs. The onset of these diseases can be triggered by direct insult to the lung tissue (e.g., an inhalation injury, a major chest injury), but can also be caused by an injectious agent such as a viral infection. Patients suffering from an acute respiratory syndrome can be treated by adjusting body positioning, managing fluid intake, sedation, and ventilator support. Each of these treatments are aimed to reduce the symptoms experienced by the patient, but they do not directly target an underlying cause nor do they directly mitigate disease progression. Thus, there remains an unmet need in the art for treatment of acute respiratory syndromes. [0005] Although modulators of plasma kallikrein activity have also been previously disclosed (see, for example, WO2008/016883, and WO2011/075684), their potential utility in the treatment or amelioration of an acute respiratory syndrome has not been previously described. [0006] The present disclosures addresses these unmet needs and provides related advantages as well. BRIEF SUMMARY [0007] In some aspects, provided herein are methods of treating an acute respiratory syndrome in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I O (ii) a compound of Formula II

O (II); or

(iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined herein. [0008] In some aspects, provided herein are methods of treating non-cardiogenic pulmonary edema in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I );

(ii) a compound of Formula II (II); or (iii) a prodrug of

Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined herein. [0009] In some aspects, provided herein are methods of treating a viral infection in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I O (ii) a compound of Formula II

O (II); or

(iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined herein. [0010] In some aspects, provided herein are methods of treating coronavirus disease 2019 (COVID-19) comprising administering to the subject an effective amount of: (i) a compound of Formula I

(ii) a compound of Formula II O (II); or (iii) a prodrug of Form

ula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined herein. [0011] In some aspects, provided herein are methods of treating systemic inflammatory response syndrome (SIRS) in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I I);

(ii) a compound of Formula II I); or

(iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as [0012] Related advantages will be apparent to a person of skill in the art upon review of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS [0013] NOT APPLICABLE DETAILED DESCRIPTION OF THE INVENTION I. General [0014] As described herein the present inventors have discovered that plasma kallikrein inhibitors, specifically, compounds of Formula I, Formula II, and prodrugs thereof effectively treat viral infections (including coronavirus infections), non-cardiogenic causes of pulmonary edema, and acute respiratory syndromes. Without being bound to any particular theory, it is believed that these compounds (or prodrugs thereof) are surprisingly effective at reducing, limiting, or eliminating pulmonary vascular leakage, disseminated intravascular coagulation (DIC), dysregulated coagulation, and/or excessive clotting, which can manifest in the above referenced conditions. Additionally, without being bound to any particular theory, it is believed that the compounds/prodrugs described herein are useful in the treatment of certain viral infections as well as non-cardiogenic causes of pulmonary edema, and acute respiratory syndromes precipitated by viral infections through the blocking of viral infective mechanisms. [0015] In a similar manner, the present inventors have discovered that subjects suffering from systemic inflammatory response syndrome (SIRS) can also benefit from the administration of plasma kallikrein inhibitors. SIRS can be viewed as having a similar pathophysiology as certain acute respiratory syndromes (e.g., ARDS) that manifest at other organs in the body. Subjects suffering from SIRS typically experience a hyper immune response leading to undesirable vascular leakage, disseminated intravascular coagulation (DIC), dysregulated coagulation, excessive clotting, shock, and/or other deleterious organ consequences (e.g., renal failure). Accordingly, without being bound to any particular theory, it is believed that the compounds/prodrugs described herein can effectively reduce, limit, or eliminate the harmful effects of SIRS, and/or in the case of viral precipitations of SIRS, block of viral infective [0016] Moreover, despite various classes of plasma kallikrein inhibitors being known, each of these classes do not operate in the same manner. For example, the currently claimed compounds surprisingly do not change blood pressure or heartbeat, suggesting that the levels of angiotensin, or the activites of angiotensin converting enzymes (ACE-1 and ACE-2) are not significantly altered. See, Example 3. Comparatively, other classes of plasma kallikrein inhibitors have been shown to increase heartbeat (Haegarda, Package Insert, FDA, 2020.) A recognized consequence of ARDS is pulmonary hypertension. Thus, the present inventors have unexpectedly discovered that the current class of plasma kallikrein inhibitors are advantageously positioned to be useful in the treatment of ARDS without deleterious side effects that may worsen a patient’s condition. [0017] Plasma kallikrein, inhibited by the currently claimed compounds, is part of the Kinin- Kallikrein System (KKS). The KKS system is interconnected to the Contact Activation System (CAS) in a number of ways including Factor XII. Without being bound to any particular theory, kallikrein inhibition with the described compounds is expected to not only reduce bradykinin levels via the KKS pathway, but also have an indirect impact on the components of the CAS system. A singular effect via the KKS pathway and a synergistic effect via the interconnected KKS and CAS pathways, separately or together, provide new pharmacological methods for the treatment of ARDS by kallikrein inhibition. II. Definitions [0018] Unless otherwise stated the following terms used in the specification and claims have the meanings given below. [0019] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C_1-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, and the like. For each of the definitions herein (e.g., alkyl, alkoxy, alkylamino, alkylthio, alkylene, haloalkyl), when a prefix is not included to indicate the number of main chain carbon atoms in an alkyl portion, the radical or portion thereof will have 12 or fewer main chain carbon atoms. [0020] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH₂CH₂CH₂CH₂-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms. [0021] The term "cycloalkyl" refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C_3-6cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices. One or two C atoms may optionally be replaced by a carbonyl. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. When a prefix is not included to indicate the number of ring carbon atoms in a cycloalkyl, the radical or portion thereof will have 8 or fewer ring carbon atoms. [0022] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NR^aR^b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like. [0023] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C_1-4 haloalkyl" is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like. [0024] The term "aryl" means a monovalent monocyclic, bicyclic or polycyclic aromatic hydrocarbon radical of 5 to 14 ring atoms which is unsubstituted or substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl cut, phenyl or phenylalkyl, aryl or arylalkyl), -(CR’R”)n-COOR (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl cut, phenyl or phenylalkyl aryl or arylalkyl) or–(CR’R”)_n-CONR^aR^b (where n is an integer from 0 to 5, R’ and R” are independently hydrogen or alkyl, and R^a and R^b are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, aryl or arylalkyl). More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted forms thereof. Similarly, the term “heteroaryl” refers to those aryl groups wherein one to five heteroatoms or heteroatom functional groups have replaced a ring carbon, while retaining aromatic properties, e.g., pyridyl, quinolinyl, quinazolinyl, thienyl, and the like. The heteroatoms are selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. For brevity, the term aryl, when used in combination with other radicals (e.g., aryloxy, arylalkyl) is meant to include both aryl groups and heteroaryl groups as described above. [0025] Substituents for the aryl groups are varied and are generally selected from: -halogen, - OR’, -OC(O)R’, -NR’R”, -SR’, -R’, -CN, -NO2, -CO₂R’, -CONR’R”, -C(O)R’, -OC(O)NR’R”, - NR”C(O)R’, -NR”C(O)₂R’, ,-NR’-C(O)NR”R”’, -NH-C(NH₂)=NH, -NR’C(NH₂)=NH, -NH- C(NH₂)=NR’, -S(O)R’, -S(O)₂R’, -S(O)₂NR’R”, -NR’S(O)₂R”, -N3, perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R’, R” and R”’ are independently selected from hydrogen, C_1-8 alkyl, C_3-6 cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C_1-4 alkyl, and unsubstituted aryloxy-C_1-4 alkyl. [0026] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH₂)_q-U-, wherein T and U are independently -NH-, -O-, -CH₂- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r-B-, wherein A and B are independently -CH₂-, -O-, -NH-, -S-, -S(O)-, -S(O)₂-, -S(O)₂NR’- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH₂)s-W- (CH₂)_t-, where s and t are independently integers of from 0 to 3, and W is -O-, -NR’-, -S-, -S(O)-, -S(O)₂-, or -S(O)₂NR’-. The substituent R’ in -NR’- and -S(O)₂NR’- is selected from hydrogen or unsubstituted C_1-6 alkyl. [0027] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). [0028] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically- acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N’-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The term "pharmaceutically acceptable" is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0029] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0030] The term "subject" as used herein is meant to include animals, such as mammals, including, but are not limited to, primates (e.g. humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human. [0031] The term "respiratory virus" as used herein refers to a virus that infects a cell of the respiratory tract. Exemplary “respiratory viruses” include, but are not limited to, influenza viruses in the Orthomyxoviridae family, parainfluenza viruses in the Paramyxoviridae family, respiratory syncytial viruses (RSV), rubella virus, adenoviruses, rhinoviruses, and coronaviruses. [0032] The term "coronavirus" as used herein refers to a genus in the family Coronaviridae, which family is in turn classified within the order Nidovirales. The coronaviruses are large, enveloped, positive-stranded RNA viruses. They have the largest genomes of all RNA viruses and replicate by a unique mechanism that results in a high frequency of recombination. The coronaviruses include antigenic groups I, II, and III. Nonlimiting examples of coronaviruses include severe acute respiratory syndrome coronavirus (SARS) coronavirus (SARS-CoV), SARS coronavirus 2 (SARS-CoV-2), MERS coronavirus, transmissible gastroenteritis virus (TGEV), human respiratory coronavirus, porcine respiratory coronavirus, canine coronavirus, feline enteric coronavirus, feline infectious peritonitis virus, rabbit coronavirus, murine hepatitis virus, sialodacryoadenitis virus, porcine hemagglutinating encephalomyelitis virus, bovine coronavirus, avian infectious bronchitis virus, and turkey coronavirus, as well as chimeras of any of the foregoing. See Lai and Holmes “Coronaviridae: The Viruses and Their Replication” in Fields Virology, (4th Ed.2001). [0033] The term "influenza virus" as used herein, refers to an RNA virus of the Orthomyxoviridae family, including influenza A, influenza B, and influenza C, and mutants thereof. Influenza A viruses contemplated herein include those viruses that have two antigenic glycosylated enzymes on their surface: neuraminidase and hemagglutinin. Various subtypes of influenza A virus that can be treated using the materials and methods of the subject invention include, but are not limited to, H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N6, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, and H10N7. Influenza B viruses include, but are not limited to, B/Yamagata and B/Victoria lineages. [0034] The term "hantavirus" as used herein refers to viruses belonging to the Bunyavirus family. These viruses are known as a single-stranded RNA virus type having three segments designated S (small), M (medium), and L (large). L typically codes for a transcriptase/replicase, M typically codes for glycoproteins G1 and G2 on the virus surface, and S typically codes a nucleocapsid protein that binds to RNA. Membors of this family include hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV). [0035] The terms "respiratory syncytial virus" and "RSV" as used herein refer to one or more members of the family Paramyxoviridae, subfamily pneumovirus, which are enveloped, single stranded antisense RNA viruses that infect the respiratory tract (Schmidt and Emmons (eds.) Diagnostic Procedures for Viral, Rickettsial and Chlamydial Infections, 6th edition, American Public Health Assoc. Inc., Washington, D.C. [1989]). There are two major strains of RSV represented by, but not limited to, Long (Group 1) ATCC VR-26, and 18537 (Group 2) ATCC VR-1401. The following five exemplary human RSV strains are available from ATCC: VR- 1400, VR-1401, VR-1540, VR-26, and VR-955. [0036] The term "adenovirus" as used herein refers to a virus of the family adenoviridae which are double-stranded DNA-containing viruses, which infect mammals and birds. The virion is 70 to 90 nm in diameter and is naked (has no envelope). The virus develops in nuclei of infected cells; isolation requires tissue cultures since laboratory animals are not susceptible to apparent infection. The family includes two genera, Mastadenovirus and Acviadenovirus. III. Detailed Description of Embodiments A. Treating Acute Respiratory Syndrome [0037] In some aspects, provided herein are methods of treating an acute respiratory syndrome in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I

(I); (ii) a compound of Formula II

); or (iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined in section F, below. [0038] In some embodiments, the methods described herein effectively reduce, ameliorate, mitigate, inhibit and/or reverse the effects of acute respiratory syndromes. In some embodiments, the methods described herein reduce, limit, or eliminate pulmonary vascular leakage associated with an acute respiratory syndrome. In some embodiments, the methods described herein reduce, limit, or eliminate disseminated intravascular coagulation (DIC) associated with an acute respiratory syndrome. In some embodiments, the methods described herein reduce, limit, or eliminate dysregulated coagulation associated with an acute respiratory syndrome. In some embodiments, the methods described herein reduce, limit, or eliminate excessive clotting associated with an acute respiratory syndrome. [0039] In some embodiments, the acute respiratory syndrome is precipitated by a non-viral insult. In some embodiments, the non-viral insult is selected from the group consisting of sepsis, pancreatitis, a blood transfusion, an inhalation injury, mechanical-ventilation injury, and a major chest injury. In some embodiments, the inhalation injury is selected from the group consisting of chemical inhalation, smoke inhalation, and vomit inhalation. [0040] In some embodiments, the acute respiratory syndrome is precipitated by a virus. In some embodiments, the virus is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus. [0041] In some embodiments, the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C. [0042] In some embodiments, the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus. [0043] In some embodiments, the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV). [0044] In some embodiments, the acute respiratory syndrome is acute respiratory distress syndrome (ARDS) [0045] In some embodiments, the acute respiratory syndrome is severe acute respiratory syndrome (SARS). B. Treating non-cardiogenic pulmonary edema [0046] In some aspects, provided herein are methods of treating non-cardiogenic pulmonary edema in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I (ii) a compound of Formula I

I O (iii) a prodrug of Form

ula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined in section F, below. [0047] In some embodiments, the methods described herein effectively reduce, ameliorate, mitigate, inhibit and/or reverse the effects of non-cardiogenic pulmonary edema. In some embodiments, the methods described herein reduce, limit, or eliminate pulmonary vascular leakage associated with non-cardiogenic pulmonary edema. In some embodiments, the methods described herein reduce, limit, or eliminate disseminated intravascular coagulation (DIC) associated with non-cardiogenic pulmonary edema. In some embodiments, the methods described herein reduce, limit, or eliminate dysregulated coagulation associated with non- cardiogenic pulmonary edema. In some embodiments, the methods described herein reduce, limit, or eliminate excessive clotting associated with non-cardiogenic pulmonary edema. [0048] In some embodiments, the non-cardiogenic pulmonary edema is precipitated by a non- viral insult. In some embodiments, the non-viral insult is selected from the group consisting of sepsis, pancreatitis, a blood transfusion, an inhalation injury, mechanical-ventilation injury, and a major chest injury. In some embodiments, wherein the inhalation injury is selected from the group consisting of chemical inhalation, smoke inhalation, and vomit inhalation. [0049] In some embodiments, the non-cardiogenic pulmonary edema is precipitated by a virus. In some embodiments, the virus is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus. [0050] In some embodiments, the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C. [0051] In some embodiments, the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus. [0052] In some embodiments, the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV). C. Treating a viral disease [0053] In some aspects, provided herein are methods of treating a viral infection in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I

(I); (ii) a compound of Formula II O ); or

(iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined in section F, below. [0054] In some embodiments, the methods described herein effectively reduce, ameliorate, mitigate, inhibit and/or reverse the effects of viral infections. In some embodiments, the methods described herein reduce, limit, or eliminate pulmonary vascular leakage associated with a viral infection. In some embodiments, the methods described herein reduce, limit, or eliminate disseminated intravascular coagulation (DIC) associated with a viral infection. In some embodiments, the methods described herein reduce, limit, or eliminate dysregulated coagulation associated with a viral infection. In some embodiments, the methods described herein reduce, limit, or eliminate excessive clotting associated with a viral infection. In some embodiments, the methods described herein reduce, limit, or eliminate viral infections by blocking one or more viral infective mechanisms. [0055] In some embodiments, the viral infection is a respiratory virus. [0056] In some embodiments, the viral infection is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus. [0057] In some embodiments, the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C. [0058] In some embodiments, the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus. [0059] In some embodiments, the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV). D. Treating coronavirus disease 2019 (COVID-19) [0060] In some aspects, provided herein are methods of coronavirus disease 2019 (COVID-19) comprising administering to the subject an effective amount of: (i) a compound of Formula I (ii) a compound of Formula II

O II); or

(iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodrugs thereof are as defined in section F, below. [0061] In some embodiments, the methods described herein effectively reduce, ameliorate, mitigate, inhibit and/or reverse the effects of COVID-19 infections. In some embodiments, the methods described herein reduce, limit, or eliminate pulmonary vascular leakage associated with coronavirus disease 2019 (COVID-19). In some embodiments, the methods described herein reduce, limit, or eliminate disseminated intravascular coagulation (DIC) associated with coronavirus disease 2019 (COVID-19). In some embodiments, the methods described herein reduce, limit, or eliminate dysregulated coagulation associated with coronavirus disease 2019 (COVID-19). In some embodiments, the methods described herein reduce, limit, or eliminate excessive clotting associated with coronavirus disease 2019 (COVID-19). In some embodiments, the methods described herein reduce, limit, or eliminate coronavirus disease 2019 (COVID-19) by blocking one or more viral infective mechanisms. E. Treating systemic inflammatory response syndrome (SIRS)

[0062] In some aspects, provided herein are methods of treating systemic inflammatory response syndrome (SIRS) in a subject comprising administering to the subject an effective amount of: (i) a compound of Formula I

(iii) a prodrug of Formula I or Formula II, wherein the variable positions of Formula I, Formula II, and prodmgs thereof are as defined in section F, below.

[0063] In some embodiments, the methods described herein effectively reduce, ameliorate, mitigate, inhibit and/or reverse the effects of systemic inflammatory response syndrome (SIRS). In some embodiments, the methods described herein reduce, limit, or eliminate vascular leakage associated with SIRS. In some embodiments, the methods described herein reduce, limit, or eliminate disseminated intravascular coagulation (DIC) associated with SIRS. In some embodiments, the methods described herein reduce, limit, or eliminate dysregulated coagulation associated with SIRS. In some embodiments, the methods described herein reduce, limit, or eliminate excessive clotting associated with SIRS. In some embodiments, the methods described herein reduce, limit, or eliminate organ failure associated with SIRS.

[0064] In some embodiments, SIRS is precipitated by a non-viral insult. In some embodiments, the non-viral insult is selected from the group consisting of sepsis, pancreatitis, a blood transfusion, a burn, and a major injury. In some embodiments, the burn is an electrical burn, a thermal burn, a chemical burn, or a radiation burn. In some embodiments, the subject has the burn on at least 10%, 20%, 30%, 40%, 50%, 60%, or more of their body. In some embodiments, the major injury is anaphylaxis, severe trauma, or a combination thereof. [0065] In some embodiments, SIRS is precipitated by a virus. In some embodiments, the virus is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus. [0066] In some embodiments, the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C. [0067] In some embodiments, the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus. [0068] In some embodiments, the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV). F. Compounds of Formula I, Formula II, and prodrugs thereof [0069] In some aspects, provided herein are methods of treating an acute respiratory syndrome, non-cardiogenic pulmonary edema, viral infections, coronavirus disease 2019 (COVID-19), and/or systemic inflammatory response syndrome (SIRS) in the subject in need thereof using a plasma kallikrein inhibitor. Plasma kallikrein inhibitors include the compounds of Formula I, Formula II, and prodrugs thereof further described below. i. Formula I [0070] In some embodiments, Formula I is used in the treatment methods described above.

wherein Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine; the subscript m is an integer of from 0 to 5; each R^a is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)₃, -OC(O)O-R¹, -OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO₂NH₂, -S(O)₂NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, - C(O)R¹, -C(O)H, -C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O)NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂ R¹, -NR¹CO₂R¹, -R¹, -CN, -NO2, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, - NH₂C(=NR¹)NH₂, -N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, - N=C=S, -Si(R¹)₃, -NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; Q^a, Q^b, and Q^c are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl and phenyl, and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five-membered ring having two double bonds; Y is a member selected from the group consisting of C and N; when Ar is a bond, m is 1; when Ar is an aromatic ring, m is an integer of from 0-5; and pharmaceutically acceptable salts thereof. [0071] In some embodiments, Ar in Formula I is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine. When Ar is a bond, m is 1. When Ar is an aromatic ring, m is an integer from 0-5. In one embodiment, Ar is benzene or pyridine. In another embodiment, Ar is a bond. [0072] In some embodiments, the subscript m in Formula I is an integer from 0 to 5. In one embodiment, m is 0. [0073] In some embodiments, each R^a in Formula I is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)₃, -OC(O)O-R¹, - OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO2NH₂, -S(O)₂NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, - C(O)H, - C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O) NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂R¹, - R¹, -CN, -NO₂, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, -NH₂C(=NR¹)NH₂, - N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, -N=C=S, -Si(R¹)₃, - NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl. In one embodiment, R¹ is C₁-C₈ alkyl. In another embodiment, R¹ is unsubstituted aryl, such as phenyl or pyridyl, or a substituted aryl, such as a substitituted phenyl or a substituted pyridyl. [0074] In some embodiments, each R^a in Formula I is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, aryl, aryl(C₁-C₈ alkyl), halogen, -NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -CN, -C(=O)(C₁-C₈ alkyl), -(C=O)NH₂, -(C=O)NH(C₁-C₈ alkyl), - C(=O)N(C₁-C₈ alkyl)2, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl), -NH(C=O)O(C₁-C₈ alkyl), - O(C=O)NH(C₁-C₈ alkyl), -SO₂(C₁-C₈ alkyl), -NHSO₂(C₁-C₈ alkyl) and -SO₂NH(C₁-C₈ alkyl). In another embodiment, each R^a is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), halogen, -CN, -NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -(C=O)CH3, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), - O(C=O)O(C₁-C₈ alkyl), -NO2, -SH, -S(C₁-C₈ alkyl), and -NH(C=O)(C₁-C₈ alkyl). In yet another embodiment, each R^a is indepedently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), phenoxy, aryloxy, halogen, -CN, -NH₂, -NH-aryl, - (C=O)CH₃, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -COO-aryl, - OC(O)-aryl, -O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl) and the like. For example, R^a is halogen, such as Cl, Br or I. [0075] In some embodiments, L in Formula I is a linking group selected from the group consisting of a bond, CH₂ and SO2. [0076] In some embodiments, Q^a, Q^b, and Q^c in Formula I are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8alkyl, halogen and phenyl, and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five-membered ring having two double bonds. [0077] In a first group of embodiments, Q^a is N and Q^b and Q^c are each selected from N, O and C(R^q). In certain instances, Q^a is N and Q^c and Q^b are each independently selected from N and C(R^q). In certain other instances, Q^a is N and Q^c and Q^b are each selected from C(R^q) and O. In yet certain other instances, Q^a is N, Q^c is a member selected from N and O, and Q^b is the other member selected from N and O. [0078] In a second group of embodiments, Q^a is O and Q^b and Q^c are each selected from N, O and C(R^q). In certain instances, Q^a is O and Q^c and Q^b are each independently selected from N and C(R^q). [0079] In a third group of embodiments, Q^a is C(R^q) and Q^b and Q^c are each selected from N, O and C(R^q). In certain instances, Q^a is C(R^q) and Q^b and Q^c are each independently selected from N and O. In certain other instances, Q^a is C(R^q) and Q^b and Q^c are each independently selected from N and C(R^q). In yet certain other instances, Q^a is C(R^q) and Q^b and Q^c are each independently selected from O and C(R^q). In one occurrence, Q^a is C(R^q), Q^b is O and Q^c is (CR^q). [0080] In some embodiments, Y in Formula I is a member selected from the group consisting of C and N. In one embodiment, Y is C, Q^a is S and Ar is selected from phenyl or pyridyl. In another embodiment, Y is N, Q^a, Q^b and Q^c are each independently C(R^q), wherein R^q is H or C_1- ₈alkyl. In one instance, Y is N, Q^a and Q^c are C(R^q) and Q^b is CH. In a preferred embodiment, Y is N. [0081] In one embodiment, L in Formula I is a bond, Y is N. In another embodiment, L is a bond, Y is N and Ar is a benzene ring. In yet another embodiment, L is CH₂ and Y is N. In still another embodiment, L is a bond and Y is C. In a further embodiment, L is CH₂ and Y is N. [0082] In some embodiments, Q^a, Q^b and Q^c are each independently CR^q. In some embodiments, L is a bond or CH₂. In some embodiments, Ar is benzene. In some embodiments, R^a is -H and C₁-C₈ alkyl. [0083] In one embodiment, Formula I has a formula set forth in Table 1 below: Table 1

[0084] In some embodiments, the compounds of formula I have a subformula Ia:

R^q and L are as defined above. In one instance, R^q is independently -H or C_1-8 alkyl and L is a bond or -CH₂-. In another instance, R^a is halo-(C₁-C₈ alkyl). For example, R^a is -CF₃,CH₂CF₃. [0085] In some embodiments, the compounds of formula I have a subformula Ib:

wherein Ar is an aromatic ring. In one instance, each R^q is independently H, C₁-C₈ alkyl or halogen. In another instance, L is a bond or CH₂. In yet another instance, Ar is benzene. In still another instance, m is 0. In one occurrence, each R^q is H, L is CH₂, Ar is benzene and m is 0. In another occurrence, each R^q is H, L is a bond, Ar is benzene and m is 0. [0086] In some embodiments a compound of Formula I is as described in WO2008/016883, filed by Activesite Pharmaceuticals Inc. on July 30, 2007 (PCT/US/2007/074761 (published 7 February 2008). The contents of this publication is incorporated by reference in its entirety for all purposes. ii. Formula II [0087] In some embodiments, Formula II is used in the treatment methods described above

wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR², -OSi(R²)₃, -OC(O)O-R², - OC(O)R², -OC(O)NHR², -OC(O)N(R²)2, -SH, -SR², -S(O)R², -S(O)₂R², -SO2NH₂, -S(O)₂NHR², -S(O)₂N(R²)2, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)2, - C(O)R², -C(O)H, -C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, NR²C(O)NHR² -NHC(O)NHR² -NR²C(O)N(R²)₂ -NHC(O)N(R²)₂ -CO ₂H -CO R² -NHCO₂ R², -NR²CO₂R², -R², -CN, -NO2, -NH₂, -NHR², -N(R²)2, -NR²S(O)NH₂, -NR²S(O)₂NHR², - NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, - N=C=S, -Si(R²)₃, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; and pharmaceutically acceptable salts thereof. [0088] In some embodiments, the subscript m in Formula II is an integer of from 0 to 5. The subscript n is an integer of from 0 to 4. The subscript q is an integer of from 0 to 1. In one embodiment, the subscript m is 0. In another embodiment, the subscript n is an integer from 0 to 2. In yet another embodiment, the subscript q is 0. In still another embodiment, the subscript q is 1. [0089] In some embodiments, L in Formula II is a linking group selected from the group consisting of a bond, CH₂ and SO2. In one embodiment, L is CH₂ or SO2. [0090] In some embodiments, each of R^b and R^c in Formula II is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR², -OSi(R²)3, -OC(O)O-R², - OC(O)R², -OC(O)NHR², -OC(O)N(R²)₂, -SH, -SR², -S(O)R², -S(O)₂R², -SO₂NH₂, -S(O)₂NHR², -S(O)₂N(R²)₂, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)₂, -C(O)R², - C(O)H, - C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O) NHR², -NR²C(O)N(R²)2, -NHC(O)N(R²)2, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², - R², -CN, -NO2, -NH₂, -NHR², -N(R²)2, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, - N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)3, - NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl. In one embodiment, R² is C₁-C₈ alkyl. In another embodiment, R² is unsubstituted aryl, such as phenyl or pyridyl, or a substituted aryl, such as a substitituted phenyl or a substituted pyridyl. [0091] In some embodiments, each of R^b and R^c in Formula II is independently selected from ^{the group consisting of C} ₁ ^-C ₈ ^{alkyl, C} ₁ ^-C ₈ ^{alkoxy, aryl, aryl(C} ₁ ^-C ₈ ^{alkyl), halogen, -NH} ₂ ^{, -} NH(C₁-C₈ alkyl) -N(C₁-C₈ alkyl)2 -CN -C(=O)(C₁-C₈ alkyl) -(C=O)NH₂ -(C=O)NH(C₁-C₈ alkyl), -C(=O)N(C₁-C₈ alkyl)2, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), - O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl), -NH(C=O)O(C₁-C₈ alkyl), -O(C=O)NH(C₁-C₈ alkyl), -SO₂(C₁-C₈ alkyl), -NHSO₂(C₁-C₈ alkyl) and -SO₂NH(C₁-C₈ alkyl). In another embodiment, each R^a is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), halogen, -CN, -NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -(C=O)CH3, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl), -NO2, -SH, -S(C₁-C₈ alkyl), and -NH(C=O)(C₁-C₈ alkyl). In yet another embodiment, each R^a is indepedently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), phenoxy, aryloxy, halogen, -CN, -NH₂, -NH-aryl, - (C=O)CH₃, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -COO-aryl, - OC(O)-aryl, -O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl) and the like. [0092] In some embodiments, when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl. When q is 1, Z is N. In some embodiments, the subscript q is 0 and Z is selected from the group consisting of O, S and NH. In some embodiments, the subscript n is 0, 1 or 2. In some embodiments, Z is O or S. In some embodiments, the subscript q is 1. In some embodiments, L is CH₂ or SO2. [0093] In some embodiments, the present invention provides compounds of formula II having a formula set forth in Table 2 below: Table 2 NH NH₂ H N^H ₂

[0094] In some embodiments, the compounds of formula II have a subformula IIa: O

wherein substituents R^b and R^c and subscripts m are as defined above. In some embodiments, L is CH₂. In some embodiments, L is SO₂. In yet another instance, m is 0. In still another instance, n is 0. [0095] In some embodiments, compounds of formula II have a subformula IIa-1:

[0096] In some embodiments a compound of Formula II is as described in WO2008/016883, filed by Activesite Pharmaceuticals Inc. on July 30, 2007 (PCT/US/2007/074761 (published 7 February 2008). The contents of this publication is incorporated by reference in its entirety for all purposes. iii. Prodrugs thereof [0097] A person of skill in the art will recognize the prodrugs of Formula I and Formula II can also be used in the treatment methods described above. Accordingly, prodrugs of Formula I and Formula II are also within the scope of the current disclosure. [0098] In some embodiments, a prodrug of Formula I is represented by Formula III

wherein Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine; the subscript m is an integer of from 0 to 5; each R^a is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)3, -OC(O)O-R¹, - OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO₂NH₂, -S(O)₂NHR¹, -S(O)₂ N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, -C(O)H, - C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O)NHR¹, - NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂R¹, - R¹, -CN, -NO₂, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, -NH₂C(=NR¹)NH₂, - N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, -N=C=S, -Si(R¹)₃, -NH- NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl or aryl; L is a linking group selected from the group consisting of a bond, CH₂ and SO2; Q^a, Q^b, and Q^c are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl and phenyl; Y is a member selected from the group consisting of C and N; , and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five-membered ring having two double bonds; and when Ar is a bond, m is 1; when Ar is an aromatic ring, m is an integer of from 0-5; X is a member selected from the group consisting of H, C_1-8 alkyl and phenyl; and pharmaceutically acceptable salts thereof. [0099] In some embodiments, Ar in Formula III is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine. When Ar is a bond, m is 1. When Ar is an aromatic ring, m is an integer from 0-5. In one embodiment, Ar is benzene or pyridine. In another embodiment, Ar is a bond. [0100] In some embodiments, X in Formula III is a member selected from the group consisting of H, C_1-8 alkyl and phenyl. In one embodiment, X is H. In another embodiment, X is C₅ alkyl. In still another embodiment, X is phenyl. [0101] The subscript m in Formula III is an integer from 0 to 5. In one embodiment, m is 0. [0102] In some embodiments, each R^a in Formula III is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)₃, -OC(O)O-R¹, - OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO2NH₂, -S(O)₂NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, - C(O)H, - C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O) NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂R¹, - R¹, -CN, -NO₂, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, -NH₂C(=NR¹)NH₂, - N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, -N=C=S, -Si(R¹)₃, - NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl or aryl. In one embodiment, R¹ is C₁-C₈ alkyl. In another embodiment, R¹ is unsubstituted aryl, such as phenyl or pyridyl, or a substituted aryl, such as a substitituted phenyl or a substituted pyridyl. [0103] In some embodiments, each R^a in Formula III is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, aryl, aryl(C₁-C₈ alkyl), halogen, -NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)₂, -CN, -C(=O)(C₁-C₈ alkyl), -(C=O)NH₂, -(C=O)NH(C₁-C₈ alkyl), - C(=O)N(C₁-C₈ alkyl)₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl), -NH(C=O)O(C₁-C₈ alkyl), - O(C =O)NH(C₁-C₈ alkyl)₂ -SO (C₁-C₈ alkyl) -NHSO₂ (C₁-C₈ alkyl) and SO ₂NH(C₁-C₈ alkyl) . In another embodiment, each R^a is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), halogen, -CN, -NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)₂, -(C=O)CH₃, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl), -NO₂, -SH, -S(C₁-C₈ alkyl), and -NH(C=O)(C₁-C₈ alkyl). In yet another embodiment, each R^a is indepedently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), phenoxy, aryloxy, halogen, -CN, -NH₂, -NH-aryl, - (C=O)CH3, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -COO-aryl, - OC(O)-aryl, -O(C=O)O(C₁-C₈ alkyl)-NO2, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl) and the like. For example, R^a is halogen, such as Cl, Br or I. [0104] In some embodiments, L in Formula III is a linking group selected from the group consisting of a bond, CH₂ and SO2. [0105] In some embodiments, Q^a, Q^b, and Q^c in Formula III are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl, halogen and phenyl. [0106] In some embodiments, Y in Formula III is selected from C and N; and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five-membered ring having two double bonds. [0107] In a first group of embodiments, Q^a is N and Q^b and Q^c are each selected from N, O and C(R^q). In certain instances, Q^a is N and Q^c and Q^b are each independently selected from N and C(R^q). In certain other instances, Q^a is N and Q^c and Q^b are each selected from C(R^q) and O. In yet certain other instances, Q^a is N, Q^c is a member selected from N and O, and Q^b is the other member selected from N and O. [0108] In a second group of embodiments, Q^a is O and Q^b and Q^c are each selected from N, O and C(R^q). In certain instances, Q^a is O and Q^c and Q^b are each independently selected from N and C(R^q). [0109] In a third group of embodiments, Q^a is C(R^q) and Q^b and Q^c are each selected from N, O and C(R^q). In certain instances, Q^a is C(R^q) and Q^b and Q^c are each independently selected from N and O. In certain other instances, Q^a is C(R^q) and Q^b and Q^c are each independently selected from N and C(R^q). In yet certain other instances, Q^a is C(R^q) and Q^b and Q^c are each independently selected from O and C(R^q). In one occurrence, Q^a is C(R^q), Q^b is O and Q^c is (CR^q). [0110] In one embodiment, Y is C, Q^a is S and Ar is selected from phenyl or pyridyl. In another embodiment, Y is N, Q^a, Q^b and Q^c are each independently C(R^q), wherein R^q is H or C_1- ₈alkyl. In one instance, Y is N, Q^a and Q^c are C(R^q) and Q^b is CH. In a preferred embodiment, Y is N. [0111] In one embodiment, L in Formula III is a bond, Y is N. In another embodiment, L is a bond, Y is N and Ar is a benzene ring. In yet another embodiment, L is CH₂ and Y is N. In still another embodiment, L is a bond and Y is C. In a further embodiment, L is SO2 and Y is N. [0112] In a preferred embodiment, Q^a, Q^b and Q^c in Formula III are each independently CR^q. In another preferred embodiment, L is a bond or CH₂. In still another preferred embodiment, Ar is benzene. In still another preferred embodiment, R^a is -H and C₁-C₈ alkyl. [0113] In each of the above embodiments, X in Formula III is a member selected from the group consisting of H, C_1-8 alkyl and phenyl. [0114] In another embodiment, the compounds of formula III have a subformula IIIa:

IIIa) wherein R^q , L and X are as defined above. In one instance, R^q is independently -H or C_1-8 alkyl and L is a bond or -CH₂-. In another instance, R^a is C₁-C₈ haloalkyl. For example, R^a is -CF₃ or -CH₂CF₃. [0115] In one embodiment, the compounds of formula III have a subformula IIIb:

wherein Ar is an aromatic ring. In one instance, each R^q is independently H, C₁-C₈ alkyl or halogen. In another instance, L is a bond or CH₂. In yet another instance, Ar is benzene. In still another instance, m is 0. In one occurrence, each R^q is H, L is CH₂, Ar is benzene and m is 0. In another occurrence, each R^q is H, L is a bond, Ar is benzene and m is 0. In each instance or occurrence, X is independently selected from the group consisting of H, C_1-8 alkyl, and phenyl. [0116] The following are mentioned as examples of compounds of general formula III: (a) (Z)-hexyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl)phenyl)methylenecarbamate (b) (Z)-hexyl amino-(4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (c) (Z)-hexyl amino- (4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (d) (Z)-hexyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (e) (Z)-hexyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (f) (Z)-methyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (g) (Z)-methyl amino-(4((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (h) (Z)-methyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (i) (Z)-methyl amino- (4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (j) (Z)-methylamino-(4-((1-benzylpyrazole-4-carbonylamino)methyl)phenyl)methylenecarbamate (k) (Z)-benzyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate (l) (Z)-benzyl amino-(4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (m)(Z)-benzyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (n) (Z)-benzyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (o) (Z)-benzyl amino-(4-(1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3- carbonylamino)phenyl)methylenecarbamate (p) (Z)-ethyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (q) (Z)-ethyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (r) (Z)-ethyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (s) (Z)-ethyl amino- (4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (t) (Z)-ethyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate (u) (Z)-propyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (v) (Z)-propyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (w)(Z)-propyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (x) (Z)-propyl amino-(4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (y) (Z)-propyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate. [0117] In some embodiments, a prodrug of Formula II is represented by Formula IV

wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO2; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR², -OSi(R²)3, -OC(O)O-R², - OC(O)R², -OC(O)NHR², -OC(O)N(R²)2, -SH, -SR², -S(O)R², -S(O)₂R², -SO2NH₂, -S(O)₂NHR², -S(O)₂ N(R²)₂, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)₂, -C(O)R², -C(O)H, - C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O)NHR², - NR²C(O)N(R²)₂, -NHC(O)N(R²)₂, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², - R², -CN, -NO₂, -NH₂, -NHR², -N(R²)₂, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, - N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)3, -NH- NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl or aryl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; X is a member selected from the group consisting of H, C_1-8 alkyl, and phenyl; and pharmaceutically acceptable salts thereof. [0118] In some embodiments, the subscript m in Formula IV is an integer of from 0 to 5. The subscript n is an integer of from 0 to 4. The subscript q is an integer of from 0 to 1. In one embodiment, the subscript m is 0. In another embodiment, the subscript n is an integer from 0 to 2. In yet another embodiment, the subscript q is 0. In still another embodiment, the subscript q is 1. [0119] In some embodiments, the subscript L in Formula IV is a linking group selected from the group consisting of a bond, CH₂ and SO₂. In one embodiment, L is CH₂ or SO₂. X is a member selected from the group consisting of H, C_1-8 alkyl and phenyl. [0120] In some embodiments, each of R^b and R^c in Formula IV is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR², -OSi(R²)₃, -OC(O)O-R², - OC(O)R², -OC(O)NHR², -OC(O)N(R²)₂, -SH, -SR², -S(O)R², -S(O)₂R², -SO₂NH₂, -S(O)₂NHR², -S(O)₂N(R²)₂, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)₂, -C(O)R², - C(O)H, - C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O) NHR², -NR²C(O)N(R²)2, -NHC(O)N(R²)2, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², - R², -CN, -NO2, -NH₂, -NHR², -N(R²)2, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, - N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)₃, - NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl or aryl. In one embodiment, R² is C₁-C₈ alkyl. In another embodiment, R² is unsubstituted aryl, such as phenyl or pyridyl, or a substituted aryl, such as a substitituted phenyl or a substituted pyridyl. [0121] In some embodiments, each of R^b and R^c in Formula IV is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, aryl, aryl(C₁-C₈ alkyl), halogen, -NH₂, - NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -CN, -C(=O)(C₁-C₈ alkyl), -(C=O)NH₂, -(C=O)NH(C₁-C₈ alkyl), -C(=O)N(C₁-C₈ alkyl)2, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), - O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl), -NH(C=O)O(C₁-C₈ alkyl), -O(C=O)NH(C₁-C₈ alkyl), -SO₂(C₁-C₈ alkyl), -NHSO₂(C₁-C₈ alkyl) and -SO₂NH(C₁-C₈ alkyl). In another embodiment, each of R^b and R^c is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), halogen, -CN, -NH₂, - NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -(C=O)CH3, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl), -NO2, -SH, -S(C₁-C₈ alkyl), and -NH(C=O)(C₁-C₈ alkyl). In yet another embodiment, each of R^b and R^c is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), phenoxy, aryloxy, halogen, -CN, -NH₂, -NH-aryl, -(C=O)CH₃, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -COO-aryl, -OC(O)-aryl, -O(C=O)O(C₁-C₈ alkyl)-NO2, -SH, -S(C₁-C₈ alkyl), - NH(C=O)(C₁-C₈ alkyl) and the like. [0122] In some embodiments, When q is 0 in Formula IV, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl. When q is 1, Z is N. In one embodiment, the subscript q is 0 and Z is selected from the group consisting of O, S and NH. In one instance, the subscript n is 0, 1 or 2. In one occurrence, Z is O or S. In another embodiment, the subscript q is 1. In one instance, L is CH₂ or SO₂. [0123] In each instance or occurrence, X in Formula IV is a member selected from the group consisting of H, C_1-8 alkyl and phenyl. [0124] In one embodiment, the compounds of formula IV have a subformula IVa:

[0125] Substituents R^b and R^c and subscripts m and n are as defined above. In one instance, L is CH₂. In another instance, L is SO₂. In yet another instance, m is 0. In still another instance, n is 0. [0126] In another embodiment, compounds of formula IV have a subformula IVa-1:

[0127] The following are mentioned as examples of particularly preferred compounds of general formula IV: (a) (Z)methylamino(4((1benzylindole3carbonylamino)methyl)phenyl)methylenecarbamate (b) (Z)-methyl amino-(4-(1-(benzenesulfonyl)indole-3-carbonylamino)methyl) phenyl)methylenecarbamate (c) (Z)-ethyl amino-(4-((1-benzylindole-3-carbonylamino)methyl)phenyl)methylenecarbamate (Z)-ethyl amino-(4-(1-(benzenesulfonyl)indole-3-carbonylamino)methyl) phenyl)methylenecarbamate. [0128] In some embodiments a prodrug of Formula I or Formula II is as described in WO2011/075684, filed by Activesite Pharmaceuticals Inc. on December 17, 2010 (PCT/US2010/061122 (published 23 June 2011). The contents of this publication is incorporated by reference in its entirety for all purposes. G. Pharmaceutical Compositions [0129] The compounds of Formula I, Formula II, and prodrugs provided herein can be administered as compositions which will typically contain a pharmaceutical carrier or diluent. [0130] In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. [0131] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications as described in U.S. Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets . These excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. In some embodiments, the tablets may also be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. [0132] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like. [0133] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0134] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0135] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0136] The pharmaceutical compositions of the invention may also be in the form of oil-inwater emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0137] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

[0138] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0139] The compositions described here may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Additionally, the compositions can be administered via ocular delivery by means of solutions or ointments. Still further, transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds described herein are employed. As used herein, topical application is also meant to include the use of mouth washes and gargles. H. Routes of Administration [0140] The present invention contemplates the administration of the compounds and compositions described herein, in any appropriate manner. The route of administration may vary depending on a variety of factors including the disease being treated and the severity of the disease. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. [0141] In some embodiments, the compounds and compositions described herein are administered orally. [0142] In some embodiments, the compounds and compositions described herein are administered subcutaneously. [0143] The dosage of the specific compounds or prodrugs described herein depends on many factors that are well known to those skilled in the art. These factors include for example, the route of administration, the indication being treated, and the potency of the particular compound. An exemplary dose is from about 0.001 µg/kg to about 100 mg/kg body weight of the subject. Determination of an effective amount is within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, an efficacious or effective amount of the a compound, a prodrug, or a composition of the present disclosure is determined by first administering a low dose or small amount of a compound, a prodrug, or a composition herein and then incrementally increasing the administered dose or dosages, until a desired effect is observed in the treated subject with minimal or no toxic side effects. Applicable methods for determining an appropriate dose and dosing schedule for administration of compounds or prodrugs the present disclosure are described, for example, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition, 2010, McGraw-Hill Professional; in a Physicians’ Desk Reference (PDR), 68^th Edition, 2014, PDR Network; in Remington: The Science and Practice of Pharmacy, 21^st Ed., 2005, supra; and in Martindale: The Complete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press., and in Martindale, Martindale: The Extra Pharmacopoeia, 31st Edition., 1996, Amer Pharmaceutical Assn, each of which are hereby incorporated herein by reference. IV. Examples Example 1: Preparation of a Plasma Kallikrein Inhibitor [0144] The acetate salt of a plasma kallikrein inhibitor (Compound 1.002) was prepared as described in the chemical synthetic procedure below.

O Ό

Example 2: In Vivo Pharmacokinetics a Plasma Kallikrein Inhibitor

[0145] In vivo pharmacokinetics of the acetate salt of Compound 1.002 upon oral delivery were evaluated in both male and female cynomolgus monkeys A suspension of Compound 1.002 in 0.4% methocel was delivered by oral gavage. Four different doses namely, 67, 200, 400 and 800 mg/kg were investigated. The following table shows Compound 1.002 plasma concentrations at different time points. The results show that at all four doses, delivered orally, Compound 1.002 concentrations are sustained up to or longer than 24 hours allowing for dosing no more frequent than once a day. BQL – below quantitation limit; SD – standard deviation; CV – coefficient of variation

Example 3: Monkey Telemetry Study [0146] A study was conducted evaluating the potential cardiovascular effects of Compound 1.002, a small molecule plasma kallikrein inhibitor (PKI) in instrumented cynomolgus monkeys when administered by oral gavage for 7 days. [0147] The study design was as follows:

^{Com ound}

[0148] The following cardiovascular parameters were evaluated for all animals for 2 hours predose up to 24 hours post dose on Days 4 and 7: systemic arterial blood pressures (mean arterial pressure, systolic and diastolic blood pressures, pulse pressure), heart rate, and electrocardiographic interval duration (PR, QRS, QT, and QTc). Qualitative evaluation of the electrocardiographic waveforms was performed on Days 4 and 7, once prior to dosing, and at approximately 1, 2, 4, 6, 8, 12, 16, 20 and 24 hours after dosing. Additional evaluations consisted of mortality and clinical observations. [0149] There were no Compound 1.002-related mortalities or clinical signs noted during the course of the study. [0150] There were no biologically significant changes noted in systemic arterial blood pressures (systolic, diastolic, mean arterial pressure, and pulse pressure), electrocardiographic duration/intervals (PR, QRS, QT and QTc), heart rate, or qualitative ECG parameters on Days 4 or 7. [0151] In conclusion, there were no Compound 1.002-related changes in systemic arterial blood pressures (systolic, diastolic, mean arterial pressure, and pulse pressure), electrocardiographic duration/intervals (PR, QRS, QT and QTc), or heart on Days 4 or 7. There were no effects of Compound 1.002 on qualitative ECG parameters as assessed on Days 4 and 7. [0152] The blood pressure results from this study indicate that Compound 1.002 does not alter the levels of the blood-pressure related factors such as angiotensin, and that Compound 1.002 does not effect the activities of the antiotensin-converting enzymes 1 or 2 (ACE-1 or ACE-2). [0153] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS: 1. A method of treating an acute respiratory syndrome in a subject comprising administering to the subject an effective amount of (i) a compound of Formula I

wherein Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine; the subscript m is an integer of from 0 to 5; each R^a is independently selected from the group consisting of cycloalkyl, (C₁-C₈)haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)₃, -OC(O)O-R¹, -OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO₂NH₂, -S(O)₂NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, -C(O)H, -C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O)NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂R¹, -R¹, -CN, -NO2, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, -NH₂C(=NR¹)NH₂, -N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, -N=C=S, -Si(R¹)₃, -NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; Q^a, Q^b, and Q^c are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl, halo and phenyl, and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five- membered ring having two double bonds; Y is a member selected from the group consisting of C and N; when Ar is a bond, m is 1; when Ar is an aromatic ring, m is an integer of from 0-5; or a pharmaceutically acceptable salts thereof; (ii) a compound of Formula II O (

II wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, (C1- C8)haloalkyl, halogen, -OH, -OR², -OSi(R²)3, -OC(O)O-R², -OC(O)R², -OC(O)NHR², -OC(O)N(R²)2, -SH, -SR², -S(O)R², -S(O)₂R², -SO2NH₂, -S(O)₂NHR², -S(O)₂N(R²)2, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)₂, -C(O)R², -C(O)H, -C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O)NHR², -NR²C(O)N(R²)₂, -NHC(O)N(R²)₂, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², -R², -CN, -NO₂, -NH₂, -NHR², -N(R²)₂, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)3, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; or a pharmaceutically acceptable salt thereof; or (iii) a prodrug of Formula I or Formula II.

2. The method of claim 1, wherein the acute respiratory syndrome is precipitated by a non-viral insult.

3. The method of claim 2, wherein the non-viral insult is selected from the group consisting of sepsis, pancreatitis, a blood transfusion, an inhalation injury, mechanical- ventilation injury, and a major chest injury.

4. The method of claim 3, wherein the inhalation injury is selected from the group consisting of chemical inhalation, smoke inhalation, and vomit inhalation.

5. The method of claim 1, wherein the acute respiratory syndrome is precipitated by a virus.

6. The method of claim 5, wherein the virus is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus.

7. The method of claim 6, wherein the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C.

8. The method of claim 6, wherein the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus.

9. The method of claim 6, wherein the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV).

10. The method of claim 1, wherein the acute respiratory syndrome is acute respiratory distress syndrome (ARDS).

11. The method of claim 1, wherein the acute respiratory syndrome is severe acute respiratory syndrome (SARS).

12. A method of treating non-cardiogenic pulmonary edema in a subject comprising administering to the subject an effective amount of (i) a compound of Formula I

wherein Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine; the subscript m is an integer of from 0 to 5; each R^a is independently selected from the group consisting of cycloalkyl, (C₁-C₈)haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)3, -OC(O)O-R¹, -OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO2NH₂, -S(O)₂NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, -C(O)H, -C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O)NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂R¹, -R¹, -CN, -NO₂, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, -NH₂C(=NR¹)NH₂, -N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, -N=C=S, -Si(R¹)3, -NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl; L is a linking group selected from the group consisting of a bond, CH₂ and SO2; Q^a, Q^b, and Q^c are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl, halo and phenyl, and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five- membered ring having two double bonds; Y is a member selected from the group consisting of C and N; when Ar is a bond, m is 1; when Ar is an aromatic ring, m is an integer of from 0-5; or a pharmaceutically acceptable salts thereof; (ii) a compound of Formula II; O

II wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, (C₁- C₈)haloalkyl, halogen, -OH, -OR², -OSi(R²)₃, -OC(O)O-R², -OC(O)R², -OC(O)NHR², -OC(O)N(R²)2, -SH, -SR², -S(O)R², -S(O)₂R², -SO2NH₂, -S(O)₂NHR², -S(O)₂N(R²)2, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)2, -C(O)R², -C(O)H, -C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O)NHR², -NR²C(O)N(R²)₂, -NHC(O)N(R²)₂, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², -R², -CN, -NO₂, -NH₂, -NHR², -N(R²)₂, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)₃, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; or a pharmaceutically acceptable salt thereof; or (iii) a prodrug of Formula I or Formula II.

13. The method of claim 12, wherein the non-cardiogenic pulmonary edema is precipitated by a non-viral insult.

14. The method of claim 13, wherein the non-viral insult is selected from the group consisting of sepsis, pancreatitis, a blood transfusion, an inhalation injury, mechanical- ventilation injury, and a major chest injury.

15. The method of claim 14, wherein the inhalation injury is selected from the group consisting of chemical inhalation, smoke inhalation, and vomit inhalation.

16. The method of claim 12, wherein the non-cardiogenic pulmonary edema is precipitated by a virus.

17. The method of claim 16, wherein the virus is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus.

18. The method of claim 17, wherein the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C.

19. The method of claim 17, wherein the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus.

20. The method of claim 17, wherein the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV).

21. A method of treating a viral infection in a subject comprising administering to the subject an effective amount of (i) a compound of Formula I

wherein Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine; the subscript m is an integer of from 0 to 5; each R^a is independently selected from the group consisting of cycloalkyl, (C₁-C₈)haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)₃, -OC(O)O-R¹, -OC(O)R¹, -OC(O)NHR¹, -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂R¹, -SO₂NH₂, -S(O)₂NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, -C(O)H, -C(=S)R¹, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -NHC(O)NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂R¹, -R¹, -CN, -NO2, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, -NH₂C(=NR¹)NH₂, -N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, -N=C=O, -N=C=S, -Si(R¹)₃, -NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; Q^a, Q^b, and Q^c are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl, halo and phenyl, and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five- membered ring having two double bonds; Y is a member selected from the group consisting of C and N; when Ar is a bond, m is 1; when Ar is an aromatic ring, m is an integer of from 0-5; or a pharmaceutically acceptable salts thereof; (ii) a compound of Formula II;

wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, (C₁- C₈)haloalkyl, halogen, -OH, -OR², -OSi(R²)₃, -OC(O)O-R², -OC(O)R², -OC(O)NHR², -OC(O)N(R²)₂, -SH, -SR², -S(O)R², -S(O)₂R², -SO₂NH₂, -S(O)₂NHR², -S(O)₂N(R²)₂, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)2, -C(O)R², -C(O)H, -C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O)NHR², -NR²C(O)N(R²)2, -NHC(O)N(R²)2, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², -R², -CN, -NO2, -NH₂, -NHR², -N(R²)2, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)₃, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; or a pharmaceutically acceptable salt thereof; or (iii) a prodrug of Formula I or Formula II.

22. The method of claim 21, wherein the viral infection is a respiratory virus.

23. The method of claim 21, wherein the viral infection is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus.

24. The method of claim 23, wherein the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C.

25. The method of claim 23, wherein the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus.

26. The method of claim 23, wherein the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV).

27. A method of treating coronavirus disease 2019 (COVID-19) comprising administering to the subject an effective amount of (i) a compound of Formula I

wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, (C₁- C₈)haloalkyl, halogen, -OH, -OR², -OSi(R²)₃, -OC(O)O-R², -OC(O)R², -OC(O)NHR², -OC(O)N(R²)2, -SH, -SR², -S(O)R², -S(O)₂R², -SO2NH₂, -S(O)₂NHR², -S(O)₂N(R²)2, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)2, -C(O)R², -C(O)H, -C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O)NHR², -NR²C(O)N(R²)2, -NHC(O)N(R²)2, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², -R², -CN, -NO₂, -NH₂, -NHR², -N(R²)₂, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)₃, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; or a pharmaceutically acceptable salt thereof; or (iii) a prodrug of Formula I or Formula II.

28. A method of treating systemic inflammatory response syndrome (SIRS) in a subject comprising administering to the subject an effective amount of (i) a compound of Formula I

wherein the subscript m is an integer of from 0 to 5; the subscript n is an integer of from 0 to 4; the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO2; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, (C₁- C₈)haloalkyl, halogen, -OH, -OR², -OSi(R²)₃, -OC(O)O-R², -OC(O)R², -OC(O)NHR², -OC(O)N(R²)₂, -SH, -SR², -S(O)R², -S(O)₂R², -SO₂NH₂, -S(O)₂NHR², -S(O)₂N(R²)₂, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)₂, -C(O)R², -C(O)H, -C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -NHC(O)NHR², -NR²C(O)N(R²)2, -NHC(O)N(R²)2, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂R², -R², -CN, -NO2, -NH₂, -NHR², -N(R²)2, -NR²S(O)NH₂, -NR²S(O)₂NHR², -NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², -N=C=O, -N=C=S, -Si(R²)₃, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently alkyl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; or a pharmaceutically acceptable salt thereof; or (iii) a prodrug of Formula I or Formula II.

29. The method of claim 28, wherein SIRS is precipitated by a non-viral insult.

30. The method of claim 29, wherein the non-viral insult is selected from the group consisting of sepsis, pancreatitis, a blood transfusion, a burn, and a major injury.

31. The method of claim 30, wherein the burn is selected from the group consisting of an electrical burn, a thermal burn, a chemical burn, or a radiation burn.

32. The method of claim 30, wherein the subject has the burn on at least 30% of their body.

33. The method of claim 30, wherein the major injury is selected from the group consisting of anaphylaxis, severe trauma, and combinations thereof.

34. The method of claim 28, wherein SIRS is precipitated by a virus.

35. The method of claim 34, wherein the virus is selected from the group consisting of an influenza virus, a coronavirus, a respiratory syncytial virus, and a hantavirus.

36. The method of claim 35, wherein the influenza virus is selected from the group consisting of influenza A, influenza B, and influenza C.

37. The method of claim 35, wherein the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and middle east respiratory syndrome (MERS) coronavirus.

38. The method of claim 35, wherein the hantavirus is selected from the group consisting of hantaan virus, seoul virus, puumala virus, prospect hill virus (PHV), and sin nombre virus (SNV).

39. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula I, wherein Ar is an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine.

40. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula I, wherein Ar is a bond and m is 1.

41. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula Ia O

42. The method of claim 39, wherein L is a bond and Y is N.

43. The method of claim 39, wherein L is a bond, Y is N and Ar is a benzene ring.

44. The method of claim 43, wherein Q^a, Q^b and Q^c are each independently C(R^q).

45. The method of claim 43, wherein Q^b is N.

46. The method of claim 39, wherein Y is C; Q^a is S and Ar is selected from phenyl or pyridyl.

47. The method of claim 46, wherein Q^c is C.

48. The method of claim 47, wherein L is CH₂ and Y is N.

49. The method of claim 48, wherein Q^a is C.

50. The method of claim 49, wherein Q^b and Q^c are each independently selected from the group consisting of N and C(R^q).

51. The method of claim 49, wherein Ar is benzene or pyridine.

52. The method of claim 39, wherein L is a bond and Y is C.

53. The method of claim 52, wherein Q^b is O; and Q^a and Q^c are each C(R^q).

54. The method of claim 39, wherein L is SO₂ and Y is N.

55. The method of claim 39, wherein each R^a is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, aryl, aryl(C₁-C₈ alkyl), halogen, -NH₂, - NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)₂, -CN, -C(=O)(C₁-C₈ alkyl), -(C=O)NH₂, -(C=O)NH(C₁-C₈ alkyl), -C(=O)N(C₁-C₈ alkyl)₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), - O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), -NH(C=O)(C₁-C₈ alkyl), -NH(C=O)O(C₁-C₈ alkyl), -O(C=O)NH(C₁-C₈ alkyl), -SO₂(C₁-C₈ alkyl), -NHSO2(C₁-C₈ alkyl) and -SO2NH(C₁-C₈ alkyl).

56. The method of claim 55, wherein each R^a is independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), halogen, -CN, - NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -(C=O)CH3, -(C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl), -NO2, -SH, -S(C₁-C₈ alkyl), and - NH(C=O)(C₁-C₈ alkyl).

57. The method of claim 56, wherein R^a is halogen.

58. The method of claim 39, where in the compound of Formula I selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

59. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula II, wherein the subscript q is 0 and Z is selected from the group consisting of O, S and NH.

60. The method of claim 59, wherein the subscript n is an integer of from 0 to 2.

61. The method of claim 60, wherein Z is O or S.

62. The method any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula II, wherein the subscript q is 1.

63. The method of claim 62, wherein L is selected from the group consisting of -CH₂- and -SO₂-.

64. The method of claim 63, wherein the subscript m is 0.

65. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula II, wherein R^b and R^c are each independently selected from the group consisting of C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, phenyl (C₁-C₈ alkyl), halogen, -CN, -NH₂, -NH(C₁-C₈ alkyl), -N(C₁-C₈ alkyl)2, -(C=O)CH3, - (C=O)NH₂, -OH, -COOH, -COO(C₁-C₈ alkyl), -OCO(C₁-C₈ alkyl), -O(C=O)O(C₁-C₈ alkyl)-NO₂, -SH, -S(C₁-C₈ alkyl), and -NH(C=O)(C₁-C₈ alkyl).

66. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound of Formula II, where in the compound of Formula II is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

67. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound having the formula

or a pharmaceutically acceptable salt thereof.

68. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound having the formula

or a pharmaceutically acceptable salt thereof.

69. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a compound having the formula

or a pharmaceutically acceptable salt thereof.

70. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a prodrug of Formula I, wherein the prodrug has the Formula III

Ill wherein

Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine, wherein when Ar is a bond, m is 1, and when Ar is an aromatic ring, m is an integer from 0-5;

X is selected from the group consisting of H, C_1-8 alkyl and phenyl; each R^a is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR¹, -OSi(R¹)₃, -OC(O)O-R¹, -

OC(O)R¹, -OC(O)NHR¹ -OC(O)N(R¹)₂, -SH, -SR¹, -S(O)R¹, -S(O)₂ R¹, -SO₂NH₂, -S(O)₂ NHR¹, -S(O)₂N(R¹)₂, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -C(O)NH₂, -C(O)NHR¹, -C(O)N(R¹)₂, -C(O)R¹, -C(O)H, -

C(=S)R¹, -NHC(O)R¹ -NR¹C(O)R¹, -NHC(O)NH₂, -NR¹C(O)NH₂, -NR¹C(O)NHR¹, -N HC(O)NHR¹, -NR¹C(O)N(R¹)₂, -NHC(O)N(R¹)₂, -CO₂H, -CO₂R¹, -NHCO₂R¹, -NR¹CO₂ R¹, -R¹, -CN, -NO2, -NH₂, -NHR¹, -N(R¹)₂, -NR¹S(O)NH₂, -NR¹S(O)₂NHR¹, - NH₂C(=NR¹)NH₂, -N=C(NH₂)NH₂, -C(=NR¹)NH₂, -NH-OH, -NR¹-OH, -NR¹-OR¹, - N=C=O, -N=C=S, -Si(R¹)₃, -NH-NHR¹, -NHC(O)NHNH₂, NO, -N=C=NR¹ and -S-CN, wherein each R¹ is independently alkyl or aryl; L is a linking group selected from the group consisting of a bond, CH₂ and SO₂; Q^a, Q^b, and Q^c are each members independently selected from the group consisting of N, S, O and C(R^q) wherein each R^q is independently selected from the group consisting of H, C_1-8 alkyl, halogen and phenyl; Y is C or N; and the ring having Q^a, Q^b, Q^c and Y as ring vertices is a five-membered ring having two double bonds; or a pharmaceutically acceptable salt thereof.

71. The method of claim 70, wherein X is selected from the group consisting of H, methyl, ethyl and pentyl.

72. The method of claim 70, wherein Q^a is N; and Q^b and Q^c are each selected from N, O and C(R^q).

73. The method of claim 70, wherein Q^a is N and Q^b and Q^c are each selected from N and C(R^q).

74. The method of claim 70, wherein Y is N, and Q^a, Q^b and Q^c are each independently C(R^q), wherein each R^q is independently H or C_1-8 alkyl.

75. The method of claim 70, wherein Y is N, Q^a and Q^c are C(R^q) and Q^b is CH.

76. The method of claim 70, wherein Y is N and Q^b is N.

77. The method of claim 70, wherein L is a bond and Y is N.

78. The method of claim 70, wherein L is a bond, Y is N, and Ar is a benzene ring.

79. The method of claim 70, wherein L is a bond.

80. The method of claim 70, wherein L is -SO₂-.

81. The method of claim 70, wherein R^a is H or C₁-C₈ alkyl.

82. The method of claim 70, wherein Q^a is O; and Q^b and Q^c are each selected from N, O and C(R^q).

83. The method of claim 70, wherein Q^a is O; and Q^b and Q^c are each selected from N and C(R^q).

84. The method of claim 70, having the formula:

IIa).

85. The method of claim 84, wherein each R^q is independently selected from the group consisting of H and C₁-C₈ alkyl; and L is a bond or –CH₂-.

86. The method of claim 84, wherein R^a is C₁-C₈ haloalkyl.

87. The method of claim 84, wherein R^a is –CF₃ or –CH₂CF₃.

88. The method of claim 70, having the formula:

IIIb) wherein Ar is an aromatic ring and X is selected from the group consisting of H, C₁-C₈ alkyl and phenyl.

89. The compound of claim 88, wherein each R^q is independently selected from the group consisting of H, halogen and C₁-C₈ alkyl.

90. The compound of claim 88, wherein L is selected from the group consisting of a bond and –CH₂-.

91. The compound of claim 88, wherein Ar is a benzene ring.

92. The compound of claim 88, wherein Ar is a benzene ring, m is 0, each R^q is H, and L is a bond.

93. The compound of claim 88, wherein Ar is a benzene ring, m is 0, each R^q is H, and L is –CH₂-.

94. The compound of claim 70, selected from the group consisting of: (a) (Z)-hexyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl)phenyl)methylenecarbamate (b) (Z)-hexyl amino-(4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (c) (Z)-hexyl amino-(4-((1-4-fluorophenyl-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (d) (Z)-hexyl amino-(4-((1-4-chlorophenyl-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (e) (Z)-hexyl amino-(4-((1-4-methoxyphenyl-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (f) (Z)-methyl amino-(4-((1-4-methoxyphenyl-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (g) (Z)-methyl amino(4-((1-4-chlorophenyl-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (h) (Z)-methyl amino-(4-((1-4-fluorophenyl-2,5-dimethyl-pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (i) (Z)-methyl amino-(4-((2,5-dimethyl-1-4-pyridylmethylpyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (j) (Z)-methyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate (k) (Z)-benzyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate (l) (Z)-benzyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate (m)(Z)-benzyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (n) (Z)- benzyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (o) (Z)-benzyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (p) (Z)-ethyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (q) (Z)-ethyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (r) (Z)-ethyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (s) (Z)-ethyl amino-(4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (t) (Z)-ethyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl) phenyl)methylenecarbamate (u) (Z)-propyl amino-(4-((1-(4-methoxyphenyl)-2,5-dimethyl-pyrrole-3-carbonylamino)methyl) phenyl)methylenecarbamate (v) (Z)-propyl amino-(4-((1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (w)(Z)-propyl amino-(4-((1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (x) (Z)-propyl amino-(4-((2,5-dimethyl-1-(4-pyridylmethyl)pyrrole-3- carbonylamino)methyl)phenyl)methylenecarbamate (y) (Z)-propyl amino-(4-((1-benzylpyrazole-4-carbonylamino)methyl)phenyl)methylenecarbamate.

95. The method of any one of claims 1 to 38, comprising administering to the subject an effective amount of a prodrug of Formula II, wherein the prodrug has the Formula IV

IV wherein the subscript m is an integer of from 0 to 5, the subscript n is an integer of from 0 to 4, the subscript q is an integer of from 0 to 1; L is a linking group selected from the group consisting of a bond, CH₂ and SO2; X is selected from the group consisting of H, C_1-8 alkyl and phenyl; each of R^b and R^c is independently selected from the group consisting of cycloalkyl, haloalkyl, halogen, -OH, -OR², -OSi(R²)3, -OC(O)O-R², - OC(O)R², -OC(O)NHR², -OC(O)N(R²)₂, -SH, -SR², -S(O)R², -S(O)₂R², -SO₂NH₂, -S(O)₂ NHR², -S(O)₂N(R²)₂, -NHS(O)₂R², -NR²S(O)₂R², -C(O)NH₂, -C(O)NHR², -C(O)N(R²)₂, -C(O)R², -C(O)H, - C(=S)R², -NHC(O)R², -NR²C(O)R², -NHC(O)NH₂, -NR²C(O)NH₂, -NR²C(O)NHR², -N HC(O)NHR², -NR²C(O)N(R²)2, -NHC(O)N(R²)2, -CO₂H, -CO₂R², -NHCO₂R², -NR²CO₂ R², -R², -CN, -NO2, -NH₂, -NHR², -N(R²)2, -NR²S(O)NH₂, -NR²S(O)₂NHR², - NH₂C(=NR²)NH₂, -N=C(NH₂)NH₂, -C(=NR²)NH₂, -NH-OH, -NR²-OH, -NR²-OR², - N=C=O, -N=C=S, -Si(R²)₃, -NH-NHR², -NHC(O)NHNH₂, NO, -N=C=NR² and -S-CN, wherein each R² is independently selected from alkyl and aryl; when q is 0, Z is a member selected from the group consisting of O, S and NR^d wherein R^d is H or C₁-C₈ alkyl; when q is 1, Z is N; or a pharmaceutically acceptable salt thereof.

96. The method of claim 95, having the formula:

.

97. The method of claim 96, wherein L is –CH₂-.

98. The method of claim 96, wherein L is –SO2-.

99. The method of claim 96, wherein m is 0.

100. The method of claim 96, wherein n is 0.

101. The method of claim 95, selected from the group consisting of: (a) methyl N-[4-[[(1-benzylindole-3-carbonyl)amino]methyl]benzene-carboximidoyl]carbamate; and (b) methyl N-[4-[[[1-(benzenesulfonyl)indole-3-carbonyl]amino]methyl]benzene- carboximidoyl]carbamate. (c) ethyl N-[4-[[(1-benzylindole-3-carbonyl)amino]methyl]benzene-carboximidoyl]carbamate; and (d) ethyl N-[4-[[[1-(benzenesulfonyl)indole-3-carbonyl]amino]methyl]benzene- carboximidoyl]carbamate.