Inhibitors of plasma kallikrein and uses thereof

Abstract

To provide compounds that inhibit the trypsin-like serine protease Plasma Kallikrein (pKal), and methods for using the compounds in the treatment of pKal-related diseases or disorders.SOLUTION: The present invention provides a compound of formula I, or its pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug. [A: substituted / unsubstituted heteroarylene, substituted / unsubstituted heterocyclylene. R1: N(RA)2 (RA: H, substituted / unsubstituted acyl, substituted / unsubstituted alkyl or the like). R2: substituted / unsubstituted aryl, substituted / unsubstituted aralkyl or the like. R3: substituted / unsubstituted alkyl, substituted / unsubstituted heteroalkyl or the like.]SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. USSN 62 / 541,403, filed August 4, 2017, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates generally to compounds that inhibit the trypsin-like serine protease plasma kallikrein (pKal), and their use in treating diseases or disorders associated with pKal (e.g., edema, such as hereditary angioedema). [Background technology]

[0003] Plasma kallikrein (pKal) is a circulating serine protease zymogen that is converted to its catalytically active form by coagulation factor XIIa and contributes to the innate inflammatory response and the intrinsic cascade of blood coagulation. In vivo, activation of this pathway occurs through interaction with polyphosphates released from activated platelets and the absence of C1 inhibitor (C1-INH), the major physiological inhibitor of pKal. pKal-mediated cleavage of high-molecular-weight kininogen yields bradykinin (BK), a potent vasodilator and proinflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent carboxypeptidase cleavage of BK yields des-Arg9-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of expression in the retina being detected in the ganglion cell layer and the inner and outer nuclear layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0004] pKal is also associated with hereditary angioedema (HAE), an autosomal dominant disorder characterized by painful, unpredictable, recurrent bouts of inflammation affecting many areas, including the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is unclear, with no known differences between ethnic groups and an estimated incidence of approximately 1 case per 50,000 people. HAE is caused by deficient (type I) or dysfunctional (type II) levels of C1-INH, bradykinin, and other circulating serine proteases that inhibit pKal. Individuals with hereditary angioedema (HAE) lack C1-INH and consequently experience excessive bradykinin production, leading to painful, debilitating, and potentially fatal bouts of swelling. If left untreated, HAE can result in a mortality rate as high as 40%, primarily due to upper airway obstruction. Summary of the Invention

[0005] The present disclosure is based, at least in part, on the development of a number of small molecule compounds that bind to and effectively inhibit the activity of plasma kallikrein. Accordingly, provided herein are pKal inhibitory compounds and uses thereof for targeting pKal and / or treating pKal-mediated diseases and disorders.

[0006] In one aspect, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, A is a substituted or unsubstituted heteroarylene or a substituted or unsubstituted heterocyclylene; R 1 is -N(R A )2; R 2is a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, -OR A , or -N(R A )2; R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-; Each R A occurrences of are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two R A groups are joined to form a substituted or unsubstituted heterocycle).

[0007] In certain embodiments, compounds of Formula I include compounds of Formula Ia, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, X is N or CR y and; Y is O, S, or NR x and; R x and R y are independently hydrogen or substituted or unsubstituted alkyl).

[0008] In certain embodiments, the compound of Formula I includes the compound of formula Ib, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0009] In certain embodiments, the compound of Formula I includes a compound of formula Ic, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0010] In certain embodiments, compounds of Formula I include compounds of Formula Id, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R wis hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl).

[0011] Exemplary compounds of Formula I include, but are not limited to, the following: 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (1); 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (2); 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (5); 2-((2R,4S)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (6); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (11); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (12); 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (13); 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (14); 2-((2S,4R)-4-amino-1-benzoylpyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (15); 3-Chlorobenzyl (2S,4R)-4-amino-2-(4-(((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)carbamoyl)thiazol-2-yl)pyrrolidine-1-carboxylate (16); 2-((2S,4R)-4-amino-1-(cyclohexanecarbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (17); 2-((2S,4R)-4-amino-1-isobutyrylpyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (18); 2-((2S,4R)-4-amino-1-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (19); 2-((2S,4R)-4-amino-1-(6-methoxyimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (20); 2-((2S,4R)-4-amino-1-(6-iodoimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (21); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-amino-6-guanidino-1-oxohexan-2-yl)thiazole-4-carboxamide (22); N 2 -(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carbonyl)-N6-carbamimidoyl-L-lysine (23); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-(dimethylamino)-6-guanidino-1-oxohexan-2-yl)thiazole-4-carboxamide (24); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-amino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (25); N-((S)-6-acetamido-1-(methylamino)-1-oxohexan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (26); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-(methylamino)-1-oxo-6-ureidohexan-2-yl)thiazole-4-carboxamide (27); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-5-guanidino-1-(methylamino)-1-oxopentan-2-yl)thiazole-4-carboxamide (28); (S)-2-(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide)-N1-methylpentanediamide (29); N-((S)-3-(1H-imidazol-4-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (30); N-((S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (31); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)thiazole-4-carboxamide (32); 2-((2S,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (35); 2-((2S,4S)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (36); 2-((2S,4R)-1-(2-naphthoyl)-4-aminopyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (40); 2-((2S,4R)-4-amino-1-(3-chloroquinoline-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (41); 2-((2S,4R)-4-amino-1-(6-chloroquinoline-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (42); 2-((2S,4R)-4-amino-1-(3-chlorobenzo[b]thiophene-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (43); 2-((2S,4R)-4-amino-1-(5-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (44); 2-((2S,4R)-4-amino-1-(5-chlorobenzo[d]thiazole-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (45); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(5-guanidinopentyl)thiazole-4-carboxamide (46); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-carbamimidoylbenzyl)thiazole-4-carboxamide (47); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)thiazole-4-carboxamide (48); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((1-aminoisoquinolin-6-yl)methyl)thiazole-4-carboxamide (49); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-(aminomethyl)benzyl)thiazole-4-carboxamide (50); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-carbamimidoylphenethyl)thiazole-4-carboxamide (51); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(2-(6-amino-2,4-dimethylpyridin-3-yl)ethyl)thiazole-4-carboxamide (52); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(2-(1-aminoisoquinolin-6-yl)ethyl)thiazole-4-carboxamide (53); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-(aminomethyl)phenethyl)thiazole-4-carboxamide (54); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)thiazole-4-carboxamide (55); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((6-chloronaphthalen-2-yl)methyl)thiazole-4-carboxamide (56); 2-((2S,4R)-4-amino-1-(5-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (57); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((5-chloro-1H-indazol-3-yl)methyl)thiazole-4-carboxamide (58); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((6-chloro-1H-indazol-3-yl)methyl)thiazole-4-carboxamide (59); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)thiazole-4-carboxamide (60); 2-((2S,4R)-4-amino-1-(5,6-dichlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (61); 2-((2S,4R)-4-amino-1-(6-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (62); 2-((2S,4R)-4-amino-1-(4-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (63); 2-((2S,4R)-4-amino-1-(5-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (64); 2-((2S,4R)-4-amino-1-(6-methylbenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (65); 2-((2S,4R)-4-amino-1-(6-chloroquinoline-3-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (66); 2-((2S,4R)-4-amino-1-(2-chloroquinoline-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (67); and pharmaceutically acceptable salts thereof.

[0012] In another aspect, there is provided a pharmaceutical composition comprising any of the compounds of Formula I described herein or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0013] In another aspect, a method of inhibiting the activity of pKal is provided, comprising contacting pKal with a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the pKal is in a cell (e.g., a human cell).

[0014] In another aspect, a method of treating a pKal-mediated disease or condition in a subject (e.g., a human patient) in need thereof is provided, comprising administering to the subject a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the pKal-mediated disease or condition is edema. In one example, the edema is hereditary angioedema. In certain embodiments, the pKal-mediated disease or condition is an ocular disease. In some examples, the ocular disease is DME, age-related macular degeneration (AMD), including wet AMD and dry AMD, or diabetic retinopathy. In certain embodiments, the pKal-mediated disease or condition is ischemia-reperfusion injury, which may be associated with a surgical procedure.

[0015] In another aspect, a kit is provided that includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In certain embodiments, the kit further includes instructions for administration (e.g., human administration).

[0016] Also within the scope of this disclosure are pharmaceutical compositions comprising any of the compounds of formula I described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use in treating pKal-mediated diseases (e.g., edema such as HAE), and the use of any of the compounds of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating any of the diseases of interest.

[0017] Details of certain embodiments of the invention are set forth in the Detailed Description of Specific Embodiments set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition Chemical Definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined as follows: thThe elements are identified according to the Periodic Table of the Elements (CAS system) on the back cover of this book, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry and specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0019] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Furthermore, the present invention encompasses compounds as individual isomers substantially free of other isomers or, alternatively, as mixtures of various isomers.

[0020] In the formula: [ka] is a single bond when the stereochemistry of the moiety directly attached to it is unspecified, [ka] is absent or a single bond, [ka] is a single or double bond.

[0021] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, replacement of a hydrogen by deuterium or tritium; 19 F 18 Replace with F, or 12 C 13 C or 14 Compounds having the present structures except for the replacement with C are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0022] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include alkyl.

[0023] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0024] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl (substituted C 1-6 alkyl, for example, -CF3, Bn, etc.

[0025] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0026] The term "hydroxyalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by hydroxyl. In some embodiments, the hydroxyalkyl moiety has 1 to 8 carbon atoms ("C 1-8In some embodiments, the hydroxyalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the hydroxyalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the hydroxyalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the hydroxyalkyl moiety has 1 to 2 carbon atoms ("C 1-2 hydroxyalkyl).

[0027] The term "alkoxy," as defined herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1-2 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0028] The term "haloalkoxy," as defined herein, represents a haloalkyl group attached to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C 1-4In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1-2 Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0029] The term "alkoxyalkyl," as defined herein, is a substituted alkyl group in which one or more hydrogen atoms are independently replaced by an alkoxy group. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms (“C 1-6 In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms (“C 1-4 In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C 1-2 alkoxyalkyl").

[0030] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-20 In some embodiments, heteroalkyl groups are saturated groups having 1 to 18 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-18In some embodiments, heteroalkyl groups are saturated groups having 1 to 16 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-16 In some embodiments, heteroalkyl groups are saturated groups having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-14 In some embodiments, heteroalkyl groups are saturated groups having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, heteroalkyl groups are saturated groups having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, heteroalkyl groups are saturated groups having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and one heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and one heteroatom in the parent chain ("heteroC 1-2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC alkyl"). In some embodiments, heteroalkyl groups, as defined herein, are partially unsaturated groups having one or more heteroatoms in the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group can include an amide or ester functionality in its parent chain, such that one or more carbon atoms is an unsaturated carbonyl group. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 It is alkyl.

[0031] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., the double bond in 2-butenyl) or terminal (e.g., the double bond in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 Alkenyl. In the alkenyl group, the C=C double bond has no specific stereochemistry. [ka] can be an (E)- or (Z)-double bond.

[0032] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms in the parent chain, at least one double bond, and one or more heteroatoms ("heteroalkenyl").2-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms in the parent chain, at least one double bond, and one or more heteroatoms ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms in the parent chain, at least one double bond, and one or more heteroatoms ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms in the parent chain, at least one double bond, and one or more heteroatoms ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms in the parent chain, at least one double bond, and one or more heteroatoms ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms in the parent chain, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms in the parent chain, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms in the parent chain, at least one double bond, and one heteroatom ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms in the parent chain, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, a heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0033] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., the triple bond in 2-butynyl) or terminal (e.g., the triple bond in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkynyl groups include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0034] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms in the parent chain, at least one triple bond, and one or more heteroatoms ("heteroalkynyl"). 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms in the parent chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms in the parent chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms in the parent chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms in the parent chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms in the parent chain, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms in the parent chain, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms in the parent chain, at least one triple bond, and one heteroatom ("heteroC 2-3In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms in the parent chain, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0035] The term "carbocyclyl" or "carbocyclic" refers to the radical of a non-aromatic ring hydrocarbon group having 3 to 14 ring carbon atoms and 0 heteroatoms in the non-aromatic ring system ("C 3-14 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including fused, bridged, or spiro ring systems, such as, for example, a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and may be saturated or have one or more double or triple bonds between carbons. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is at the carbocyclyl ring; in such instances, the number of carbons still designates the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-14In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0036] In some embodiments, a "carbocyclyl" is a saturated monocyclic carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0037] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system (a "bicyclic heterocyclyl") or a tricyclic system (a "tricyclic heterocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. A heterocyclyl polycyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is at the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is at the heterocyclyl ring; in such instances, the number of ring members still designates the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0038] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0039] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazomethane, 1H-benzo[e][1,4]dihydrobenzoyl ... Zepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0040] The term "aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring arrangement) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). Aryl also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such instances, the number of carbon atoms still designates the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0041] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, with the point of attachment on the alkyl portion.

[0042] The term "heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared among the ring arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared among the ring arrangement) ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valence allows. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is at the heteroaryl ring; in such instances, the number of ring members still designates the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such instances, the number of ring members designates the number of ring members of the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0043] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0044] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0045] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0046] The term "unsaturated bond" refers to a double or triple bond.

[0047] The terms "unsaturated" or "partially unsaturated" refer to a moiety that includes at least one double or triple bond.

[0048] The term "saturated" refers to a moiety that does not contain any double or triple bonds, ie, the moiety contains only single bonds.

[0049] The addition of the suffix "-ene" to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0050] Unless otherwise expressly provided, groups may be optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present in a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any substituent described herein that results in the formation of a stable compound. The present invention contemplates all such combinations that result in a stable compound.For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein which satisfy the valences of the heteroatoms and result in the formation of a stable moiety. The present invention is not intended to be limited in any way by the exemplary substituents described herein.

[0051] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )3, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2Raa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(Rcc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X groups; - is the counterion; Or two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced with; R aa Each instance of 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aagroups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bbgroups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with X groups; - is the counterion; R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff)2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may combine to form =O or =S; X - is the counterion; R ee Each instance of 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ffgroups join to form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(=NH)NH(C 1-6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2(C 1-6 alkyl), -SO2O(C 1-6 alkyl), -OSO2(C 1-6 alkyl), -SO(C 1-6 alkyl), -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal Rgg The substituents may combine to form =O or =S; X - is the counterion.

[0052] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0053] The term "hydroxyl" or "hydroxy" refers to the group -OH. By extension, the term "substituted hydroxyl" or "substituted hydroxyl" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb )2) a group selected from 2 (wherein X - , R aa , R bb , and R cc is as defined herein).

[0054] The term "amino" refers to the group -NH. By extension, the term "substituted amino" refers to mono-, di-, or tri-substituted amino. In certain embodiments, "substituted amino" is a mono- or di-substituted amino group.

[0055] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, such as -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb )2) a group selected from 2 (wherein R aa , R bb , and R cc is as defined herein, and the group —NH(R bb )R bb is not hydrogen).

[0056] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2) a group selected from 2 (wherein Raa , R bb , and R cc is as defined herein, except that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0057] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - A group selected from the group bb and X - is as defined herein).

[0058] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa A group selected from the group aa and R bb is as defined herein).

[0059] The term "sulfinyl" refers to the group -S(=O)R aa (R in the formula aa is as defined herein).

[0060] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1)N(R X1 )2, wherein R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or diarylamino, or mono- or di-heteroarylamino; or two R X1The groups together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

[0061] The term "carbonyl" refers to a group in which the carbon directly attached to the parent molecule is sp 2 are mixed (sp 2 hybridized), oxygen, nitrogen, or sulfur substituted groups, such as ketones (e.g., -C(=O)R aa ), carboxylic acids (e.g., -COH), aldehydes (-CHO), esters (e.g., -COR aa , -C(=O)SR aa , -C(=S)SR aa ), amides (e.g., -C(=O)N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2), and imines (e.g., -C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NRbb )N(R bb )2)(R in the formula aa and R bb represents a group selected from:

[0062] The term "oxo" refers to the group =O and the term "thioxo" refers to the group =S.

[0063] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl, or two R cc groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc , and R dd is as defined herein.

[0064] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0065] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0066] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa), including, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethyl-2-(2-methyl-2-phenylpropanol), 2-trimethyl-2-(2-methyl ... Methylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t- Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate , alkyl dithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-( Trifluoromethyl-6-chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl Methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate , p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,Examples include 6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0067] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ), including, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide amide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0068] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1 ,1,4,4-Tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pi Pyroolin-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1 ,1-Dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0069] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa, -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2(wherein, X - , R aa , R bb , and R cc (wherein 1 is as defined herein). Oxygen protecting groups are well known in the art and are described in "Protecting Groups in Organic Synthesis," by T.W. Greene and P.G.M. Wuts, 30th ed., incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0070] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl, methyl ... Dimethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]phenanthroline [Nyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxyethyl, ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-( Imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), di Methylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxy acetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-napthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,Examples of oxygen protecting groups include 4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (E E), 2-methyl(methy)oxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0071] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa)3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb ) 2) 2 (wherein R aa , R bb , and R cc (wherein s is as defined herein). Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0072] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged ion to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., containing one formal negative charge). Anionic counterions can also be multivalent (i.e., containing more than one formal negative charge), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 -ions of sulfonates (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), ions of carboxylates (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions that may be multivalent include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0073] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. See, for example, Smith, March's Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. Optionally, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). Optionally, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. Optionally, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. Alternatively, the leaving group can be a phosphine oxide (e.g., the phosphine oxide formed during the Mitsunobu reaction), or an internal leaving group such as an epoxide or cyclic sulfate. Non-limiting examples of other leaving groups include water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa, -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2(R in the formula aa , R bb , and R cc is as defined herein).

[0074] As used herein, the use of the phrase "at least one example" refers not only to 1, 2, 3, 4, or more examples, but also to a range, for example, 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 examples.

[0075] A "non-hydrogen group" refers to any group defined by a particular variable that is not hydrogen.

[0076] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is in no way intended to be limited by the above recitation of exemplary substituents.

[0077] Other definitions The following definitions are of more general terms used throughout this disclosure.

[0078] As used herein, the term "salt" refers to any salt and includes pharmaceutically acceptable salts.

[0079] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Alkyl)4 - Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and cations of amines formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0080] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, usually by solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric and non-stoichiometric solvates. In certain instances, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0081] The term "hydrate" refers to a compound that is combined with water. Generally, the number of water molecules contained in a hydrate of a compound is in a defined ratio to the number of molecules of the compound in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), lower order hydrates (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0082] The terms "tautomer" or "tautomeric" refer to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa) and at least one change in valence. The exact ratio of these tautomers varies depending on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction providing a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0083] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0084] Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, e.g., is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of the asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by means of the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0085] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystal ratio, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0086] The term "prodrug" refers to a compound having a cleavable group that, upon solvolysis or under physiological conditions, becomes a compound described herein that is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Derivatives of other compounds described herein are active in both their acid and acid-derivative forms, but often offer advantages in mammalian organisms, such as solubility, tissue compatibility, or delayed release, in the acid-labile form (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting a substituted or unsubstituted amine with the parent acid compound, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from pendant acidic groups on the compounds described herein are specific prodrugs. In some cases, it may be desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, aryl, C 7-12 Substituted aryl, and C 7-12 Esters of arylalkyl may be preferred.

[0087] The terms "composition" and "formulation" are used interchangeably.

[0088] A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly)) or a non-human animal. In certain embodiments, the non-human animal is a mammal, e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird, e.g., a chicken, duck, goose, or turkey). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0089] The term "biological sample" refers to any sample, including tissue samples (e.g., tissue portions and tissue needle biopsies); cell samples (e.g., cell smears (e.g., pap or blood smears), or cell samples obtained by microdissection); whole organism samples (e.g., yeast or bacterial samples); or cell fractions, fragments, or organelles (e.g., samples obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by open biopsy or needle biopsy), nipple fluid, breast milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any substance containing biomolecules derived from a first biological sample.

[0090] The term "target tissue" refers to any biological tissue (including a group of cells, a body part, or an organ) or portion thereof of a subject to which the compounds, particles, and / or compositions of the present invention are delivered, including blood and / or lymph. A target tissue can be an abnormal or unhealthy tissue that may need to be treated. A target tissue can also be a normal or healthy tissue that is at higher than normal risk of developing an abnormal or unhealthy condition that may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A "non-target tissue" refers to any biological tissue (including a group of cells, a body part, or an organ) or portion thereof of a subject that is not a target tissue, including blood and / or lymph.

[0091] The terms "administer," "administering," or "administration" refer to the implantation, absorption, ingestion, injection, inhalation, or other introduction of a compound described herein or a composition thereof into or onto a subject.

[0092] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered when no signs or symptoms of a disease are present. For example, treatment may be administered to a suspected subject prior to the onset of symptoms (e.g., in light of the history of symptoms). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0093] The terms "condition," "disease," and "disorder" are used interchangeably.

[0094] An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound described herein in a single administration. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple administrations.

[0095] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for pKal inhibition. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating edema (e.g., HAE or DME). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting pKal and treating edema (e.g., HAE or DME).

[0096] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a disease state or one or more signs or symptoms associated with a disease state, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease state. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for pKal inhibition. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating edema (e.g., HAE). In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting pKal and treating edema (e.g., HAE).

[0097] As used herein, the term "inhibit" or "inhibition" in reference to an enzyme, e.g., in the context of pKal, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction in the level of enzyme activity, e.g., pKal activity, to a level that is statistically significantly lower than an initial level, which may be, e.g., a baseline level of enzyme activity. In some embodiments, the term refers to a reduction in the level of enzyme activity, e.g., pKal activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the initial level, which may be, e.g., a baseline level of enzyme activity.

[0098] The terms "biologic," "biological agent," and "biological product" refer to a wide range of products, including vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biological materials may include carbohydrates, proteins, or nucleic acids, or complex combinations of these materials, or may be living entities such as cells and tissues. Biological materials may be isolated from a variety of natural sources (e.g., humans, animals, microorganisms) or may be produced by biotechnological and other techniques.

[0099] The terms "small molecule" or "small molecule therapeutic" refer to molecules having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., via chemical synthesis). Small molecules are typically organic compounds (i.e., contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocycles, etc.). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges are also possible (e.g., at least about 200 g / mol and up to about 500 g / mol). In certain embodiments, the small molecule is a therapeutically active agent, such as a pharmaceutical (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this example, the small molecule is also referred to as an "organometallic small molecule." Preferred small molecules are biologically active in that they produce a biological effect in an animal, preferably a mammal, and more preferably a human. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a pharmaceutical. Preferably, but not necessarily, the pharmaceutical is one that has already been deemed safe and effective for use in humans or animals by the appropriate government agency or regulatory body.For example, drugs approved for human use are listed by the FDA at 21 CFR §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference; drugs for veterinary use are listed by the FDA at 21 CFR §§ 500-589, which are incorporated herein by reference. All of the listed drugs are considered acceptable for use in accordance with the present invention.

[0100] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, usually useful effect. For example, a therapeutic agent may treat, alleviate, and / or prevent a disease. As disclosed herein, a therapeutic agent may be a biological or small molecule therapeutic.

[0101] Detailed Description of Specific Embodiments Several biological therapies have been developed to acutely and prophylactically treat plasma kallikrein-associated inflammation, including C1 esterase inhibitor replacements (human and recombinant), peptide and antibody inhibitors of pKal, and bradykinin antagonists. However, an orally bioavailable small molecule inhibitor of pKal has not yet been achieved. The present disclosure stems from the recognition that targeting pKal activity via small molecule therapy provides novel compounds, compositions, and methods useful for inhibiting pKal and the role of pKal in excessive bradykinin production, and thereby treating associated diseases (e.g., edema such as HAE or DME).

[0102] Provided herein are inhibitors of plasma kallikrein, such as inhibitors of the active form of plasma kallikrein. In one aspect, the present disclosure provides compounds of Formula I, as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. These compounds are useful for inhibiting the activity of pKal in a subject, and are therefore useful for treating diseases mediated by pKal, such as edema.

[0103] compound The compounds described herein interact with pKal. As described herein, the therapeutic effect may be the result of the inhibition, modulation, binding, and / or modification of pKal by the compounds described herein. In certain embodiments, the compounds inhibit, modulate, and / or modify pKal by binding to the active site of pKal. The compounds may be provided in any of the compositions, kits, or methods described herein as their pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0104] Provided are compounds of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, A is a substituted or unsubstituted heteroarylene or a substituted or unsubstituted heterocyclylene; R 1 is -N(R A )2; R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, -OR A , or -N(R A )2; R 3is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-; R A each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A The groups are joined to form a substituted or unsubstituted heterocycle.

[0105] A group In certain embodiments, A is a substituted or unsubstituted heteroarylene or a substituted or unsubstituted heterocyclylene. In certain embodiments, A is a substituted or unsubstituted heteroarylene. In certain embodiments, A is a substituted or unsubstituted 5- to 6-membered heteroarylene. In certain embodiments, A is an unsubstituted 5- to 6-membered heteroarylene. In certain embodiments, A is a substituted or unsubstituted 6-membered heteroarylene. In certain embodiments, A is an unsubstituted 6-membered heteroarylene. In certain embodiments, A is a substituted or unsubstituted 5-membered heteroarylene. In certain embodiments, A is an unsubstituted 5-membered heteroarylene.

[0106] In certain embodiments, A is a substituted or unsubstituted 3- to 14-membered heterocyclylene. In certain embodiments, A is a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclylene. In certain embodiments, A is a substituted or unsubstituted 6- to 14-membered bicyclic heterocyclylene. In certain embodiments, A is a substituted or unsubstituted 6- to 14-membered tricyclic heterocyclylene. In certain embodiments, A is a substituted or unsubstituted 5- to 10-membered heterocyclylene containing 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, A is a substituted or unsubstituted 5- to 8-membered heterocyclylene containing 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, A is a substituted or unsubstituted 5-6-membered heterocyclylene containing 1-4 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5-6-membered heterocyclylene containing 1-3 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5-6-membered heterocyclylene containing 1-2 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5-6-membered heterocyclylene containing one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0107] In certain embodiments, A is a substituted or unsubstituted aziridinylene, oxiranylene, thiiranylene, azetidinylene, oxetanylene, thietanylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothiophenylene, dihydrothiophenylene, pyrrolidinylene, dihydropyrrolylene, pyrrolylene-2,5-dione, dioxolanylene, oxathiolanylene, dithiolanylene, triazolinylene, oxadiazolinylene, thiazole, thiazole, thiazole-2,5-dione ... Thiadiazolinylene, piperidinylene, tetrahydropyranylene, dihydropyridinylene, thianylene, piperazinylene, morpholinylene, dithianylene, dioxanylene, triazinylene, azepanylene, oxepanylene, thiepanylene, azocanylene, oxecanylene, thiocanylene, indolinylene, isoindolinylene, dihydrobenzofuranylene, dihydrobenzothienylene, tetrahydrobenzothienylene, tetrahydrobenzofuranylene , tetrahydroindolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, decahydroquinolinylene, decahydroisoquinolinylene, octahydrochromenylene, octahydroisochromenylene, decahydronaphthyridinylene, decahydro-1,8-naphthyridinylene, octahydropyrrolo[3,2-b]pyrrole, indolinylene, phthalimidylene, naphthalimidylene, chromanylene, chromenylene, 1H-benzo[e][1,4]diazepinylene, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolylene, 5,6 -dihydro-4H-furo[3,2-b]pyrrolylene, 6,7-dihydro-5H-furo-[3,2-b]pyranylene, 5,7-dihydro-4H-thieno[2,3-c]pyranylene, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinylene, 2,3-dihydrofuro[2,3-b]pyridinylene, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinylene, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinylene, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinylene, or 1,2,3,4-tetrahydro-1,6-naphthyridinylene.

[0108] In certain embodiments, A is a substituted or unsubstituted 5- to 14-membered heteroarylene. In certain embodiments, A is a substituted or unsubstituted 5- to 8-membered monocyclic heteroarylene. In certain embodiments, A is a substituted or unsubstituted 8- to 14-membered bicyclic heteroarylene (e.g., a fused bicyclic heteroarylene). In certain embodiments, A is a substituted or unsubstituted 10- to 14-membered tricyclic heteroarylene (e.g., a fused tricyclic heteroarylene). In certain embodiments, A is a substituted or unsubstituted 5- to 10-membered heteroarylene containing 1-4 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5- to 8-membered heteroarylene containing 1-4 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5- or 6-membered heteroarylene containing 1 to 4 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5-membered heteroarylene containing 1 to 4 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5- or 6-membered heteroarylene containing 1 to 3 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5-membered heteroarylene containing 1 to 3 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5- or 6-membered heteroarylene containing 1 to 2 ring heteroatoms (each heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, A is a substituted or unsubstituted 5-membered heteroarylene containing 1 to 2 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.In certain embodiments, A is a substituted or unsubstituted 5- to 6-membered heteroarylene containing one ring heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, A is a substituted or unsubstituted 5-membered heteroarylene containing one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0109] In certain embodiments, A is selected from the group consisting of substituted and unsubstituted pyrrolylene, furanylene, thiophenylene, imidazolylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, triazolylene, oxadiazolylene, thiadiazolylene, tetrazolylene, pyridinylene, pyridazinylene, pyrimidinylene, pyrazinylene, triazinylene, tetrazinylene, azepinylene, oxepinylene, thiepinylene, indolylene, isoindolylene, indazolylene, benzyl, benzo ... and benzotriazolylene, benzothiophenylene, isobenzothiophenylene, benzofuranylene, benzisofuranylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzoxadiazolylene, benzothiazolylene, benzisothiazolylene, benzothiadiazolylene, imidazopyridinylene, indolizinylene, prinylene, naphthyridinylene, pteridinylene, quinolinylene, isoquinolinylene, cinnolinylene, quinoxalinylene, phthalazinylene, quinazolinylene, phenanthridinylene, dibenzofuranylene, carbazolylene, acridinylene, phenothiazinylene, phenoxazinylene, or phenazinylene.

[0110] In certain embodiments, A has the formula: [ka] (In the formula, X is N or CR y and Y is O, S, or NR x and; R x and R y are independently hydrogen or substituted or unsubstituted alkyl. is.

[0111] In certain embodiments, A has the formula: [ka] (In the formula, X is CR y and; Y is O, S, or NR x and; R x and R y are independently hydrogen or substituted or unsubstituted alkyl. is.

[0112] In certain embodiments, A has the formula: [ka] (In the formula, X is N; Y is O, S, or NR x and; R x is hydrogen or substituted or unsubstituted alkyl) is.

[0113] In certain embodiments, A has the formula: [ka] (In the formula, X is N; Y is O or S) is.

[0114] In certain embodiments, A has the formula: [ka] (In the formula, X is N; Y is S) is.

[0115] In certain embodiments, A has the formula: [ka] is.

[0116] In certain embodiments, A has the formula: [ka] is.

[0117] In certain embodiments, A has the formula: [ka] is.

[0118] In certain embodiments, A has the formula: [ka] is.

[0119] R 1 base In certain embodiments, R 1 is -N(R A )2.

[0120] In certain embodiments, R 1 is -N(R A )2 and R A each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two RA The groups are joined to form a substituted or unsubstituted heterocycle. In certain embodiments, R 1 -NHR A and R A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.

[0121] In certain embodiments, R 1 is -N(R A )2 and R A Each occurrence of R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group. 1 -NHR A and R A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group.

[0122] In certain embodiments, R 1 is -N(R A )2 and R A is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, R 1 -NHR A and R A is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

[0123] In certain embodiments, R 1 is -N(R A )2 and R AEach occurrence of is independently hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted alkyl. In certain embodiments, R 1 -NHR A and R A is hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted alkyl.

[0124] In certain embodiments, R 1 is -N(R A )2 and R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 1 -NHR A and R A is hydrogen or substituted or unsubstituted alkyl.

[0125] In certain embodiments, R 1 is -N(R A )2 and R A Each occurrence of is independently substituted or unsubstituted alkyl. In certain embodiments, R 1 is -N(R A )2 and R A Each occurrence of is independently an unsubstituted alkyl.

[0126] In certain embodiments, R 1 is -NH2.

[0127] R 2 base In certain embodiments, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, -OR A, or -N(R A )2.

[0128] In certain embodiments, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2. In certain embodiments, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2 and R A each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two R A The groups are joined to form a substituted or unsubstituted heterocyclic ring.

[0129] In certain embodiments, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, or -OR A and;R A is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or an oxygen protecting group. 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or -OR Aand R A is a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaralkyl, or an oxygen protecting group.

[0130] In certain embodiments, R 2 is substituted or unsubstituted aryl. In certain embodiments, R 2 is a substituted or unsubstituted 6-14 membered aryl. In certain embodiments, R 2 is a substituted or unsubstituted monocyclic aryl. In certain embodiments, R 2 is a substituted or unsubstituted bicyclic aryl. In certain embodiments, R 2 is a substituted or unsubstituted tricyclic aryl. In certain embodiments, R 2 is a substituted or unsubstituted phenyl, naphthyl, or anthracenyl. In certain embodiments, R 2 is substituted or unsubstituted phenyl. In certain embodiments, R 2 is substituted phenyl. In certain embodiments, R 2 is unsubstituted phenyl. In certain embodiments, R 2 is substituted or unsubstituted naphthyl. In certain embodiments, R 2 is substituted naphthyl. In certain embodiments, R 2 is unsubstituted naphthyl. In certain embodiments, R 2 is substituted or unsubstituted anthracenyl. In certain embodiments, R 2 is substituted anthracenyl. In certain embodiments, R 2 is unsubstituted anthracenyl.

[0131] In certain embodiments, R 2 is a substituted or unsubstituted heteroaryl. In certain embodiments, R 2is a substituted or unsubstituted 5-14 membered heteroaryl. In certain embodiments, R 2 is a substituted or unsubstituted 5-8 membered monocyclic heteroaryl. In certain embodiments, R 2 is a substituted or unsubstituted 8-14 membered bicyclic heteroaryl (e.g., a fused bicyclic heteroaryl). In certain embodiments, R 2 is a substituted or unsubstituted 10-14 membered tricyclic heteroaryl (e.g., a fused tricyclic heteroaryl). In certain embodiments, R 2 is a substituted or unsubstituted 8-14 membered bicyclic heteroaryl containing 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 8-10 membered bicyclic heteroaryl containing 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted fused 8-10 membered bicyclic heteroaryl containing 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 8-10 membered fused bicyclic heteroaryl containing 1-3 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 8-10 membered fused bicyclic heteroaryl containing 1-2 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur.

[0132] In certain embodiments, R 2is a substituted or unsubstituted pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl , benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, imidazopyridinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, or phenazinyl.

[0133] In certain embodiments, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl. In certain embodiments, R 2 is a substituted or unsubstituted imidazopyridinyl, quinolinyl, benzothiophenyl, or benzothiazolyl. 2 is a substituted imidazopyridinyl, quinolinyl, benzothiophenyl, or benzothiazolyl. 2 is a substituted imidazopyridinyl.

[0134] In certain embodiments, R 2 is the expression: [ka] (In the formula, R wis hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl) is.

[0135] In certain embodiments, R 2 is the expression: [ka] (In the formula, R w is halogen, alkoxy, or haloalkyl) is.

[0136] In certain embodiments, R 2 is the expression: [ka] (In the formula, R w is halogen or haloalkyl) is.

[0137] In certain embodiments, R 2 is the expression: [ka] is.

[0138] In certain embodiments, R 2 is the expression: [ka] is.

[0139] In certain embodiments, R 2 is the expression: [ka] is.

[0140] In certain embodiments, R 2 is the expression: [ka] is.

[0141] In certain embodiments, R 2 is the expression: [ka] is.

[0142] In certain embodiments, R 2 is the expression: [ka] is.

[0143] R 3 base In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A In certain embodiments, R 3is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-, R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0144] In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A)-, -S-, -S(O)-, or -S(O)2-, R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0145] In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0146] In certain embodiments, R 3 is a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0147] In certain embodiments, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0148] In certain embodiments, R 3 is a substituted or unsubstituted alkyl, and as valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is a substituted or unsubstituted alkyl, and as valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R AEach occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0149] In certain embodiments, R 3 is a substituted or unsubstituted heteroalkyl, and where valences allow, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is a substituted or unsubstituted heteroalkyl, and where valences allow, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0150] In certain embodiments, R 3 is a substituted or unsubstituted aralkyl, and as valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is a substituted or unsubstituted aralkyl, and as valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0151] In certain embodiments, R 3 is a substituted or unsubstituted heteroaralkyl, and as valences permit, R 3Any carbon atom in the A -, -C(O)-, or -C(=NR A In certain embodiments, R 3 is a substituted or unsubstituted heteroaralkyl, and as valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced with R A Each occurrence of is independently hydrogen or substituted or unsubstituted alkyl.

[0152] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; and, where valences permit, R c Any carbon in A -, -C(O)-, or -C(=NR A )- may be replaced with R d is hydrogen, substituted or unsubstituted alkyl, -C(O)N(R A )2, or -C(O)OR A and; R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0153] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R d is hydrogen, -C(O)N(R A )2, or -C(O)OR A and; R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0154] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0155] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0156] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon in A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0157] In certain embodiments, R 3 is the expression: [ka] (In the formula, R cis substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0158] In certain embodiments, R 3 is the expression: [ka] and (In the formula, R c is a substituted or unsubstituted alkyl, and as valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0159] In certain embodiments, R 3 is the expression: [ka] (In the formula, R cis substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0160] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is a substituted or unsubstituted alkyl, and as valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0161] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R cAny carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0162] In certain embodiments, R 3 is the expression: [ka] (In the formula, R c is a substituted or unsubstituted alkyl, and as valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl) is.

[0163] In certain embodiments, R 3 is the expression: [ka] is.

[0164] In certain embodiments, R 3 is the expression: [ka] is.

[0165] In certain embodiments, R 3 is the expression: [ka] is.

[0166] In certain embodiments, R 3 is the expression: [ka] is.

[0167] In certain embodiments, R 3 is the expression: [ka] is.

[0168] In certain embodiments, R 3 is the expression: [ka] is.

[0169] R A base In certain embodiments, R A are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two R A The groups are joined to form a substituted or unsubstituted heterocycle. In certain embodiments, R A are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom. A are independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, R Aare independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, R A are independently hydrogen or substituted or unsubstituted C 1-6 In certain embodiments, R A are independently hydrogen or unsubstituted C 1-6 In certain embodiments, R A are independently hydrogen or unsubstituted C 1-4 In certain embodiments, R A are independently hydrogen or unsubstituted C 1-2 In certain embodiments, R A is hydrogen. In certain embodiments, R A is an unsubstituted C 1-2 It is alkyl.

[0170] Formula I Embodiments In certain embodiments, the compound of Formula I is a compound of Formula Ia, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, X is N or CR y and Y is O, S, or NR x and R x and R y are independently hydrogen or substituted or unsubstituted alkyl).

[0171] In certain embodiments of Formula Ia, X is N and Y is O, S, or NR x is.

[0172] In certain embodiments of formula Ia, Y is O or S.

[0173] In certain embodiments of formula Ia, X is N and Y is O or S.

[0174] In certain embodiments of Formula Ia, Y is S.

[0175] In certain embodiments of Formula Ia, X is N and Y is S.

[0176] In certain embodiments of Formula Ia, R A Each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom. In certain embodiments of Formula Ia, R A Each occurrence of is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

[0177] In certain embodiments of Formula Ia, R 1 is -NH2.

[0178] In certain embodiments of Formula Ia, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0179] In certain embodiments of Formula Ia, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0180] In certain embodiments of Formula Ia, R 2 is a substituted or unsubstituted heteroaryl.

[0181] In certain embodiments of Formula Ia, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl.

[0182] In certain embodiments of Formula Ia, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-.

[0183] In certain embodiments of Formula Ia, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0184] In certain embodiments of Formula Ia, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0185] In certain embodiments, the compound of Formula Ia is a compound of Formula Ia-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0186] In certain embodiments, the compound of Formula I is a compound of Formula Ib, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0187] In certain embodiments of Formula Ib, R A Each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom. In certain embodiments of Formula Ib, R A Each occurrence of is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

[0188] In certain embodiments of Formula Ib, R 1 is -NH2.

[0189] In certain embodiments of Formula Ib, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0190] In certain embodiments of Formula Ib, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0191] In certain embodiments of Formula Ib, R 2 is a substituted or unsubstituted heteroaryl.

[0192] In certain embodiments of Formula Ib, R 2is a substituted or unsubstituted fused bicyclic heteroaryl.

[0193] In certain embodiments of Formula Ib, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-.

[0194] In certain embodiments of Formula Ib, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0195] In certain embodiments of Formula Ib, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0196] In certain embodiments, the compound of Formula Ib is a compound of Formula Ib-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0197] In certain embodiments, the compound of Formula I is a compound of Formula Ic, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0198] In certain embodiments of Formula Ic, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0199] In certain embodiments of Formula Ic, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0200] In certain embodiments of Formula Ic, R 2 is a substituted or unsubstituted heteroaryl.

[0201] In certain embodiments of Formula Ic, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl.

[0202] In certain embodiments of Formula Ic, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-.

[0203] In certain embodiments of Formula Ic, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0204] In certain embodiments of Formula Ic, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0205] In certain embodiments of Formula Ic, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0206] In certain embodiments of Formula Ic, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl; R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0207] In certain embodiments, the compound of formula Ic is a compound of formula Ic-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0208] In certain embodiments, the compound of Formula I is a compound of Formula Id, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R w is hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl).

[0209] In certain embodiments of Formula Id, R w is halogen, alkoxy, haloalkoxy, or haloalkyl.

[0210] In certain embodiments of Formula Id, R w is halogen, haloalkoxy, or haloalkyl.

[0211] In certain embodiments of Formula Id, R w is halogen or haloalkyl.

[0212] In certain embodiments of Formula Id, R w is a halogen.

[0213] In certain embodiments of Formula Id, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-.

[0214] In certain embodiments of Formula Id, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0215] In certain embodiments of Formula Id, R 3 is a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0216] In certain embodiments of Formula Id, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0217] In certain embodiments, the compound of formula Id is a compound of formula Id-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0218] In certain embodiments, the compound of Formula I is a compound of Formula Ie, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R d is hydrogen, -C(O)N(R A )2, or -C(O)OR A and; R Aeach occurrence of is independently hydrogen or substituted or unsubstituted alkyl).

[0219] In certain embodiments of formula Ie, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0220] In certain embodiments of formula Ie, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0221] In certain embodiments of formula Ie, R 2 is a substituted or unsubstituted heteroaryl.

[0222] In certain embodiments of formula Ie, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl.

[0223] In certain embodiments, the compound of formula Ie is a compound of formula Ie-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0224] In certain embodiments, the compound of Formula I is a compound of Formula If, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R cis substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl).

[0225] In certain embodiments of formula If, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0226] In certain embodiments of formula If, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0227] In certain embodiments of formula If, R 2 is a substituted or unsubstituted heteroaryl.

[0228] In certain embodiments of formula If, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl.

[0229] In certain embodiments, the compound of formula If is a compound of formula If-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0230] In certain embodiments, the compound of formula If is a compound of formula If-2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0231] In certain embodiments, the compound of formula I is a compound of formula Ig, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0232] In certain embodiments of Formula Ig, R A is hydrogen or substituted or unsubstituted alkyl. In certain embodiments of formula Ig, R A is hydrogen. In certain embodiments of Formula Ig, R A is unsubstituted alkyl.

[0233] In certain embodiments of Formula Ig, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0234] In certain embodiments of Formula Ig, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0235] In certain embodiments of Formula Ig, R 2 is a substituted or unsubstituted heteroaryl.

[0236] In certain embodiments of Formula Ig, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl.

[0237] In certain embodiments, the compound of formula Ig is a compound of formula Ig-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0238] In certain embodiments, the compound of formula Ig is a compound of formula Ig-2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0239] In certain embodiments, the compound of Formula I is a compound of Formula Ih, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R c is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with RA each occurrence of is independently hydrogen or substituted or unsubstituted alkyl).

[0240] In certain embodiments of formula Ih, R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR A , or -N(R A )2.

[0241] In certain embodiments of formula Ih, R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0242] In certain embodiments of formula Ih, R 2 is a substituted or unsubstituted heteroaryl.

[0243] In certain embodiments of formula Ih, R 2 is a substituted or unsubstituted fused bicyclic heteroaryl.

[0244] In certain embodiments, the compound of formula Ih is a compound of formula Ih-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0245] In certain embodiments, the compound of Formula I is a compound of Formula Ii, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R wis hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl; R c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with; R d is hydrogen, -C(O)N(R A )2, or -C(O)OR A and R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl).

[0246] In certain embodiments of Formula Ii, R w is halogen, alkoxy, haloalkoxy, or haloalkyl. In certain embodiments of Formula Ii, R w is halogen, haloalkoxy, or haloalkyl. In certain embodiments of Formula Ii, R w is halogen or haloalkyl. In certain embodiments of Formula Ii, R w is halogen. In certain embodiments of Formula Ii, R w is fluoro, chloro, bromo, or iodo. In certain embodiments of Formula Ii, R w is chloro, bromo, or iodo. In certain embodiments of Formula Ii, R w is chloro. In certain embodiments of Formula Ii, R w is bromo. In certain embodiments of Formula Ii, R w is iodine.

[0247] In certain embodiments of Formula Ii, R 3is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, -C(=NR A )-, -S-, -S(O)-, or -S(O)2-.

[0248] In certain embodiments of Formula Ii, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0249] In certain embodiments of Formula Ii, R 3 is a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0250] In certain embodiments of Formula Ii, R 3 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and, where valences permit, R 3 Any carbon atom in the A -, -C(O)-, or -C(=NR A )- may be replaced.

[0251] In certain embodiments, the compound of Formula Ii is a compound of Formula Ii-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0252] In certain embodiments, the compound of Formula I is a compound of Formula Ij, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R w is hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl; R c is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl).

[0253] In certain embodiments of formula Ij, R w is halogen, alkoxy, haloalkoxy, or haloalkyl. In certain embodiments of formula Ij, R w is halogen, haloalkoxy, or haloalkyl. In certain embodiments of formula Ij, R wis halogen or haloalkyl. In certain embodiments of formula Ij, R w is halogen. In certain embodiments of formula Ij, R w is fluoro, chloro, bromo, or iodo. In certain embodiments of formula Ij, R w is chloro, bromo, or iodo. In certain embodiments of formula Ij, R w is chloro. In certain embodiments of formula Ij, R w In certain embodiments of Formula Ij, R w is iodine.

[0254] In certain embodiments of formula Ij, R A is hydrogen. In certain embodiments of formula Ij, R A is unsubstituted alkyl.

[0255] In certain embodiments, the compound of formula Ij is a compound of formula Ij-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0256] In certain embodiments, the compound of formula Ij is a compound of formula Ij-2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0257] In certain embodiments, the compound of Formula I is a compound of Formula Ik, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka] (In the formula, R w is hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl; R c is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R c Any carbon of A -, -C(O)-, or -C(=NR A )- may be replaced with R A each occurrence of is independently hydrogen or substituted or unsubstituted alkyl).

[0258] In certain embodiments of formula Ik, R w is halogen, alkoxy, haloalkoxy, or haloalkyl. In certain embodiments of formula Ik, R w is halogen, haloalkoxy, or haloalkyl. In certain embodiments of formula Ik, R w is halogen or haloalkyl. In certain embodiments of formula Ik, R w is halogen. In certain embodiments of formula Ik, R w is fluoro, chloro, bromo, or iodo. In certain embodiments of formula Ik, R w is chloro, bromo, or iodo. In certain embodiments of formula Ik, R w In certain embodiments of formula Ik, R w is bromo. In certain embodiments of Formula Ik, R w is iodine.

[0259] In certain embodiments of formula Ik, R A is hydrogen. In certain embodiments of formula Ik, R Ais unsubstituted alkyl.

[0260] In certain embodiments, the compound of formula Ik is a compound of formula Ik-1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [ka]

[0261] In certain embodiments, the compound of Formula I is one of the following compounds in Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [Table 1] TIFF0007785108000072.tif232162TIFF0007785108000073.tif227162TIFF0007785108000074.t if219162TIFF0007785108000075.tif210162TIFF0007785108000076.tif225162TIFF0007785108 000077.tif226162TIFF0007785108000078.tif213162TIFF0007785108000079.tif221162TIFF00 07785108000080.tif211162TIFF0007785108000081.tif226162TIFF0007785108000082.tif51162

[0262] In certain embodiments, compounds of Formula I have an EC50 of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. 50 inhibits pKal.

[0263] Pharmaceutical Compositions, Kits, and Administration The present disclosure also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0264] In certain embodiments, the compound of Formula I is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a pKal-mediated disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing or reducing the risk of a pKal-mediated disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for alleviating one or more symptoms of edema (e.g., HAE or DME) or reducing the risk of an edema attack in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing the onset of edema, such as HAE or DME. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of pKal in a subject or cell.

[0265] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or a reptile.

[0266] In certain embodiments, an effective amount is an amount effective to inhibit the activity of pKal by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of pKal by a range between a percentage described in this paragraph and another percentage described in this paragraph.

[0267] The present disclosure provides pharmaceutical compositions comprising compounds that interact with pKal for use in treating a pKal-mediated disease or disorder in a subject in need thereof.

[0268] The compounds or compositions described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically effective agents and / or prophylactically effective agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., efficacy and / or effectiveness) of treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, and / or reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It should also be understood that the therapies used can achieve desirable effects for the same disorder and / or can achieve different effects. In certain embodiments, the pharmaceutical compositions described herein comprising a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is not present in a pharmaceutical composition comprising one of the compound and the additional pharmaceutical agent, but is present when both are included.

[0269] The compound or composition may be administered simultaneously with, before, or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically effective agents. Pharmaceutical agents also include prophylactically effective agents. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a pKal-mediated disorder, such as edema. Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compounds or compositions described herein in a single dose, or may be administered separately in different doses. The particular combination to use in a regimen will take into consideration the compatibility of the additional pharmaceutical agent(s) with the compounds described herein and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the combined additional pharmaceutical agent(s) will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination are lower than the levels used individually.

[0270] In certain embodiments, the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a solution for parenteral injection. In certain embodiments, the pharmaceutical composition is a solution for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a solution for intravenous injection (e.g., an aqueous solution). In certain embodiments, the pharmaceutical composition is a solution for subcutaneous injection (e.g., an aqueous solution).

[0271] After formulation with appropriate pharmaceutically acceptable excipients at desired dosages, the pharmaceutical compositions of the present disclosure may be administered to humans and other animals by oral, parenteral, intracisternal, intraperitoneal, topical, buccal, etc. administration, depending on the disease or condition being treated.

[0272] In certain embodiments, pharmaceutical compositions comprising a compound of Formula I are administered orally or parenterally (depending on the mode of administration) at a dosage level of each pharmaceutical composition sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more administrations over one or several days. In certain embodiments, the effective amount per administration ranges from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 10 mg / kg, of subject body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be administered at a dosage level sufficient to deliver about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, more preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times per day, twice per day, once per day, every other day, every three days, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations). In certain embodiments, the compositions described herein are administered at a dose below the dose at which the agent produces a nonspecific effect.

[0273] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0274] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such methods include the step of bringing into association a composition comprising a compound of Formula I with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single-dose or multi-dose unit.

[0275] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of active ingredient generally corresponds to the dose of the active ingredient administered to a subject, and / or a convenient fraction of that dose, such as one-half or one-third of that dose.

[0276] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional components in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain 0.1 to 100% (w / w) of the active ingredient.

[0277] Pharmaceutically acceptable additives used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Additives such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and perfumes may also be present in the compositions.

[0278] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0279] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), crystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0280] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, etc.), and the like. ), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80) ), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylethylene glycol monolaurate,Triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0281] Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0282] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0283] Exemplary antioxidants include α-tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium disulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium disulfite, and sodium sulfite.

[0284] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0285] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0286] Exemplary alcoholic preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0287] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0288] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium disulfite, potassium sulfite, potassium disulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0289] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline solution, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0290] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0291] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seed, borage, cade, chamomile, canola, caraway, carnauba, castor bean, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grapeseed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea Oils of citric acid, citric acid, citric acid, citric acid esters ...

[0292] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavorings, and perfumes. In certain embodiments for parenteral administration, the agents of the invention are mixed with solubilizing agents such as CREMOPHOR EL® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0293] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated by known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include, among others, water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0294] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0295] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is present in at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) excipients or fillers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders. The formulation may be mixed with a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0296] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. These can optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0297] The active ingredient may also be in microencapsulated form with one or more of the additives described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active agent may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0298] Formulations suitable for topical administration include liquid or semi-liquid preparations, such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes; or solutions or suspensions, such as drops. Formulations for topical administration to the surface of the skin can be prepared by dispersing the drug in a dermatologically acceptable carrier, such as a lotion, cream, ointment, or soap. Useful carriers can form a film or layer on the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance absorption to tissue surfaces. For example, hydroxypropyl cellulose or fibrinogen / thrombin solutions can be used effectively. Alternatively, tissue-coating solutions, such as pectin-containing formulations, can be used. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present disclosure contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of active substances to the body.Such dosage forms can be made by dissolving or dispersing the active substance in a suitable medium.Absorption enhancers can also be used to increase the flux of the active substance through the skin.This rate can be controlled by providing a rate-controlling membrane or dispersing the active substance in a polymer matrix or gel.

[0299] Additionally, carriers for topical formulations can be in the form of hydroalcoholic systems (e.g., liquids and gels), anhydrous oil- or silicone-based systems, or emulsion systems, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. Emulsions can cover a wide range of viscosities, including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like. Emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and water-based mousse systems.

[0300] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). The provided kits may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form.

[0301] Thus, in one aspect, a kit is provided comprising a first container containing a compound or pharmaceutical composition described herein. In certain embodiments, the kit is useful for treating a pKal-mediated disease in a subject in need thereof. In certain embodiments, the kit is useful for preventing a pKal-related disease in a subject in need thereof. In certain embodiments, the kit is useful for reducing the risk of developing a pKal-related disease in a subject in need thereof. In certain embodiments, the kit is useful for inhibiting the activity of pKal in a subject or cell.

[0302] In certain embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide for treatment of a pKal-mediated disease in a subject in need thereof. In certain embodiments, the kit and instructions provide for prevention of a pKal-mediated disease in a subject in need thereof. In certain embodiments, the kit and instructions provide for reduction of the risk of developing a pKal-mediated disease in a subject in need thereof. In certain embodiments, the kit and instructions provide for inhibition of pKal activity in a subject or cell. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

[0303] Treatment method The present disclosure provides the use of any of the pKal inhibitory compounds described herein for inhibiting the activity of pKal, which is useful for treating pKal-mediated diseases and pathologies.Exemplary pKal-mediated disorders include edema, which refers to swelling of the whole or part of a subject's body due to inflammation or injury when microvessels become leaky and release fluid into nearby tissues.In some cases, the edema is HAE.In other cases, the edema occurs in the eye, such as diabetic macular edema (DME).

[0304] In some embodiments, the pKal-mediated disease described herein is an ocular disorder, such as a disorder associated with vascular leakage caused by abnormal pKal activity. Examples include, but are not limited to, DME, wet age-related macular degeneration (wAMD) and dry age-related macular degeneration (dAMD), and diabetic retinopathy. In other embodiments, the pKal-mediated disease is ischemia-reperfusion injury or systemic inflammatory response, which may be associated with surgical procedures.

[0305] Additionally, any of the pKal inhibitory compounds described herein can be used to reduce blood loss in a subject, such as a human patient undergoing a surgical procedure. The pKal inhibitory compounds can be used concomitantly with an anti-thrombolytic or anti-fibrinolytic agent. Optionally, the pKal inhibitory compounds can be used to preserve organs in vitro.

[0306] The present disclosure provides methods for inhibiting the activity of pKal. In certain embodiments, the present application provides methods for inhibiting the activity of pKal in vitro by contacting pKal molecules in a sample, such as a biological sample, with any of the pKal inhibitory compounds described herein. In certain embodiments, the present application provides methods for inhibiting the activity of pKal in vivo by delivering an effective amount of any of the pKal inhibitory compounds described herein to a subject in need of treatment via an appropriate route.

[0307] In certain embodiments, the method comprises administering any of the pKal inhibitory compounds described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof (e.g., a subject, such as a human patient, having edema). In certain embodiments, the method comprises administering to a subject in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0308] In certain embodiments, the subject treated by any of the methods described herein is a human patient who has, is suspected of having, or is at risk of having edema, such as HAE or diabetic macular edema (DME). A subject with edema can be identified by routine medical examination, such as a clinical test. A subject suspected of having edema can exhibit one or more symptoms of the disease / disorder. A subject at risk of edema can be a subject with one or more risk factors associated with the disease, such as a subject with a deficiency of C1-INH in HAE.

[0309] In certain embodiments, provided herein are methods for alleviating one or more symptoms of HAE in a human patient suffering from an attack of HAE. Such patients may be identified by routine medical procedures. An effective amount of one or more pKal inhibitory compounds may be provided to the human patient via an appropriate route, such as those described herein. The pKal inhibitory compounds described herein may be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0310] In another embodiment, provided herein is a method for reducing the risk of HAE attacks in a human patient with quiescent HAE. Such patients can be identified based on various factors, including a history of HAE attacks. An effective amount of one or more pKal inhibitory compounds can be provided to the human patient via an appropriate route, such as those described herein. The pKal inhibitory compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0311] In yet another embodiment, provided herein is prophylactic treatment of HAE in human patients at risk for HAE attacks with one or more pKal inhibitory compounds described herein. Patients suitable for such prophylactic treatment may be human subjects with a history of HAE attacks (e.g., human subjects experiencing more than two attacks per month). Alternatively, patients suitable for prophylactic treatment may be human subjects without a history of HAE attacks but with one or more risk factors for HAE (e.g., family history, genetic deletion of the C1-INH gene, etc.). Such prophylactic treatment may include a pKal inhibitory compound described herein as the sole active agent, or may include additional anti-HAE agents, such as those described herein.

[0312] In certain embodiments, provided herein are methods for preventing or reducing ocular edema in a subject (e.g., a human patient). In some examples, the human patient is a diabetic patient with, suspected of, or at risk of diabetic macular edema (DME). DME is a proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leakage, and retinal thickening in diabetes mellitus due to leakage of fluid from blood vessels in the macula. To carry out this method, an effective amount of one or more pKal inhibitory compounds described herein or a pharmaceutically acceptable salt thereof can be delivered to the eye of a subject in need of treatment. For example, the compound can be delivered by intraocular or intravitreal injection. The subject can be treated with the pKal inhibitor compound described herein as the sole active agent or in combination with another DME treatment. Non-limiting examples of treatments for DME include laser coagulation, steroids, agents targeting the VEGF pathway (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

[0313] In certain embodiments, the methods disclosed herein include administering to a subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, or composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0314] In certain embodiments, the subject to be treated is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject to be treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0315] Certain methods described herein may include administering one or more additional pharmaceutical agents in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as the compound of Formula I or at a different time from the compound of Formula I. For example, the compound of Formula I and any additional pharmaceutical agents may be on the same or different dosing schedules. The administration of all or a portion of the compound of Formula I may occur before the administration of all or a portion of the additional pharmaceutical agents, after the administration of all or a portion of the additional pharmaceutical agents, within the administration schedule of the additional pharmaceutical agents, or in combination. The timing of administration of the compound of Formula I and the additional pharmaceutical agents may be different for different additional pharmaceutical agents.

[0316] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in treating edema, such as HAE or DME. Examples of such agents are provided herein. [Example]

[0317] Example In order that the invention described herein may be more fully understood, the following examples are provided: The embodiments described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way to limit the scope thereof.

[0318] Example 1: Exemplary synthetic schemes and procedures for synthesizing exemplary compounds of Formula I

[0319] All reactions were carried out under an atmosphere of dry nitrogen unless otherwise noted. TLC plates were visualized under ultraviolet light. Flash chromatography refers to column chromatography on silica gel (40-60 μm) using a glass column. Alternatively, automated chromatography was performed using Biotage normal-phase and reverse-phase silica cartridges using a Biotage SP1 or Biotage Isolera system with ultraviolet detection at 220 nm or 254 nm. Further details can be found in the relevant experimental procedures.

[0320] The following system was used for LCMS: Agilent 6120 (Binary Gradient Module pump), XBridge analytical column C18, 5 μm, 4.6 × 50 mm, 25 °C, 5 μL injection volume, 2 mL / min. A gradient of acetonitrile in 0.1% aqueous ammonium acetate was used with the following timing: [Table 2]

[0321] The following system was used for HPLC (but not mass spectrometry): Waters 2767 (Binary Gradient Module pump), XBridge prep C18 column, 5 μm, 19 × 150 mm, 15 mL / min, 25 °C; gradient of 30 to 80% acetonitrile in 0.1% aqueous ammonium bicarbobate over 9.5 min; or gradient of 30 to 80% acetonitrile in 0.1% aqueous ammonium hydroxide over 9.5 min; or gradient of 30 to 80% acetonitrile in 0.1% aqueous 2,2,2-trifluoroacetic acid over 9.5 min.

[0322] NMR spectra were obtained at 400 MHz ( 1 H), 376MHz ( 19 F) or 75MHz ( 13 Measurements were performed on a Varian Mercury spectrometer operating at 1000 Hz (C). The solvent used for the samples is specified in the experimental procedure for each compound. 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (1) [ka]

[0323] Step 1: Synthesis of (2R,4S)-2-benzyl 1-tert-butyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.0 g, 13.0 mmol) in methanol (50 mL) was cooled to 0 °C. Aqueous cesium carbonate solution (2.12 g in 32 mL of water) was added. The solution was concentrated, and sufficient N,N-dimethylformamide was added to azeotrope with water to leave a white solid, which was dissolved in N,N-dimethylformamide (60 mL). Benzyl bromide (1.5 mL, 13.0 mmol) was added at 0 °C, and the mixture was stirred vigorously at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in ethyl acetate (40 mL) and washed with water (2 × 40 mL) and brine (2 × 40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel flash chromatography (petroleum ether:ethyl acetate=50:50) to give (2R,4S)-2-benzyl 1-tert-butyl 4-hydroxypyrrolidine-1,2-dicarboxylate (4.18 g) as a colorless oil. 1 H NMR (400Hz, CDCl3) δ 7.35-7.34 (m, 5 H), 5.23-5.07 (m, 2 H), 4.51-4.41 (m, 2 H), 3.65-3.46 (m, 2 H), 2.33-2.23 (m, 1 H), 2.09-2.03 (m, 1H), 1.45-1.35 (s, 9H)

[0324] Step 2: Synthesis of (2R,4R)-2-benzyl 1-tert-butyl 4-azidopyrrolidine-1,2-dicarboxylate A solution of diethyl azodicarboxylate (6.78 g, 39.0 mmol of a 40% solution in toluene) and diphenylphosphoryl azide (10.2 g, 39.0 mmol) in tetrahydrofuran (15 mL) was added dropwise over 30 minutes to a solution of (2R,4S)-2-benzyl 1-tert-butyl 4-hydroxypyrrolidine-1,2-dicarboxylate (4.18 g, 13 mmol) and triphenylphosphine (10.2 g, 39.0 mmol) in tetrahydrofuran (50 mL) at 0 °C. The resulting mixture was stirred at room temperature for 24 hours. After adding ethanol (20 mL), the solvent was concentrated in vacuo to dryness. The resulting residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate=80:20 to 70:30) to give (2R,4R)-2-benzyl 1-tert-butyl 4-azidopyrrolidine-1,2-dicarboxylate as a yellowish oil. MS(ESI) m / z 291.1 [M+H-56]+

[0325] Step 3: Synthesis of (2R,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. To a solution of (2R,4R)-2-benzyl 1-tert-butyl 4-azidopyrrolidine-1,2-dicarboxylate (4.49 g, 12.9 mmol) in methanol (30 mL) was added palladium on carbon (10%, 449 mg). The reaction vessel was evacuated by aspirator and thoroughly purged with hydrogen (three times), and the resulting heterogeneous mixture was stirred at room temperature under a hydrogen balloon for 24 hours. The mixture was filtered through a pad of Celite, and the pad was washed with methanol. The filtrate was concentrated in vacuo to give (2R,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (3 g), which was used in the next step without purification. MS (ESI) m / z 175.1 [M+H-56] +

[0326] Step 4: Synthesis of (2R,4R)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. To a solution of (2R,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (3 g, crude, 12.9 mmol) in tetrahydrofuran (30 mL) was added 10% aqueous sodium bicarbonate (40 mL). This solution was pre-cooled to 0° C. before adding N-(9-fluorenylmethoxycarbonyloxy)succinimide (4.37 g, 13 mmol) dissolved in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to leave a residue that was dissolved in ethyl acetate (100 mL) and treated with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×100 mL), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue that was purified by silica gel flash chromatography (ethyl acetate:methanol=70:30) to give (2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (4 g) as a white solid. 1 H NMR (400Hz, CDCl3) δ 7.73-7.71(m, 2 H), 7.58-7.48 (m, 2 H), 7.37-7.33 (m, 2 H), 7.29-7.26 (m, 2 H), 4.29-4.16 (m, 5 H), 3.69-3.44 (m, 2 H), 2.45 (s, 1 H), 2.31-2.14 (m, 2 H), 1.43 (s, 9 H)

[0327] Step 5: Synthesis of (2R,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamoylpyrrolidine-1-carboxylate. To a solution of (2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (4 g, 8.83 mmol) in dioxane (30 mL) at 25° C., pyridine (1.06 g, 13.24 mmol), di-tert-butyl dicarbonate (2.86 g, 13.24 mmol), and then ammonium bicarbonate (1.06 g, 13.24 mmol) were added. The mixture obtained after the addition was stirred at 25° C. for 16 hours. After removing the solvent, the residue was diluted with ethyl acetate (150 mL) and washed with water (200 mL x 3), 1N hydrochloride acid (200 mL), and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue that was purified by silica gel flash chromatography (ethyl acetate) to give (2R,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamoylpyrrolidine-1-carboxylate (2.7 g) as a white solid. MS (ESI) m / z: 452.1 [M+H] +

[0328] Step 6: Synthesis of (2R,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamothioylpyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamoylpyrrolidine-1-carboxylate (2.7 g, 6 mmol) in tetrahydrofuran (50 mL) at 25 °C was added Lawesson's reagent (1.21 g, 3 mmol). The resulting mixture was stirred at 55 °C for 16 hours. After removing the solvent, the residue was diluted with water and extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give (2R,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamothioylpyrrolidine-1-carboxylate (2.3 g) as a white solid. MS(ESI) m / z: 468.2 [M + H] +

[0329] Step 7: Synthesis of ethyl 2-((2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate. To a solution of (2R,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamothioylpyrrolidine-1-carboxylate (2.3 g, 4.9 mmol) in ethanol (60 mL) at 25 °C, ethyl 3-bromo-2-oxopropanoate (1.15 g, 5.9 mmol) and calcium carbonate (1.47 g, 14.7 mmol) were added. The resulting mixture was stirred at 70 °C for 5 hours. After the reaction was completed, the mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate (40 mL × 4). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give ethyl 2-((2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (1.6 g) as a yellow oil. MS(ESI) m / z: 464.2 [M + H] +

[0330] Step 8: Synthesis of ethyl 2-((2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate. To a solution of 7-chloro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.71 g, 3.6 mmol) in N,N-dimethylformamide (25 mL) at 25 °C was added ethyldiisopropylamine (DIEA, 1.19 g, 9 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.72 g, 4.5 mmol). Ethyl 2-((2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (1.4 g, 3.0 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed, the residue was diluted with water, extracted with ethyl acetate (40 mL × 3), washed with 1N lithium chloride (30 mL × 3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica column chromatography (petroleum ether:acetic acid = 1:1) to give ethyl 2-((2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (800 mg) as a white solid. MS(ESI) m / z: 642.2[M + H] +

[0331] Step 9: Synthesis of 2-((2R,4R)-4-amino-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid. To a solution of ethyl 2-((2R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (800 mg, 1.25 mmol) in methanol (20 mL), tetrahydrofuran (30 mL), and water (30 mL) at room temperature, lithium hydroxide (102 mg, 2.5 mmol) was added. After the addition, the resulting mixture was stirred at room temperature for 16 hours. The organic solvent was removed from the mixture to give 2-((2R,4R)-4-amino-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid as an aqueous solution. MS(ESI) m / z 392.2 [M + H] +

[0332] Step 10: Synthesis of 2-((2R,4R)-4-((tert-butoxycarbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid. To a solution of 2-((2R,4R)-4-amino-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (crude, 1.25 mmol) in water (approximately 20 mL) and methanol (30 mL) was added triethylamine (252 mg, 2.5 mmol). After adding di-tert-butyl dicarbonate (BocO, 269 mg, 1.25 mmol), the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by reverse-phase LC (acetonitrile in water: 10-95%) to give 2-((2R,4R)-4-((tert-butoxycarbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (300 mg) as a white solid. MS(ESI) m / z 492.2 [M + H] +

[0333] Step 11: Synthesis of 2-((2R,4R)-(4-tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide. To a solution of 2-((2R,4R)-4-((tert-butoxycarbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (150 mg, 0.3 mmol) in N,N-dimethylformamide (10 mL) at room temperature, (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (122 mg, 0.3 mmol), ethyldiisopropylamine (DIEA, 200 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 117 mg, 0.61 mmol), and 1-hydroxybenzotriazole (HOBt, 41 mg, 0.3 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed, and the residue was diluted with water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by prep-TLC (methanol:dichloromethane = 1:15) to give 2-((2R,4R)-(4-tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (160 mg) as a white solid. MS(ESI) m / z 875.2 [M + H] +

[0334] Step 12: Synthesis of 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (1). To a solution of 2-((2R,4R)-(4-tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (160 mg, 0.25 mmol) in dichloromethane (5 mL) at room temperature was added hydrochloric acid / ethyl acetate (3 N, 10 mL). The resulting mixture was stirred at 25° C. for 6 hours. The mixture was concentrated and the resulting residue was purified by reverse-phase HPLC (ACN / 0.1% TFA in water) to give 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (50 mg) as a white solid. MS(ESI) m / z 575.0 [M + H] + . 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.80 (br, 2H), 8.76 (br, 1H), 8.59 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.23-8.14 (m, 1H), 7.85-7.80 (m, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.03 (br, 4H), 5.67 (t, J = 7.2 Hz ,1H), 4.62-4.57 (m, 1H), 4.47-4.30 (m, 1H), 4.27-4.22 (m, 1H), 4.07-4.00 (m, 1H), 3.12-3.08 (m, 2H), 2.89-2.85 (m, 1H), 2.70-2.65 (m, 1H), 2.61 (d, J = 4.8 Hz, 3H), 1.80-1.73 (m, 2H), 1.50-1.44 (m, 2H), 1.36-1.23(m, 2H) 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (2) [ka]

[0335] Compound 2 was synthesized by the method for the synthesis of compound 1, but using (R)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide in step 11. MS(ESI) m / z 575.0 [M + H] + . 1H NMR (400 MHz, DMSO) δ 9.01(s, 1 H), 8.81 (br, 3H), 8.56(s, 1H), 8.37(d, J = 8.4 Hz ,1H), 8.26 (s, 1 H), 8.18-8.16(m, 1H), 7.88-7.80(m, 1H), 7.79(d, J = 9.6 Hz, 1H), 7.57 (d, J = 9.6 Hz,1H), 7.53-6.8 (m, 4H), 5.68(t, J = 7.2 Hz, 1H), 4.79-4.74 (m, 1H), 4.47-4.34 (m, 1H), 4.26-4.21 (m, 1H), 4.08-4.00 (m, 1H), 3.14-3.09 (m, 2H), 2.89-2.80 (m, 1H), 2.70-2.63(m, 1H), 2.59(d, J = 4.4 Hz, 3H), 1.85-1.74 (m, 2H), 1.53-1.43 (m, 2H), 1.41-1.22(m, 2H) 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (3) [ka]

[0336] Step 1: Synthesis of (R)-benzyl 2-carbamoylpyrrolidine-1-carboxylate. To a solution of (R)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (15 g, 60.2 mmol) in dioxane (200 mL), pyridine (6.19 g, 78.26 mmol), di-tert-butyl dicarbonate (16.9 g, 78.26 mmol), and then ammonium bicarbonate (6.19 g, 78.26 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. After removing the solvent, the residue was diluted with 150 mL of ethyl acetate and washed with water (200 mL × 3), 1N hydrochloric acid (200 mL), and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give (R)-benzyl 2-carbamoylpyrrolidine-1-carboxylate (16.15 g) as a yellow oil. MS (ESI) m / z 249.1 [M + H] +

[0337] Step 2: Synthesis of (R)-benzyl 2-carbamothioylpyrrolidine-1-carboxylate. To a solution of (R)-benzyl 2-carbamoylpyrrolidine-1-carboxylate (5.4 g, 21.8 mmol) in tetrahydrofuran (120 mL) was added Lawesson's reagent (4.84 g, 11.98 mmol). The resulting mixture was stirred at 55 °C for 16 hours. After removing the solvent, the residue was diluted with 200 mL of water and extracted with ethyl acetate (40 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica column chromatography (petroleum ether:ethyl acetate = 1:1) to give (R)-benzyl 2-carbamothioylpyrrolidine-1-carboxylate (4.97) as a yellow oil. MS (ESI) m / z 265.1 [M + H] +

[0338] Step 3: Synthesis of (R)-ethyl 2-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate. To a solution of (R)-benzyl 2-carbamothioylpyrrolidine-1-carboxylate (4.67 g, 17.69 mmol) in ethanol (60 mL), ethyl 3-bromo-2-oxopropanoate (5.18 g, 26.54 mmol) and calcium carbonate (5.30 g, 53.07 mmol) were added. The resulting mixture was stirred at 70° C. for 5 hours. The mixture was concentrated, and the residue was diluted with 100 mL of water and ethyl acetate (40 mL×4). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give (R)-ethyl 2-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (4.9 g) as a yellow oil. MS(ESI) m / z 361.1 [M + H] +

[0339] Step 4: Synthesis of (R)-ethyl 2-(pyrrolidin-2-yl)thiazole-4-carboxylate. (R)-Ethyl 2-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (1.0 g, 2.78 mmol) was added to a solution of hydrobromic acid in acetic acid (30%, 60 mL). The resulting mixture was stirred at room temperature for 16 hours. After removing the solvent, (R)-ethyl 2-(pyrrolidin-2-yl)thiazole-4-carboxylate hydrobromide (853.5 mg) was used in the next step without further purification. MS (ESI) m / z 227.1 [M + H] +

[0340] Step 5: Synthesis of (R)-ethyl 2-(1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate. To a solution of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid (454.1 mg, 2.31 mmol) in N,N-dimethylformamide (25 mL) at room temperature was added (R)-ethyl 2-(pyrrolidin-2-yl)thiazole-4-carboxylate hydrobromide (853.5 mg, 2.78 mmol), ethyldiisopropylamine (DIEA, 1.49 g, 11.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 662.8 mg, 3.47 mmol), and 1-hydroxybenzotriazole (HOBt, 626.6 mg, 4.62 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed, and the residue was diluted with 30 mL of water, extracted with chloroform:isopropanol (v:v=3:1, 30 mL×4), and washed with 1N hydrochloric acid (30 mL) and saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give (R)-ethyl 2-(1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (321 mg) as a white solid. MS(ESI) m / z 405.1 [M + H] +

[0341] Step 6: Synthesis of (R)-2-(1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid. To a solution of (R)-ethyl 2-(1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (321.0 mg, 0.80 mmol) in methanol (20 mL), tetrahydrofuran (30 mL), and water (30 mL) was added lithium hydroxide (166.8 mg, 3.98 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 2). The pH of the aqueous layer was adjusted to 2-3 with 1 N hydrochloride and concentrated. The residue was diluted with methanol:dichloromethane (v:v=1:10, 20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-2-(1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (487 mg) as a white solid. MS(ESI) m / z 377.1 [M + H] +

[0342] Step 7: Synthesis of 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide. To a solution of (R)-2-(1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (200 mg, 0.53 mmol) in N,N-dimethylformamide (10 mL) was added (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (187.7 mg, 0.47 mmol), ethyldiisopropylamine (DIEA, 343.1 g, 2.66 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 252.7 mg, 1.32 mmol), and 1-hydroxybenzotriazole (HOBt, 193.8 mg, 1.43 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed, and the residue was diluted with 50 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (methanol:dichloromethane = 1:10) to give 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (220 mg) as a yellow solid. MS(ESI) m / z 760.3 [M + H] +

[0343] Step 8: Synthesis of 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (3). To a solution of 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (220 mg, 0.29 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 6 hours. The mixture was concentrated, and the residue was purified by RP-HPLC (0.1% NH in ACN / HO) to give 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (71.2 mg) as a white solid. MS (ESI) m / z 560.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.87 (s, 0.7H), 8.83 (s, 0.3 H), 8.40 (s, 0.7H), 8.36 (s, 0.3H), 8.17 (s, 1.4H), 8.09 (s, 0.6H),7.74-7.69 (m, 1H), 7.55-7.50 (m, 0.7H), 7.43-7.39 (m, 1H), 7.33-7.29 (m, 0.3H), 6.77-6.74 (m, 0.3H), 5.59-5.55 (m, 0.7H), 4.44-4.35 (m, 2H), 4.18-4.11 (m, 1H), 3.78-3.72 (m, 1H), 3.05 (s, 2H), 2.62 (s, 3H), 2.46-2.32 (m, 2H), 2.17-1.97 (m, 3H), 1.80-1.63 (m, 3H), 1.51-1.42 (m, 2H), 1.35-1.23 (m, 3H) 2-((R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (4) [ka]

[0344] Compound 4 was synthesized by the method for the synthesis of compound 3, but using (R)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide in step 7. MS(ESI) m / z 560.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.87 (s, 0.7H), 8.83 (s, 0.3H), 8.40 (s, 0.7H), 8.38 (s, 0.3H), 8.17 (s, 1.4H), 8.09 (s, 0.6H), 7.74-7.71 (m, 1H), 7.55-7.50 (m, 0.7H), 7.43-7.39 (m, 1H), 7.35-7.32 (m, 0.3H), 6.77-6.75 (m, 0.3H), 5.59-5.55 (m, 0.7H), 4.47-4.37 (m, 2H), 4.19-4.11 (m, 1H), 3.77-3.74 (m, 1H), 3.03 (s, 2H), 2.61 (s, 3H), 2.44-2.33 (m, 2H), 2.16-1.96 (m, 3H), 1.82-1.64 (m, 3H), 1.47-1.45 (m, 2H), 1.33-1.23 (m, 3H) 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (5) [ka]

[0345] Step 1: Synthesis of 2-((2R,4R)-4-acetamido-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid. To a solution of 2-((2R,4R)-4-amino-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (180 mg) in water (approximately 20 mL) and methanol (30 mL) was added triethylamine (137 mg, 1.35 mmol). After adding acetic anhydride (46 mg, 0.45 mmol), the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse-phase LC (acetonitrile in water: 10-95%) to give 2-((2R,4R)-4-acetamido-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (110 mg) as a white solid. MS(ESI) m / z 434.1 [M+H] +

[0346] Step 2: Synthesis of 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide. To a solution of 2-((2R,4R)-4-acetamido-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (110 mg, 0.253 mmol) in N,N-dimethylformamide (10 mL) was added (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (102 mg, 0.253 mmol), ethyldiisopropylamine (DIEA, 166 mg, 1.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 97 mg, 0.507 mmol), and 1-hydroxybenzotriazole (HOBt, 35 mg, 0.253 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed, and the residue was diluted with 50 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-TLC (methanol:dichloromethane = 1:15) to give 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (140 mg) as a white solid. MS(ESI) m / z 817.3 [M + H] +

[0347] Step 3: Synthesis of 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide. To a solution of 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (140 mg, 0.17 mmol) in dichloromethane (5 mL) was added hydrochloric acid / ethyl acetate (10 mL, 3N). The resulting mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated and the residue was purified by RP-HPLC (0.1% TFA in ACN / HO) to give 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide hydrochloride salt (40 mg) as a white solid. MS(ESI) m / z 617.0 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 9.08(s, 1 H),8.75 (s, 1H), 8.50(d, J = 6.4 Hz, 1H), 8.27(s, 1H), 8.14(d, J = 8.4 Hz, 1H), 7.89-7.78(m, 3H), 5.61(t, J = 8.0 Hz, 1H), 4.53-4.36 (m, 3 H), 3.90-3.78 (m, 1H), 3.10-3.05 (m, 2H), 2.77-2.65 (m, 1H), 2.61(d, J = 4.4 Hz, 3H), 2.36-2.26 (m, 1H), 1.83 (s, 3H), 1.80-1.67 (m, 2H), 1.51-1.44 (m, 2H), 1.36-1.23(m, 2H) 2-((2R,4S)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (6) [ka]

[0348] Compound 6 was synthesized according to the method for the synthesis of compound 1, starting in step 1 with (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid. MS(ESI) m / z 575.0[M + H]+. 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.72 (br, 3H), 8.59 (s, 1H), 8.24-8.23 (m, 2H), 8.16-8.11 (m, 1H), 7.84-7.77 (m, 2H), 7.64-7.57 (m, 1H), 7.55-6.86 (m, 5H), 5.79 (t, J = 6.8 Hz, 1H), 4.55-4.41 (m, 3H), 4.10-4.00 (m, 1H), 3.09-3.08 (m, 2H), 2.77-2.65 (m, 2H), 2.62 (2s, 3H), 1.80-1.69 (m, 2 H), 1.49-1.46 (m, 2 H), 1.36-1.23 (m, 2 H) 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (7) [ka]

[0349] Step 1: Synthesis of (2R,4S)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate. To a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (6.0 g, 26 mmol) in dioxane (60 mL), pyridine (3.0 mL, 37 mmol), di-tert-butyl dicarbonate (7.3 g, 34 mmol), and then ammonium bicarbonate (2.7 g, 34 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. After removing the solvent, the residue was diluted with 200 mL of ethyl acetate and washed with water (30 mL × 3), 1N hydrochloric acid (30 mL), and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue, which was purified by silica gel flash chromatography (ethyl acetate:methanol=8:1) to give (2R,4S)-tert-butyl 2-carbamoyl-4-hydroxylpyrrolidine-1-carboxylate (5.8 g) as a white solid. MS(ESI) m / z 231.1 [M + H] +

[0350] Step 2: Synthesis of (2R,4S)-tert-butyl 4-(benzoyloxy)-2-carbamoylpyrrolidine-1-carboxylate. To a solution of (2R,4S)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate (5.8 g, 25 mmol) in dichloromethane (120 mL) was added benzoyl chloride (4.3 g, 31 mmol) and 4-dimethylaminopyridine (3.7 g, 31 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The solvent was removed, and the residue was diluted with water (100 mL), extracted with dichloroform (120 mL × 3), washed with saturated aqueous sodium bicarbonate (100 mL), and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica column chromatography (ethyl acetate) to give (2R,4S)-tert-butyl 4-(benzoyloxy)-2-carbamoylpyrrolidine-1-carboxylate (7.1 g) as a colorless oil. MS (ESI) m / z 335.2 [M + H] +

[0351] Step 3: Synthesis of (2R,4S)-tert-butyl 4-(benzoyloxy)-2-carbamothioylpyrrolidine-1-carboxylate. To a solution of (2R,4S)-tert-butyl 4-(benzoyloxy)-2-carbamoylpyrrolidine-1-carboxylate (7.2 g, 22 mmol) in tetrahydrofuran (120 mL) at 25 °C was added Lawesson's reagent (4.8 g, 12 mmol). The resulting mixture was stirred at 55 °C for 16 hours. After removing the solvent, the residue was diluted with 50 mL of water and extracted with ethyl acetate (50 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give (2R,4S)-tert-butyl 4-(benzoyloxy)-2-carbamothioylpyrrolidine-1-carboxylate (4.9 g) as a green solid. MS(ESI) m / z 351.1 [M + H] +

[0352] Step 4: Synthesis of ethyl 2-((2R,4S)-4-(benzoyloxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate. To a solution of (2R,4S)-tert-butyl 4-(benzoyloxy)-2-carbamothioylpyrrolidine-1-carboxylate (4.9 g, 14 mmol) in ethanol (110 mL), ethyl 3-bromo-2-oxopropanoate (4.1 g, 21 mmol) and calcium carbonate (4.0 g, 40 mmol) were added. The resulting mixture was stirred at 70° C. for 4 hours. The solid was filtered off and the filtrate was concentrated to give the crude product, which was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give ethyl 2-((2R,4S)-4-(benzoyloxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (4.2 g) as a yellow oil. MS(ESI) m / z 447.2 [M + H] +

[0353] Step 5: Synthesis of ethyl 2-((2R,4S)-4-(benzoyloxy)pyrrolidin-2-yl)thiazole-4-carboxylate. A solution of ethyl 2-((2R,4S)-4-(benzoyloxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (2.7 g, 6.1 mmol) in hydrochloric acid / ethyl acetate (3 M, 20 mL) was stirred at room temperature for 1 hour. After removing the solvent, the residue was neutralized with sodium hydroxide (aqueous) to a pH of about 8 and then extracted with ethyl acetate (40 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give ethyl 2-((2R,4S)-4-(benzoyloxy)pyrrolidin-2-yl)thiazole-4-carboxylate (2.0 g crude) as a yellow oil, which was used in the next step without further purification. MS(ESI) m / z 347.1 [M + H] +

[0354] Step 6: Synthesis of ethyl 2-((2R,4S)-4-(benzoyloxy)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate. To a solution of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid (1.4 g, 6.9 mmol) in N,N-dimethylformamide (35 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3.3 g, 8.7 mmol) and ethyldiisopropylamine (3.7 g, 29 mmol). The mixture was stirred at room temperature for 20 minutes. Then, ethyl 2-((2R,4S)-4-(benzoyloxy)pyrrolidin-2-yl)thiazole-4-carboxylate (2.0 g, 5.8 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solvent was removed, and the residue was diluted with 30 mL of water, extracted with ethyl acetate (40 mL × 3), and washed with 1N lithium chloride (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate = 1:1) to give ethyl 2-((2R,4S)-4-(benzoyloxy)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (2.1 g) as a yellow solid. MS(ESI) m / z 525.1 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.85 (d, J = 1.2 Hz, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.74-7.61 (m, 2H), 7.59-7.49 (m, 2H), 7.41 (dd, J = 9.6, 2.0 Hz, 1H), 5.80 (t, J = 8.0 Hz, 1H), 5.66 (s, 1H), 4.73 (d, J = 13.2 Hz, 1H), 4.47 (dd, J = 13.2, 4.0 Hz, 1H), 4.34-4.27 (m, 2H), 2.81-2.76 (m, 1H), 2.68-2.61 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H)

[0355] Step 7: Synthesis of 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)thiazole-4-carboxylic acid. To a solution of ethyl 2-((2R,4S)-4-(benzoyloxy)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (600 mg, 1.1 mmol) in methanol (30 mL) and tetrahydrofuran (30 mL) was added lithium hydroxide (2 M, 2.0 mL, 4.0 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with hydrochloric acid (2 N) and the pH was adjusted to 6. After removal of the solvent, the crude product was purified by RP-LC (acetonitrile in water: 10-95%) to give 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)thiazole-4-carboxylic acid (329 mg) as a white solid. MS(ESI) m / z 393.0 [M + H] +

[0356] Step 8: Synthesis of 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide. To a solution of 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)thiazole-4-carboxylic acid (119 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 171 mg, 0.5 mmol) and ethyldiisopropylamine (193 mg, 1.5 mmol). The mixture was stirred at room temperature for 20 minutes. Next, (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (122 mg, 0.3 mmol) was added. The mixture was stirred for 2 hours. The solvent was removed, and the residue was diluted with 10 mL of water, extracted with ethyl acetate (20 mL × 3), and washed with 1N lithium chloride (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica column chromatography (dichloromethane:methanol = 12:1) to give 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (179 mg) as a colorless oil. MS(ESI) m / z 776.3 [M + H] +

[0357] Step 9: Synthesis of 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide. 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (141 mg, 0.2 mmol) in hydrochloric acid / ethyl acetate (3N, 5 mL) was stirred at room temperature for 1 hour. The solvent was removed and the crude product was purified by RP-HPLC (0.1% NH in ACN / HO) to give 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (45 mg) as a white solid. MS(ESI) m / z 576.0 [M + H] + . 1H NMR (400 MHz, DMSO) δ 8.86 (s, 0.84 H), 8.81 (s, 0.16 H), 8.41 (s, 0.84 H), 8.34 (s, 0.16 H), 8.18 (s, 0.84 H), 8.05 (s, 0.16 H), 7.72 (d, J = 9.6 Hz, 0.84 H), 7.55 (d, J = 9.6 Hz, 0.16 H), 7.41 (dd, J = 1.6, 10.0 Hz, 0.84 H), 7.32 (dd, J = 1.6, 10.0 Hz, 0.16 H), 6.77-6.75 (m, 0.16 H), 5.59 (t, J = 8.0 Hz, 0.84 H), 4.46-4.41 (m, 2.0 H), 4.29-4.18 (m, 2.0 H), 3.01 (t, J = 6.4 Hz, 2.0 H), 2.66 (s, 3.0 H), 2.40-2.38 (m, 1.0 H), 2.31-2.28 (m, 1H), 1.77-1.67 (m, 2H), 1.48-1.44 (m, 2H), 1.30-1.26 (m, 2H) 2-((2R,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (8) [ka]

[0358] Compound 8 was synthesized by a method similar to that used to synthesize compound 7, but using (R)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide in step 8. MS(ESI) m / z 576.0 [M + H] + . 1H NMR (400 MHz, DMSO) δ 8.91 (d, J = 1.2 Hz, 0.84 H), 8.85 (s, 0.14 H), 8.46 (s, 0.86 H), 8.38 (s, 0.14 H), 8.23 ​​(s, 0.86 H), 8.10 (s, 0.14 H), 7.77 (d, J = 9.6 Hz, 0.86 H), 7.59 (d, J = 9.6 Hz, 0.14 H), 7.46 (dd, J = 2.0, 9.6 Hz, 0.86 H), 7.39 (dd, J = 1.6, 9.6 Hz, 0.14H), 6.81-6.77 (m, 0.14H), 5.64 (t, J = 8.0 Hz, 0.86H), 4.50-4.47 (m, 2H), 4.34-4.24 (m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.66 (s, 3H), 2.45-2.42 (m, 1H), 2.34-2.31 (m, 1H), 1.82-1.74 (m, 2H), 1.54-1.49 (m, 2H), 1.38-1.33 (m, 2H) 2-((2R,4R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (9) [ka]

[0359] Compound 9 was synthesized from (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid by a method similar to that used to synthesize compound 7. MS(ESI) m / z 576.0 [M + H] + . 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1 H), 8.41 (s, 1 H), 8.15 (s, 2 H), 7.72 (d, J = 12.0 Hz, 1 H), 7.50 - 7.44 (m,1 H), 5.63 - 5.60 (m, 1 H), 4.51 - 4.49 (m, 2 H), 4.46 - 4.40 (m, 2 H), 3.64 (br, 3 H), 3.06 (t, J = 7.6 Hz, 2 H), 2.66 - 2.65 (m, 3 H), 2.26 - 2.20 (m, 1 H), 1.84 - 1.66 (m, 2 H), 1.56 - 1.46 (m, 2 H), 1.48 - 1.44 (m, 2 H), 1.34 - 1.26 (m,4 H) 2-((2R,4R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (10) [ka]

[0360] Compound 10 was synthesized in a manner similar to that used to synthesize compound 9, using (R)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide in step 8. MS(ESI) m / z 576.0 [M + H] + . 1H NMR (400 MHz, DMSO+D2O) δ 8.82 (s, 1H), 8.42 (s, 1 H), 8.14 (s, 2 H), 7.73 (d, J = 9.6 Hz, 1 H), 7.49 -7.43 (m,1 H), 5.62 -5.58 (m, 1 H), 4.48 - 4.40 (m, 3 H), 4.39 - 4.31(m, 1 H), 4.29 - 4.21 (m, 1 H), 3.64 (br, 3 H), 3.06 (t, J = 6.4 Hz, 2 H), 2.64 (s, 3 H), 2.24 - 2.20 (m, 2 H), 1.82 - 1.67 (m, 2 H), 1.50 -1.39 (m, 2 H), 1.33-1.22 (m, 4 H) 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (11) [ka]

[0361] Step 1: Synthesis of (2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid [ka]

[0362] To a solution of (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (30 g, 0.13 mol) in tetrahydrofuran (600 mL) was added aqueous sodium bicarbonate (NaCO, 40 g, 0.377 mol in 240 mL of HO). The mixture was cooled to 0° C., and then a solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (12.3 g, 36.45 mmol) dissolved in tetrahydrofuran (20 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to remove tetrahydrofuran. The aqueous layer was adjusted to pH 6 with hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude residue (2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (59 g) as a white solid, which was used in the next step without further purification. MS(ESI) m / z 353.1 [M-Boc] +

[0363] Step 2: Synthesis of (2S,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamoylpyrrolidine-1-carboxylate [ka]

[0364] To a mixture of (2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (59 g crude, 0.13 mol, 1 eq.), pyridine (56.6 mL, 0.52 mol, 4 eq.), and di-tert-butyl dicarbonate (59.3 mL, 0.26 mol, 2 eq.) in dioxane (600 mL) was added ammonium bicarbonate (21 g, 0.26 mol, 2 eq.). The mixture was stirred at room temperature for 16 hours. TLC showed that the starting material had disappeared. The mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=2:1 (vs. ethyl acetate)) to give (2S,4R)-tert-butyl-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamoyl pyrrolidine-1-carboxylate (58 g) as a white solid. MS (ESI) m / z 452.2 [M + H] + ; 352.2 [M+H-Boc] +

[0365] Step 3: Synthesis of (2S,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamothioylpyrrolidine-1-carboxylate [ka]

[0366] To a solution of (2S,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamoylpyrrolidine-1-carboxylate (59 g, 0.13 mol, 1 equiv.) in tetrahydrofuran (500 mL) was added Lawesson's reagent (28.4 g, 71.5 mmol, 0.55 equiv.). The resulting mixture was stirred at 55° C. for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=4:1 to 1:1) to give (2S,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamothioylpyrrolidine-1-carboxylate (49.8 g) as a white solid. MS(ESI) m / z 468.2 [M + H] +

[0367] Step 4: Synthesis of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate [ka]

[0368] To a solution of (2S,4R)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carbamothioylpyrrolidine-1-carboxylate (49.8 g, 106.6 mmol, 1 equiv.) in ethanol (60 mL), ethyl 3-bromo-2-oxopropanoate (20 mL, 31 g, 160 mmol, 1.5 equiv.) and calcium carbonate (32 g, 320 mmol, 3 equiv.) were added. The resulting mixture was stirred at 70° C. for 5 hours. TLC showed the complete disappearance of the starting material. The mixture was filtered, and the filtrate was concentrated. The residue was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and filtered to give solution 5 and the de-Boc product 6. To this solution 5 was added triethylamine (44.4 mL, 32.3 g, 320 mmol, 3 equiv.) and di-tert-butyl dicarbonate (36.4 mL, 34.58 g, 160 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to give ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (26 g) as a brown solid. MS (ESI) m / z 564.2 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1 H), 7.74-7.76 (m, 2 H), 7.57-7.56 (m, 2 H), 7.42-7.39 (m, 2 H), 7.33-7.26 (m, 2 H), 5.35-5.24 (m, 1 H), 4.89 (s, 1 H), 4.43-4.39 (m, 4 H), 4.33-4.30 (m, 1 H), 4.21-4.18 (m, 1 H), 3.93-3.85 (m, 1 H), 3.47-3.26 (m, 1 H), 2.69-2.24 (m, 2H), 1.46-1.32 (m, 12H)

[0369] Step 5: Synthesis of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate [ka]

[0370] A solution of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (26 g, 46.2 mmol) in hydrochloric acid / ethyl acetate (3 N, 500 mL) was stirred at room temperature for 4 hours. The mixture was concentrated, diluted with water, the pH adjusted to 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (22 g) as a brown solid. MS (ESI) m / z 464.2 [M + H] +

[0371] Step 6: Synthesis of ethyl 2-(2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate [ka]

[0372] To a solution of 7-chloro-imidazo[1,2-a]pyridine-2-carboxylic acid (1.65 g, 8.41 mmol) in N,N-dimethylformamide (20 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3.7 mg, 9.71 mmol) and ethyl diisopropylamine (4.2 g, 32.4 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes. Ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (3.0 g, 6.47 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (3.0 g) as a yellow solid. MS(ESI) m / z 642.2 [M + H] +

[0373] Step 7: Synthesis of 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid [ka]

[0374] To a solution of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (2.0 g, 3.11 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added aqueous lithium hydroxide (2 N, 4 mL, 8.0 mmol). The resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated to provide 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid as an aqueous solution, which was used directly in the next step without further purification. MS (ESI) m / z 392.1 [M + H] +

[0375] Step 8: Synthesis of 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid [ka]

[0376] To a solution of 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (3.11 mmol) in water (10 mL), methanol (10 mL), and tetrahydrofuran (10 mL) was added triethylamine (1.80 g, 18.5 mmol) and di-tert-butyl dicarbonate (1.6 g, 7.4 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated, and the residue was purified by RP-LC (acetonitrile in water: 10% to 95%) to give 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (700 mg) as a white solid. MS (ESI) m / z 492.1 [M + H] +

[0377] Step 9: 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide [ka]

[0378] To a solution of 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (90 mg, 0.2 mmol) in N,N-dimethylformamide (3 mL) was added ethyldiisopropylamine (DIEA, 200 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 117 mg, 0.61 mmol), 1-hydroxybenzotriazole (HOBt, 41 mg, 0.3 mmol), and (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (853.5 mg, 2.78 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed, and the residue was diluted with 50 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by RP-HPLC (0.1% NH in ACN / H2O) to give 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (80 mg) as a white solid. MS (ESI) m / z 875.4 [M + H] +

[0379] Step 10: Synthesis of 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (11) [ka]

[0380] A solution of 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (80 mg, 0.09 mmol) in hydrochloric acid / ethyl acetate (3N, 10 mL) was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was lyophilized to give 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (40 mg) as a yellow solid. MS (ESI) m / z 575.0 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 8.97 (d, J = 1.2 Hz, 0.75 H), 8.91 (s, 0.25 H), 8.57 (s, 0.75 H), 8.48 (s, 0.25 H), 8.24 (s, 0.75 H), 8.16 (s, 0.25 H), 7.76 (d, J = 10.0 Hz, 0.75 H), 7.62 (d, J = 10.0 Hz, 0.25 H), 7.55 (dd, J = 1.6; 9.6 Hz, 0.75 H), 7.45 (dd, J = 1.6; 9.6 Hz, 0.25 H), 6.90 (d, J = 8.4 Hz, 0.25 H), 5.79 (t, J = 6.8 Hz, 0.75 H), 4.57-3.99 (m, 4.0 H), 3.09 (t, J = 7.2 Hz, 2.0 H), 2.78-2.64 (m, 2.0 H), 2.61 (s, 3H), 1.78-1.67 (m, 2 H), 1.52-1.43 (m, 2 H), 1.35-1.23 (m, 2 H) 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (12) [ka]

[0381] Compound 12 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide as the starting material in step 9. MS (ESI) m / z 575.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.03 (s, 1H), 8.79-8.76 (br, 3H), 8.63 (s, 1H), 8.25-8.22 (m, 2H), 8.17-8.13 (m, 1H), 7.88-7.78 (m, 2H), 7.66-7.58 (m, 1H), 7.49-7.00 (br, 3H), 5.80 (t, J = 7.2 Hz, 1H), 4.57-4.53 (m, 1H), 4.49-4.43 (m, 2H), 4.11-4.00 (m, 1H), 3.10-3.16 (m, 2H), 2.67-2.66 (m, 2H), 2.62 (s, 3H), 1.79-1.72 (m, 2H), 1.49-1.46 (m, 2H), 1.34-1.28 (m, 2H) 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (13) [ka]

[0382] Step 1: Synthesis of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate [ka]

[0383] To a solution of imidazo[1,2-a]pyridine-2-carboxylic acid (262 mg, 1.62 mmol) in N,N-dimethylformamide (5 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 616 mg, 1.62 mmol) and ethyldiisopropylamine (697 mg, 5.40 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes. Ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (500 mg, 1.08 mmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was concentrated, dissolved in ethyl acetate, and washed with 1N lithium chloride. The organic layer was concentrated to give ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate as a brown solid. MS(ESI) m / z 608.2 [M + H] +

[0384] Step 2: Synthesis of 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid [ka]

[0385] To a solution of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (655 mg, 1.08 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was added lithium hydroxide (2N, 2.16 mL, 4.32 mmol). The resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated to give 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (385 mg crude), which was used directly in the next step. MS (ESI) m / z 358.0 [M + H] +

[0386] Step 3: Synthesis of 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid [ka]

[0387] To a solution of 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (385 mg, 1.08 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was added triethylamine (0.3 mL, 2.16 mmol) and di-tert-butyl dicarbonate (BocO, 0.5 mL, 2.16 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in water, hexane was added, and extracted with water. The pH of the aqueous layer was adjusted to approximately 4 with 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were concentrated and purified by RP-LC (acetonitrile in water: 10% to 95%) to give 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (280 mg) as a white solid. MS(ESI) m / z 458.1 [M + H] +

[0388] Step 4: Synthesis of 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide [ka]

[0389] To a solution of 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (140 mg, 0.306 mmol) in N,N-dimethylformamide (3 mL) was added ethyldiisopropylamine (DIEA, 151 mg, 1.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 147 mg, 0.765 mmol), and 1-hydroxybenzotriazole (HOBt, 50 mg, 0.368 mmol). After stirring at room temperature for 0.5 hours, (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (148 mg, 0.368 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated, dissolved in ethyl acetate, and washed with 1N lithium chloride. The organic layer was concentrated and purified by RP-HPLC (0.1% NH in ACN / HO) to give 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (110 mg) as a white solid. MS (ESI) m / z 841.4 [M + H] +

[0390] Step 5: Synthesis of 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (13) [ka]

[0391] A solution of 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (110 mg, 0.131 mmol) in hydrochloric acid / ethyl acetate (3N, 20 mL) was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was lyophilized to give 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide salt (60 mg) as a pink solid. MS (ESI) m / z 541.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.89-8.74 (m, 5H), 8.29-8.10 (m, 3H), 7.87-7.63 (m, 3H), 7.56-6.94 (br, 4H), 5.82 (t, J = 7.6 Hz, 1H), 4.65-4.36 (m, 4H), 4.15-4.02 (m, 2H), 3.11-3.06 (m, 2H), 2.74-2.63 (m, 2H), 2.60 (d, J = 4.4 Hz, 3H), 1.78-1.67 (m, 2H), 1.52-1.43 (m, 2H), 1.35-1.23 (m, 2 H) 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (14) [ka]

[0392] Step 1: Synthesis of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate [ka]

[0393] To a solution of 1,2-dimethyl-1H-imidazole-4-carboxylic acid (200 mg, 1.4 mmol) in N,N-dimethylformamide (5 mL) at 25° C. was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 814 mg, 2.1 mmol) and ethyl diisopropylamine (553 mg, 4.3 mmol). The mixture was stirred at room temperature for 20 minutes, and then ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (500 g, 1.1 mmol) was added. The mixture was stirred for 2 hours and concentrated. The residue was diluted with 20 mL of water, extracted with ethyl acetate (30 mL x 3), and washed with 1N lithium chloride (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated to give ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (837 mg) as a brown oil, which was used without further purification. MS (ESI) m / z 586.1 [M + H] +

[0394] Step 2: Synthesis of 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid [ka]

[0395] To a solution of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (900 mg, 0.6 mmol) in methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL) at 25° C. was added lithium hydroxide (1.3 mL, 2.6 mmol). After the addition, the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid as an aqueous solution, which was used without further purification. MS (ESI) m / z 336.2 [M + H] +

[0396] Step 3: Synthesis of 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid [ka]

[0397] To a solution of 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (0.6 mmol) in water (2 mL) and methanol (8 mL) at 25 °C, 4-dimethylaminopyridine (117 mg, 1.0 mmol) and di-tert-butyl dicarbonate (BocO, 207 mg, 1.0 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours, concentrated, diluted with water (40 mL), and the mixture was extracted with petroleum ether (40 mL × 3). The pH of the aqueous layer was adjusted to approximately 6 with hydrochloride (2 N) and concentrated. The residue was purified by RP-LC (acetonitrile in water: 10% to 95%) to give 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (140 mg) as a white solid. MS (ESI) m / z 436.2 [M + H] +

[0398] Step 4: Synthesis of 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide [ka]

[0399] To a solution of 2-((2S,4R)-4-((tert-butoxycarbonyl)amino)-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (8,100 mg, 0.2 mmol) in N,N-dimethylformamide (3 mL) at 25° C. was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 131 mg, 0.4 mmol) and ethyldiisopropylamine (89 mg, 0.7 mmol). The mixture was stirred at room temperature for 20 minutes. Next, (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide (100 mg, 0.3 mmol) was added, and the mixture was stirred for 2 h at 25° C. The solvent was removed, and the residue was purified by RP-HPLC (0.1% NH in ACN / HO) to give 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (130 mg) as a white solid. 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 11.49 (s, 1H), 8.29-8.26 (m, 1H), 8.13 (s, 1H), 8.09-8.02 (m, 2H), 7.65-7.62 (m, 1H), 7.33-7.23 (m, 1H), 5.58 (t, J = 6.8 Hz, 1H), 4.44-3.92 (m, 4H), 3.59-3.53 (m, 3H), 3.28-3.23 (m, 2H), 2.60 (d, J = 8.4 Hz, 3H), 2.32-2.16 (m, 5H), 1.78-1.65 (m, 2H), 1.52-1.24 (m, 31H)

[0400] Step 5: Synthesis of 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (14) [ka]

[0401] A solution of 2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-(2,3-bis(tert-butoxycarbonyl))guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (130 mg, 0.16 mmol) in hydrochloric acid / ethyl acetate (3N, 10 mL) was stirred at 25° C. for 4 hours. The solvent was evaporated and the residue was lyophilized to give 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide hydrochloride salt (65 mg) as a yellow solid. MS (ESI) m / z 519.1 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.85 (s, 3H), 8.40 (s, 1H), 8.26-8.22 (m, 2H), 8.13 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.49-7.05 (br, 2H), 5.77 (t, J = 7.2 Hz, 1H), 4.46-4.11 (m, 4H), 3.99-3.91 (br, 3H), 3.79 (s, 3H), 3.12-3.07 (m, 2H), 2.77-2.60 (m, 8H), 1.80-1.72 (m, 2H), 1.49-1.46 (m, 2H), 1.33-1.29 (m, 2H) 2-((2S,4R)-4-amino-1-benzoylpyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (15) [ka] Compound 15 was synthesized by a method similar to that used to synthesize compound 14, using benzoic acid in step 1. MS (ESI) m / z 501.0. [M + H] + 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.71-8.45 (m, 3H), 8.25-8.11 (m, 3H), 7.85-7.29 (m, 10H), 5.76-6.65 (m, 1H), 4.48-4.39 (m, 1H), 4.15-4.11 (m, 1H), 3.95-3.94 (m, 1H), 3.71-3.63 (m, 2H), 3.08 (q, J = 6.4 Hz, 2H), 2.75-2.69 (m, 1H), 2.62 (s, 3H), 1.77-1.66 (m, 2 H), 1.50-1.41 (m, 2 H), 1.37-1.24 (m, 2 H)

[0402] (2S,4R)-3-Chlorobenzyl 4-amino-2-(4-(((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)carbamoyl)thiazol-2-yl)pyrrolidine-1-carboxylate (16) [ka]

[0403] Compound 16 was synthesized in a manner similar to that used to synthesize compound 14, starting with step 2 and using ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(((3-chlorobenzyl)oxy)carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate. MS (ESI) m / z 565.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.73 (s, 3H), 8.25-8.06 (m, 3H), 7.81-7.79 (m, 1H), 7.49-6.97 (br, 9H), 5.53-5.42 (m, 1H), 5.13-4.97 (m, 2H), 4.44-4.42 (m,1H), 3.93-3.79 (m, 3H), 3.08 (s, 2H), 2.68-2.37(m, 5H), 1.76-1.71 (m, 2H), 1.49-1.46 (m, 2H), 1.36-1.21 (m, 2H)

[0404] Synthesis of ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(((3-chlorobenzyl)oxy)carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate [ka]

[0405] To a solution of (3-chloro-phenyl)-methanol (149 mg, 1.04 mmol) in dichloromethane (4 mL), 1,1'-carbonyldiimidazole (CDI, 169 mg, 1.04 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Next, ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidin-2-yl)thiazole-4-carboxylate (400 mg, 0.864 mmol) was added. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated and purified by silica column chromatography (petroleum ether:ethyl acetate=4:1) to provide ethyl 2-((2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(((3-chlorobenzyl)oxy)carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (356 mg) as a white solid. MS (ESI) m / z 632.1 [M + H] + 2-((2S,4R)-4-amino-1-(cyclohexanecarbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (17) [ka]

[0406] Compound 17 was synthesized by a method similar to that used to synthesize compound 14, using cyclohexanecarboxylic acid in step 1. MS (ESI) m / z 507.3 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.85-8.07 (m, 8H), 7.82-6.97 (m, 4H), 5.82-5.47 (m, 1H), 4.44 (q, J = 5.6 Hz, 1H), 4.04-3.76 (m, 3H), 3.11-3.08 (m, 2H), 2.61 (d, J = 4.4 Hz, 3H), 2.57-2.34 (m, 3H), 1.78-1.63 (m, 6H), 1.49-1.45 (m, 2H), 1.40-1.16(m, 8H) 2-((2S,4R)-4-amino-1-isobutyrylpyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (18) [ka]

[0407] Compound 18 was synthesized by a method similar to that used to synthesize compound 14, using isobutyric acid in step 1. MS (ESI) m / z 467.1 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.63 (br, 3H), 8.21 (s, 1H), 8.11-8.05 (m, 1H), 7.75-7.69 (m, 1H), 7.50-7.20 (br, 2H), 5.51-5.48 (m, 1H), 4.47-4.42 (m, 1H), 4.02-3.72 (m, 7H), 3.10-3.05 (m, 2H), 2.76-2.71 (m, 1H), 2.61 (d, J = 4.4 Hz, 3H), 2.57-2.53 (m, 2H), 1.82-1.62 (m, 2H), 1.50-1.45 (m, 2H), 1.33-1.23 (m, 2H) 2-((2S,4R)-4-amino-1-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (19) [ka]

[0408] Compound 19 was synthesized by a method similar to that used to synthesize compound 14, using 6-trifluoromethyl-imidazo[1,2-a]pyridine-2-carboxylic acid in step 1. MS (ESI) m / z 609.0 [M+H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.35-9.30 (m, 1H), 8.71-8.59 (m, 4H), 8.23-8.07 (m, 3H), 7.90-7.74 (m, 2H), 7.66-7.56 (m, 2H), 7.55-6.78 (m, 4H), 5.80 (t, J = 6.8 Hz, 1H), 4.60-4.40 (m, 3H), 4.17-4.15 (m, 1H), 3.17-3.07 (m, 2H), 2.76-2.60 (m, 5H), 1.78-1.70 (m, 2H), 1.50-1.45 (m, 2H), 1.36-1.30 (m, 2H) 2-((2S,4R)-4-amino-1-(6-methoxyimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (20) [ka]

[0409] Compound 20 was synthesized by a method similar to that used to synthesize compound 14, using 6-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid in step 1. MS (ESI) m / z 571.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.80 (br, 4H), 8.60 - 8.52 (m, 1H), 8.26 - 8.10 (m, 3H), 7.90 - 7.74 (m, 2H), 7.65 - 7.56 (m, 1H), 7.42 (br, 3H), 5.82 (t, J = 6.4 Hz, 1H), 4.53 - 4.35 (m, 4H), 4.17 (s, 2H), 3.88 (s, 3H), 3.14 - 3.06 (m, 2H), 2.80 - 2.65 (m, 2H), 2.61 - 2.59 (m, 3H), 1.82 - 1.68 (m, 2H), 1.52 - 1.42 (m, 2H), 1.38 - 1.26 (m, 2H) 2-((2S,4R)-4-amino-1-(6-iodoimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (21) [ka]

[0410] Compound 21 was synthesized by a method similar to that used in the synthesis of 14, using 6-iodoimidazo[1,2-a]pyridine-2-carboxylic acid in step 1. MS(ESI) m / z 666.9. [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.14 (s, 1H), 8.78 (br, 3H), 8.61 (s, 1H), 8.24 (s, 2H), 8.20 - 8.09 (m, 1H), 7.90 - 7.74 (m, 2H), 7.70 - 7.56 (m, 1H), 7.52 - 6.72 (m, 3H), 5.80 (t, J = 6.0 Hz, 1H), 4.60 - 4.50 (m, 2H), 4.48 - 4.40 (m, 4H), 4.03 (s, 1H), 3.15 - 3.05 (m, 2H), 2.80 - 2.62 (m, 2H), 2.60 (s, 3H), 1.85 - 1.65 (m, 2H), 1.52 - 1.40 (m, 2H), 1.38 - 1.26 (m, 2H) Synthesis of 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-amino-6-guanidino-1-oxohexan-2-yl)thiazole-4-carboxamide (22) [ka]

[0411] Compound 22 was synthesized by a method similar to that used in the synthesis of 14, using (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl)guanidino)-hexanamide in step 9. MS (ESI) m / z 561.0 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.06 (s ,1H), 8.80-8.76 (m, 3H), 8.66 (s, 1H), 8.25 (s, 1H), 8.17-8.12 (m, 1H), 7.86-7.80 (m,2H), 7.37 (br, 1H), 7.66-7.62 (m,1H), 7.54-6.80 (br,6H), 5.80 (t, J =7.2 Hz,1H), 4.55-4.42 (m, 3H), 4.12-4.11 (m, 1H), 3.13-3.08 (m, 2H), 2.74-2.62 (m, 2H), 1.83-1.73 (m, 2H), 1.50-1.47 (m, 2H),1.34-1.23 (m, 2H) (S)-2-(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamido)-6-guanidinohexanoic acid (23) [ka]

[0412] Step 1: Synthesis of (S)-methyl 2-(2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamido)-6-(2,3-bis(tert-butoxycarbonyl)guanidine-hexanoate [ka]

[0413] To a solution of 2-((2R,4R)-4-((tert-butoxycarbonyl)amino)-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid (150 mg, 0.305 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was added (S)-methyl 2-Amino-6-(2,3-bis(tert-butoxycarbonyl)guanidino)hexanoate ((S)-2, 122 mg, 0.305 mmol), ethyldiisopropylamine (DIEA, 179 mg, 0.915 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 146 mg, 0.762 mmol), and 1-hydroxybenzotriazole (HOBt, 42 mg, 0.305 mmol) were added. The resulting mixture was stirred overnight. The solvent was removed, and the residue was diluted with 50 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-TLC (methanol:dichloromethane=1:15) to give (S)-methyl 2-(2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide)-6-(2,3-bis(tert-butoxycarbonyl)guanidinohexanoate) (70 mg) as a white solid. MS (ESI) m / z 876.4 [M + H] +

[0414] Step 2: Synthesis of (S)-2-(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamido)-6-guanidinohexanoic acid (23) [ka]

[0415] To a solution of (S)-methyl 2-(2-((2S,4R)-4-(tert-butoxycarbonyl)amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide)-6-(2,3-bis(tert-butoxycarbonyl)guanidinohexanoate (70 mg, 0.080 mmol) in 5 mL of methanol and 5 mL of tetrahydrofuran was added 5 mL of aqueous lithium hydroxide (13 mg, 0.024 mmol). After 1 h, LCMS showed the reaction was complete, and the mixture was concentrated. The residue was dissolved in dichloromethane (5 mL) and hydrochloric acid / ethyl acetate (3N, 10 mL) was added. The resulting mixture was stirred for 6 h and concentrated. The residue was purified by RP-HPLC (0.1% TFA in ACN / HO) to give (S)-2-(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide)-6-guanidinohexanoic acid hydrochloride salt (30 mg) as a white solid. MS (ESI) m / z 561.9 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.01 (s, 1H), 8.64 (s, 1H), 8.52-8.45 (m, 1H), 8.22 (br, 2H), 8.09-8.07 (m, 1H), 7.83-7.81 (m, 2H), 7.65-7.62 (m, 1H), 7.55-6.80 (m, 5H), 5.72 (t, J = 6.4 Hz, 1H), 4.80-4.44 (m, 3H), 4.03-4.01 (m, 1H), 3.10-3.08 (m, 2H), 2.61(s, 3H), 2.45-2.41 (m, 2H), 1.82 (s, 3H), 1.81-1.72 (m, 2H), 1.49-1.46 (m, 2H), 1.33-1.30 (m, 2H) 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-(dimethylamino)-6-guanidino-1-oxohexan-2-yl)thiazole-4-carboxamide (24) [ka]

[0416] Compound 24 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl)guanidino)-N,N-dimethylhexanamide in step 9. MS (ESI) m / z 589.0 [M + H]+. 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.04 (s, 1H), 8.80-8.76 (m, 3H), 8.63 (s, 1H), 8.24 (s, 1H), 8.18-8.17 (m, 1H), 7.93-7.86 (m, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.63-7.53 (m, 1H), 7.54-6.80 (br, 4H), 5.79 (t, J =7.2 Hz, 1H), 4.93-4.88 (m, 1H), 4.56-4.36 (m, 2H), 4.10-4.08 (m, 1H), 3.12-3.04 (m, 2H), 3.08 (s, 3H), 2.86 (s, 3H), 2.73-2.59 (m, 2H), 1.77-1.67 (m, 2H), 1.51-1.44 (m, 2H), 1.37-1.30 (m, 2H) 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-amino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (25) [ka]

[0417] Compound 25 was synthesized by the same reaction sequence as compound 11, using tert-butyl (S)-(5-amino-6-(methylamino)-6-oxohexyl)carbamate in step 9. MS (ESI) m / z 533.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.04 (s, 1H), 8.80 (br, 3H), 8.63 (s, 1H), 8.24-8.20 (m, 2H), 8.16-8.08(m, 3H), 7.81-7.79(m, 1H), 7.62-7.60 (m, 1H), 5.80(t, J = 6.0 Hz, 1H), 4.56-4.53 (m, 1H), 4.45-4.42(m, 2H), 4.13-4.02 (m, 1H), 2.74-2.60 (m, 7H), 1.81-1.72 (m, 2H), 1.59-1.58(m, 2H), 1.36-1.32(m, 2H) N-((S)-6-acetamido-1-(methylamino)-1-oxohexan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (26) [ka]

[0418] Compound 26 was synthesized by a method similar to that used to synthesize compound 11, using (S)-6-acetamido-2-amino-N-methylhexanamide in step 9. MS (ESI) m / z 575.0 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.97 (d, J = 0.8 Hz, 1H), 8.74-8.67 (m, 3H), 8.55 (d, J = 9.6 Hz, 1H), 8.24 (d, J = 10.4 Hz, 1H), 8.16-8.08 (m, 2H), 7.93 (br, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.56-7.53 (m, 1H), 5.80-5.65 (m, 1H), 4.69-4.00 (m, 4H), 3.00-2.97 (m, 2H), 2.86-2.59 (m, 5H), 1.78-1.70 (m, 5H), 1.41-1.23 (m, 4H)

[0419] Step 1: Synthesis of (S)-benzyl (6-amino-1-(methylamino)-1-oxohexan-2-yl)carbamate [ka]

[0420] To a solution of (S)-benzyl tert-butyl (6-(methylamino)-6-oxohexane-1,5-diyldicarbamate (1.0 g, 2.5 mmol) in ethyl acetate (5 mL) at 25° C. was added hydrochloric acid / ethyl acetate (3 N, 20 mL). After the addition, the resulting mixture was stirred at 25° C. for 2 hours. The mixture was concentrated to give (S)-benzyl (6-amino-1-(methylamino)-1-oxohexane-2-yl)carbamate (800 mg, crude) as a white solid, which was used without further purification. MS (ESI) m / z 294.2 [M + H] +

[0421] Step 2: Synthesis of (S)-benzyl (6-acetamido-1-(methylamino)-1-oxohexan-2-yl)carbamate [ka]

[0422] A solution of (S)-benzyl (6-amino-1-(methylamino)-1-oxohexan-2-yl)carbamate (400 mg, 1.21 mmol) and triethylamine (1.38 g, 13.7 mmol) in dichloromethane (20 mL) was stirred at 25° C. for 10 minutes and cooled to 0° C. Acetyl chloride (129 mg, 1.64 mmol) was added. The mixture was stirred at 0° C. for 1 hour. Water (25 mL) and dichloromethane (25 mL) were added, and the organic layer was dried and concentrated to give (S)-benzyl (6-acetamido-1-(methylamino)-1-oxohexan-2-yl)carbamate (265 mg) as a white solid, which was used in the next step without further purification. MS (ESI) m / z 336.2 [M + H] +

[0423] Step 3: Synthesis of (S)-6-acetamido-2-amino-N-methylhexanamide [ka]

[0424] A solution of (S)-benzyl (6-acetamido-1-(methylamino)-1-oxohexan-2-yl)carbamate (50 mg, 0.15 mmol) in hydrogen bromide (3N in acetic acid, 1 mL) was stirred for 2 hours and concentrated to give (S)-6-acetamido-2-amino-N-methylhexanamide (30 mg, crude) as a yellow oil, which was used without further purification. MS (ESI) m / z 202.2 [M + H] + 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-(methylamino)-1-oxo-6-ureidohexan-2-yl)thiazole-4-carboxamide (27) [ka]

[0425] Compound 27 was synthesized in a manner similar to that used to synthesize compound 11, using (S)-2-amino-N-methyl-6-ureidohexanamide in step 9. MS (ESI) m / z 576.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.98 (s, 1H), 8.65 (s, 3H), 8.56 (s, 1H), 8.23 ​​(s, 1H), 8.16-8.08 (m, 2H), 7.77 (d, J = 10.0 Hz, 1H), 7.55 (dd, J = 9.6, 2.0 Hz, 1H), 5.79 (t, J = 7.2 Hz, 1H), 5.30-5.29 (br, 4H), 4.55-4.00 (m, 4H), 2.99 (t, J = 6.4 Hz, 2H), 2.68-2.60 (m, 5H), 1.77-1.69 (m, 2H), 1.42-1.24 (m, 4H)

[0426] Step 1: Synthesis of (S)-benzyl (1-(methylamino)-1-oxo-6-ureidohexan-2-yl)carbamate [ka]

[0427] To a mixture of (S)-benzyl (6-amino-1-(methylamino)-1-oxohexan-2-yl)carbamate (157 mg, 0.54 mmol) in hydrochloride (0.5 mL) and water (1 mL) was added potassium cyanate (437 mg, 5.4 mmol in 0.5 mL of HO). The mixture was stirred at 90 °C for 4 h and diluted with water (10 mL). The aqueous layer was neutralized to pH 8 with aqueous NaOH (2 N). The solid was precipitated and filtered to give (S)-benzyl (1-(methylamino)-1-oxo-6-ureidohexan-2-yl)carbamate (310 mg) as a white solid, which was used without further purification. MS (ESI) m / z 337.2 [M + H] +

[0428] Step 2: Synthesis of (S)-2-amino-N-methyl-6-ureidohexanamide [ka]

[0429] A mixture of (S)-benzyl (1-(methylamino)-1-oxo-6-ureidohexan-2-yl)carbamate (40 mg, 0.12 mmol) in hydrogen bromide (3N in acetic acid, 1 mL) was stirred at 25 °C for 2 h and concentrated to give (S)-2-amino-N-methyl-6-ureidohexanamide (59 mg, crude) as a yellow oil, which was used without further purification. MS (ESI) m / z 203.1 [M + H] + 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-5-guanidino-1-(methylamino)-1-oxopentan-2-yl)thiazole-4-carboxamide (28) [ka]

[0430] Compound 28 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylpentanamide in step 9. MS (ESI) m / z 561.0 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.93 (s, 1H), 8.60-8.58 (br, 3H), 8.49(s, 1H), 8.23(s ,1H), 8.21-8.13(m, 1H), 7.86-7.72(m, 2H), 7.58-6.8 (m, 4H), 5.78(t, J = 8.4 Hz, 1H), 4.59-4.43 (m, 3H), 4.10-4.00 (m, 1H), 3.14-3.09 (m, 2H), 2.67-2.55 (m, 5H), 1.82-1.70 (m, 2H), 1.47-1.44 (m, 2H)

[0431] Step 1: Synthesis of (S)-2-benzylcarbamate-6-(2,3-bis(tert-butoxycarbonyl))guanidino-pentanamide [ka]

[0432] To a solution of (S)-benzyl (5-amino-1-(methylamino)-1-oxopentan-2-yl)carbamate (crude, 2.1 mmol) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.915 g, 3.15 mmol) in dichloromethane (10 mL) at 25° C., ethyldiisopropylamine (DIEA, 1.34 g, 10.5 mmol) was added. After the addition, the resulting mixture was stirred at 25° C. overnight. The mixture was concentrated, and the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give (S)-2-benzylcarbamate-6-(2,3-bis(tert-butoxycarbonyl))guanidino-pentanamide (560 mg) as a colorless oil. MS (ESI) m / z 522.1 [M + H] +

[0433] Step 2: Synthesis of (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylpentanamide [ka]

[0434] To a solution of (S)-2-benzylcarbamate-6-(2,3-bis(tert-butoxycarbonyl))guanidino-pentanamide (560 mg, 1.07 mmol) in methanol (20 mL) at 25° C. was added Pd / C (56 mg, 10%). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration through a pad of Celite, the filtrate was concentrated to give (S)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylpentanamide (300 mg) as a colorless oil. MS (ESI) m / z 380.4 [M + H] + (S)-2-(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide)-N1-methylpentanediamide (29) [ka]

[0435] Compound 29 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-N1-methylpentanediamide in step 9. MS (ESI) m / z 532.9 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.92-8.88 (m, 1H), 8.56-8.35 (m, 5H), 8.20-8.06 (m, 2H), 7.74-7.62 (m, 1H), 7.48-7.39 (m, 2H), 6.97-6.86 (m, 1H), 5.77 (t, J = 5.2 Hz, 1H), 4.57-4.53 (m, 1H), 4.49-4.44 (m, 1H),4.39-4.30 (m, 1H), 4.25-4.23 (m, 1H), 2.60-2.58 (m, 5H), 2.14-2.10 (m, 2H), 2.02-1.88 (m, 2H) N-((S)-3-(1H-imidazol-4-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (30) [ka]

[0436] Compound 30 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-N-methyl-3-(1-trityl-1H-imidazol-4-yl)propanamide in step 9. MS (ESI) m / z 541.9 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 14.66 (br, 1H), 14.44 (br,1H), 9.03-8.94 (m, 2H), 8.80-8.74 (m, 3H), 8.56-8.40 (m, 2H), 8.29-8.13 (m, 2H), 7.76 (d, J = 9.6 Hz,1H), 7.59-7.39 (m, 2H), 5.78 (t, J = 6.4 Hz, 1H), 4.78-4.76 (m, 1H), 4.60-4.55 (m, 1H), 4.49-4.42 (m, 1H), 4.15-4.08 (m,1H), 3.30-3.23 (m, 2H), 2.64-2.62 (m, 2H), 2.61 (s, 3H) N-((S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (31) [ka]

[0437] Compound 31 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-3-(1H-indol-3-yl)-N-methylpropanamide in step 9. MS (ESI) m / z 591.2 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 10.83 (s, 1H), 8.86 (s, 1H), 8.39 (s, 1H), 8.11-7.94 (m, 3H), 7.71 (d, J = 4.0 Hz, 1H),7.57 (d, J = 4.0 Hz, 1H), 7.42-7.31 (m, 2H), 7.14-6.96 (m, 3H), 5.63-5.57 (m, 1H), 4.68-4.64 (m, 1H), 4.40-4.35 (m, 1H), 3.98-3.70 (m, 2H), 3.57-3.43 (m, 4H), 3.20-3.18 (m, 2H), 2.58 (d, J = 4.0 Hz, 3H), 2.31-2.11 (m, 2H)

[0438] (S)-2-Amino-3-(1H-indol-3-yl)-N-methylpropanamide [ka]

[0439] A solution of (S)-methyl 2-amino-3-(1H-indol-3-yl)propanoate (254 mg, 1.0 mmol) and methylamine (5 mL, 10 mmol) in ethanol (5 mL) was heated at 40° C. for 48 hours. The mixture was concentrated in vacuo to give (S)-2-amino-3-(1H-indol-3-yl)-N-methylpropanamide (130 mg) as a yellow solid. MS (ESI) m / z 218.1 [M + H] + N-((S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (32) [ka]

[0440] Compound 32 was synthesized by a method similar to that used to synthesize compound 11, using (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide in step 9. MS (ESI) m / z 568.1 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.88 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 8.05-7.96 (m, 3H), 7.73 (d, J = 4.0 Hz, 1H), 7.43-7.40 (m, 1H), 7.00 (d, J = 4.2 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.63-5.60 (m, 1H), 4.58-4.55 (m, 1H), 4.42-4.37(m, 1H), 3.92-3.88 (m, 1H), 3.72-3.69 (m, 1H), 2.99-2.89 (m, 2H), 2.60-2.51 (m, 3H), 2.27-2.15 (m, 2H)

[0441] (S)-2-Amino-3-(4-hydroxyphenyl)-N-methylpropanamide [ka]

[0442] A solution of (S)-methyl 2-amino-3-(4-hydroxyphenyl)propanoate (231 mg, 1.0 mmol) and methylamine (2N, 5 mL, 10 mmol) in ethanol (5 mL) was heated in a sealed tube at 40° C. for 48 hours. After cooling, the mixture was concentrated in vacuo to give the title compound (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide (120 mg) as a yellow solid. MS (ESI) m / z 195.1 [M + H] + 2-((S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (33) [ka]

[0443] Compound 33 was synthesized by a method similar to that used to synthesize compound 3, using (S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid in step 1. MS (ESI) m / z 560.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.87 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.9 (br, 2H), 7.72 (d, J = 9.6 Hz, 1H), 7.41 (dd, J = 10, 1.6 Hz, 1H), 5.57(m, J = 8.4, 2.8 Hz, 1H), 4.44-4.34 (m, 2H), 4.18-4.11 (m, 1H), 3.78-3.72 (m, 1H), 3.05-3.01 (m, 2H), 2.62 (s, 3H), 2.46-2.32 (m, 2H), 2.17-2.06(m, 2H), 1.80-1.63 (m, 2H), 1.51-1.42 (m, 2H), 1.36-1.20(m, 2H) 2-((S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (34) [ka]

[0444] Compound 34 was synthesized by a method similar to that used to synthesize compound 4, using (S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid in step 1. MS (ESI) m / z 560.0 [M + H] + . 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.87 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.9 (br, 2H), 7.72 (d, J = 9.6 Hz, 1H), 7.41 (dd, J = 10, 1.6 Hz, 1H), 5.57(m, J = 8.4, 2.8 Hz, 1H), 4.44-4.34 (m, 2H), 4.18-4.11 (m, 1H), 3.78-3.72 (m, 1H), 3.05-3.01 (m, 2H), 2.62 (s, 3H), 2.46-2.32 (m, 2H), 2.17-2.06(m, 2H), 1.80-1.63 (m, 2H), 1.51-1.42 (m, 2H), 1.36-1.20 (m, 2H) 2-((2S,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (35) [ka]

[0445] Compound 35 was synthesized by a method similar to that used to synthesize compound 5, using 2-((2S,4R)-4-amino-1-(7-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid in step 1. MS (ESI) m / z 617.0 [M + H] + ; 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.01 (s, 1H), 8.64 (s, 1H), 8.52-8.45 (m, 1H), 8.22 (br, 2H), 8.09-8.07 (m, 1H), 7.83-7.81 (m, 2H), 7.65-7.62(m, 1H), 7.55-6.80(m, 5H), 5.72 (t, J = 6.4 Hz, 1H), 4.80-4.44 (m, 3H), 4.03-4.01 (m, 1H), 3.10-3.08 (m, 2H), 2.61(s, 3H), 2.45-2.41(m, 2H), 1.82 (s, 3H), 1.81-1.72 (m, 2H), 1.49-1.46 (m, 2H), 1.33-1.30 (m, 2H) 2-((2S,4S)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (36) [ka]

[0446] Compound 36 was synthesized in a manner similar to that used to synthesize compound 1, but starting with (2S,4S)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid in step 4. MS (ESI) m / z 575.2 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.99 (s, 1H), 8.81 (br, 3H), 8.54 (s, 1H), 8.35 (d, J = 4.0 Hz, 1H), 8.25-8.15 (m, 2H), 7.83-7.76 (m, 2H), 7.53-7.51 (m, 3H), 7.41-6.81 (m, 3H), 5.68-5.65 (m, 1H), 4.70-4.66 (m, 1H), 4.34-4.28 (m, 2H), 4.00 (s, 1H), 3.13-3.10 (m, 2H), 2.82-2.76 (m, 1H), 2.68-2.56(m, 4H), 1.80-1.78 (m, 2H), 1.48-1.46 (m, 2H), 1.36-1.30 (m, 2H) 2-((2S,4S)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (37) [ka]

[0447] Compound 37 was synthesized by a method similar to that used to synthesize compound 7, using (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid in step 1. MS (ESI) m / z 576.0 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.86 (d, J = 1.2 Hz, 1H), 8.81 - 8.75 (m, 1H), 8.40 (s, 1H), 8.26 - 8.18 (m, 1H), 8.11 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.82 - 7.60 (m, 4H), 7.42 - 7.39 (dd, J = 9.6, 2.0 Hz, 1H), 5.60 - 5.54 (m, 1H), 4.50 - 4.24 (m, 4H), 3.54 - 3.52 (m, 1H), 3.08 - 2.98 (m, 2H), 2.65 - 2.60 (m, 3H), 2.18 - 2.14 (m, 1H), 2.03 - 1.95 (m, 1H), 1.70 - 1.64 (m, 2H), 1.52 - 1.42 (m, 2H), 1.38 - 1.28 (m, 2H) 2-((2S,4R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (38) [ka]

[0448] Compound 38 was synthesized by a method similar to that used to synthesize compound 7, using (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid in step 1. MS (ESI) m / z 576.0 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.87 (s, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.41 (dd, J = 9.6, 2.0 Hz, 1H), 5.59 (t, J = 8.0 Hz, 1H), 4.46-4.42 (m, 2H), 4.30-4.19 (m, 2H), 3.77-3.18 (m, 4H), 3.03-3.02 (m, 2H), 2.61 (s, 3H), 2.38-2.36 (m, 1H), 2.28-2.25(m, 1H), 1.75-1.68 (m, 2H), 1.46-1.45 (m, 2H), 1.32-1.27(m, 2H) 2-((2S,4R)-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)-4-hydroxypyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (39) [ka]

[0449] Compound 39 was synthesized by a method similar to that used to synthesize compound 7, using (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid in step 1 and (R)-2-amino-6-(2,3-bis(tert-butoxycarbonyl))guanidino-N-methylhexanamide in step 8. MS (ESI) m / z 776.3 [M + H] + . 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 11.50 (s, 1H), 8.87 (d, J = 1.2 Hz, 1H), 8.40 (s, 1H), 8.31-8.26 (m, 1H), 8.16 (s, 1H), 8.08-8.03 (m, 2H), 7.72 (d, J = 9.6 Hz, 1H), 7.41 (dd, J = 9.6, 2.4 Hz, 1H), 5.59 (t, J = 8.0 Hz, 1H), 5.17 (d, J = 3.2 Hz, 1H), 4.45-4.18 (m, 4H), 3.26-3.23 (m, 2H), 2.62 (d, J = 4.4 Hz, 3H), 2.42-2.24 (m, 2H), 1.76-1.64 (m, 2H), 1.50-1.38 (m, 2H) 2-((2S,4R)-1-(2-naphthoyl)-4-aminopyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (40) [ka]

[0450] Compound 40 was synthesized by a method similar to that used to synthesize compound 14, using 2-naphthoic acid in step 1. MS (ESI) m / z 551.2 [M + H] + ; 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.81 (br, 1H), 8.56 (s, 3H), 8.28-8.00 (m, 7H), 7.75-7.62 (m, 4H), 5.81 (t, J = 7.6 Hz, 1H), 4.50-4.45 (m, 1H), 4.26-4.21 (m, 1H), 4.14 (br, 4H), 4.05-3.97 (m, 1H), 3.73 (d, J =12.0 Hz, 1H), 3.12-3.07 (m, 2H), 2.78-2.63 (m, 5H), 1.81-1.71 (m, 2H), 1.48-1.47 (m, 2H), 1.33-1.31 (m, 2H) 2-((2S,4R)-4-amino-1-(3-chloroquinoline-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (41) [ka]

[0451] Compound 41 was synthesized by a method similar to that used to synthesize compound 14, using 3-chloroquinoline-6-carboxylic acid in step 1. MS (ESI) m / z 586.0 [M + H] + ; 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 9.04 (br, 2H), 8.95 - 8.75 (m, 3H), 8.55 - 8.15 (m, 4H), 8.04 - 7.90 (m, 2H), 7.68 - 6.88 (m, 3H), 5.85 (br, 1H), 4.91 - 4.40(m, 4H), 4.38 - 4.18 (m, 1H), 4.15 - 3.98 (m, 1H), 3.78 (d, J = 9.2 Hz ,1H), 3.13 (s, 2H), 2.88 - 2.68 (m, 2H),, 2.65 (s, 3H), 1.88 - 1.71 (m, 2H), 1.50 (br, 2H), 1.35 (br, 2H) 2-((2S,4R)-4-amino-1-(6-chloroquinoline-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (42) [ka]

[0452] Compound 42 was synthesized by a method similar to that used to synthesize compound 14, using 6-chloroquinoline-2-carboxylic acid in step 1. MS (ESI) m / z 568.1 [M + H] + ; 1 H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.78 (s, 2H), 8.62-8.46 (m, 3H), 8.27-8.18 (m, 4H), 8.16-7.91 (m, 2H), 7.90-6.40 (m, 4H), 6.43-5.81 (m, 1H), 4.71-4.68 (m, 2H), 4.49-4.40 (m, 2H), 4.18-4.07 (m, 2H), 3.12-3.08 (m, 2H), 2.75-2.71 (m, 2H), 2.69-2.62 (m, 3H), 1.81-1.67 (m, 2H), 1.48-1.45 (m, 2H), 1.35-1.29 (m, 2H) 2-((2S,4R)-4-amino-1-(3-chlorobenzo[b]thiophene-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (43) [ka]

[0453] Compound 43 was synthesized by a method similar to that used to synthesize compound 14, using 3-chlorobenzo[b]thiophene-6-carboxylic acid in step 1. MS (ESI) m / z 591.1 [M + H] +; 1 H NMR (400 MHz, DMSO) δ 8.80-8.79 (br, 1H), 8.56 (br, 3H), 8.41 (s, 1H), 8.28 (s, 1H), 8.20-8.19 (m, 1H), 8.17-8.15 (m, 1H), 8.12 (s, 1H),7.93-7.91 (m, 1H), 7.75-7.30(m, 2H), 7.60-6.80(br, 3H), 5.79 (t, J = 7.2 Hz, 1H), 4.21-4.17 (m, 1H), 4.03-3.96 (m, 1H), 3.70-3.67 (m, 1H), 3.11-3.06(m, 2H), 2.66(s, 3H), 1.80-1.71(m, 2H), 1.50-1.46 (m, 2H), 1.34-1.23 (m, 2H) 2-((2S,4R)-4-amino-1-(5-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (44) [ka]

[0454] Compound 44 was synthesized by a method similar to that used to synthesize compound 14, using 3-chlorobenzo[b]thiophene-6-carboxylic acid in step 1. MS (ESI) m / z 591.1 [M + H] + ; 1H NMR (400 MHz, DMSO) δ 9.41 (br, 1H), 8.74-8.60 (m, 4 H), 8.25-8.05 (m, 6 H), 7.73 (d, J = 4.8 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.39-6.99 (br, 3H), 5.78 (t, J = 7.6 Hz, 1H), 4.46-4.42 (m, 2H), 4.21-4.04 (m, 2H), 3.11-3.07 (m, 2H), 2.77-2.61 (m, 5H), 1.80-1.68 (m, 2H), 1.50-1.46 (m, 2H), 1.32-1.30 (m, 2H) 2-((2S,4R)-4-amino-1-(5-chlorobenzo[d]thiazole-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (45) [ka]

[0455] Compound 45 was synthesized by a method similar to that used to synthesize compound 14, using 5-chlorobenzo[d]thiazole-2-carboxylic acid in step 1. MS(ESI) m / z 592.1 [M + H] + ; 1H NMR (400 MHz, DMSO, mixture of rotamers) δ 8.62-8.55 (m, 3H), 8.29-8.26 (m, 2H), 8.19-8.11 (m, 2H), 8.01-7.97 (m, 1H), 7.70-7.64 (m, 2H), 7.44-6.99 (m, 5H), 5.82-5.32 (m, 1H),4.55-4.50 (m, 1H), 4.47-4.42 (m, 1H), 4.18-4.10 (m, 2H), 3.11-3.05 (m, 2H), 2.88-2.84 (m, 1H), 2.72...

Claims

1. 1. A pharmaceutical composition for preventing or reducing plasma kallikrein (pKal) mediated edema in the eye of a subject in need thereof, said pharmaceutical composition comprising a compound of Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein A is a substituted or unsubstituted heteroarylene or a substituted or unsubstituted heterocyclylene; R １ is -N(R Ａ ) ２ and R ２ is a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, -OR Ａ , or -N(R Ａ ) ２ and R ３ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl, and, where valences allow, R ３ Any carbon atom in the group may optionally be —O—, —NR Ａ -, -C(O)-, -C(=NR Ａ )-, -S-, -S(O)-, or -S(O) ２ - may be replaced with R Ａ each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two R Ａ the groups are joined to form a substituted or unsubstituted heterocycle; Nitrogen protecting groups include -OH, -OR ａａ , -N(R ｃｃ ) ２ , -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｃｃ ) R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ ) N (R ｃｃ ) ２ , -SO ２ N (R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, Hetero C １－１０ Alkyl, Hetero C ２－１０ Alkenyl, Hetero C ２－１０ Alkynyl, C ３－１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６－１４ aryl, or 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ is substituted with a group, The oxygen protecting group is -R ａａ , -N(R ｂｂ ) ２ , -C(=O)SR ａａ , -C(=O)R ａａ , -CO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ ) R ａａ , -C(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ ) N (R ｂｂ ) ２ , -S(=O)R ａａ , -SO ２ R ａａ , -Si(R ａａ ) ３ , -P(R ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X － , -P(OR ｃｃ ) ２ , -P(OR ｃｃ ) ３ ＋ X － , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , or -P(=O)(N(R ｂｂ ) ２ ) ２ and R ａａ Each instance of is independently １－１０ Alkyl, C １－１０ Perhaloalkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, Hetero C １－１０ Alkyl, Hetero C ２－１０ Alkenyl, Hetero C ２－１０ Alkynyl, C ３－１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６－１４ aryl, and 5- to 14-membered heteroaryl, or two R ａａ groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; R ｂｂ Each instance of is independently hydrogen, —OH, —OR ａａ , -N(R ｃｃ ) ２ , -CN, -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ ) N (R ｃｃ ) ２ , -SO ２ N (R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(N(R ｃｃ ) ２ ) ２ , C １－１０ Alkyl, C １－１０ Perhaloalkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, Hetero C １－１０ Alkyl, Hetero C ２－１０ Alkenyl, Hetero C ２－１０ Alkynyl, C ３－１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６－１４ aryl, and 5- to 14-membered heteroaryl, or two R ｂｂ groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; R ｃｃ Each instance of is independently hydrogen, C １－１０ Alkyl, C １－１０ Perhaloalkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, Hetero C １－１０ Alkyl, Hetero C ２－１０ Alkenyl, Hetero C ２－１０ Alkynyl, C ３－１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６－１４ aryl, and 5- to 14-membered heteroaryl, or two R ｃｃ groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; R ｄｄ Each instance of is independently a halogen, —CN, —NO ２ , -N ３ , -SO ２ H, -SO ３ H, —OH, —OR ｅｅ , -ON(R ｆｆ ) ２ , -N(R ｆｆ ) ２ , -N(R ｆｆ ) ３ ＋ X － , -N(OR ｅｅ ) R ｆｆ , -SH, -SR ｅｅ , -SSR ｅｅ , -C(=O)R ｅｅ , -CO ２ H, -CO ２ R ｅｅ , —OC(═O)R ｅｅ , -OCO ２ R ｅｅ , -C(=O)N(R ｆｆ ) ２ , -OC(=O)N(R ｆｆ ) ２ , -NR ｆｆ C(=O)R ｅｅ , -NR ｆｆ CO ２ R ｅｅ , -NR ｆｆ C(=O)N(R ｆｆ ) ２ , -C(=NR ｆｆ ) OR ｅｅ , -OC(=NR ｆｆ ) R ｅｅ , -OC(=NR ｆｆ ) OR ｅｅ , -C(=NR ｆｆ ) N (R ｆｆ ) ２ , -OC(=NR ｆｆ ) N (R ｆｆ ) ２ , -NR ｆｆ C (=NR ｆｆ ) N (R ｆｆ ) ２ , -NR ｆｆ SO ２ R ｅｅ , -SO ２ N (R ｆｆ ) ２ , -SO ２ R ｅｅ , -SO ２ OR ｅｅ , -OSO ２ R ｅｅ , -S(=O)R ｅｅ , -Si(R ｅｅ ) ３ , -OSi(R ｅｅ ) ３ , -C(=S)N(R ｆｆ ) ２ , -C(=O)SR ｅｅ , -C(=S)SR ｅｅ , -SC(=S)SR ｅｅ , -P(=O)(OR ｅｅ ) ２ , -P(=O)(R ｅｅ ) ２ , -OP(=O)(R ｅｅ ) ２ , -OP(=O)(OR ｅｅ ) ２ , C １－６ Alkyl, C １－６ Perhaloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, Hetero C １－６ Alkyl, Hetero C ２－６ Alkenyl, Hetero C ２－６ Alkynyl, C ３－１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R ｇｇ or two geminal R ｄｄ the substituents may be linked to form =O or =S; R ｅｅ Each instance of is independently １－６ Alkyl, C １－６ Perhaloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, Hetero C １－６ Alkyl, Hetero C ２－６ Alkenyl, Hetero C ２－６ Alkynyl, C ３－１０ Carbocyclyl, C ６－１０ aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R ｇｇ substituted with a group; R ｆｆ Each instance of is independently hydrogen, C １－６ Alkyl, C １－６ Perhaloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, Hetero C １－６ Alkyl, Hetero C ２－６ Alkenyl, Hetero C ２－６ Alkynyl, C ３－１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, or two R ｆｆ groups joined to form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｇｇ substituted with a group; R ｇｇ Each instance of is independently a halogen, —CN, —NO ２ , -N ３ , -SO ２ H, -SO ３ H, —OH, —OC １－６ Alkyl, -ON(C １－６ alkyl) ２ , -N(C １－６ alkyl) ２ , -N(C １－６ alkyl) ３ ＋ X － , —NH(C １－６ alkyl) ２ ＋ X － , -NH ２ (C １－６ alkyl) ＋ X － , -NH ３ ＋ X － , -N(OC １－６ alkyl) (C １－６ alkyl), -N(OH)(C １－６ alkyl), -NH(OH), -SH, -SC １－６ Alkyl, -SS(C １－６ alkyl), -C(=O)(C １－６ alkyl), —CO ２ H, -CO ２ (C １－６ alkyl), —OC(═O)(C １－６ alkyl), —OCO ２ (C １－６ alkyl), —C(═O)NH ２ , -C(=O)N(C １－６ alkyl) ２ , -OC(=O)NH(C １－６ alkyl), -NHC(=O)(C １－６ alkyl), -N(C １－６ alkyl)C(=O)(C １－６ alkyl), -NHCO ２ (C １－６ alkyl), -NHC(=O)N(C １－６ alkyl) ２ , -NHC(=O)NH(C １－６ alkyl), -NHC(=O)NH ２ , -C(=NH)O(C １－６ alkyl), —OC(═NH)(C １－６ alkyl), —OC(═NH)OC １－６ Alkyl, -C(=NH)N(C １－６ alkyl) ２ , -C(=NH)NH(C １－６ alkyl), -C(=NH)NH ２ , -OC(=NH)N(C １－６ alkyl) ２ , -OC(=NH)NH(C １－６ alkyl), —OC(═NH)NH ２ , -NHC(=NH)N(C １－６ alkyl) ２ , -NHC(=NH)NH ２ , -NHSO ２ (C １－６ alkyl), -SO ２ N (C １－６ alkyl) ２ , -SO ２ NH (C １－６ alkyl), -SO ２ NH ２ , -SO ２ (C １－６ alkyl), -SO ２ O (C １－６ alkyl), -OSO ２ (C １－６ alkyl), -SO(C １－６ alkyl), -Si(C １－６ alkyl) ３ , —OSi(C １－６ alkyl) ３ -C(=S)N(C １－６ alkyl) ２ , C(=S)NH(C １－６ alkyl), C(=S)NH ２ , -C(=O)S(C １－６ alkyl), -C(=S)SC １－６ Alkyl, -SC(=S)SC １－６ Alkyl, -P(=O)(OC １－６ alkyl) ２ , -P(=O)(C １－６ alkyl) ２ , -OP(=O)(C １－６ alkyl) ２ , -OP(=O)(OC １－６ alkyl) ２ , C １－６ Alkyl, C １－６ Perhaloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, Hetero C １－６ Alkyl, Hetero C ２－６ Alkenyl, Hetero C ２－６ Alkynyl, C ３－１０ Carbocyclyl, C ６－１０ aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R ｇｇ the substituents may be linked to form =O or =S; X － is the counterion; Pharmaceutical compositions.

2. 2. The pharmaceutical composition of claim 1, wherein A is a substituted or unsubstituted heteroarylene.

3. R Ａ 3. The pharmaceutical composition of claim 1 or 2, wherein each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom.

4. The compound has the formula Ia: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein R １ , R ２ and R ３ is as defined in claim 1, X is N or CR ｙ and Y is O, S, or NR ｘ and R ｘ and R ｙ are independently hydrogen or substituted or unsubstituted alkyl; The pharmaceutical composition according to any one of claims 1 to 3.

5. The compound has formula Ib: 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein R １ , R ２ and R ３ is as defined in claim 1 The pharmaceutical composition according to any one of claims 1 to 4.

6. R １ is -NH ２ The pharmaceutical composition according to any one of claims 1 to 5, wherein

7. The compound has formula Ic: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein R ２ and R ３ is as defined in claim 1 The pharmaceutical composition according to any one of claims 1 to 6.

8. R ２ is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, -OR Ａ , or -N(R Ａ ) ２ The pharmaceutical composition according to any one of claims 1 to 7, wherein

9. R ２ The pharmaceutical composition of any one of claims 1 to 8, wherein is substituted or unsubstituted heteroaryl.

10. R ２ The pharmaceutical composition of any one of claims 1 to 8, wherein is a substituted or unsubstituted fused bicyclic heteroaryl.

11. The compound has formula Id: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein R ３ is as defined in claim 1, R ｗ is hydrogen, halogen, alkoxy, alkoxyalkyl, haloalkoxy, or haloalkyl; The pharmaceutical composition according to any one of claims 1 to 10.

12. R ３ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted acyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, and, where valences permit, R ３ Any carbon atom in the formula (I) may optionally be —O—, —NR Ａ -, -C(O)-, -C(=NR Ａ )-, -S-, -S(O)-, or -S(O) ２ The pharmaceutical composition according to any one of claims 1 to 11, wherein - is optionally replaced by.

13. R ３ is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and where valences allow, R ３ Any carbon atom in the formula (I) may optionally be —O—, —NR Ａ -, -C(O)-, or -C(=NR Ａ 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the hydroxyl group is optionally replaced with hydroxyl group.

14. 1. A pharmaceutical composition for preventing or reducing plasma kallikrein (pKal)-mediated edema in the eye of a subject in need thereof, comprising: The pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; The compound is 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (1); 2-((2R,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (2); 2-((2R,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (5); 2-((2R,4S)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (6); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (11); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (12); 2-((2S,4R)-4-amino-1-(imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (13); 2-((2S,4R)-4-amino-1-(1,2-dimethyl-1H-imidazole-4-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (14); 2-((2S,4R)-4-amino-1-benzoylpyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (15); 3-Chlorobenzyl (2S,4R)-4-amino-2-(4-(((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)carbamoyl)thiazol-2-yl)pyrrolidine-1-carboxylate (16); 2-((2S,4R)-4-amino-1-(cyclohexanecarbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (17); 2-((2S,4R)-4-amino-1-isobutyrylpyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (18); 2-((2S,4R)-4-amino-1-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (19); 2-((2S,4R)-4-amino-1-(6-methoxyimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (20); 2-((2S,4R)-4-amino-1-(6-iodoimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (21); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-amino-6-guanidino-1-oxohexan-2-yl)thiazole-4-carboxamide (22); N ２ -(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carbonyl)-N6-carbamimidoyl-L-lysine (23); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-(dimethylamino)-6-guanidino-1-oxohexan-2-yl)thiazole-4-carboxamide (24); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-amino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (25); N-((S)-6-acetamido-1-(methylamino)-1-oxohexan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (26); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-1-(methylamino)-1-oxo-6-ureidohexan-2-yl)thiazole-4-carboxamide (27); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-5-guanidino-1-(methylamino)-1-oxopentan-2-yl)thiazole-4-carboxamide (28); (S)-2-(2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide)-N1-methylpentanediamide (29); N-((S)-3-(1H-imidazol-4-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (30); N-((S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)-2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)thiazole-4-carboxamide (31); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-3-(4-hydroxyphenyl)-1-(methylamino)-1-oxopropan-2-yl)thiazole-4-carboxamide (32); 2-((2S,4R)-4-acetamido-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (35); 2-((2S,4S)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (36); 2-((2S,4R)-1-(2-naphthoyl)-4-aminopyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (40); 2-((2S,4R)-4-amino-1-(3-chloroquinoline-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (41); 2-((2S,4R)-4-amino-1-(6-chloroquinoline-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (42); 2-((2S,4R)-4-amino-1-(3-chlorobenzo[b]thiophene-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (43); 2-((2S,4R)-4-amino-1-(5-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (44); 2-((2S,4R)-4-amino-1-(5-chlorobenzo[d]thiazole-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (45); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(5-guanidinopentyl)thiazole-4-carboxamide (46); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-carbamimidoylbenzyl)thiazole-4-carboxamide (47); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)thiazole-4-carboxamide (48); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((1-aminoisoquinolin-6-yl)methyl)thiazole-4-carboxamide (49); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-(aminomethyl)benzyl)thiazole-4-carboxamide (50); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-carbamimidoylphenethyl)thiazole-4-carboxamide (51); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(2-(6-amino-2,4-dimethylpyridin-3-yl)ethyl)thiazole-4-carboxamide (52); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(2-(1-aminoisoquinolin-6-yl)ethyl)thiazole-4-carboxamide (53); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-(4-(aminomethyl)phenethyl)thiazole-4-carboxamide (54); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)thiazole-4-carboxamide (55); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((6-chloronaphthalen-2-yl)methyl)thiazole-4-carboxamide (56); 2-((2S,4R)-4-amino-1-(5-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((R)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (57); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((5-chloro-1H-indazol-3-yl)methyl)thiazole-4-carboxamide (58); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((6-chloro-1H-indazol-3-yl)methyl)thiazole-4-carboxamide (59); 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)thiazole-4-carboxamide (60); 2-((2S,4R)-4-amino-1-(5,6-dichlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (61); 2-((2S,4R)-4-amino-1-(6-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (62); 2-((2S,4R)-4-amino-1-(4-chlorobenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (63); 2-((2S,4R)-4-amino-1-(5-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (64); 2-((2S,4R)-4-amino-1-(6-methylbenzo[b]thiophene-2-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (65); 2-((2S,4R)-4-amino-1-(6-chloroquinoline-3-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (66); or 2-((2S,4R)-4-amino-1-(2-chloroquinoline-6-carbonyl)pyrrolidin-2-yl)-N-((S)-6-guanidino-1-(methylamino)-1-oxohexan-2-yl)thiazole-4-carboxamide (67); or a pharmaceutically acceptable salt thereof; Pharmaceutical compositions.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the edema is diabetic macular edema (DME).

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the subject is a diabetic patient who has, is suspected of having, or is at risk for diabetic macular edema (DME).

17. 17. The pharmaceutical composition of any one of claims 1 to 16, further comprising an additional agent for treating diabetic macular edema (DME).

18. 18. The pharmaceutical composition of claim 17, wherein the additional agent is a steroid, an agent that targets the VEGF pathway, or an anti-PDGF agent.

19. The pharmaceutical composition according to any one of claims 1 to 18, which is an ophthalmic formulation.

20. The pharmaceutical composition according to any one of claims 1 to 19, which is suitable for intraocular or intravitreal injection.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the subject is a human.

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