Boronic Acid Derivatives and Therapeutic Uses Thereof - Patent application

Abstract

To provide methods of treating diseases.SOLUTION: Disclosed herein are antimicrobial compounds, compositions, pharmaceutical compositions, and the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents. Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient. Other embodiments disclosed herein include a method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof a compound disclosed herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 660,729, filed April 20, 2018, entitled "BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF," which is incorporated by reference in its entirety.

[0002] background FIELD OF THE INVENTION The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to boronic acid antibacterial compounds, compositions, their preparation, and their use as therapeutic agents. [Background technology]

[0003] 2. Description of Related Art Antibiotics have been an effective means of treating infectious diseases for the past half century. From the development of antibiotic therapy until the late 1980s, control of bacterial infections was nearly complete in developed countries. However, in response to the pressures of antibiotic use, numerous resistance mechanisms have spread, threatening the clinical usefulness of antibacterial therapy. The rise of antibiotic-resistant strains has become particularly common in large hospitals and nursing care centers. The consequences of this rise in resistance include greater morbidity and mortality, longer patient hospital stays, and increased treatment costs.

[0004] Various bacteria have evolved β-lactam-inactivating enzymes, or β-lactamases, that neutralize the effectiveness of various β-lactam antibiotics. β-lactamases can be classified into four classes based on their amino acid sequence: Ambler's classes A, B, C, and D. Classes A, C, and D enzymes include serine-based β-lactamases, while the less frequently encountered class B enzymes are zinc-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between different strains and species. The rapid spread of bacterial resistance and the emergence of multidrug-resistant strains severely limits available β-lactam treatment options.

[0005] The increase in class D β-lactamase-expressing bacterial strains, such as Acinetobacter baumannii, poses an emerging multidrug resistance threat. A. baumannii strains express class A, C, and D β-lactamases. Class D β-lactamases, such as those of the OXA family, are particularly effective at destroying carbapenem-type β-lactam antibiotics, such as imipenem, the active carbapenem component of Merck's Primaxin® (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428; 2006, 50, 2280; Bou, G. et al., J. Antimicrob. Agents Chemother. 2000, 44, 1556). This poses an imminent threat to the effective use of this class of drugs to treat and prevent bacterial infections. In fact, the number of cataloged serine-based β-lactamases has exploded from fewer than 10 in the 1970s to over 300 variants. These challenges have prompted the development of five "generations" of cephalosporins. When broad-spectrum cephalosporins were first introduced into clinical practice, they were designed to protect against the common class A beta-lactamases, They resisted hydrolysis by TEM-1 and SHV-1, but the development of resistant strains due to single amino acid substitutions in TEM-1 and SHV-1 led to the emergence of extended-spectrum β-lactamase (ESBL) phenotypes.

[0006] Novel β-lactamases have recently emerged that hydrolyze the carbapenem class of antibacterial agents, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other β-lactam antibiotics. These carbapenemases belong to molecular classes A, B, and D. Class A carbapenemases of the KPC type are primarily isolated from Klebsiella pneumoniae, but have now been reported in other Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. KPC carbapenemases were first described in North Carolina in 1996 and have since become widespread in the United States. KPC carbapenemases are particularly problematic in the New York City area, where several reports of spread within large hospitals and patient morbidity have been reported. These enzymes have also recently been reported in France, Greece, Sweden, and the United Kingdom, and a major outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems may be associated with poor outcomes.

[0007] Zinc-dependent class B metallo-β-lactamases are primarily represented by the VIM, IMP, and NDM types. IMP- and VIM-producing K. pneumoniae were first recognized in Japan in the 1990s and southern Europe in 2001, respectively. IMP-positive strains remain common in Japan and have caused major hospital outbreaks in China and Australia. However, the prevalence of IMP-producing Enterobacteriaceae in other parts of the world appears to have been somewhat limited. VIM-producing Enterobacteriaceae can be isolated frequently in Mediterranean countries, leading to outbreaks in Greece. Isolation of VIM-producing strains remains rare in Northern Europe and the United States. In stark contrast, NDM-producing K. pneumonia isolates are characterized by their rapid spread from their epicenter in the Indian subcontinent to Western Europe, North America, Australia, and the Far East. Furthermore, the NDM gene has rapidly spread to various species other than K. pneumonia.

[0008] Plasmid-expressed class D carbapenemases belong to the OXA-48 type. OXA-48-producing K. pneumoniae was first detected in Turkey in 2001. The Middle East and North Africa remain the major epicenters of infection; however, recent isolation of OXA-48-type-producing organisms in India, Senegal, and Argentina suggests a possible global spread. The isolation of OXA-48 in bacteria other than K. pneumonia highlights the potential for widespread use of OXA-48.

[0009] Treatment of strains producing any of these carbapenemases with carbapenems can be associated with poor outcomes.

[0010] Another mechanism of β-lactamase-mediated resistance to carbapenems involves a permeability or efflux mechanism accompanied by overproduction of β-lactamase. One example is the loss of porins accompanied by overproduction of ampC β-lactamase, which leads to resistance to imipenem in Pseudomonas aeruginosa. Efflux pump overexpression accompanied by overproduction of ampC β-lactamase can also lead to resistance to carbapenems such as meropenem. Therefore, there is a need for improved β-lactamase inhibitors. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15 [Non-patent document 2] Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269 [Non-patent document 3] Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280 [Non-patent document 4] Bou, G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556 Summary of the Invention [Means for solving the problem]

[0012] Some embodiments disclosed herein include a compound represented by formula (I) or formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein:

[0013] G is -OR 1 -C(O)R 1 , -C(O)(CH2) 0-3 SR 1 , -C(O)(CH2) 1-3 R 1 , -C(O)OR 1 , -C(O)NR 1 R 2 , -C(O)NR 1 OR 2 , -N3, -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 C(O)NR 2 R 3 , -NR 1 C(O)OR 2 , -NR 1 S(O)2R 2 , -NR 1 S(O)NR 2 R 3 , -C(=NR 1 )R 2 , -C(=NR 1 )NR 2 R3 , -NR 1 CR 2 (=NR 3 ), -NR 1 C(=NR 2 )NR 3 R 4 , -S(O)2R 1 , with C being substituted as needed 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 5- to 10-membered heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3~7 Carbocyclyl-C 1~6 Alkyl, optionally substituted 5- to 10-membered heterocyclyl-C 1~6 Alkyl, optionally substituted C 6~10 Aryl-C 1~6 Alkyl and optionally substituted 5- to 10-membered heteroaryl-C 1~6 is selected from the group consisting of alkyl,

[0014] R 1 , R 2 , R 3 and R 4 are each independently -H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted C 6~10 Aryl-C 1~6 selected from the group consisting of alkyl and optionally substituted 5-10 membered heteroaryl;

[0015] J is for CR 5 and N,

[0016] L is CR 6 and N,

[0017] M is for CR 7 and N,

[0018] R 5 , R 6 and R 7 are each independently -H, -OR 8 , halogen, -CF3, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6~10 selected from the group consisting of aryl, optionally substituted 5-10 membered heteroaryl, cyano, C1-C6 alkoxy(C1-C6)alkyl, aryloxy, and sulfhydryl (mercapto);

[0019] R 8 is hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 6~10 selected from the group consisting of aryl and optionally substituted 5-10 membered heteroaryl;

[0020] R is -H, -C 1~9 Alkyl, -CR 9 R 10 OC(O)C 1~9 Alkyl, -CR 9 R 10 OC(O)OC 1~9 Alkyl, -CR 9 R 10 OC(O)C 6~10 Aryl, -CR 9 R 10 OC(O)OC 6~10 aryl, [ka] -CR 9 R 10 OC(O)C 3~7 Carbocyclyl, -CR 9 R 10 OC(O)OC 3~7 Carbocyclyl, -CR 9 R 10 OC(O)(5-10 membered heterocyclyl) and -CR 9 R 10 selected from the group consisting of OC(O)O(5-10 membered heterocyclyl);

[0021] R 9 and R 10 -H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 5- to 10-membered heterocyclyl, optionally substituted C 6~10 is independently selected from the group consisting of aryl and optionally substituted 5-10 membered heteroaryl.

[0022] Other embodiments disclosed herein include pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.

[0023] Other embodiments disclosed herein include a method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof a compound disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0024] In some embodiments, compounds are provided that include a boronic acid moiety and act as antimicrobial agents and / or enhancers of antimicrobial agents. Various embodiments of these compounds include compounds having the structure of Formula (I) above, or a pharmaceutically acceptable salt thereof.

[0025] Some embodiments of the compounds of Formula (I) and (II), or pharmaceutically acceptable salts thereof, have the following stereochemistry as shown in the structure of Formula (Ia) or Formula (IIa). [ka]

[0026] Some embodiments of the compounds of Formula (I) and (II), or pharmaceutically acceptable salts thereof, have the following stereochemistry as shown in the structure of Formula (Ib) or Formula (IIb). [ka]

[0027] Some embodiments of the compounds of formula (I) and (II), or pharmaceutically acceptable salts thereof, are represented by formula (Ic) or formula (IIc): [ka] This includes compounds having the structure:

[0028] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), G is -OR 1 , N3, -NR 1 R 2 , N.R. 1 C(O)R 2 , with C being substituted as needed 1~4 It is selected from the group consisting of alkyl and optionally substituted 5-10 membered heteroaryl.

[0029] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), G is -OR 1 is.

[0030] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), G is selected from the group consisting of -OH, -OMe, -OBn, -CHOH, N, NH, -NHC(=O)H, -NHC(=O)CH, and [ka] is selected from the group consisting of:

[0031] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), G is selected from the group consisting of -OH and -OBn.

[0032] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), G is —OH.

[0033] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), M is CR 7 and R 7 -H, -OR 8 and halogen.

[0034] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), R 8 is replaced as necessary 1~4 It is alkyl.

[0035] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), M is selected from the group consisting of -CH, -COMe, CF and N.

[0036] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), M is -COMe.

[0037] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), R is —H.

[0038] Some embodiments include: [ka] or a pharmaceutically acceptable salt thereof.

[0039] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphs. Furthermore, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein. Included in the range.

[0040] Those skilled in the art will recognize that some of the structures depicted herein may be resonances or tautomers of compounds that may be properly represented, even if kinetically, by other chemical structures. Those skilled in the art will recognize that such structures may represent only a very small fraction of a sample of such compound(s). While such compounds are considered to be within the scope of the depicted structures, such resonances or tautomers are not represented herein.

[0041] In some embodiments, due to the facile exchange of the boron ester, the compounds described herein may be converted to alternative forms or may exist in equilibrium with these forms. Thus, in some embodiments, the compounds described herein may exist in a combination of one or more of these forms. For example, as shown below, the compounds disclosed herein may exist in a cyclic form as a cyclic boronic acid monoester as shown in Formula I, or in an acyclic form as a boronic acid as shown in Formula II, or may exist as a mixture of the above two forms depending on the medium. When G is -OH or NHR2, the compound of Formula II may cyclize to give the compound of Formula III, where G" is O or NR2. In this case, the compound may exist as a mixture of all three forms depending on the medium. [ka]

[0042] In some embodiments, the compounds described herein may exist as cyclic dimers as shown below in formula (A), or cyclic trimers as shown below in formula (B), or cyclic tetramers as shown below in formula (C), or as acyl dimers, trimers, or tetramers, etc. [ka]

[0043] Isotopes may exist in the compounds described. Each chemical element shown in the compound structure may include any isotope of said element. For example, in the compound structure, a hydrogen atom may be explicitly disclosed or may be understood as being represented in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, when referring to a compound herein, all possible isotopic forms are encompassed unless the context clearly dictates otherwise. definition

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications and other publications referred to in this specification are incorporated by reference in their entirety.In this specification, in the event that there are multiple definitions for a term, the definition in this section shall prevail unless otherwise specified.

[0045] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas their parent is not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A non-limiting example of a prodrug would be a compound that is administered as an ester ("prodrug") to facilitate passage across cell membranes where water solubility would be detrimental to transport, but then, once inside the cell where water solubility is beneficial, is metabolically hydrolyzed to the carboxylic acid, the active entity. A further example of a prodrug would be a short-chain peptide (polyamino acid) bonded to an acid group, in which case the peptide is metabolized to release the active moiety. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985). , which is incorporated herein by reference in its entirety.

[0046] The term "prodrug ester" refers to the derivative of the compound disclosed herein, which is formed by adding any of several ester-forming groups that undergo hydrolysis under physiological conditions.Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and other such groups known in the art, including (5-R-2-oxo-1,3-dioxolen-4-yl) methyl groups.Other examples of prodrug ester groups are described, for example, in T. Higuchi's and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application", edited by EB Roche, Pergamon Press: New York, pp. 14-21 (1987) (Cal (The text provides examples of esters useful as prodrugs for compounds containing a carboxyl group.) Each of the above references is incorporated herein by reference in its entirety.

[0047] "Metabolites" of the compounds disclosed herein include active species produced upon introduction of the compounds into a biological milieu.

[0048] "Solvate" refers to a compound formed by the interaction of a solvent and a compound, metabolite, or salt thereof described herein. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0049] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound without being biologically or otherwise undesirable for use in a pharmaceutical product. In many cases, the compounds herein are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups, or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases that can be used to make salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., and particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts.Organic bases that can be used to make salts include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.Many such salts are known in the art, as described in WO87 / 05297 (Johnston et al.), published September 11, 1987 (the entirety of which is incorporated herein by reference).Some examples of pharmaceutically acceptable base addition salts of the compounds disclosed herein are represented by the formula (I-salt) or (II-salt): [ka] (wherein Z is an alkali metal or NH4 + (It can be) It has the following structure.

[0050] As used herein, "C a ~C b " or "C a~b " (where "a" and "b" are integers) refers to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, "C1-C4 alkyl" or "C 1~4 An "alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0051] The term "halogen" or "halo" as used herein means any one of the radiostable atoms of column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0052] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (whenever alkyl groups appear herein, numerical ranges such as "1 to 20" refer to each integer in the given range. For example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified). The alkyl group can be a medium-sized alkyl having 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the present compounds is defined as "C 1~4By way of example only, "C 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0053] As used herein, "alkoxy" refers to the formula -OR, where R is an alkyl group selected from the group consisting of alkoxy, ... 1~9 and alkyl as defined above, such as "alkoxy."

[0054] As used herein, "alkylthio" refers to the formula -SR, where R is an alkyl group selected from the group consisting of methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, iso-butyl mercapto, sec-butyl mercapto, tert-butyl mercapto, and the like. 1~9 alkyl as defined above, such as "alkylthio" and the like.

[0055] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. Alkenyl groups can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Alkenyl groups can also be medium-sized alkenyls having from 2 to 9 carbon atoms. Alkenyl groups can also be lower alkenyls having from 2 to 4 carbon atoms. The alkenyl groups of the present compounds are defined as "C 2~4 Alkenyl" or similar designations. By way of example only, "C 2~4"Alkenyl" indicates that there are 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0056] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. Alkynyl groups can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Alkynyl groups can also be medium-sized alkynyls having from 2 to 9 carbon atoms. Alkynyl groups can also be lower alkynyls having from 2 to 4 carbon atoms. The alkynyl groups of the present compounds are defined as "C 2~4 By way of example only, "C" may be designated as "alkynyl" or similar designations. 2~4 "Alkynyl" indicates that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0057] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur, in the backbone. Heteroalkyl groups can have from 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" where no numerical range is specified. Heteroalkyl groups can also be medium-sized heteroalkyls having from 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having from 1 to 4 carbon atoms. The heteroalkyl groups of the present compounds are defined as "C 1~4 A heteroalkyl group may be designated "heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4 "Heteroalkyl" indicates that the heteroalkyl chain has from 1 to 4 carbon atoms and that one or more heteroatoms are present in the backbone of the chain.

[0058] The term "aromatic" refers to a ring or ring system having a conjugated pi-electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic (e.g., pyridine) groups. The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0059] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, all rings in the system are aromatic. Aryl groups can have from 6 to 18 carbon atoms, although this definition also encompasses occurrences of the term "aryl" where no numerical range is specified. In some embodiments, aryl The aryl group has 6 to 10 carbon atoms. 6~10 aryl," "C6 or C 10The aryl group may be designated "aryl" or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0060] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is an alkyl group selected from the group consisting of aryl, aryloxy, arylthio ... 6~10 aryloxy" or "C 6~10 "arylthio" refers to a group in which the aryl is as defined above.

[0061] "Aralkyl" or "arylalkyl" refers to any group including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. 7~14 An aryl group is attached as a substituent via an alkylene group, such as "aralkyl." In some cases, the alkylene group may be a lower alkylene group (i.e., C 1~4 alkylene group).

[0062] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur, in the ring backbone. When heteroaryl is a ring system, all rings in the system are aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5- to 7-membered heteroaryl," "5- to 10-membered heteroaryl," or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0063] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group bonded as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group may be a lower alkylene group (i.e., C 1~4 alkylene group).

[0064] As used herein, "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When a carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged, or spiro-linked fashion. A carbocyclyl may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclyl group can have 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclyl" where no numerical range is specified. A carbocyclyl group may also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group may also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is defined as "C 3~6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohex ... These include sil, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl and spiro[4.4]nonanyl.

[0065] "(Carbocyclyl)alkyl" refers to "C alkyl," including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. 4~10 A carbocyclyl group is attached as a substituent via an alkylene group, such as "(carbocyclyl)alkyl." In some cases, the alkylene group is a lower alkylene group.

[0066] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or carbocyclyl ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0067] As used herein, "cycloalkenyl" refers to a carbocyclyl ring or ring system having at least one double bond, wherein none of the rings in the ring system are aromatic. An example is cyclohexenyl.

[0068] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in fused, bridged, or spiro-bonded configurations. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either the non-aromatic or aromatic ring in the ring system. Heterocyclyl groups can have 3 to 20 ring members (i.e., the number of atoms comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocyclyl" where no numerical range is specified. Heterocyclyl groups may also be medium-sized heterocyclyls having 3 to 10 ring members. Heterocyclyl groups may also be heterocyclyls having 3 to 6 ring members. Heterocyclyl groups may also be designated as "3- to 6-membered heterocyclyl" or similar names. In preferred 6-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 to 3 of O, N or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N or S.Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, and the like. hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0069] "(Heterocyclyl)alkyl" refers to a group that is bonded as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0070] As used herein, "acyl" refers to a group selected from the group consisting of -C(=O)R, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0071] An "O-carboxy" group refers to an "-OC(=O)R" group, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0072] A "C-carboxy" group refers to a "-C(=O)OR" group, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl). Non-limiting examples include carboxyl (i.e., —C(═O)OH).

[0073] A "cyano" group refers to a "-CN" group.

[0074] A "cyanato" group refers to an "-OCN" group.

[0075] An "isocyanato" group refers to a "-NCO" group.

[0076] A "thiocyanato" group refers to a "-SCN" group.

[0077] An "isothiocyanato" group refers to a "-NCS" group.

[0078] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0079] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0080] The "S-sulfonamide" group is "-SO2NR A R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0081] An "N-sulfonamide" group is a group consisting of -N(R A )SO2R B ” group (wherein, R A and R b are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0082] The "O-carbamyl" group is "-OC(=O)NR A R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0083] The "N-carbamyl" group is defined as "-N(R A )OC(=O)R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0084] The "O-thiolvaminyl" group is "-OC(=S)NR A R B ” (in the formula, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0085] The "N-thiocarbamyl" group is defined as "-N(R A )OC(=S)R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0086] A "C-amide" group is a group that is defined as "-C(=O)NRA R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0087] An "N-amide" group is defined as "-N(R A )C(=O)R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0088] The "amino" group is "-NR A R B ” group (wherein, R A and R B are each independently, as defined herein, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl).

[0089] An "aminoalkyl" group refers to an amino group attached via an alkylene group.

[0090] The "alkoxyalkyl" group is "C 2~8 "alkoxyalkyl" refers to an alkoxy group attached via an alkylene group, such as "alkoxyalkyl."

[0091] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted," that group includes C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl (halo ... aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy (optionally substituted with halo, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, aryl "Optionally substituted" means substituted by one or more substituents independently selected from thio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted," that group can be substituted with the above substituents.

[0092] In some embodiments, the substituted group(s) are individually substituted with one or more substituent(s) independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0093] It should be understood that certain radical naming conventions can include either monoradicals or diradicals, depending on the context. For example, if a substituent requires two points of attachment to the rest of the molecule, the substituent is understood to be a diradical. For example, a substituent specified as alkyl, which requires two points of attachment, includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene."

[0094] As used herein, "alkylene" means a branched or straight-chain, fully saturated diradical chemical group containing only carbon and hydrogen, attached to the rest of the molecule through two points of attachment (e.g., alkanediyl). Alkylene groups can have 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkylene where no numerical range is specified. Alkylene groups can also be medium-sized alkylenes having 1 to 9 carbon atoms. Alkylene groups can also be lower alkylenes having 1 to 4 carbon atoms. An alkylene group is defined as "C 1~4 By way of example only, "C 1~4 "Alkylene" indicates that there are 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propane-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0095] As used herein, "alkenylene" refers to a straight or branched chain diradical chemical group containing only carbon and hydrogen, containing at least one carbon-carbon double bond attached to the rest of the molecule through two points of attachment. An alkenylene group can have 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkenylene where no numerical range is specified. An alkenylene group can also be a medium-sized alkenylene having 2 to 9 carbon atoms. An alkenylene group can also be a lower alkenylene having 2 to 4 carbon atoms. An alkenylene group is defined as "C 2~4 Alkenylene" or similar designations. By way of example only, "C 2~4 "Alkenylene" means that there are 2 to 4 carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, buta-1,3-dienylene, butene-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-2-ene-1,1 -diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propene-1,1-diyl and 2,2-dimethyl-ethen-1,1-diyl.

[0096] When two R groups are described as "together with the atom to which they are attached" forming a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), it is intended that the collective unit consisting of the atom and the two R groups be the recited ring. This ring is not specifically limited by the definition of each of the R groups when taken individually. For example, the following substructure: [ka] exists and R1 and R 2 is defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the following substructure: [ka] wherein Ring A is the nitrogen-containing heterocyclyl ring as depicted. It means having.

[0097] Similarly, when two "adjacent" R groups are said to form a ring "together with the atom to which they are attached," it is meant that the collective unit consisting of that atom, the intervening bond, and the two R groups is the recited ring. For example, the substructure: [ka] exists and R 1 and R 2 is defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the atom to which they are attached form an aryl or carbocyclyl, R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the following substructure: [ka] where A is an aryl ring or carbocyclyl containing the double bond shown. It means having.

[0098] Where a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is to be understood that the substituent may be attached in any directional configuration unless otherwise indicated. Thus, for example, -AE- or [ka] A substituent depicted as includes both orientations where the substituent is oriented such that A is attached at the leftmost point of attachment of the molecule, and also includes the case where A is attached at the rightmost point of attachment of the molecule.

[0099] As used herein, an "isostere" of a chemical group is another chemical group that exhibits the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because tetrazole mimics the properties of carboxylic acid, even though both have very different molecular formulas. Tetrazole is one of many possible isostere replacements for carboxylic acid. Other contemplated carboxylic acid isosteres include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHS02R, -COHNS02R, and -CONRCN (where R is hydrogen, C, as defined herein). 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl). Additionally, carboxylic acid isosteres can include 5- to 7-membered carbocyclic or heterocyclic rings containing any combination of CH, O, S, or N, in any chemically stable oxidation state, where any of the atoms in the ring structure are optionally substituted at one or more positions. The following structures are non-limiting examples of contemplated carbocyclic and heterocyclic isosteres: Atoms in the ring structure may be optionally substituted at one or more positions with R, as defined above. [ka]

[0100] When a chemical substituent is attached to a carboxylic acid isostere, it is also contemplated that the compound will retain the properties of a carboxylic acid isostere. When a carboxylic acid isostere is optionally substituted with one or more moieties selected from R as defined above, it is contemplated that the substitution and position of substitution will be selected such that R does not eliminate the carboxylic acid isostere properties of the compound. Similarly, when one or more R substituents on a carbocyclic or heterocyclic carboxylic acid isostere disrupt the carboxylic acid isostere properties of the compound, it is also contemplated that the placement of such substituent(s) will not result in substitution at one or more atoms that maintain or are integral to the carboxylic acid isostere properties of the compound.

[0101] Other carboxylic acid isosteres not specifically exemplified herein are also contemplated.

[0102] The term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or combination thereof. An "agent" or "test agent" includes, but is not limited to, for example, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. An "agent" or "test agent" can be a natural product, a synthetic or chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms "agent," "substance," and "compound" are used interchangeably herein.

[0103] The term "analog" is used herein to refer to a molecule that is structurally similar to a reference molecule, but that has been modified in a targeted and controlled manner by replacing certain substituents of the reference molecule with alternative substituents. Analogs are expected by those skilled in the art to exhibit the same, similar, or improved utility compared to the reference molecule. The synthesis and screening of analogs to identify variants of known compounds with improved characteristics (such as higher binding affinity for a target molecule) is a well-known technique in medicinal chemistry.

[0104] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including primates (chimpanzees, apes, monkeys) and humans, cattle, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, but also includes many other species.

[0105] The term "microbial infection" refers to the invasion of a host organism by a pathogenic microorganism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal. , including the excessive growth of microorganisms normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) causes damage to the host mammal. Thus, a mammal is "suffering" a microbial infection when excessive numbers of microbial populations are present in or on the body of a mammal, or when the effects of the presence of a microbial population(s) damage the cells or other tissues of the mammal. Specifically, this description applies to bacterial infections. The compounds of the preferred embodiments are also useful for treating microbial growth, or contamination of cell cultures or other media, or inanimate surfaces, or objects, and it should be noted that nothing herein should limit the preferred embodiments to the treatment of only higher organisms, unless expressly so specified in the claims.

[0106] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various auxiliary substances as commonly used in the art may be included. Considerations for the inclusion of various ingredients in pharmaceutical compositions are discussed, for example, in Gilman, eds. ... et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0107] "Subject," as used herein, means a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, e.g., a chicken, and any other vertebrate or invertebrate.

[0108] "Effective amount" or "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent effective to alleviate to some extent one or more symptoms of a disease or condition or reduce the likelihood of their occurrence, including curing the disease or condition. "Cure" means that the symptoms of the disease or condition are gone; however, some long-term or permanent effects (such as extensive tissue damage) may exist even after a cure is achieved.

[0109] "Treat," "treatment," or "treating," as used herein, refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition but who is susceptible to, or otherwise at risk for, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who exhibits symptoms of a disease or condition. Preparation method

[0110] The compounds disclosed herein can be synthesized by the methods described below or by modifications of these methods. Means for modifying the methods include, among other things, temperatures, solvents, reagents, etc., known to those skilled in the art. In general, during any of the methods for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be done using conventional protecting groups such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), both of which are incorporated herein by reference in their entireties. Protecting groups may be removed at a convenient later stage using methods known in the art. Synthetic chemical transformations useful in synthesizing applicable compounds are well known in the art. These methods are well known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH, both of which are incorporated herein by reference in their entirety. Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995. The routes shown and described in the specification are exemplary only, and they are not intended to, nor should they be construed to, limit the scope of the claims in any way. Those skilled in the art will recognize modifications of the disclosed syntheses and will be able to devise alternative routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims.

[0111] In the following schemes, the protecting groups for the oxygen atoms are selected for their compatibility with the required synthetic steps and for the compatibility of the introduction and deprotection steps with the overall synthetic scheme (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)). Protecting groups specific to boronic acid derivatives and / or isomers are also used. The treatment of asymmetric directing groups is described in a recent review of boronic acid chemistry: D.G. Hall (Ed.), Boronic Acids. Preparation and Application in Organic Synthesis and Medicine, Wiley VCH (2005), all of which are incorporated herein by reference in their entirety, as well as in an earlier review: Matteson, D.S. (1988). Asymmetric synthesis with The synthesis of boronic esters is described in Accounts of Chemical Research, 21(8), 294-300 and Matteson, DS (1989). Tetrahedron, 45(7), 1859-1885. The latter review article also describes a method for the stereoselective insertion of a halomethine functionality next to a boronic ester, which is used in the following synthetic scheme:

[0112] In addition to standard acid-catalyzed deprotection, specific methods for removing boronic acid protecting groups and / or stereodirecting groups include fluoride-based methods (Yuen, AKL, & Hutton, CA (2005). Tetrahedron Letters, 46(46), 7899-7903, which is incorporated herein by reference in its entirety) or periodate oxidation (Coutts, SJ, et al. (1994). Tetrahedron Letters, 35(29), 5109-5112, which is incorporated herein by reference in its entirety) can also be used to prepare the compounds disclosed herein. It can be used.

[0113] In strategies using pinanediol or other diol-based chiral auxiliaries for the stereospecific introduction of new chiral centers, early steps of the chemistry involving a boronic acid intermediate can be carried out to a chiral boronic ester, or alternatively, a non-chiral borate / boronic ester intermediate can be used early and then transesterified with a chiral diol prior to the step requiring stereoselection. Synthesis of Compounds of Formula I

[0114] The following example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0115] Compounds of formula (Ia) where R is H can be prepared from key intermediates V', XIII', and XX' and XXVI' as illustrated in Schemes 1-11, which can be made by known reactions (Boronic Acids: Preparations and Applications in Organic Synthesis, Medicine and Materials, DG Hall, ed., Wiley-VCH, Weinheim, 2011, which is incorporated herein by reference in its entirety). The methods in the following sections are defined with respect to the pure enantiomers of formula (Ia). These methods are also adaptable to prepare other enantiomers of compounds of formula (Ic), or to prepare racemic mixtures by modifying the stereospecific steps. Scheme 1 [ka]

[0116] Compounds of formula (Ia) can be prepared starting from a protected aryl or heteroaryl intermediate of formula II′ by a sequence of double Matteson homologation (J. Org. Chem., 2013, 78, 10009-10023, which is incorporated herein by reference in its entirety). Compounds of formula II' can be prepared from commercially available salicylic acid derivatives using methods described in Protecting Groups in Organic Chemistry (ed. J. F. W. McOmie, Plenum, 1973, which is incorporated herein by reference in its entirety; Protecting Groups in Organic Synthesis P. G. M. Wutts, T. W. Green, Wiley, New York, 1999, which is incorporated herein by reference in its entirety). By using conventional protecting groups for R' and R'', such as The aryl compounds of formula I' can be obtained from the compounds of formula I' by several previously known methods (WO0458679, which is incorporated herein by reference in its entirety). The aryl compounds of formula I' can be obtained by boronation using well-known and available methods (Chem. Rev. 2010, 110, 890-931, which is incorporated herein by reference in its entirety) and the desired chiral auxiliary. Formation of the boronic ester in Scheme 1 provides the precursor for Matteson homologation. Compounds of formula III', where X = Cl, R' is Boc, R" is t-butyl, or R' and R" are protected together as isopropylidene or any other group protected individually or together in a cyclic form, can be prepared from compounds of formula II' by chloromethylene-inserting homologation with good stereocontrol under Matteson reaction conditions (WO 0946098, incorporated herein by reference in its entirety). Compounds of formula III', where X is bromo, can be prepared similarly to the chloro compounds of Scheme 1 using dibromomethane (J. Am. Chem. Soc. 1990, 112, 3964-969, incorporated herein by reference in its entirety). Halo derivatives of formula III', where X is Cl or Br, can be prepared by halogenation. Stereospecific substitution with vinylmagnesium, or allylmagnesium halide, or t-butyl acetate enolate (Tetrahedron 2005, 61, 4427-4536, the entire contents of which are incorporated herein by reference) gives compounds of formula IV'. These intermediates of formula IV' can be further processed to homologate the unsubstituted methylene under Matteson reaction conditions. The intermediates thus obtained can be further modified by converting the G' group to a G substituent. The G' group, such as a vinyl or allyl functionality, can be converted to a G substituent by periodate acid. The aldehyde functionality can be converted to a substituted amine by reductive amination to a G-substituted compound of formula V'.

[0117] Simultaneous deprotection of the pinane ester and salicylic acid protecting groups of the compound of Formula V' can be achieved by heating with dilute HCl to give the desired compound of Formula (Ia). This conversion can also be achieved by treatment with BCl or BBr (WO09064414, incorporated herein by reference in its entirety). Alternatively, deprotection can be achieved by transesterification with isobutyl boronic acid in the presence of dilute acid (WO09064413, incorporated herein by reference in its entirety) or by other known methods (J. Org. Chem. (2010), 75, 468-471, incorporated herein by reference in its entirety).

[0118] The salicylic acid derivative of formula I', where Y' is a leaving group, undergoes a coupling reaction with the acetate Reformatsky reagent under Negishi conditions to give an intermediate of formula VI', where X' is OR''' (Tetrahedron, 2014, 1508-1515, J. Org. Chem., 2013, 78, 8250-8266, incorporated herein by reference in its entirety) (Scheme 2). Such intermediates can be alkylated with halomethyleneboronic acid ester derivatives VIIA, followed by modification of the ester by selective hydrolysis and reduction to give compounds of formula V' with high stereoselectivity (J. Am. Chem. Soc., 2011, 133, 11936-11939, incorporated herein by reference in its entirety). The intermediate of formula VI' can be prepared by the methyl group. Upon ethyleneation, the derivative of formula VII' is obtained (J. Org. Chem., 1986, 51, 2981-2988, which is incorporated herein by reference in its entirety). The intermediate of formula VII' is Asymmetric boronation under known conditions provides compounds of formula V' (J. Am. Chem. Soc., 2010, 132, 10630-10633, incorporated herein by reference in its entirety). Such asymmetric boronation also occurs when X' is -NOR 1 This may be feasible if: The intermediate of formula V' can be further converted to a compound of formula (Ia) under the conditions described in Scheme 1. Scheme 2 [ka]

[0119] In an alternative sequence, compounds of formula (Ia) can be prepared by boracarboxylation of an acetylenic intermediate of formula VIII' followed by asymmetric hydrogenation, as shown in Scheme 3. The aryl or heteroaryl derivatives of formula I' can undergo a Pd-mediated coupling reaction to give acetylene-substituted compounds with TMS acetylene. Boracarboxylation of alkynes with diborane compounds and carbon dioxide in the presence of N-heterocyclic carbene copper(I) complexes as catalysts regioselectively and stereoselectively affords α,β-unsaturated β-boralactone derivatives via borylcupration / carboxylation (J. Am. Chem. Soc. 2012, 134, 2012, incorporated herein by reference in its entirety). 14314-14317). These resulting derivatives are carboxylic acid esters and boronic acid esters. The compound of formula X' can be obtained by asymmetric hydrogenation of the intermediate of formula IX' (Chem. Rev. 2003, 103, 3029-3070, which is incorporated herein by reference in its entirety) to obtain the enantiomerically pure compound of formula X'. Such compounds can be further converted to compounds of formula V' by selective hydrolysis and reduction to give the appropriate G substituent, which upon final deprotection gives compounds of formula (Ia) by the steps described in Scheme 1 above. Scheme 3 [ka]

[0120] G=-NR 1 C(O)R 4 , -NR 1 C(O)NR 1 R 2 or -NR 1 C(O)OR 3 Compounds of formula (Ia) where G is —CHCO tBu, via compounds of formula V' where R' and R" together form a protected isopropylidene. Such compounds can be converted to amides by selective hydrolysis of the t-butyl ester and Curtius rearrangement (see Chem. Rev. 1999, 104:111-113, which is incorporated herein by reference in its entirety). 1988, 88, 297-368; Org. Lett., 2005, 4107-4110), followed by deprotection and amide formation to give compounds of formula XIII'. Compounds of formula XII' can also be converted by hydrolysis to compounds of formula (Ia) where G is -NHC(O)-OR. Scheme 4 [ka]

[0121] In an alternative route shown in Scheme 5, compounds of formula (Ia) can be obtained via an intermediate of formula XVII'. Such intermediates of formula XVII' can be prepared by asymmetric hydroboration (J. Am. Chem. Soc. 2014, 136, 15501-15504) and transesterification of 1,1'-disubstituted alkenes of formula XVI'. Intermediates of formula XVI' can be obtained by coupling a substituted 2-bromo-propene derivative with a boronic acid of formula XIV' via a palladium-catalyzed reaction. Intermediates of formula XVII' can be further converted to compounds of formula V' by conversion of the G' group to G (selective hydrolysis from the ester to the acid, followed by conversion to an alcohol or amide), using the transformations shown in Schemes 3 and 4. Scheme 5 [ka]

[0122] Compounds of formula (Ia) can also be prepared in a convergent manner via intermediates of formula XX', as shown in Scheme 6. Such intermediates of formula XX' are prepared by palladium-catalyzed coupling of a substituted diboronic ester precursor of formula XIX' (Org. Lett., 2014, 16, 6240-6243) with a precursor of formula I'. The phosphate esters are prepared from the propargyl derivatives of formula XVIII' by utilizing an Ir-catalyzed method (J. Am. Chem. Soc., 2010, 132, 2548-2549). The intermediate of formula XX' (G' can be -OTIPS or -CO2Me or -CONR'R'' for further modification or deprotection) is known to undergo enantioselective hydrogenation (Angew. Chem. Int. Ed., 2011, 50, 1-6; Chem. Eur. J., 2012, 18, 6724-6728) to give the intermediate of formula XXI'. As described above, modification of the G' group to G and deprotection of XXI' leads to the compound of formula (Ia). Scheme 6 [ka]

[0123] In an alternative synthetic route shown below, compounds of formula (Ia) can be prepared by nickel-catalyzed boron insertion of benzofuran derivatives of formula XXV' (J. Am. Chem. Soc., 2016, 138, 15315-15318), giving intermediates of formula XXVI'. Antitioselective hydrogenation (Angew. Chem. Int. Ed., 2011, 50, 1-6; Chem. Eur. J., 2012, 18, 6724-6728), followed by modification and deprotection of the G' group, such oxaborinane intermediates give compounds of formula (Ia). Benzofuran derivatives of formula XXV' can be prepared by several different known methods, including cyclization of intermediates of formula XXIV' (Org. Biomol. Chem., 2016, 14, 8074-8087). Such intermediates of formula XXIV' can be obtained by alkylation of appropriately substituted phenol derivatives of formula XXIII' with substituted bromoacetone derivatives of formula XXII' (Tetrahedron, 2013, 69, 5937-5944). Scheme 7 [ka]

[0124] Alternatively, intermediates of formula XXIX', which can be characterized in the route to obtaining compounds of formula (Ia), can be prepared as shown in Scheme 8. Such intermediates of formula XXIX' can be synthesized from compounds of formula XXVII', in which X' is a triflate, bromo, or iodo group, by utilizing the Reformatsky reagent of bromomethylene acetate (J. Org. Chem., 2013, 78, 8250-8266; Chem Lett., 1993, 845-848, the entire contents of which are incorporated herein by reference). Compounds of formula XXVIII', in which X' is substituted with a bromo or iodo group, can be obtained from commercially available appropriately protected 2,5-hydroxybenzoic acid derivatives (J. Med. Chem., 2003, 46, 3437-3440, the entire contents of which are incorporated herein by reference). Intermediates of formula XXXVIII' can be prepared by the previously described method ( They can also be prepared by carboxylation of derivatives of formula XXXVII', where Z' is fluoro or OR' or SR', according to WO12106995, the entire contents of which are incorporated herein by reference. Scheme 8 [ka]

[0125] In another exemplary synthetic route, as shown in Scheme 9, compounds of Formula XXXII' can be prepared from the salicylic acid derivative of compounds of Formula XXXI'. Compounds of Formula XXX' can be prepared by diallylation under basic conditions followed by thermal Claisen rearrangement (Org. React. 1975, 22, 1-252, which is incorporated herein by reference in its entirety), and and ester hydrolysis to afford compounds of formula XXXI'. Such compounds, upon protection and oxidation followed by esterification, provide phenylacetic acid derivatives of formula XXXII'. Compounds of formula XXXII' can be further transformed as shown in Scheme 2 above. Compounds of formula XXX' can also undergo the steps listed in Scheme 8 above to form ortho-carboxylate-substituted compounds of formula XXIX'. Scheme 9 [ka] Prodrug synthesis

[0126] Compounds of formula (Ia) where R is a prodrug moiety can be synthesized by a variety of known methods to generate various carboxylic acid prodrugs (Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed., Springer, New York, 2007, incorporated herein by reference in its entirety). These prodrugs include, but are not limited to, substituted or unsubstituted alkyl esters, (acyloxy)alkyl esters (Synthesis 2012, 44, 207, incorporated herein by reference in its entirety), [(alkoxycarbonyl)oxy]methyl esters (WO10097675, incorporated herein by reference in its entirety), or (oxodioxolyl)methyl esters (J. Med. Chem. 1996, 39, incorporated herein by reference in its entirety). 323-338). Such prodrugs include those where R=H (Formula XXXIII'). The esters of formula (Ia) can be prepared by treatment in the presence of an alcohol (ROH) under acidic or neutral conditions (e.g., carbodiimide coupling), or by base-promoted esterification with RX, where X is a leaving group, in the presence of a suitable base.

[0127] One exemplary, but non-limiting, general synthetic route for preparing prodrugs is shown below in Scheme 10. A boronic acid of Formula XXXIII' can be reacted with a chloro- or bromo-substituted prodrug moiety to form a prodrug of Formula (Ia) where R is the prodrug moiety. Examples of prodrug moieties R include -C 1~9 Alkyl, -CR 9 R 10 OC(O)C 1~9 Alkyl, -CR 9 R 10 OC(O)OC 1~9 Alkyl, -CR 9 R 10 OC(O)C 3~7 Carbocyclyl, -CR 9 R 10OC(O)OC 3~7 Carbocyclyl, -CR 9 R 10 OC(O)(5-10 membered heterocyclyl), -CR 9 R 10 OC(O)O(5-10 membered heterocyclyl) and [ka] It could be. Scheme 10 [ka]

[0128] Alternatively, a boronic acid ester of Formula XXXIV′ or the corresponding trifluoroboronic acid ester (Chem. Rev. 2008, 108, which is incorporated herein by reference in its entirety) can be prepared. 288-325) have also been used to introduce prodrugs, and these esters have been used to prepare the final prodrugs. The prodrug can also be converted to a prodrug (Scheme 11). Such carboxylic acids (XXXIV') can be prepared from compounds of formula V' by selective deprotection of OR'. The prodrug group may also be introduced earlier in the sequence in compounds of formula IV' where R' is R. Such a sequence, in which the prodrug is introduced earlier in the intermediate, is only feasible if the ester is sufficiently stable under the final deprotection conditions to remove the phenol protecting group and the boronic ester group. Scheme 11 [ka] Administration and Pharmaceutical Compositions

[0129] The compounds are administered at therapeutically effective doses. While human dosage levels for the compounds described herein have not yet been optimized, generally, daily doses can range from about 0.25 mg / kg to about 120 mg / kg or more of body weight, from about 0.5 mg / kg or less to about 70 mg / kg of body weight, from about 1.0 mg / kg to about 50 mg / kg, or from about 1.5 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg human, the dosage ranges would likely be from about 17 mg per day to about 8,000 mg per day, from about 35 mg or less per day to about 7,000 mg or more per day, from about 70 mg per day to about 6,000 mg per day, from about 100 mg per day to about 5,000 mg per day, or from about 200 mg to about 3,000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease condition being treated, the severity of the affliction, the manner and scheduling of administration, and the judgment of the prescribing physician.

[0130] The administration of the compounds disclosed herein or their pharmaceutically acceptable salts can be by any of the accepted modes of administration for drugs that perform similar functions, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal or ocular administration. Oral and parenteral administration are conventional for treating the indications that are the subject of preferred embodiments.

[0131] The useful compounds described above can be formulated into pharmaceutical compositions for use in treating these conditions. See Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, incorporated by reference in its entirety. (2005) are used. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0132] In addition to the above-mentioned useful selected compounds, some embodiments include compositions containing a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. In addition, various auxiliary substances commonly used in the art may be included. Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, the entire contents of which are incorporated herein by reference. There are.

[0133] Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS®; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0134] The choice of pharmaceutically acceptable carrier to be used in association with the subject compounds will basically depend on the way the compound is to be administered.

[0135] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration to an animal, preferably a mammalian subject, in a single dose in accordance with principles of good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is to be administered once per day or once per course of treatment. Such dosage forms are contemplated for administration once, twice, three or more times per day, and may be administered as an infusion or as a continuous infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), and may be given more than once during a course of treatment, although single administration is not specifically excluded. Those skilled in the art will recognize that the present formulations are not specifically intended for an entire course of treatment, and such decisions are left to those skilled in the art of formulation and treatment.

[0136] As described above, useful compositions can be administered via a variety of routes, including oral, nasal, rectal, topical (transdermal), and intravenous routes. The composition may be in any of a variety of forms suitable for intraocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral administration routes. Those skilled in the art will appreciate that oral and nasal compositions include compositions administered by inhalation and made using available methods. Depending on the particular route of administration desired, various pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmaceutically active substances may be included that do not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to achieve a practical amount of substance to be administered per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0137] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, powdered, enteric-coated, sugar-coated, film-coated, or multiple-compressed, and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorings, and flavorings.

[0138] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets may contain inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmelose. ;Conventional pharmaceutically compatible adjuvants are usually included as lubricants, such as magnesium stearate, stearic acid, and talc. Glidants, such as silicon dioxide, can be used to improve the flow characteristics of powder mixtures. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules usually contain one or more solid diluents as disclosed above. The selection of carrier components is not critical and depends on secondary considerations, such as taste, cost, and storage stability, which can be easily determined by those skilled in the art.

[0139] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate, and typical wetting agents include lecithin and polysorbate 80. Typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more ingredients, such as sweeteners, flavoring agents, and coloring agents, as disclosed above.

[0140] Such compositions may also be coated by conventional methods, usually with a pH or time dependent coating, to provide the desired topical application in the gastrointestinal tract. The compound of interest is released at or near the time of administration, or at various times, to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes, and shellac.

[0141] The compositions described herein may optionally include other pharmaceutical actives.

[0142] Other compositions that are useful for achieving systemic delivery of target compound include sublingual, oral and nasal dosage forms.These compositions usually comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.The glidant, lubricant, sweetener, colorant, antioxidant and flavoring agent disclosed above can also be included.

[0143] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered topically to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may necessitate less-than-optimal comfort. If comfort cannot be maximized, the liquid should be formulated so that it is tolerable to patients for topical ophthalmic use. Furthermore, ophthalmically acceptable liquids should either be packaged for single use or contain a preservative to prevent contamination over multiple uses.

[0144] For ophthalmic application, solution or medicine is often prepared using physiological saline solution as the main vehicle.Ophthalmic solution should preferably be maintained at a comfortable pH using an appropriate buffer system.Preparation may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0145] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.A useful surfactant is, for example, Tween® 80.Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0146] If necessary or convenient, tonicity agents may be added, including but not limited to salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity agent.

[0147] Various buffers and means for adjusting the pH may be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Buffers thus include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. Acids or bases may be used to adjust the pH of these formulations, if necessary.

[0148] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0149] Another excipient component that may be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may be used instead or in conjunction with it.

[0150] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may generally include a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0151] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients include, but are not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid, which may be included to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Additionally, acceptable excipients are described in Powell, et al., both of which are incorporated herein by reference in their entirety. al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332. Antimicrobial agents including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol may also be included to provide an antibacterial or fungistatic solution.

[0152] Compositions for intravenous administration may be provided to the caregiver in a solid form that is reconstituted in water immediately before administration with a suitable diluent, such as sterile water, saline, or dextrose. In other embodiments, the compositions are provided in a solution that is ready to be administered parenterally. In yet other embodiments, the compositions are provided in a solution that is further diluted before administration. In embodiments that involve administering a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents before administration, or the two agents may be administered separately.

[0153] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of one of ordinary skill in the art. Treatment method

[0154] Some embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions comprising the compounds described herein. Some methods include administering to a subject in need thereof a compound, composition, or pharmaceutical composition described herein. In some embodiments, the subject may be an animal, e.g., a mammal (including a human). In some embodiments, the bacterial infection comprises a bacterium described herein. As recognized from the above, methods of treating bacterial infections include methods of preventing bacterial infections in subjects at risk of bacterial infection.

[0155] In some embodiments, the subject is a human.

[0156] Further embodiments include administering to a subject in need thereof a combination of compounds. The combination can include a pharmaceutical composition comprising the compound, composition, and additional pharmaceutical agent described herein.

[0157] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein with an additional pharmaceutical agent. "Co-administration" means that two or more pharmaceutical agents may be found in a patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the pharmaceutical agents are administered simultaneously. In one such embodiment, the combined administration is achieved by combining the pharmaceutical agents in a single dosage form. In another embodiment, the pharmaceutical agents are administered sequentially. In one embodiment, the pharmaceutical agents are administered by the same route, such as orally. In another embodiment, the pharmaceutical agents are administered by different routes, such as one being administered orally and the other being administered intravenously.

[0158] Examples of additional pharmaceutical agents include antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and anti-allergic agents.

[0159] Preferred embodiments include combinations of the compounds, compositions, or pharmaceutical compositions described herein with antibacterial agents, such as β-lactams. Examples of such β-lactams include amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin ... Docillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (e.g., dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephalosporin Faroridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflur, cephradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, These include cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam and carumonam.

[0160] Preferred embodiments include β-lactams such as ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem and panipenem.

[0161] Additional preferred embodiments include β-lactams such as aztreonam, tigemonam and carumonam.

[0162] Some embodiments include combinations of the compounds, compositions and / or pharmaceutical compositions described herein with additional agents, including monobactams. Examples of monobactams include aztreonam, tigemonam, nocardicin A, carumonam, and tabtoxin. In some such embodiments, the compounds, compositions and / or pharmaceutical compositions comprise a class A, C or D β-lactamase inhibitor. Some embodiments include co-administering one or more additional agents with the compounds, compositions or pharmaceutical compositions described herein.

[0163] Some embodiments include a combination of a compound, composition and / or pharmaceutical composition described herein with an additional agent comprising a Class B β-lactamase inhibitor. Examples of Class B β-lactamase inhibitors include ME1071 (Yoshikazu Ishii et al., "In "Vitro Potentiation of Carbapenems with ME1071, a Novel Metallo-β-Lactamase Inhibitor, Against Metallo-β-Lactamase Producing Pseudomonas aeruginosa Clinical Isolates." Antimicrob. Agents Chemother. doi:10.1128 / AAC.01397-09 (July 2010)). Some embodiments include co-administering one or more additional agents with a compound, composition, or pharmaceutical composition described herein.

[0164] Some embodiments include combinations of a compound, composition and / or pharmaceutical composition described herein with an additional agent, wherein the additional agent comprises one or more agents comprising a class A, B, C or D β-lactamase inhibitor. Some embodiments include co-administering a compound, composition or pharmaceutical composition described herein with one or more additional agents. Cases

[0165] The compounds described herein and compositions comprising the compounds can be used to treat bacterial infection.The bacterial infection that can be treated by the compounds, compositions and methods described herein can include a wide range of bacteria.Exemplary organisms include gram-positive bacteria, gram-negative bacteria, aerobic bacteria and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Bacillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.

[0166] Further examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida、Stenotrophomonas maltophilia、Burkholderia cepacia、Aeromonas hydrophilia、Escherichia coli、Citrobacter freundii、Salmonella typhimurium、Salmonella typhi、Salmonella paratyphi、Salmonella enteritidis、Shigella dysenteriae、Shigella flexneri、Shigella sonnei、Enterobacter cloacae、Enterobacter aerogenes、Klebsiella pneumoniae、Klebsiella oxytoca、Serratia marcescens、Francisella tularensis、Morganella morganii、Proteus mirabilis、Proteus vulgaris、Providencia alcalifaciens、Providencia re ttgeri、Providencia stuartii、Acinetobacter baumannii、Acinetobacter calcoaceticus、Acinetobacter haemolyticus、Yersinia enterocolitica、Yersinia pestis、Yersinia pseudotuberculosis、Yersinia intermedia、Bordetella pertussis、Bordetella parapertussis、Bordetella bronchiseptica、Haemophilus influenzae、Haemophilus parainfluenzae、Haemophilus haemolyticus、Haemophilus parahaemolyticus、Haemophilus ducreyi、Pasteurella multocida、Pasteurella haemolytica、Branhamella catarrhalis、Helicobacter pylori、Campylobacter fetus、Campylobacter jejuni、Campylobacter coli、Borrelia burgdorferi、Vibrio cholerae、Vibrio parahaemolyticus、Legionella pneumophila、Listeria monocytogenes、Neisseria gonorrhoeae、Neisseria meningitidis、Kingella、Moraxella、Gardnerella vaginalis、Bacteroides fragilis、Bacteroides distasonis、Bacteroides 3452A homology group、Bacteroides vulgatus、Bacteroides ovalus、Bacteroides thetaiotaomicron、Bacteroides uniformis、Bacteroides eggerthii、Bacteroides splanchnicus、Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus Includes Staphylococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus.

[0167] The following examples are included to further illustrate the present invention. These examples, of course, should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that one skilled in the art, given this disclosure and the skill in the art, may prepare and use the present invention without the need for comprehensive examples. The following examples further describe the present invention and are used for illustrative purposes only and should not be considered limiting. [Example]

[0168] General Procedure The materials used in the preparation of the cyclic boronic ester derivatives described herein can be made by known methods or are commercially available. It will be clear to those skilled in the art that methods for preparing precursors and functional groups related to the compounds described are generally described in the literature, including the procedures described in, for example, US7271186 and WO2009064414, each of which is incorporated by reference in its entirety. In these reactions, it is also possible to use variants that are known per se to those skilled in the art, but which are not specified in more detail. A skilled artisan, given the literature and this disclosure, is fully equipped to prepare any compound.

[0169] Those skilled in the art of organic chemistry will recognize that these manipulations can be readily performed without further instruction, i.e., are well within the scope and practice of the art. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic etherification, esterification, and saponification. These manipulations are discussed in standard textbooks such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry, which is incorporated herein by reference in its entirety.

[0170] Those skilled in the art will readily recognize that certain reactions are best performed if other functional groups in the molecule are masked or protected, thus avoiding any undesired side reactions and / or improving the yield of the reaction. Often, those skilled in the art will utilize protecting groups to achieve such improved yields or avoid undesired reactions. These reactions can be found in the literature and are also well within the scope of those skilled in the art. Numerous examples of these manipulations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007).

[0171] The following example schemes are provided for the reader's guidance and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it is clear that other routes can be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. Those skilled in the art are fully equipped to prepare these compounds by such methods as are shown in the literature and this disclosure. The compound numbers used in the synthetic schemes illustrated below are intended only for those specific schemes and should not be interpreted or confused with the same numbers in other sections of this application.

[0172] The trademarks used herein are merely examples and represent exemplary materials used at the time of the present invention. Those skilled in the art will recognize that variations in lots, manufacturing methods, etc. are to be expected. Therefore, the examples and the trademarks used in the examples are non-limiting and are not intended to be limiting, but merely examples of how a person skilled in the art may select to perform one or more embodiments of the present invention.

[0173] The following abbreviations have the meanings indicated: [Table 6]

[0174] The following example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds provided herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. Example 1 2-Hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 1) [ka] Step 1: Synthesis of 1B

[0175] To a mixture of compound 1A (20 g, 116 mmol, 1.0 equiv.) and DMAP (4.2 g, 34 mmol, 0.3 equiv.) in DCM (200 mL) was added BocO (37.8 g, 173 mmol, 1.5 equiv.), and the resulting solution was stirred at room temperature for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (PE / EA = 50:1 to 20:1) to give compound 1B (31 g, 98%) as a light yellow oil. Step 2: Synthesis of 1C

[0176] To a solution of compound 1B (34 g, 125 mmol, 1.0 equiv.) in THF (350 mL) was added LDA (75 mL, 150 mmol, 1.2 equiv.) dropwise at −78° C. The resulting solution was slowly warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (PE / EA = 50:1 to 20:1) to give compound 1C (21.8 g, 64%) as a light yellow oil. Step 3: Synthesis of 1D

[0177] To a solution of compound 1C (21.8 g, 79.8 mmol, 1.0 equiv) in DCM (110 mL) was added TFA (110 mL) at room temperature. After 16 h at this temperature, the mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (PE / EA = 50:1 to 10:1) to give compound 1D (13.9 g, 80%) as a white solid. Step 4: Synthesis of 1E

[0178] To a solution of compound 1D (14.7 g, 68 mmol, 1.0 equiv.) in TFA (95 mL) was added DMF (65 mL) at 0° C., followed by the simultaneous slow addition of acetone (50.6 mL) and TFAA (65 mL). After 16 hours at 100° C. under a nitrogen atmosphere, the mixture The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (PE / EA=50:1 to 10:1) to give compound 1E (7.7 g, 44%) as a yellow solid. Step 5: Synthesis of 1F

[0179] To a mixture of compound 1E (5 g, 19.53 mmol, 1.0 equiv.) in dioxane (50 mL), B2 ((+)-pinanediol)2 (10.5 g, 29.30 mmol, 1.5 equiv.), PdCl2(dppf) (797 mg, 0.98 mmol, 0.05 equiv.), and KOAc (3.8 g, 39.06 mmol, 2.0 equiv.) were added. The mixture was stirred overnight at 95 °C under a nitrogen atmosphere. The mixture was filtered, and the filtrate was diluted with EA and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 1:0 to 10:1) to give compound 1F (2.0 g, 29%). Step 6: Synthesis of 1G

[0180] To a solution of compound 1F (1.0 g, 2.81 mmol, 1.0 equiv.) in THF (10 mL) was added 1F' (1.3 g, 5.62 mmol, 2.0 equiv.), Pd(PPh3)4 (162 mg, 0.14 mmol, 0.05 equiv.), and 2N Na2CO3 (7.0 mL, 14.0 mmol, 5 equiv.). The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was then diluted with EA, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 1:0 to 10:1) to give compound 1G (715 mg, 78%). Step 7: Synthesis of 1H

[0181] To a solution of 2 M BH3-S(Me)2 (1.2 mL, 2.47 mmol, 2.0 equiv) in dry THF (10 mL) was slowly added a solution of compound 1G (400 mg, 1.24 mmol, 1.0 equiv) in dry THF (1 mL) at -15 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h, quenched with water, and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in dry THF (8 mL), and 2,3-dimethylbutane-2,3-diol (292 mg, 2.47 mmol, 2.0 equiv) was added. The reaction mixture was stirred at room temperature overnight. The reaction was then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 30:1 to 10:1) to give compound 1H (106 mg, 19%). Step 8: Synthesis of 1I

[0182] To a solution of compound 1H (120 mg, 0.266 mmol, 1.0 equiv.) in HO / ACN (1 mL / 1 mL) was added 0.5 M NaOH (1 mL, 0.5 mmol, 1.8 equiv.), and the resulting mixture was stirred at room temperature for 3 h. This mixture was then purified by preparative HPLC (under neutral conditions) to give compound 1I (50 mg, 60%). Step 9: Synthesis of 1

[0183] To a solution of compound 1I (110 mg, 0.70 mmol, 1.0 equiv.) in MeOH (10 mL) was added Pd / C (11 mg, 10%, w / w). The resulting mixture was stirred at room temperature under 1 atm of H for 4 hours. After filtration through a pad of Celite®, the filtrate was purified by preparative HPLC (under acidic conditions) to give compound 1 (20 mg, 26%). LC-MS: 221 [MH] - [ka] Example 2 Disodium salt of 4-(benzyloxymethyl)-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 2) [ka] Step 1: Synthesis of 2B

[0184] To a suspension of 2,6-dimethoxybenzoic acid (2A) (50 g, 274 mmol) in CHCl (200 mL) was added bromine (14.06 mL, 274 mmol, 1 equiv.) in CHCl (20 mL) slowly over 8 h. After stirring overnight at room temperature, the light orange slurry was heated and some of the solvent (methyl bromide, hydrogen bromide, and CHCl) was removed by distillation at atmospheric pressure (a total volume of 100 mL was distilled). Ethanol (150 mL) was added, and the remaining CHCl was distilled off at atmospheric pressure, slowly raising the bath temperature to 90 °C. Upon completion of distillation (1 h), the heterogeneous mixture was cooled to room temperature. After stirring at room temperature for 1 h, the slurry was cooled to 0 °C. After stirring at 0 °C for 2 h, the solid was collected by filtration. The filtrate was recycled to wash the flask and stir bar. The solid was washed with ethanol (2 x 50 mL) at 0°C, air-dried, and then dried under high vacuum to give compound 2B (58.23 g, 85.9%) as white fine needles. Step 2: Synthesis of 2C

[0185] The contents of a 10 mL syringe charged with trifluoroacetic anhydride (11.25 mL, 81 mmol, 2 equiv.) and a 20 mL syringe charged with acetone (17 mL, 232 mmol, 5.7 equiv.) were simultaneously dispensed via syringe pump over 24 h into a clear solution of 2B (10 g, 40 mmol) in TFA (10 mL) at 70 °C. After 1 h, the starting material began to crystallize. Addition of TFA (5 mL) gave a clear solution. After an additional 1 h at 70 °C, the solution became slightly heterogeneous. Upon complete addition, HPLC indicated an 89:11 ratio of product to starting material. After stirring overnight at 70 °C, the ratio was 92:8. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), and filtered over a pad of Celite®, washing the flask with ethyl acetate (2 × 10 mL). The clear black filtrate was concentrated to dryness. The solid was dissolved in ethyl acetate (50 mL) and CH2Cl2 (10 mL, The brown / black solution was concentrated to dryness. The residue was dissolved in ethyl acetate (10 mL) and the mixture was heated to reflux. Heptane (3×10 mL) was added and the mixture was refluxed (the product began to crystallize after the final addition of heptane). The heterogeneous mixture was refluxed for 15 minutes and allowed to cool to room temperature. After stirring for 2 hours at room temperature and 2 hours at 0° C., the solid was collected by filtration. The filtrate was recycled to wash the flask. The solid was washed with 3:1 heptane / ethyl acetate (2×10 mL) at 0° C., air-dried, and then dried under high vacuum to give compound 2C (8.83 g, 76%) as a light brown powder. Step 3: 2D synthesis

[0186] To a mixture of compound 2C (10.0 g, 3.5 mmol, 1.0 equiv.) in dioxane (300 mL), B2 ((+)-pinanediol) (18.8 g, 52.5 mmol, 1.5 equiv.), PdCl(dppf) (2.8 g, 3.5 mmol, 0.1 equiv.), and KOAc (6.86 g, 70 mmol, 2.0 equiv.) were added. Under a nitrogen atmosphere, the mixture was stirred at 96 °C overnight. The mixture was then filtered, and the filtrate was diluted with EA, washed with water and brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 30:1 to 5:1) and triturated with PE / EA (10:1) to give compound 2D (7.9 g, 58%). Step 4: Synthesis of 2E

[0187] To a mixture of compound 2D (7.3 g, 19.06 mmol, 1.0 equiv.) in THF (120 mL) was added bromide 1F' (5.6 g, 24.8 mmol, 1.3 equiv.), Pd(PPh3)4 (1.1 g, 0.95 mmol, 0.05 equiv.), and 2N Na2CO3 (48 mL, 95 mmol, 5.0 equiv.). The mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. The mixture was filtered, and the filtrate was extracted with EA and HO. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 20:1 to 5:1) to give compound 2E (9.0 g, 100%, contained some pinanediol). Step 5: Synthesis of 2F

[0188] A solution of compound 2E (15 g, 42.37 mmol, 1.0 equiv) in dry THF (50 mL) was slowly added to a solution of 2 M BH3-S(Me)2 (32 mL, 63.56 mmol, 1.5 equiv) in dry THF (300 mL) at -15 °C under a nitrogen atmosphere. The mixture was then removed from the water bath and stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in dry THF (150 mL), pinacol (7.5 g, 63.56 mmol, 1.5 equiv) was added, and the resulting mixture was stirred at room temperature overnight. The reaction was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 30:0 to 5:1) to give compound 2F (8 g, 39%). Step 6: Synthesis of 2

[0189] To a solution of compound 2F (8 g, 16.59 mmol, 1.0 equiv.) in HO / ACN (7 mL / 15 mL) was added 3 M NaOH (11.1 mL, 33.3 mmol, 2 equiv.), and the mixture was stirred at room temperature for 20 h. The mixture was purified by preparative HPLC to give compound 2 (6 g, 100%). LC-MS: 343 [M+H] + [ka] Example 3 2-Hydroxy-4-(hydroxymethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (compound 3) [ka]

[0190] To a solution of compound 2 (2.0 g, 5.85 mmol, 1.0 equiv) in methanol (20 mL) was added 1 N HCl (to adjust the pH of the solution to 5-6) and Pd / C (200 mg, 10% W / W). The mixture was stirred under H at room temperature for 16 h, filtered through Celite®, and purified by preparative HPLC (under acidic conditions) to give compound 3 (310 mg, 21%). LC-MS: 253 [M+H] + [ka] Example 4 (4R)-2-Hydroxy-4-(hydroxymethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaboriline-8-carboxylic acid and (4S)-2-Hydroxy-4-(hydroxymethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaboriline-8-carboxylic acid (Compounds 4 and 5) [ka]

[0191] 2-Hydroxy-4-(hydroxymethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (compound 3) (1.03 g) was separated by chiral column (Superchiral S-AD, hexane / EtOH / MeOH / formic acid = 60 / 13 / 27 / 0.01, v / v / v / v) to give compound 4 (344 mg, 33%) and compound 5 (410 mg, 39%). Compounds 4 and 5 are depicted as stereoisomers in the scheme above, but the absolute stereochemistry of the individual isomers has not yet been determined. Compound 4: LC-MS: 251 [MH] - [ka] Compound 5: LC-MS: 251 [MH] - [ka] Example 5 7-Fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 6) [ka] Step 1: Synthesis of Compound 6A

[0192] Compound 6A was prepared from the Boc-t-butyl ester intermediate (previously described in WO2015 / 179308) by TFA deprotection (described in Example 1, Step 3) followed by isopropylidene protection (described in Example 2, Step 2). Step 2: Synthesis of Compound 6B

[0193] To a mixture of bromide compound 6A (20.0 g, 72.99 mmol, 1.0 equiv.) in dioxane (200 mL) was added B2 ((+)-pinanediol)2 (39.2 g, 109.5 mmol, 1.5 equiv.), PdCl2(dppf) (3.0 g, 3.65 mmol, 0.05 equiv.), and KOAc (14.3 g, 145.9 mmol, 2.0 equiv.). The mixture was stirred overnight at 95 °C under a nitrogen atmosphere. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 1:0 to 10:1) to give compound 6B (13.5 g, 49%). Step 3: Synthesis of Compound 6C

[0194] To a mixture of compound 6B (13.5 g, 36.1 mmol, 1.0 equiv.) in THF (90 mL) was added 1F' (12.2 g, 54.14 mmol, 1.5 equiv.), Pd(PPh3)4 (2.1 g, 1.80 mmol, 0.05 equiv.), and 2N Na2CO3 (90 mL, 180.5 mmol, 5.0 equiv.). Under a nitrogen atmosphere, the mixture was stirred at 80 °C overnight. Then, the mixture was filtered through a pad of Celite®, and water was added. The mixture was extracted with EA. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 50:1 to 10:1) to give compound 6C (9.8 g, 79%). Step 4: Synthesis of Compound 6D

[0195] To a solution of 2M BH3-S(Me)2 (1.5 mL, 2.92 mmol, 2.0 equiv) in dry THF (10 mL) was slowly added a solution of compound 6C (500 mg, 1.462 mmol, 1.0 equiv) in dry THF (2 mL) at -15 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours, quenched with water, and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in dry THF (8 mL). To the resulting mixture was added 2,3-dimethylbutane-2,3-diol (345 mg, 2.92 mmol, 2.0 equiv). The reaction was stirred at room temperature overnight. The reaction was then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EA=30:0 to 10:1) to give compound 6D (188 mg, 27%). Step 5: Synthesis of Compound 6E

[0196] To a solution of compound 6D (188 mg, 0.4 mmol, 1.0 equiv.) in HO / ACN (1 mL / 1 mL) was added 3M NaOH (0.26 mL, 0.8 mmol, 2.0 equiv.), and the resulting mixture was stirred at room temperature overnight. The crude product 6E was used directly in the next step. Step 6: Synthesis of Compound 6

[0197] To the crude 6E was added Pd / C (18 mg, 10% w / w). The mixture was stirred under H2 at room temperature overnight. After filtration, the mixture was purified by preparative HPLC (under neutral conditions) to give 8 mg of compound 6. LC-MS: 282 [M+MeCN+H] + ;239 [MH] - [ka] Example 6 (4R)-7-Fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaboriline-8-carboxylic acid and (4S)-7-Fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaboriline-8-carboxylic acid (Compounds 7 and 8) [ka]

[0198] 7-Fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (compound 6) was separated by HPLC using a chiral column (Superchiral S-AD, hexane / EtOH / MeOH / TFA=90 / 3.3 / 6.7 / 0.05 (v / v / v)) to give compound 7 (40.8 mg, 16%) and compound 8 (33.0 mg, 13%). Compounds 7 and 8 are depicted as stereoisomers in the scheme above, but the absolute stereochemistry of the individual isomers has not yet been determined. Compound 7: LC-MS: 239 [MH] - [ka] Compound 8: LC-MS: 239 [MH] - [ka] Example 7 2-Hydroxy-4-(hydroxymethyl)-3,4-dihydrooxaborinino[6,5-c]pyridine-8-carboxylic acid (Compound 9) [ka] Step 1: Synthesis of Compound 9B

[0199] Compound 9A (Tetrahedron, 2011, 67, 8757-8762) in dioxane (10 mL) To a mixture of B2 ((+)-pinanediol)2 (1.67 g, 4.67 mmol, 1.5 equiv.), PdCl2(dppf) (255 mg, 0.31 mmol, 0.1 equiv.), and KOAc (916 mg, 9.35 mmol, 3.0 equiv.) was added. Under a nitrogen atmosphere, the mixture was stirred at 55 °C overnight. The mixture was filtered, and the filtrate was extracted with EA and HO. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA / DCM = 30:1:0 to 5:1:1) to give compound 9B (1.1 g, 84%). Step 2: Synthesis of Compound 9C

[0200] To a mixture of compound 9B (1.1 g, 2.61 mmol, 1.0 equiv.) in THF (90 mL) was added 1F' (1.18 g, 5.22 mmol, 2.0 equiv.), Pd(PPh3)4 (151 mg, 0.13 mmol, 0.05 equiv.), and 2N Na2CO3 (6.5 mL, 13.0 mmol, 5 equiv.). The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was then filtered, and the filtrate was washed with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EA = 20:1 to 5:1) to give compound 9C (978 mg, 96%). Step 3: Synthesis of Compound 9D

[0201] To a mixture of compound 9C (350 mg, 0.90 mmol, 1.0 equiv.) in methanol (2 mL), B2 ((+)-pinanediol)2 (370 mg, 1.03 mmol, 1.15 equiv.), Cu2O (10 mg, 0.072 mmol, 0.08 equiv.), PPh3 (26 mg, 0.099 mmol, 0.11 equiv.), and KH2PO4 (188 mg, 1.079 mmol, 1.2 equiv.) were added. The mixture was stirred at 40 °C under a nitrogen atmosphere for 2.5 h. The mixture was then filtered, the filtrate was washed with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 20:1 to 2:1) to give compound 9D (350 mg, 68%). Step 4: Synthesis of Compound 9

[0202] To a solution of compound 9D (197 mg, 0.411 mmol, 1.0 equiv) in DCM (1.5 mL) was added 1 M BBr3 (1.3 mL, 1.30 mmol, 5 equiv), and the mixture was stirred at room temperature for 1 h. The mixture was then purified by preparative HPLC (under acidic conditions) to give compound 9 (5.5 mg). LC-MS: 224 [M+H] + [ka] Example 8 4-(Benzyloxymethyl)-2-hydroxy-3,4-dihydrooxaborinino[6,5-c]pyridine-8-carboxylic acid (Compound 10) disodium salt [ka] Step 1: Synthesis of Compound 10A

[0203] A mixture of compound 9D (130 mg, 0.228 mmol, 1.0 equiv) and Pd / C (13 mg, 10% w / w) in methanol (2 mL) was stirred under H at room temperature for 2 days. The resulting mixture was filtered and purified by preparative TLC to give compound 10A (70 mg, 64%). Step 2: Synthesis of Compound 10

[0204] To a solution of compound 10A (30 mg, 0.063 mmol, 1.0 equiv) in HO / ACN (0.5 mL / 0.5 mL) was added TFA (0.01 mL, 0.125 mmol, 2 equiv), TES (0.05 mL), and i-BuB(OH) (13 mg, 0.125 mmol, 2 equiv). The mixture was stirred overnight at 25 °C and adjusted to pH 10-11 with 0.5 N NaOH (0.25 mL). The resulting mixture was stirred at room temperature for 2 h and purified by preparative HPLC (under neutral conditions) to give compound 10 (3.4 mg). LC-MS: 314 [M+H] + [ka] Example 9 2-Hydroxy-7-methoxy-4-(methoxymethyl)-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 11) [ka] Step 1: Synthesis of Compound 11A

[0205] To a solution of BH3-S(Me)2 (28.2 mL, 56.4 mmol, 2.0 equiv) in dry THF (60 mL) was added compound 2E (10 g, 28.2 mmol, 1 equiv) at -15 °C. The mixture was warmed to room temperature and stirred for 3.5 h. TLC showed that no compound 2E remained. The mixture was diluted with water (30 mL) and extracted with EA (2 x 60 mL). The organic phase was dried over Na2SO4 and concentrated to give a residue that was used in the next step without further purification.

[0206] The residue prepared above was dissolved in dry THF (60 mL). To this solution was added (+)-pinanediol (9.6 g, 56.4 mmol, 2.0 equivalents). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash column chromatography (PE / EA=5:1) to give compound 11A (11 g, impure). Step 2: Synthesis of Compound 11B

[0207] To a solution of crude compound 11A (5.3 g) in methanol (53 mL) was added 10% Pd / C (530 mg, 10% w / w) at room temperature. The mixture was stirred overnight. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (PE / EA=2:1) ​​to give compound 11B (1.2 g, 20%, 2 steps). Step 3: Synthesis of Compound 11C

[0208] To a mixture of compound 11B (250 mg, 0.56 mmol, 1.0 equiv.) in dry DCM (5 mL) was added trimethyloxonium tetrafluoroborate (167 mg, 1.13 mmol, 2.0 equiv.) and CsCO (183.5 mg, 0.563 mmol, 1.0 equiv.). The mixture was stirred overnight at 25 °C under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with DCM. The DCM layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel to give compound 11C (161 mg, 62%). Step 2: Synthesis of Compound 11

[0209] To a solution of compound 11C (155 mg, 0.34 mmol, 1.0 equiv) in HO / ACN (1.5 mL / 1.5 mL) was added 3N NaOH (0.34 mL, 1.02 mmol, 3 equiv). The mixture was stirred at 25 °C overnight. To the mixture were added TFA (0.06 mL), TES (0.06 mL), and i-BuB(OH) (68 mg, 0.68 mmol, 2 equiv). The resulting mixture was stirred at 25 °C for 1 hour and purified by preparative HPLC (under acidic conditions) to give compound 11 (57 mg, 63%). LC-MS: 267 [M+H] + [ka] Example 10 2-Hydroxy-4-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 12) [ka] Step 1: Synthesis of Compound 12B

[0210] HBr gas was generated by dropwise addition of PBr (10.5 mL, 110 mmol) to water (6.0 mL, 330 mmol) at room temperature. The generated HBr gas was dissolved in EtN in DCM (300 mL) at 0 °C. + Br - (97.0 g, 0.3 mol, 1.2 equiv.) was bubbled through a solution of 3-butyn-1-ol (12A, 19.0 mL, 0.25 mol, 1.0 equiv.) in HBr. To this HBr solution was added 3-butyn-1-ol (12A, 19.0 mL, 0.25 mol, 1.0 equiv.) and the solution was heated at 40° C. for 5 h. Removal of the solvent followed by distillation gave 3-bromo-3-buten-1-ol, 12B (27.9 g, 73%). Step 2: Synthesis of Compound 12C

[0211] To a solution of 3-bromo-3-buten-1-ol (12B) (13.0 g, 86.1 mmol, 1.0 equiv) in DCM (250 mL) was added imidazole (7.74 g, 114 mmol, 1.3 equiv), DMAP (2.15 g, 18.0 mmol, 0.2 equiv), and TBSCl (14.5 g, 96.2 mmol, 1.1 equiv) at room temperature. The reaction was stirred at room temperature for 3 h, filtered, washed with brine, dried over MgSO, concentrated, and purified by FCC (SiO, hexane) to give compound 12C (16.8 g, 73%). Step 3: Synthesis of Compound 12D

[0212] To a solution of 2D (503 mg, 1.30 mmol, 1.0 equiv) in THF (3.6 mL) was added alkene 12C (688 mg, 2.60 mmol, 2.0 equiv), followed by a 2 M solution of KCO (1.6 mL, 3.2 mmol, 2.5 equiv). After bubbling N through the solution for 10 min, Pd(PPh) (147 mg, 0.13 mmol, 0.1 equiv) was added and the reaction mixture was heated to 70 °C for 16 h. The reaction was quenched with NaHCO (saturated aq.), extracted with EtOAc (2x), dried over NaSO, and purified. Concentration and purification by FCC (SiO 2 , 10% EtOAc / hexanes) gave compound 12D (360 mg, 70%) as an orange oil. Step 4: Synthesis of Compounds 12E and 12F

[0213] To a solution of 12D (274 mg, 0.70 mmol, 1.0 equiv) in THF (14 mL) at 0 °C was added BH-S(Me) (1.2 equiv, 0.42 mL, 2 M in THF, 0.84 mmol, 1.2 equiv). The reaction was allowed to warm slowly to room temperature and stirred for 2 h. (+)-Pinanediol (291 mg, 1.7 mmol, 2.4 equiv) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with HO, extracted with EtOAc (3×), dried over NaSO, and concentrated. The residue was purified by FCC (SiO, 40% EtOAc / hexanes) to give a mixture of 12E and 12F (109 mg), which was used in the next step without further purification. Step 5: Synthesis of Compound 12

[0214] A mixture of compounds 12E and 12F (109 mg) was dissolved in acetonitrile (3.0 mL) and a 3 M solution of NaOH (1.2 mL) was added at room temperature. The reaction mixture was stirred for 24 hours. The resulting solution was adjusted to pH 2-3 using 6 N HCl. i-Bu(OH)2 (53 mg) was added. The reaction was stirred overnight and purified by preparative HPLC to give compound 12 (7.5 mg, 4%) as a white fluffy solid. LC-MS: 267.2 [M+1] + [ka] Example 11 2-Hydroxy-4-(hydroxymethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (compound 3)

[0215] Compound 3 (described in Example 3) was also prepared using the following alternative synthetic procedure. [ka] Step 1: Synthesis of Compound 3C

[0216] Compound 3A (J. Org. Chem., 2016, 81, 4269-4279) (26g, 0.123mo A solution of bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.826 g, 1.23 mmol, 0.015 equiv.) in toluene (260 mL) was heated to 80° C. and stirred overnight under N. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography (PE / EA=5:1) to give compound 3C (35.7 g, 86%). Step 2: Synthesis of compound 3D

[0217] To a solution of compound 3C (5.0 g, 9.881 mmol, 1.1 equiv) in THF (50 mL) was added compound 2C (2.57 g, 8.983 mmol, 1.0 equiv), PdCl(dppf) (368 mg, 0.494 mmol, 0.05 equiv), water (1.625 g, 98.81 mmol, 10 equiv), and KPO·3H0 (7.175 g, 29.644 mmol, 3.0 equiv). The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was filtered, and the filtrate was diluted with EA and H0. The layers were separated, and the organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give compound 3D (4.79 g, 82%). Step 3: Synthesis of Compound 3E

[0218] To a solution of compound 3D (34 g, 58.0 mmol, 1.0 equiv.) in THF (300 mL) was added TBAF (18.1 g, 69.6 mmol, 1.2 equiv.) at room temperature. The mixture was stirred at room temperature for 3 hours, and TLC showed that no compound 3D remained. The resulting mixture was diluted with water (150 mL) and extracted with EA (2×300 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (PE / EA=1:1) to give compound 3E (16.1 g, 81%). Step 4: Synthesis of Compound 3F

[0219] To a solution of compound 3E (16 g, 37.21 mmol) in methanol (160 mL) was added PtO (1.6 g, 10% w / w) under N and then replaced with hydrogen. The mixture was stirred at room temperature for 6 hours. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give compound 3F (13.6 g, 87%). Step 5: Synthesis of Compound 3G

[0220] To a solution of compound 3F (13.4 g, 31.02 mmol, 1.0 equiv) in THF (150 mL) was added 3N aqueous HCl (51.7 mL, 155.1 mmol, 5.0 equiv) at room temperature. The mixture was stirred overnight, and LC-MS showed that 10% of compound 3F remained. Next, additional 3N HCl (20.7 mL, 61.02 mmol, 2.0 equiv) was added. The mixture was stirred at room temperature for 3 hours, at which point LC-MS showed that the starting material was completely consumed. Water (75 mL) was added to the reaction mixture, and the resulting solution was extracted with EA (2×75 mL). The organic phase was washed with water (75 mL), brine (75 mL), dried over sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (PE / EA=1:1) to give compound 3G (6.7 g, 75%). Step 6: Synthesis of Compound 3

[0221] To a solution of compound 3G (7.0 g, 23.9 mmol, 1.0 equiv) in HO / CHCN (35 mL / 35 mL) at room temperature was added 3N NaOH (16 mL, 47.8 mmol, 2.0 equiv) at room temperature. The mixture was stirred at room temperature for 1.5 h, and TLC showed that no 3G remained. 3N HCl was then added to adjust the solution to pH ∼2. The resulting solution was stirred at room temperature overnight and lyophilized. The solid was dissolved in water (20 mL) and extracted with EA (5 × 20 mL). The organic layer was dried and concentrated to give crude compound 3 (5.4 g). This compound was further purified by preparative HPLC (under acidic conditions) to give pure compound 3. LC-MS: 253 [M+H] + [ka] Example 12 Disodium salt of 4-(formamidomethyl)-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 13) [ka] Step 1: Synthesis of Compound 13A

[0222] To a mixture of compound 11B (1.5 g, 3.38 mmol, 1.0 equiv.) in DCM (10 mL) was added CBr4 (1.68 g, 5.07 mmol, 1.5 equiv.) and PPh3 (1.33 g, 5.07 mmol, 1.5 equiv.). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 30:1 to 5:1) to give compound 13A (1.1 g, 64%). Step 2: Synthesis of Compound 13B

[0223] To a solution of compound 13A (280 mg, 0.55 mmol, 1.0 equiv) in DMF (8 mL) was added NaN (108 mg, 1.66 mmol, 3.0 equiv). The mixture was stirred at 48 °C for 19 h under a nitrogen atmosphere. The mixture was then filtered, and the filtrate was diluted with EA. The organic layer was washed with water and brine, dried over NaSO, and concentrated in vacuo to give crude compound 13B (250 mg, 96%), which was used in the next step without further purification. Step 3: Synthesis of Compound 13C

[0224] To a mixture of compound 13B (250 mg, 0.533 mmol, 1.0 equiv.) in MeOH (30 mL) was added Pd / C (25 mg, 10% w / w) under a hydrogen atmosphere. The mixture was stirred at room temperature for 2 days. The mixture was then filtered, and the filtrate was concentrated in vacuo to give crude compound 13C (220 mg, 93%), which was used in the next step without further purification. Step 4: Synthesis of Compound 13D

[0225] To a mixture of compound 13C (500 mg, 1.13 mmol, 1.0 equiv.) in DCM (10 mL) under N2, EDCI (433 mg, 2.26 mmol, 2.0 equiv.), DMAP (14 mg, 0.113 mmol, 0.1 equiv.), and formic acid (104 mg, 2.26 mmol, 2.0 equiv.) were added. The mixture was stirred at room temperature for 4 hours. The resulting mixture was then purified by preparative HPLC to give compound 13D (230 mg, 45%). Step 5: Synthesis of Compound 13

[0226] To a solution of compound 13D (120 mg, 0.255 mmol, 1.0 equiv.) in HO / ACN (1 mL / 1 mL) was added 3N NaOH (0.17 mL, 0.509 mmol, 2 equiv.). The mixture was stirred at room temperature for 2 hours. To the reaction mixture, TFA (0.06 mL) and TES (0.06 mL) were added slowly, followed by i-BuB(OH) (52 mg, 0.509 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 1 hour, concentrated, and purified by preparative HPLC (under acidic conditions) to give the acid form of compound 13 (25 mg).

[0227] To a solution of the acid form of compound 13 (25 mg, 0.089 mmol, 1.0 equiv.) in HO / ACN (0.2 mL / 0.2 mL) was added 3 N NaOH (0.06 mL, 0.18 mmol, 2 equiv.), and the mixture was stirred at room temperature for 0.5 h and purified by preparative HPLC (under neutral conditions) to give compound 13 (17 mg, 55%). LC-MS: 280 [M+H] + ;278 [MH] - [ka] Example 13 Disodium salt of 4-(aminomethyl)-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 14) [ka]

[0228] To a solution of compound 13C (180 mg, 0.406 mmol, 1.0 equiv) in HO / ACN (1 mL / 1 mL) was added TFA (0.2 mL) and TES (0.2 mL), followed by i-BuB(OH) (83 mg, 0.812 mmol, 2 equiv). The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in CHCN / HO, and the pH of the solution was adjusted to approximately pH 10 with 3 N NaOH. The mixture was purified by preparative HPLC (neutral conditions) to give compound 14 (30 mg, 29%). LC-MS: 252 [M+H] + [ka] Example 14 Disodium salt of 4-(azidomethyl)-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 15) [ka]

[0229] To a solution of compound 13B (200 mg, 0.255 mmol, 1.0 equiv) in HO / ACN (0.5 mL / 0.5 mL) was added TFA (0.06 mL) and TES (0.06 mL), followed by i-BuB(OH) (87 mg, 0.853 mmol, 2 equiv). The mixture was stirred at 27 °C for 8 hours. The reaction mixture was then concentrated at room temperature, and 3N NaOH (0.28 mL, 0.84 mmol, 2 equiv) was added to the crude. The mixture was stirred at room temperature overnight, concentrated, and purified by preparative HPLC (neutral conditions) to give compound 15 (39 mg, 33%). LC-MS: 278 [M+H] + , 555 [2M+H] + and 535 [2M-H] - [ka] Example 15 Disodium salt of 2-hydroxy-4-[[4-(hydroxymethyl)triazol-1-yl]methyl]-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 16) [ka] Step 1: Synthesis of Compound 16A

[0230] To a solution of compound 13B (140 mg, 0.30 mmol, 1.0 equiv.) in 1,2-dichlorobenzene (2 mL) was added triisopropyl(prop-2-ynoxy)silane (127 mg, 0.60 mmol, 2.0 equiv.). The reaction was heated at 120 °C under a nitrogen atmosphere. The mixture was stirred overnight. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE / EA=1:1) to give compound 16A (80 mg, 51%). Step 2: Synthesis of Compound 16

[0231] To a solution of compound 16A (80 mg, 0.12 mmol, 1.0 equiv.) in HO / ACN (1 mL / 1 mL) was added 3N NaOH (0.12 mL, 0.36 mmol, 3 equiv.). The mixture was stirred overnight at room temperature, and then TFA (1 mL), TES (1 mL), and i-BuB(OH) (23 mg, 0.235 mmol, 2 equiv.) were slowly added. The reaction mixture was stirred for an additional hour at room temperature, concentrated, and purified by preparative HPLC (under acidic conditions) to give compound 16B (27 mg) in acid form. To a solution of compound 16B acid (27 mg, 0.081 mmol, 1.0 equiv.) in HO / ACN (0.2 mL / 0.2 mL) was added 3N NaOH (0.06 mL, 0.18 mmol, 2 equiv.). The mixture was stirred at room temperature for 30 min and then triturated with H2O / acetone (1:20) to give compound 16 (17 mg, 53%). LC-MS: 334 [M+H] + [ka] Example 16 Disodium salt of 4-(acetamidomethyl)-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 17) [ka] Step 1: Synthesis of Compound 17A

[0232] To a mixture of compound 13C (150 mg, 0.34 mmol, 1.0 equiv.) in DCM (5 mL) under N2, acetyl chloride (52 mg, 0.68 mmol, 2.0 equiv.) and triethylamine (0.14 mL, 1.02 mmol, 3.0 equiv.) were added. The reaction was stirred at room temperature for 1 hour. The resulting mixture was diluted with DCM and washed with water to give crude compound 17A (160 mg, 92%), which was used in the next step without further purification. Step 2: Synthesis of Compound 17

[0233] To a solution of compound 17A (150 mg, 0.31 mmol, 1.0 equiv.) in HO / ACN (1.5 mL / 1.5 mL) was added 3N NaOH (0.31 mL, 0.93 mmol, 3 equiv.). The mixture was stirred at room temperature for 3 hours, and then TFA (1.5 mL) and TES (1.5 mL) were added slowly, followed by i-BuB(OH) (62 mg, 0.62 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 1 hour and then purified by preparative HPLC (under acidic conditions) to give the acid form of 17. To a solution of the acid form of 17 (62 mg, 0.21 mmol, 1.0 equiv.) in HO / ACN (0.2 mL / 0.2 mL) was added 1N NaOH (0.41 mL, 0.41 mmol, 2 equiv.). The mixture was stirred at room temperature for 3 hours, and then TFA (1.5 mL) and TES (1.5 mL) were added slowly, followed by i-BuB(OH) (62 mg, 0.62 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 1 hour and then purified by preparative HPLC (under acidic conditions) to give the acid form of 17. After stirring at room temperature for 30 minutes and lyophilization, the solid was triturated with a solution of water and acetone (1:20) to give Compound 17 (40 mg, 22%). LC-MS: 294 [M+H] + , 292 [MH] - [ka] Example 17 Aztreonam potentiation

[0234] The potency and spectrum of β-lactamase inhibitors (BLIs) were determined by assessing their potentiation activity against aztreonam in a dose-titration potentiation assay using various bacterial strains resistant to aztreonam due to the expression of various β-lactamases. Aztreonam is a monobactam antibiotic that is hydrolyzed by the majority of β-lactamases belonging to classes A or C (but not B or D). The potentiation effect was observed as the ability of BLI compounds to inhibit growth in the presence of subinhibitory concentrations of aztreonam. MICs for the test strains ranged from 64 μg / mL to greater than 128 μg / mL. Aztreonam was present in the test medium at 4 μg / mL. Compounds were tested at concentrations up to 20 μg / mL. In this assay, compound potency was measured at 4 μg / mL of aztreonam (MPC). @4 The BLI concentrations were reported as the minimum concentration of BLI required to inhibit bacterial growth in the presence of aztreonam potentiation (MPC) against various strains overexpressing class A (ESBL and KPC) and class C β-lactamases. @4 ) are summarized in Table 1. The aztreonam MIC for each strain is also shown. Table 1. BLI potentiation of aztreonam against strains expressing class A and class C enzymes activity [Table 1] X = MPC @4 ≦ 5 μg / mL Y = 5 μg / mL < MPC @4 ≦ 20 μg / mL Z = MPC @4 > 20 μg / mL Example 18 Enhancement of Tigemonum

[0235] Selected β-lactamase inhibitors were also tested for their ability to potentiate the monobactam tigemonam. The potentiation effect was observed as the ability of the BLI compounds to inhibit growth in the presence of sub-inhibitory concentrations of tigemonam. MICs for the test strains varied from 16 μg / mL to greater than 64 μg / mL. Tigemonam was present in the test medium at 4 μg / mL. Compounds were tested at concentrations up to 20 μg / mL. In this assay, compound potency was measured using a 4 μg / mL tigemonam (MPC @4 The BLI concentrations were reported as the minimum concentration of BLI required to inhibit bacterial growth in the presence of β-lactamases. Table 2 shows the effects of tigemonam-enhanced BLI (MPC) on various strains overexpressing class A (ESBL) and class C β-lactamases. @4 ) are summarized in Table 1. The MIC of tigemonum for each strain is also shown. Table 2. Activity of BLI to enhance tigemonum against strains expressing class A and class C enzymes [Table 2-1] [Table 2-2] X = MPC @4 ≦ 5 μg / mL Y = 5 μg / mL < MPC @4 ≦ 20 μg / mL Z = MPC @4 > 20 μg / mL Example 19 Biapenem enhancement

[0236] The ability of β-lactamase inhibitors to potentiate the carbapenem biapenem against strains producing class A (KPC), class D (OXA-48), and class B (metallo β-lactamases, NDM-1 and VIM-1) carbapenemases was also tested. The potentiation effect was observed as the ability of BLI compounds to inhibit growth in the presence of subinhibitory concentrations of biapenem. The biapenem MICs for the test strains ranged from 16 to 32 μg / mL. Biapenem was present in the test medium at 1 μg / mL. Compounds were tested at concentrations up to 20 μg / mL. In this assay, compound potency was measured at 1 μg / mL of biapenem (MPC). @1 The BLI concentrations were reported as the minimum concentration of BLI required to inhibit bacterial growth in the presence of bisphosphonates (BPC), ... @1 The BLI efficacy of each strain is summarized in the table. The biapenem MIC for each strain is also shown. . Table 3. Activity of BLIs potentiating biapenem against strains expressing class A (KPC), class D (OXA-48), and class B (NDM-1 and VIM-1) carbapenemases [Table 3-1] [Table 3-2] X = MPC @1 ≦ 5 μg / mL Y = 5 μg / mL < MPC @1 ≦ 20 μg / mL Z = MPC @1 > 20 μg / mL Example 20 Meropenem augmentation

[0237] The ability of β-lactamase inhibitors to potentiate the carbapenem meropenem against strains of Acinetobacter baumannii producing class D (OXA-23 and OXA-72) carbapenemases was also tested. The potentiation effect was observed as the ability of BLI compounds to inhibit growth in the presence of subinhibitory concentrations of meropenem. Meropenem MICs for the test strains ranged from 32 to greater than 64 μg / mL. Meropenem was present at 8 μg / mL in the test medium. Compounds were tested at concentrations up to 20 μg / mL. In this assay, compound potency was measured against 8 μg / mL of meropenem (MPC). @8 The results are reported as the minimum concentration of BLI required to inhibit bacterial growth in the presence of meropenem potentiation (MPC) for two carbapenemase-overexpressing strains, OXA-72 and OXA-23. @8 The BLI efficacy of each strain is summarized in Table 1. Meropenem MICs for each strain are also shown. Table 4. Class D carbapenemases expressed by strains derived from Acinetobacter baumannii BLI activity to enhance meropenem [Table 4] X = MPC @1 ≦ 5 μg / mL Y = 5 μg / mL < MPC @1 ≦ 20 μg / mL Z = MPC @1 > 20 μg / mL

[0238] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula (I) or Formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: G is -OR 1 -C(O)R 1 , -C(O)(CH 2 ) 0-3 SR 1 , -C(O)(CH 2 ) 1-3 R 1 , -C(O)OR 1 , -C(O)NR 1 R 2 , -C(O)NR 1 OR 2 、-N 3 , -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 C(O)NR 2 R 3 , -NR 1 C(O)OR 2 , -NR 1 S(O) 2 R 2 , -NR 1 S(O) 2 NR 2 R 3 , -C(=NR 1 )R 2 , -C(=NR 1 )NR 2 R 3 , -NR 1 CR 2 (=NR 3 ), -NR 1 C(=NR 2 )NR 3 R 4 , -S(O) 2R 1 , with C being substituted as needed 1~10 Alkyl, optionally substituted C 2~10 Alkenyl, optionally substituted C 2~10 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 5- to 10-membered heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3~7 Carbocyclyl-C 1~6 Alkyl, optionally substituted 5- to 10-membered heterocyclyl-C 1~6 Alkyl, optionally substituted C 6~10 Aryl-C 1~6 Alkyl and optionally substituted 5- to 10-membered heteroaryl-C 1~6 is selected from the group consisting of alkyl, R 1 、R 2 、R 3 and R 4 are each independently -H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted C 6~10 Aryl-C 1~6 selected from the group consisting of alkyl and optionally substituted 5-10 membered heteroaryl; J is for CR 5 and N, L is CR 6 and N, M is for CR 7 and N, R 5 、R 6 and R 7 are each independently -H, -OR 8 , halogen, -CF 3 , with C being substituted as needed 2 ~C 6 Alkenyl, optionally substituted C 2 ~C 6 Alkynyl, optionally substituted C 1 ~C 6 Heteroalkyl, optionally substituted C 3 ~C 7 Carbocyclyl, optionally substituted 5- to 10-membered heterocyclyl, optionally substituted C6~10 Aryl, optionally substituted 5- to 10-membered heteroaryl, cyano, C 1 ~C 6 Alkoxy (C 1 ~C 6 ) selected from the group consisting of alkyl, aryloxy, and sulfhydryl (mercapto); R 8 is hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C 6~10 selected from the group consisting of aryl and optionally substituted 5-10 membered heteroaryl; R is -H, -C 1~9 Alkyl, -CR 9 R 10 OC(O)C 1~9 Alkyl, -CR 9 R 10 OC(O)OC 1~9 Alkyl, -CR 9 R 10 OC(O)C 6~10 Aryl, -CR 9 R 10 OC(O)OC 6~10 aryl,

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Claims

1. A therapeutically effective amount of a compound of formula (Ic) or (IIc): 【Chemistry 49】 or a pharma- ceutically acceptable salt thereof, G is -OH, -OMe, -OBn, -CH 2 OH, N 3 , NH 2 , -NHC(=O)H, -NHC(=O)CH 3 and 【Chemistry 50】 is selected from the group consisting of M is selected from the group consisting of CR 7 and N; R 7 is selected from the group consisting of -H, -OR 8 and halogen; R 8 is optionally substituted C 1-4 alkyl; and R is -H) and a pharma- ceutical acceptable excipient.

2. The composition of claim 1 further comprising an additional pharmaceutical agent.

3. 3. The composition of claim 2, wherein the additional pharmaceutical agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents and anti-allergic agents.

4. The composition of claim 3, wherein the additional pharmaceutical agent is a β-lactam antibacterial agent.

5. The β-lactam antibacterial agent may be amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, methampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, fumaricillin, furanil ... Phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, raspenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cephazedone, cefazaflur, cephradium , cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cef 5. The composition of claim 4, which is selected from the group consisting of fupodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441 and RWJ-333442.

6. 5. The composition of claim 4, wherein the β-lactam antibacterial agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem and panipenem.

7. 5. The composition of claim 4, wherein the β-lactam antibacterial agent is selected from aztreonam, tigemonam, BAL30072, SYN2416 or carumonam.

8. 1. A composition for use in a method of treating a bacterial infection, comprising a compound represented by formula (Ic) or (IIc): 【Chemistry 49】 or a pharma- ceutically acceptable salt thereof, G is -OH, -OMe, -OBn, -CH 2 OH, N 3 , NH 2 , -NHC(=O)H, -NHC(=O)CH 3 and 【Chemistry 50】 is selected from the group consisting of M is selected from the group consisting of CR 7 and N; R 7 is selected from the group consisting of -H, -OR 8 and halogen; R 8 is optionally substituted C 1-4 alkyl; and R is -H.

9. 9. The composition of claim 8, wherein the composition is administered in combination with an additional pharmaceutical agent.

10. 10. The composition of claim 9, wherein the additional pharmaceutical agent is selected from the group consisting of antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents and anti-allergic agents.

11. The composition of claim 10, wherein the additional pharmaceutical agent is a β-lactam antibacterial agent.

12. The β-lactam antibacterial agent may be amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, methampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, fumaricillin, furanil ... Phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, raspenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cephazedone, cefazaflur, cephradium , cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cef 12. The composition of claim 11, which is selected from the group consisting of fupodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441 and RWJ-333442.

13. 12. The composition of claim 11, wherein the beta-lactam antibacterial agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem.

14. 12. The composition of claim 11, wherein the β-lactam antibacterial agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN2416 and carumonam.

15. The aforementioned infections include Pseudomonas acidovarans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis、Mrrganellamrganii、Proteus mrabilis、rerulgaris、rovidencia alkalifaciens、rovidencia rettgerirr stuartii、Acinetobacter baumannii、Bordetella pertussis、Bordetella para pertussis、Bordetella bronchiseptica、Haemophilus ducrey, Pasteurella multicida, Pasteurella haemolytica, Ranhamella catarrhalis, Orrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides dystonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumonia, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. ]yaaaoooon9. The composition of claim 8, comprising a bacterium selected from the group consisting of Staphylococcus haemolyticus, Staphylococcus hominis and Staphylococcus saccharolyticus.

16. wherein the infection is caused by Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggertii and Bacteroides9. The composition of claim 8, comprising a bacterium selected from the group consisting of: S. splanchnicus.

17. The pharmaceutical composition of claim 1, wherein G is -OH.

18. The pharmaceutical composition of claim 1, wherein M is selected from the group consisting of -CH, -COMe, CF and N.

19. The pharmaceutical composition of claim 1, wherein M is -COMe.

20. The pharmaceutical composition of claim 1, wherein R 8 is C 1-4 alkyl.

21. The compound of claim 1, 【Chemistry 51】 or a pharma- ceutically acceptable salt thereof.

22. The compound of claim 1, 【Chemistry 52】 or a pharma- ceutically acceptable salt thereof.

23. The compound of claim 22, 【Chemistry 53】 or a pharma- ceutically acceptable salt thereof.

24. The compound comprising: 【Chemical 54】 or a pharma- ceutically acceptable salt thereof.

25. The compound of claim 1, 【Chemistry 55】 or a pharma- ceutically acceptable salt thereof.

26. The compound of claim 1, 【Chemistry 56】 or a pharma- ceutically acceptable salt thereof.

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