Boronic acid derivatives and therapeutic uses thereof

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 Apr. 20, 2018, entitled “BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF”, which is incorporated herein 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 Art

[0003] Description of Related Art Antibiotics have been an effective means for treating infectious diseases for the past half - century. From the development of antibiotic therapies until the late 1980s, in developed countries, the management of bacterial infections was almost complete. However, in response to the pressure of antibiotic use, numerous resistance mechanisms have spread, threatening the clinical usefulness of antibacterial therapies. The increase in antibiotic - resistant strains has become common, particularly in large hospitals and nursing homes. The consequences of the increase in resistant strains include a further increase in morbidity and mortality, longer hospital stays for patients, and increased treatment costs.

[0004] Various bacteria have evolved β-lactam-inactivating enzymes, namely β-lactamases that nullify the effectiveness of various β-lactam antibiotics. β-lactamases can be classified into four classes based on their amino acid sequences, namely Ambler's classes A, B, C, and D. Enzymes of classes A, C, and D include β-lactamases with a serine in the active site, and the less frequently encountered class B enzymes are Zn-dependent. These enzymes catalyze the chemical breakdown of β-lactam antibiotics and inactivate these antibiotics. Some β-lactamases can move within and between various strains and species. The rapid spread of bacterial resistance and the emergence of multidrug-resistant strains have significantly restricted the available β-lactam treatment options.

[0005] The increase in β-lactamase-expressing bacterial strains that are class D, such as Acinetobacter baumannii, poses a threat of emerging multidrug resistance. A. baumannii strains express β-lactamases of classes A, C, and D. Class D β-lactamases, such as the OXA family, are particularly effective in destroying carbapenem-type β-lactam antibiotics, for example, 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). Therefore, there is an urgent threat of using the drugs in such classification effectively to treat and prevent bacterial infections. In fact, the number of serine-based β-lactamases listed in the catalog has exploded from less than 10 in the 1970s to more than 300 variants. These problems have promoted the development of 5 "generations" of cephalosporins. When the broad-spectrum cephalosporins were first introduced into clinical practice, they were resistant to hydrolysis by the frequently seen class A β-lactamases, TEM-1 and SHV-1. However, the emergence of resistant strains due to the occurrence of single amino acid substitutions in TEM-1 and SHV-1 has led to the emergence of the extended-spectrum β-lactamase (ESBL) phenotype.

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

[0007] Zinc-dependent class B metallo-β-lactamases are mainly represented by the VIM, IMP and NDM types. *K. pneumoniae* producing IMP and VIM were first recognized in Japan in the 1990s and in southern Europe in 2001, respectively. IMP-positive strains are still numerous in Japan and have also caused hospital outbreaks in China and Australia. However, the spread of IMP-producing *Enterobacteriaceae* in other countries of the world seems to have been somewhat limited. Enterobacteria producing VIM can be isolated frequently in the countries of the Mediterranean and have reached epidemic proportions in Greece. In northern Europe and the United States, the isolation of VIM-producing strains remains low. In stark contrast, the characteristic of *K. pneumoniae* isolates producing NDM is its rapid spread from the Indian subcontinent, which is its epicenter, to Western Europe, North America, Australia and the Far East. Furthermore, the NDM gene has rapidly spread to various species other than *K. pneumoniae*.

[0008] Class D carbapenemases that express plasmids belong to the OXA-48 type. K. pneumoniae that produces OXA-48 was first detected in Turkey in 2001. The Middle East and North Africa remain the main centers of infection. However, the recent isolation of organisms producing the OXA-48 type in India, Senegal, and Argentina suggests a potential global spread. The isolation of OXA-48 from bacteria other than K. pneumoniae emphasizes the potential for the spread of OXA-48.

[0009] Treatment of strains producing any of these carbapenemases with carbapenem can be associated with a poor outcome.

[0010] Another mechanism of β-lactamase-mediated resistance to carbapenem involves permeability or efflux mechanisms associated with overproduction of β-lactamase. An example is the loss of porins associated with overproduction of ampC β-lactamase, which confers resistance to imipenem in Pseudomonas aeruginosa. Overexpression of efflux pumps associated with overproduction of ampC β-lactamase may also confer resistance to carbapenems such as meropenem. Therefore, improved β-lactamase inhibitors are needed.

Prior Art Documents

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Means for Solving the Problems

[0012] Some embodiments disclosed herein relate to compounds having the structure of formula (I) or formula (II):

Chemical Formula

[0013] 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(=NR1 )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) 2 R 1 ,optionally substituted C 1~10 alkyl, optionally substituted C 2~10 alkenyl, optionally substituted C 2~10 alkynyl, optionally substituted C 3~7 carbocyclic, optionally substituted 5- to 10-membered heterocyclic, optionally substituted C 6~10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3~7 carbocyclic-C 1~6 alkyl, optionally substituted 5- to 10-membered heterocyclic-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 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 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C 6~10 aryl, optionally substituted C 6~10 aryl-C 1~6 alkyl and optionally substituted 5- to 10-membered heteroaryl selected from the group consisting of,

[0015] J is selected from the group consisting of CR 5 and N,

[0016] L is selected from the group consisting of CR 6 and N,

[0017] M is selected from the group consisting of CR 7 and N,

[0018] R 5 , R 6 and R 7 are each independently -H, -OR 8 , halogen, -CF 3 , optionally substituted C 2 ~C 6 alkenyl, optionally substituted C 2 ~C 6 alkynyl, optionally substituted C 1 ~C 6 heteroalkyl, optionally substituted C 3 ~C 7 carbocyclic, optionally substituted 5- to 10-membered heterocyclic, optionally substituted C 6~10 aryl, optionally substituted 5- to 10-membered heteroaryl, cyano, C 1 ~C 6 alkoxy(C 1 ~C 6 )alkyl, aryloxy and sulfhydryl (mercapto), and are selected from the group consisting of

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

[0020] R is -H, -C1~9 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, [Chemical Formula] -CR 9 R 10 OC(O)C 3~7 Carbocyclic, -CR 9 R 10 OC(O)OC 3~7 Carbocyclic, -CR 9 R 10 OC(O)(5- to 10-membered heterocycle) and -CR 9 R 10 Selected from the group consisting of OC(O)O(5- to 10-membered heterocycle),

[0021] R 9 and R 10 are independently selected from the group consisting of -H, optionally substituted C 1~4 alkyl, optionally substituted C 3~7 carbocyclic, optionally substituted 5- to 10-membered heterocycle, optionally substituted C 6~10 aryl and optionally substituted 5- to 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 methods of treating or preventing a bacterial infection, the method 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 that act as antimicrobial agents and / or as potentiators of antimicrobial agents. Various embodiments of these compounds include compounds having the structure of formula (I) above or pharmaceutically acceptable salts thereof.

[0025] Some embodiments of the compounds of formula (I) and (II), or pharmaceutically acceptable salts thereof, have the following stereochemistry represented by the structure of formula (Ia) or formula (IIa). **CHEMICAL STRUCTURE**

[0026] Some embodiments of the compounds of formula (I) and (II), or pharmaceutically acceptable salts thereof, have the following stereochemistry represented by the structure of formula (Ib) or formula (IIb). **CHEMICAL STRUCTURE**

[0027] Some embodiments of the compounds of formula (I) and (II), or pharmaceutically acceptable salts thereof, are of formula (Ic) or formula (IIc): **CHEMICAL STRUCTURE** and include compounds having the structure.

[0028] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), G is -OR 1 , N 3 , -NR 1 R2 、 NR 1 C(O)R 2 、 optionally substituted C 1~4 alkyl and optionally substituted 5- to 10-membered heteroaryl selected from the group consisting of.

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

[0030] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), G is -OH, -OMe, -OBn, -CH 2 OH, N 3 、 NH 2 、 -NHC(=O)H, -NHC(=O)CH 3 and

Chemical formula

[0031] In some embodiments of the compounds 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 the compounds of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), M is CR 7 is, R 7 is, -H, -OR 8 and halogen selected from the group consisting of.

[0034] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), R 8 is optionally substituted C 1~4 alkyl.

[0035] In some embodiments of the compounds 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 compounds 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 are as follows:

Chemical formula

[0039] When the compounds disclosed herein have at least one chiral center, those compounds may exist as individual enantiomers and diastereomers, or as mixtures of such isomers including racemates. The separation of individual isomers, or the selective synthesis of individual isomers, is effected by applying various methods well 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. Further, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms, including any polymorphs, are included within the scope of the compounds disclosed herein. Additionally, some of the compounds disclosed herein may form hydrates with water (i.e., hydrates) or solvates with common organic solvents. Unless otherwise indicated, such solvates are within the scope of the compounds disclosed herein.

[0040] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that may be appropriately represented by other chemical structures, even if kinetic. Those skilled in the art will recognize that such structures may represent only a very small fraction of a sample of such compound(s). Such compounds are considered to be within the scope of the structures shown, but such resonance forms or tautomers are not represented herein.

[0041] In some embodiments, for easy exchange of the boron ester, the compounds described herein may be converted to alternative forms or may exist in equilibrium with this form. Thus, in some embodiments, the compounds described herein may exist in combination with one or more of these forms. For example, as shown below, the compounds disclosed herein may exist as a cyclic boronic acid monoester as Formula I, or as an acyclic form as a boronic acid as Formula II, or depending on the medium, may exist as a mixture of the two above forms. G is -OH or NHR 2 When is, the compound of Formula II may cyclize to give a compound of Formula III where G’’ is O or NR 2 In this case, this compound may exist as a mixture of all three forms depending on the medium.

Chemical Structure

[0042] In some embodiments, the compounds described herein may exist as a cyclic dimer as Formula (A), or as a cyclic trimer as Formula (B), as a cyclic tetramer as Formula (C), or as an acyl dimer, trimer or tetramer, etc., as shown below.

Chemical Structure

[0043] Isotopes may be present in the described compounds. 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 to be represented in the present 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). Thus, when referring to a compound in this specification, unless the context specifically indicates otherwise, all possible isotopic forms are included. Definition

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

[0045] A "prodrug" refers to an agent that is converted into the parent drug in vivo. In some situations, prodrugs can be more easily administered than the parent drug, so prodrugs are often useful. They can, for example, be bioavailable by oral administration while their parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Without limitation, an example of a prodrug is a compound that is administered as an ester (the "prodrug") that facilitates passage through cell membranes where water solubility is detrimental to transport, but then, once inside the cell where water solubility is beneficial, undergoes hydrolysis by metabolism to become the carboxylic acid that is the active entity. A further example of a prodrug can be a single-chain peptide (polyamino acid) attached to an acid group, in which case the peptide is metabolized to the active moiety It is exposed. 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 hereby incorporated by reference in its entirety.

[0046] The term "prodrug ester" refers to a derivative of a compound disclosed herein formed by imparting any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art including the (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other examples of prodrug ester groups can be found, for example, in T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press: New York, 14-21 (1987) (which presents examples of esters useful as prodrugs for compounds containing a carboxyl group). The above references are each hereby incorporated by reference in their entirety.

[0047] The "metabolites" of the compounds disclosed herein include the active species produced when the compounds are introduced into a biological environment.

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

[0049] The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the compound and which are not biologically or otherwise undesirable when used in pharmaceuticals. In many cases, the compounds herein are capable of forming acid and / or base salts because of 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. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of 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, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Examples of inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., and particularly preferred are salts of ammonium, potassium, sodium, calcium and magnesium. Examples of organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine, etc. Many such salts are known in the art as described in WO87 / 05297 (Johnston et al.) published on September 11, 1987 (which is hereby incorporated by reference in its entirety). Some examples of pharmaceutically acceptable base addition salts of the compounds disclosed herein are of formula (I-salt) or (II-salt): [Chemical] (wherein Z is an alkali metal or NH 4 + and can be) has the structure of

[0050] As used herein, "C a ~C b " or "C a~b " (wherein "a" and "b" are integers) refers to the number of carbon atoms in the specified group. That is, the group can contain "a" to "b" (including "a" and (b)) carbon atoms. Thus, for example, "C 1 ~C 4 alkyl" or "C 1~4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.

[0051] The term "halogen" or "halo", as used herein, means any one of the radiation-stable atoms in column 7 of the periodic table of the elements, for example, fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0052] As used herein, "alkyl" refers to a fully saturated (i.e., containing no double or triple bonds), straight-chain or branched hydrocarbon chain. An alkyl group can have from 1 to 20 carbon atoms (when an alkyl group appears in this specification, the numerical range such as "1 to 20" always refers to each integer within 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 20 (including this) carbon atoms, but this definition also includes the occurrence of the term "alkyl" for which no numerical range is specified). The alkyl group may 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 compound may be designated as "C 1~4 alkyl" or a similar name. By 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, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are by no means 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 alkyl as defined above, including, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, etc., of "C 1~9 alkoxy".

[0054] As used herein, "alkylthio" refers to the formula -SR, where R is alkyl as defined above, including, but not limited to, methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, etc., of "C1~9 It is alkyl as defined above such as "alkylthio".

[0055] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon chain containing one or more double bonds. An alkenyl group can have 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. The alkenyl group can also be a medium-sized alkenyl having 2 to 9 carbon atoms. The alkenyl group can also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group of the present compound can be designated as "C 2~4 alkenyl" or a similar name. By way of example only, "C 2~4 alkenyl" indicates that there are 2 to 4 carbon atoms in the alkenyl chain, that is, 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-chain or branched hydrocarbon chain containing one or more triple bonds. An alkynyl group can have 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. The alkynyl group can also be a medium-sized alkynyl having 2 to 9 carbon atoms. The alkynyl group can also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group of the present compound can be designated as "C 2~4 alkynyl" or a similar name. By way of example only, "C 2~4"Alkynyl" means that there are 2 to 4 carbon atoms in the alkynyl chain, that is, 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 not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

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

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

[0059] As used herein, "aryl" refers to an aromatic ring or aromatic ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring skeleton. When aryl is a ring system, all of the rings in this system are aromatic. An aryl group can have 6 to 18 carbon atoms, but this definition also encompasses occurrences of the term "aryl" where no numerical range is specified. In some embodiments, the aryl group has 6 to 10 carbon atoms. An aryl group may be designated by "C 6~10 aryl", "C 6 or C 10 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- (wherein R is aryl as defined above, including but not limited to aryloxy such as phenyloxy) and "C 6~10 aryloxy" or "C 6~10 arylthio").

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

[0062] As used herein, "heteroaryl" refers to an aromatic ring or aromatic ring system (i.e., two or more fused rings sharing 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 of the rings in the system are aromatic. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses occurrences of the term "heteroaryl" for which a numerical range is not specified. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl group can be designated as a "5- to 7-membered heteroaryl", a "5- to 10-membered heteroaryl", or a similar name. 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] "Heteroalkyl" or "heteroarylalkyl" is a heteroaryl group attached 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 is a lower alkylene group (i.e., a C 1~4 alkylene group).

[0064] As used herein, "carbocyclic" means a non-aromatic cyclic ring or non-aromatic cyclic ring system that contains only carbon atoms in the ring system skeleton. When the carbocyclic is a cyclic ring system, two or more rings may be bonded together in a fused form, a bridged form, or a spiro-bonded form. The carbocyclic may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclic includes cycloalkyl, cycloalkenyl, and cycloalkynyl. The carbocyclic group can have 3 to 20 carbon atoms, but this definition also includes occurrences of the term "carbocyclic" where no numerical range is specified. The carbocyclic group may also be a medium-sized carbocyclic having 3 to 10 carbon atoms. The carbocyclic group can also be a carbocyclic having 3 to 6 carbon atoms. The carbocyclic group may be designated as "C 3~6 carbocyclic" or a similar name. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohex yl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0065] "(Carbocyclic)alkyl" is a carbocyclic group bonded as a substituent via an alkylene group, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some cases, the alkylene group is a lower alkylene group. 4~10 (Carbocyclic)alkyl", etc.

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

[0067] As used herein, "cycloalkenyl" means a carbocyclic ring or carbocyclic ring system having at least one double bond, wherein the rings in the ring system are carbocyclic rings or carbocyclic ring systems that are not aromatic. One example is cyclohexenyl.

[0068] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or non-aromatic ring system containing at least one heteroatom in the ring skeleton. Heterocyclyls may be joined together in fused, bridged or spiro-linked forms. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom(s) can be present in either a non-aromatic or aromatic ring in the ring system. A heterocyclyl group can have from 3 to 20 ring members (i.e., the number of atoms making up the ring skeleton, including carbon atoms and heteroatoms), but this definition also encompasses occurrences of the term "heterocyclyl" where no numerical range is specified. A heterocyclyl group may also be a medium-sized heterocyclyl having from 3 to 10 ring members. A heterocyclyl group may also be a heterocyclyl having from 3 to 6 ring members. A heterocyclyl group may be designated as a "3- to 6-membered heterocyclyl" or a similar name. In a preferred 6-membered monocyclic heterocyclyl, the heteroatom(s) are selected from 1 to 3 of O, N or S, and in a preferred 5-membered monocyclic heterocyclyl, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N or S.Examples of heterocyclic 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, 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” is a heterocyclyl group bonded as a substituent through an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0070] As used herein, “acyl” refers to -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 as defined herein. Non - limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl.

[0071] The "O-carboxy" group refers to the "-OC(=O)R" group (wherein R is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic as defined herein).

[0072] The "C-carboxy" group refers to the "-C(=O)OR" group (wherein R is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic as defined herein). Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0073] The "cyano" group refers to the "-CN" group.

[0074] The "cyanato" group refers to the "-OCN" group.

[0075] The "isocyanato" group refers to the "-NCO" group.

[0076] The "thiocyanato" group refers to the "-SCN" group.

[0077] The "isothiocyanato" group refers to the "-NCS" group.

[0078] The "sulfinyl" group refers to the "-S(=O)R" group (wherein R is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic as defined herein).

[0079] The "sulfonyl" group refers to "-SO2 The "R" group (wherein R is, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic selected therefrom).

[0080] The "S-sulfonamide" group means the "-SO 2 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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic selected therefrom).

[0081] The "N-sulfonamide" group means the "-N(R A )SO 2 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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic selected therefrom).

[0082] The "O-carbamyl" group means the "-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, C3~7 Carbocyclic, C 6~10 (selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic).

[0083] The term "N-carbamyl" group refers to the group "-N(R A )OC(=O)R B " (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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic).

[0084] The term "O-thiocarbamyl" group refers to "-OC(=S)NR A R B " (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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic).

[0085] The term "N-thiocarbamyl" group refers to the group "-N(R A )OC(=S)R B " (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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic).

[0086] The "C-amide" group refers to the "-C(=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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic selected).

[0087] The "N-amide" group refers to the "-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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic selected).

[0088] The "amino" group refers to the "-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 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic selected).

[0089] The "aminoalkyl" group refers to an amino group bonded via an alkylene group.

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

[0091] As used herein, a substituted group is derived from an unsubstituted parent group, in which case one or more hydrogen atoms are replaced by another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", the group is C 1 ~C 6 alkyl, C 1 ~C 6 alkenyl, C 1 ~C 6 alkynyl, C 1 ~C 6 heteroalkyl, C 3 ~C 7 carbocyclic (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy, optionally substituted), C 3 ~C 7 -carbocyclic-C 1 ~C 6 -alkyl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy, optionally substituted), 5- to 10-membered heterocyclyl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy yl, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy, optionally substituted), 5- to 10-membered heterocyclyl-C 1 ~C 6-alkyl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy optionally substituted therewith), aryl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy optionally substituted therewith), aryl (C 1 ~C 6 )alkyl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy optionally substituted therewith), 5- to 10-membered heteroaryl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy optionally substituted therewith), 5- to 10-membered heteroaryl (C 1 ~C 6 )alkyl (halo, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkyl and C 1 ~C 6 haloalkoxy optionally substituted therewith), halo, cyano, hydroxy, C 1 ~C 6 alkoxy, C 1 ~C6 Alkoxy(C 1 ~C 6 )alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C 1 ~C 6 )alkyl (e.g., -CF 3 ), halo(C 1 ~C 6 )alkoxy (e.g., -OCF 3 ), C 1 ~C 6 alkylthio, arylthio, amino, amino(C 1 ~C 6 )alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo(=O), and is meant to be substituted with one or more substituents independently selected therefrom. When a group is described as "optionally substituted", the group may be substituted with the above substituents.

[0092] In some embodiments, the substituted group(s) is / are individually substituted with one or more substituent(s), and is / are independently selected from C 1 ~C 4 alkyl, amino, hydroxy and halogen.

[0093] It should be understood that certain radical naming conventions can include either a monoradical or a diradical depending on the context. For example, when a substituent requires two attachment points to the rest of the molecule, the substituent is understood to be a diradical. For example, a substituent specified as an alkyl that requires two attachment points is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2- includes radicals such as. Other radical naming rules 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, bonded to the remainder of the molecule through two attachment points (e.g., alkanediyl). An alkylene group can have 1 to 20 carbon atoms, but this definition also encompasses occurrences of the term alkylene where no numerical range is specified. The alkylene group may also be a medium-sized alkylene having 1 to 9 carbon atoms. The alkylene group can also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as " 1~4 alkylene" or a similar name. By way of example only, " 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" means a straight-chain or branched-chain diradical chemical group containing only carbon and hydrogen, having at least one carbon-carbon double bond, and bonded to the remainder of the molecule through two attachment points. An alkenylene group can have 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term alkenylene where no numerical range is specified. The alkenylene group can also be a medium-sized alkenylene having 2 to 9 carbon atoms. The alkenylene group can also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as " 2~4may be designated by "alkenylene" or a similar name. By way of example only, "C 2~4 "alkenylene" indicates 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, propene-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, butene-1,1-diyl, buta-1,3-diene-1,1-diyl, but-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-ethene-1,1-diyl.

[0096] When two R groups are described as forming a ring (e.g., a carbocyclic, heterocyclic, aryl or heteroaryl ring) "together with the atoms to which they are attached", the set unit consisting of those atoms and the two R groups is intended to be the recited ring. This ring, when employed individually, is not particularly limited by the respective definitions of the R groups. For example, the following substructures:

Chemical formula

Chemical formula

[0097] Similarly, when it is stated that two "adjacent" R groups "together with the atoms to which they are attached" form a ring, it means that the set unit consisting of this atom, the intervening bond, and the above two R groups becomes the ring listed. For example, the following partial structure:

Chemical formula

Chemical formula

[0098] When a substituent is shown as a diradical (i.e., having two bonding points to the rest of the molecule), it should be understood that the substituent can be bonded in a stereoconfiguration with any orientation, unless otherwise specified. Thus, for example, -AE- or

Chemical formula

[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 resembles 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 -SO 3 H, -SO 2 HNR, -PO 2 (R) 2 , -PO 3 (R) 2 , -CONHNHSO 2 , -COHNSO 2 R and -CONRCN (wherein R is selected from 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 3- to 10-membered heterocyclyl as defined herein). Further, a carboxylic acid isostere can include a 5- to 7-membered carbocyclic or heterocyclic ring containing any combination of CH 2 , O, S or N in any chemically stable oxidation state, where any of the atoms of the ring structure are optionally substituted at one or more positions. The following structures are non-limiting examples of contemplated carbocyclic and heterocyclic isosteres. The atoms of the ring structure may be optionally substituted at one or more positions by R as defined above.

Chemical formula

[0100] When a chemical substituent is attached to a carboxylic acid isostere, it is also contemplated that the compound retains the properties of the carboxylic acid isostere. When the carboxylic acid isostere is optionally substituted by one or more moieties selected from R as defined above, the substitution and the position of substitution are contemplated to be selected such that R does not abolish 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) is not a substitution at one or more atoms that maintains or is integral with 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. "Agent" or "test agent" includes, but is not limited to, for example, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. "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 "analogue" is used herein to refer to a molecule that is structurally similar to a reference molecule but is modified in a targeted and controlled manner by replacing specific substituents of the reference molecule with alternative substituents. Analogues are expected by those skilled in the art to exhibit the same, similar or improved utility when compared to the reference molecule. The synthesis and screening of analogues to identify variants of known compounds with improved characteristics (such as higher binding affinity for a target molecule) are well-known techniques in medicinal chemistry.

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

[0105] The term "microbial infection" refers to the invasion of a host organism by pathogenic microorganisms, regardless of whether the organism is a vertebrate, invertebrate, fish, plant, bird or mammal. This includes the overgrowth of microorganisms that are normally present in or on the body surface 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, when an excessive number of microbial populations are present in or on the body of a mammal, or when the presence of the microbial population(s) affects and damages the cells or other tissues of a mammal, the mammal is "suffering from" a microbial infection. Specifically, this description applies to bacterial infections. The compounds of the preferred embodiments are also useful for the growth of microorganisms, or the contamination of cell cultures or other media, or inanimate surfaces, or for treating an object, and it should be noted that, unless expressly specified as such in the claims, there is no intention in this specification to limit the preferred embodiments to the treatment of higher organisms only.

[0106] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional medium or agent is contemplated in the therapeutic composition, except when any of them are incompatible with the active ingredient. In addition, various adjuvants as commonly used in the art may be included. Considerations for including the various components in the pharmaceutical composition are incorporated herein by reference in their entirety, for example, Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press is described therein.

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

[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 to reduce the likelihood of their onset, including cure of the disease or condition. "Cure" means the absence of symptoms of the disease or condition, however, there may be present some long-term or permanent effects (such as extensive tissue damage) even after a cure has been 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 has not yet exhibited symptoms of a disease or condition but who is susceptible to or at risk of 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 treating a subject who exhibits symptoms of a disease or condition. Preparation method

[0110] The compounds disclosed in this specification can be synthesized by the methods described below, or by modifications of these methods. Means for modifying this method include, inter alia, temperatures, solvents, reagents, etc. known to those skilled in the art. In general, during any of the methods for preparing the compounds disclosed in this specification, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules involved. This can be achieved by 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 entirety. The protecting groups can be removed at a convenient later stage using methods known from the art. Synthetic chemical transformations useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described in this specification are merely illustrative and are in no way intended, nor should they be construed, to limit the scope of the claims in any way. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and 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 scheme, the protecting group for the oxygen atom is selected with respect to its compatibility with the required synthetic steps, as well as 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)). The handling of protecting groups and / or stereodirecting groups specific to boronic acid derivatives is described in the recent review of boronic acid chemistry, D.G. Hall (Ed.), Boronic Acids. Preparation and Application in Organic Synthesis and Medicine, Wiley VCH (2005), which is hereby incorporated by reference in its entirety, as well as the earlier reviews: Matteson, D. S. (1988). Asymmetric synthesis with boronic esters. Accounts of Chemical Research, 21(8), 294-300 and Matteson, D. S. (1989). Tetrahedron, 45(7), 1859-1885). The last review article also describes methods for the stereoselective insertion of a halomethine functional group adjacent to a boronic ester, which are used in the following synthetic scheme.

[0112] ​In addition to standard acid-catalyzed deprotection, special methods for removing boronic acid protecting groups and / or stereogenic groups include methods using fluoride (Yuen, A. K. L., & Hutton, C. A. (2005). Tetrahedron Letters, 46(46), 7899-7903, which is hereby incorporated by reference in its entirety) or periodic acid oxidation (Coutts, S. J., et al. (1994). Tetrahedron Letters, 35(29), 5109-5112, which is hereby incorporated by reference in its entirety) and can also be used in the preparation of the compounds disclosed herein. can be used.

[0113] In strategies using chiral auxiliaries based on pinanediol or other diols for the stereospecific introduction of new chiral centers, the early stages of the chemistry of boronic acid intermediates can be carried out on chiral boronic esters or, alternatively, achiral borate / boronic ester intermediates can be used at an early stage and then transesterified with a chiral diol prior to the step where stereoselection is required. Synthesis of Compounds of Formula I

[0114] The following example schemes are presented for the guidance of the reader and summarize methods that are exemplary of ways to make the compounds encompassed herein. Further, 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 variable groups are as defined above.

[0115] The compounds of formula (Ia) where R is H can be prepared from the important intermediates V’, XIII’, 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, D.G. Hall, ed., Wiley-VCH, Weinheim, 2011, which is hereby incorporated by reference in its entirety). The methods in the following items are specified with respect to the pure enantiomers of formula (Ia). These methods are also adaptable for the preparation of the compounds of formula (Ic) which are the other enantiomers, or for the preparation of racemic mixtures by modifying the steps that define the stereochemistry. Scheme 1 [Chemical formula]

[0116] The compounds of formula (Ia) can be prepared starting from the protected aryl or heteroaryl intermediates of formula II’ by a series of double Matteson homologations (J. Org. Chem., 2013, 78, 10009-10023, which is hereby incorporated by reference in its entirety). The compounds of formula II’ are prepared from commercially available salicylic acid derivatives using conventional protecting groups for R’ and R’’ such as those described in Protecting Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum, 1973; and Protecting Groups in Organic Synthesis P.G.M. Wutts, T.W. Green, Wiley, New York, 1999, both of which are hereby incorporated by reference in their entirety). ​It can be obtained from the compound of formula I' by some previously known methods (WO0458679, which is incorporated herein by reference in its entirety). The aryl compounds of formula I' can be obtained by boronation by well-known available methods (Chem. Rev. 2010, 110, 890-931, which is incorporated herein by reference in its entirety), and the formation of the desired chiral auxiliary group is used When the boronic ester formation is carried out, a precursor for Matteson homologation is obtained. The compound 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 cyclic form, can be prepared from the compound of formula II' by homologation with chloromethylene insertion with good stereocontrol under Matteson reaction conditions (WO0946098, which is incorporated herein by reference in its entirety). The compound of formula III' where X is bromo can be prepared in the same manner as the chloro compound in Scheme 1 using dibromomethane (J. Am. Chem. Soc. 1990, 112, 3964-969, which is incorporated herein by reference in its entirety). The halo derivatives of formula III' where X is Cl or Br are subject to stereospecific substitution with vinylmagnesium halide, or allylmagnesium halide, or the enolate of t-butyl acetate (Tetrahedron 2005, 61, 4427-4536, which is incorporated herein by reference in its entirety), to give the compound of formula IV'. These intermediates of formula IV' can be further treated under Matteson reaction conditions for homologation of unsubstituted methylene. The intermediates thus obtained can be further modified by conversion of the G' group to the G substituent of the G group. The G' group such as vinyl or allyl functional group can be converted to the corresponding alcohol or acid or aldehyde by periodate oxidation or ozonolysis. The aldehyde functional group can be converted to a substituted amine by reductive amination to the G-substituted compound of formula V'.

[0117] The simultaneous deprotection of the pinan ester protecting group and the salicylic acid protecting group of the compound of formula V’ can be achieved by heating with dilute HCl, and the desired compound of formula (Ia) is obtained. This conversion can also be achieved by treatment with BCl 3 or BBr 3 (WO09064414, which is hereby incorporated by reference in its entirety). Alternatively, the deprotection can be effected by transesterification with isobutyl boronic acid in the presence of dilute acid (WO09064413, which is hereby incorporated by reference in its entirety) or by other known methods (J. Org. Chem. (2010), 75, 468 - 471, which is hereby incorporated by reference in its entirety).

[0118] The salicylic acid derivative of formula I’ in which Y’ is a leaving group undergoes a coupling reaction with the Reformatsky reagent of the acetate ester under Negishi conditions to give an intermediate of formula VI’ in which X’ is OR’’’. (Tetrahedron, 2014, 1508 - 1515, J. Org. Chem., 2013, 78, 8250 - 8266, which are hereby incorporated by reference in their entirety) (Scheme 2). Alkylation of such an intermediate with a halomethylene boronic ester derivative VIIA, followed by modification of the ester by selective hydrolysis and reduction, gives the compound of formula V’ with high stereoselectivity (J. Am. Chem. Soc., 2011, 133, 11936 - 11939, which is hereby incorporated by reference in its entirety). The intermediate of formula VI’ undergoes methylenation to give a derivative of VII’ (J. Org. Chem., 1986, 51, 2981 - 2988, which is hereby incorporated by reference in its entirety). The intermediate of formula VII’ undergoes asymmetric boronation under known conditions to give the compound of formula V’ (J. Am. Chem. Soc., 2010, 132, 10630 - 10633, which is hereby incorporated by reference in its entirety). Such asymmetric boronations may also be achievable when X’ is -NOR 1 The intermediate of formula V’ can be further converted to a compound of formula (Ia) under the conditions described in Scheme 1. Scheme 2

Chemical formula

[0119] Alternatively, the compound of formula (Ia) can be prepared by the borylcarboxylation reaction of the acetylene intermediate of formula VIII’ followed by asymmetric hydrogenation as shown in Scheme 3. The formula I’ which is an aryl or heteroaryl derivative undergoes a Pd-mediated coupling reaction to obtain an acetylene-substituted compound having TMS acetylene. By the borylcarboxylation of an alkyne with a diborane compound and carbon dioxide in the presence of an N-heterocyclic carbene copper(I) complex as a catalyst, a regioselective and stereoselective α,β-unsaturated β-borolactone derivative is obtained by borylcopperation / carboxylation (J. Am. Chem. Soc. 2012, 134, 14314-14317, which is incorporated herein by reference in its entirety). Such obtained derivatives can be converted to carboxylic acid esters and boronic acid esters to obtain an intermediate of formula IX’. By utilizing the asymmetric hydrogenation of the intermediate of formula IX’ (Chem. Rev. 2003, 103, 3029-3070, which is incorporated herein by reference in its entirety), a pure compound of formula X’ can be obtained as an enantiomer. Such a compound can be further converted to a compound of formula V’ by selective hydrolysis and reduction to obtain an appropriate G-substituted product, which, upon final deprotection, gives a compound of formula (Ia) by the process described in Scheme 1 above. Such a compound can be further converted to a compound of formula V’ by selective hydrolysis and reduction to obtain an appropriate G-substituted product, which, upon final deprotection, gives a compound of formula (Ia) by the process described in Scheme 1 above. Scheme 3

Chemical formula

[0120] G = -NR 1 C(O)R 4 、 -NR 1 C(O)NR 1 R 2 or -NR 1 C(O)OR 3 The compound of formula (Ia) in which is, as shown in Scheme 4, a carboxylic acid ester of formula XI’ (where G is -CH 2 CO 2 t Bu and R’ and R’’ together form a protecting isopropylidene) can be prepared via the compound of formula V’. Such compounds are converted to amides by hydrolysis of the selective t-butyl ester and Curtius rearrangement (Chem. Rev., 1988, 88, 297 - 368; Org. Lett., 2005, 4107 - 4110, which are hereby incorporated by reference in their entirety), and then the compound of formula XIII’ can be obtained by deprotection and amide formation. The compound of formula XII’ can also be converted by hydrolysis to a compound of formula (Ia) in which G is -NHC(O)-O-R. Scheme 4 Scheme 4

Chemical Structure

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

Chemical formula

[0122] The compound of formula (Ia) can also be prepared by a convergent method shown in Scheme 6 via the intermediate of formula XX'. Such an intermediate of formula XX' is prepared by palladium-catalyzed coupling of a substituted diboron ester precursor of formula XIX' (Org. Lett., 2014, 16, 6240 - 6243) with the precursor of formula I'. The diboron ate of formula XIX' is prepared from the propargyl derivative of formula XVIII' by using an Ir-catalyzed method (J. Am. Chem. Soc., 2010, 132, 2548 - 2549). Such an intermediate of formula XX' (G' is -OTIPS or -CO for further modification or deprotection) 2It can be Me or -CONR’R’’) undergoes enantioselective hydrogenation (Angew. Chem. Int. Ed., 2011, 50, 1 - 6; Chem. Eur. J., 2012, 18, 6724 - 6728) and is known to become an intermediate of formula XXI’. As described above, modification of the G’ group to G and deprotection of XXI’ result in the compound of formula (Ia). Scheme 6

Chemical formula

[0123] In the alternative synthetic route shown below, the compound of formula (Ia) can be prepared by boron insertion of a benzofuran derivative of formula XXV’ catalyzed by nickel (J. Am. Chem. Soc., 2016, 138, 15315 - 15318), and an intermediate of formula XXVI’ is obtained. E nantioselective 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 an oxaborinane intermediate gives the compound of formula (Ia). The benzofuran derivative of formula XXV’ can be prepared by several known different methods including cyclization of the intermediate of formula XXIV’ (Org. Biomol. Chem., 2016, 14, 8074 - 8087). Such an intermediate of formula XXIV’ can be obtained by alkylation of a suitably substituted phenol derivative of formula XXIII’ with a substituted bromoacetone derivative of formula XXII’ (Tetrahedron, 2013, 69, 5937 - 5944). Scheme 7

Chemical formula

[0124] Alternatively, the intermediate of formula XXIX’, which can be characterized in the route for obtaining the compound of formula (Ia), can be prepared as shown in Scheme 8. Such an intermediate of formula XXIX’ can be synthesized from a compound 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 entireties of which are incorporated herein by reference). The compound of formula XXVIII’ in which X’ is substituted by a bromo group or an iodo group can be obtained from a commercially available 2,5 - hydroxy - benzoic acid derivative that is appropriately protected (J. Med. Chem., 2003, 46, 3437 - 3440, the entirety of which is incorporated herein by reference). The intermediate of formula XXXVIII’ can also be prepared by carboxylation of a derivative of formula XXXVII’ in which Z’ is fluoro or OR’ or SR’ by the method described previously ( WO12106995, the entirety of which is incorporated herein by reference). Scheme 8 [Chemical Structure Diagram]

[0125] In another exemplary synthetic route, as shown in Scheme 9, the compound of formula XXXII’ can be prepared from a salicylic acid derivative of the compound of formula XXXI’. The compound of formula XXX’ can be prepared by diallylation under basic conditions followed by thermal Claisen rearrangement (Org. React. 1975, 22, 1 - 252, the entirety of which is incorporated herein by reference), and also When the ester hydrolysis is carried out, a compound of formula XXXI’ is obtained. Such a compound leads to a phenylacetic acid derivative of formula XXXII’ by protection and oxidation and subsequent esterification. The compound of formula XXXII’ can be further converted as shown in Scheme 2 above. The compound of formula XXX’ can also undergo the steps listed in Scheme 8 above to form an ortho-carboxylate-substituted compound of formula XXIX’. Scheme 9 [Chemical formula] Synthesis of prodrugs

[0126] Compounds of formula (Ia) in which R is a prodrug moiety can be synthesized by various known methods for generating various carboxylic acid prodrugs (Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed., Springer, New York, 2007, which is hereby incorporated 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, which is hereby incorporated by reference in its entirety), [(alkoxycarbonyl)oxy]methyl esters (WO10097675, which is hereby incorporated by reference in its entirety) or (oxodioxolyl)methyl esters (J. Med. Chem. 1996, 39, 323 - 338, which is hereby incorporated by reference in its entirety). Such prodrugs can be prepared from compounds of formula (Ia) where R = H (formula XXXIII’) by treatment with acid or under neutral conditions (e.g., carbodiimide coupling) in the presence of an alcohol (ROH), or by base-promoted esterification with RX where X is a leaving group in the presence of a suitable base.

[0127] ​One example, but a non-limiting general synthetic route for preparing a prodrug, is shown in Scheme 10 below. The 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 moiety R are -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 10 OC(O)OC 3~7 carbocyclyl, -CR 9 R 10 OC(O)(5- to 10-membered heterocyclyl), -CR 9 R 10 OC(O)O(5- to 10-membered heterocyclyl) and

Chemical Formula

Chemical Formula

[0128] Alternatively, the boronic acid esters of formula XXXIV’ or the corresponding trifluoroboronic acid esters (Chem. Rev. 2008, 108, which are hereby incorporated by reference in their entirety) can also be utilized for the introduction of prodrugs to convert those esters to the final pro drugs. It can also be converted to a prodrug (Scheme 11). Such a carboxylic acid (XXXIV’) can be prepared from the compound of formula V’ by selective deprotection of OR’. The prodrug group may also be introduced at an early stage in the compound of formula IV’ where R’ is R. Such an order in which the prodrug is introduced earlier into the intermediate is only feasible if this ester is sufficiently stable under the final deprotection conditions for removing the phenolic protecting group and the boronic acid ester group. Scheme 11

Chemical formula

[0129] The present compound is administered at a therapeutically effective dosage. The human dosage levels for the compounds described herein have not yet been optimized, but generally, the daily dosage can be about 0.25 mg / kg to about 120 mg / kg or more per body weight, about 0.5 mg / kg or less to about 70 mg / kg per body weight, about 1.0 mg / kg to about 50 mg / kg, or about 1.5 mg / kg to about 10 mg / kg per body weight. Thus, for administration to a 70 kg human, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg or less per day to about 7000 mg or more per day, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg per day to about 3000 mg per day. Of course, the amount of the active compound administered will depend on the subject being treated and the disease state, the severity of the affliction, the form and schedule of administration, as well as the judgment of the prescribing physician.

[0130] Administration of the compounds or pharmaceutically acceptable salts thereof disclosed herein can be by any of the acceptable administration forms of agents that serve a similar utility, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, intravaginal, rectal, or intraocular administration. Oral and parenteral administrations are conventional for treating the symptoms that are the subject of the preferred embodiments.

[0131] The useful compounds described above can be formulated into pharmaceutical compositions for use in treating these conditions. Standard pharmaceutical formulation techniques such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005) are used. Accordingly, some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs, and solvates), 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 terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any solvent, dispersion medium, coating agent, 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. The use of any conventional medium or agent in a therapeutic composition is contemplated, except when it is incompatible with the active ingredient. Further, various adjuvants as commonly used in the art may be included. Considerations for including the various components in a pharmaceutical composition are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is hereby incorporated by reference in its entirety. are.

[0133] Some examples of substances that can act as a pharmaceutically acceptable carrier or its components are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; 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; emulsifying agents such as TWEENS®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring and odor-masking agents; tabletting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0134] The selection of a pharmaceutically acceptable carrier to be used in connection with the subject compound is basically determined by the manner in which the compound is to be administered.

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

[0136] As noted above, useful compositions are available by a variety of routes of administration, e.g., oral, nasal, rectal, topical (transdermal It may be in any of various forms suitable for intraocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parenteral administration routes. Those skilled in the art understand that oral and nasal compositions are compositions administered by inhalation and include compositions prepared using available methods. Depending on the particular desired administration route, various pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Pharmaceutically active substances may be included as necessary, which do not substantially interfere with the inhibitory activity of the compound. The amount of the carrier used in conjunction with the present compound is sufficient to achieve a realistic amount of the substance for administration per unit dose of the compound. Techniques and compositions for preparing 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 multi-compressed and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavoring agents, flow-inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and foaming preparations reconstituted from foaming granules, including suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, melting agents, colorants and flavoring agents.

[0138] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically 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 ; and commonly include conventional pharmaceutically compatible adjuvants as lubricants such as magnesium stearate, stearic acid, and talc. Glidants such as silicon dioxide may be used to improve the flow characteristics of the powder mixture. Colorants such as FD&C dyes may be added for appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The choice of carrier component is not critical and can be readily made by one skilled in the art, depending on secondary considerations such as taste, cost, and storage stability.

[0139] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for the preparation of 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 components such as the sweetening, flavoring, and coloring agents disclosed above.

[0140] Such compositions may also be coated, by conventional methods, usually with a pH- or time-dependent coating agent, so that, in the gastrointestinal tract, the subject compound is released in the vicinity of the desired local application or at various times to extend the desired action. Such dosage forms usually include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coating agents, waxes, and shellac.

[0141] The compositions described herein may optionally contain other pharmaceutically active agents.

[0142] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal dosage forms. Such compositions usually contain one or more of soluble filler substances such as sucrose, sorbitol, and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. The flow promoters, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0143] Liquid compositions formulated for topical ophthalmic use are formulated to be topically administrable 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 such that it is tolerated by the patient for topical ophthalmic use. Additionally, the ophthalmically acceptable liquid should either be packaged for single use or contain a preservative to prevent contamination over multiple uses.

[0144] ​For ophthalmic administration, solutions or medicaments are often prepared using an aqueous saline solution as the major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

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

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

[0147] As long as the resulting preparation is ophthalmically acceptable, various buffers and means for adjusting the pH may be used. For many compositions, the pH will be between 4 and 9. Thus, buffers include acetate buffer, citrate buffer, phosphate buffer and borate buffer. If necessary, an acid or base may be used to adjust the pH of these formulations.

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

[0149] Other excipient components that may be included in the ophthalmic preparation are chelating agents. A useful chelating agent is sodium edetate, although other chelating agents may also be used instead of or in combination with it.

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

[0151] Regarding intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent such as physiological saline or dextrose solution. Suitable excipients include, but are not limited to, NaOH, sodium carbonate, sodium acetate, HCl and citric acid and may be included to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, 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. Further, acceptable excipients are those of both which are incorporated herein by reference in their entirety, Powell, et It is described in 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. As follows Antimicrobial agents, including but not limited to phenylmercury nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol, are also included to achieve antibacterial or antifungal solutions.

[0152] Compositions for intravenous administration may be provided in yet another solid form that is reconstituted immediately prior to administration with a suitable diluent such as sterile water, saline, or dextrose in water and passed to the caregiver. In other embodiments, the composition is provided as a ready-to-administer solution for parenteral administration. In yet other embodiments, the composition is provided as a solution that is further diluted prior to administration. In embodiments that include the step of administering a combination of the compounds and another agent described herein, these combinations may be passed to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0153] The actual dosage of the active compounds described herein depends on the specific compound and the condition being treated, and the selection of the appropriate dosage is well within the knowledge of those skilled in the art. Treatment method

[0154] Some embodiments of the present invention include methods of treating bacterial infections with a composition comprising the present compound and 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 can be an animal, such as a mammal (including a human). In some embodiments, the bacterial infection includes the bacteria described herein. As will be appreciated from the foregoing, methods of treating bacterial infections include methods of preventing bacterial infections in a subject 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 a compound, composition, additional medicament described herein.

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

[0158] Examples of additional medicaments include antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and anti-allergy 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), chromocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamesillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (e.g., dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, cefazolin, cefacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cefapirin, cefatrizine, cefazedone, cefazafur, cefradine, cefuroxime, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefotiam hexetil, cefibuten, cefthiofur, ceftezoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftobiprole medocaril, cefquinome, cefovecin, aztreonam, tigemonam and carumonam.

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

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

[0162] Some embodiments include a combination of a compound, composition and / or pharmaceutical composition described herein with an additional agent comprising a monobactam. Examples of monobactams include aztreonam, tigemonam, nocardicin A, carumonam and tabtoxin. One In some such embodiments, the compound, composition and / or pharmaceutical composition comprises a class A, C or D β-lactamase inhibitor. Some embodiments include the step of co-administering one or more additional agents with a compound, composition or pharmaceutical composition 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 the step of co-administering one or more additional agents with a compound, composition or pharmaceutical composition described herein.

[0164] Some embodiments include a combination of a compound, composition, and / or pharmaceutical composition described herein with an additional agent, where the additional agent includes one or more agents including a class A, B, C, or D β-lactamase inhibitor. Some embodiments include the step of co-administering a compound, composition, or pharmaceutical composition described herein with one or more additional agents. Case

[0165] The compounds described herein, and compositions containing such compounds, can be used to treat bacterial infections. Bacterial infections treatable by the compounds, compositions, and methods described herein can include a wide spectrum 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, Baccillus, 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 It includes Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus.

[0167] To further illustrate the present invention, the following examples are included. Of course, these examples should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the scope of those skilled in the art and are considered to fall within the scope of the present invention as described and claimed herein. The reader will recognize that those skilled in the art given the present disclosure and the state of the art will be able to prepare and use the present invention without the need for comprehensive examples. The following examples further illustrate the present invention and are used for illustrative purposes only and should not be considered as limitations.

Examples

[0168] General procedure The substances used in the preparation of the cyclic boronic acid ester derivatives described herein can be prepared by known methods or are commercially available. Claimed herein Methods for preparing precursors and functional groups related to the compounds in question are generally described in the literature, including the procedures described in, for example, US7271186 and WO2009064414, the entireties of which are incorporated by reference. It will be apparent to those skilled in the art that in these reactions, variations that are known per se to those skilled in the art but not specified in more detail can also be used. Those skilled in the art to whom the literature and the present disclosure are presented are fully versed in preparing any compound.

[0169] Those skilled in the art of organic chemistry can readily perform the operations without further guidance, that is, it is recognized that performing these operations is well within the scope and practice of those skilled in the art. These include the reduction of a carbonyl compound to its corresponding alcohol, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic etherification, esterification, and saponification. These operations are discussed in standard textbooks such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (the entirety of which is incorporated herein by reference).

[0170] Those skilled in the art will readily recognize that a reaction proceeds best when other functional groups in the molecule are masked or protected, thus avoiding any undesirable side reactions and / or improving the yield of this reaction. In many cases, those skilled in the art utilize protecting groups that achieve such an improvement in yield or avoid undesirable reactions. These reactions are found in the literature and are also well within the scope of those skilled in the art. Numerous examples of these operations 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 presented for the guidance of the reader and represent preferred ways of making the compounds exemplified herein. These methods are illustrative and not limiting, and it will be apparent that other routes can be used to prepare these compounds. Such methods specifically include solid-phase based chemistries, including combinatorial chemistry. Those skilled in the art are fully versed in preparing these compounds by such methods as are shown in the literature and in this disclosure. The numbers of the compounds used in the synthetic schemes illustrated below are intended for those particular schemes only and should not be construed as being the same as, or confused with, the same numbers in other items of this application.

[0172] The trademarks used herein are for illustrative purposes only and represent exemplary substances in use at the time of the invention. Those skilled in the art will recognize that variations such as lot, manufacturing method, etc. are to be expected. Accordingly, the examples and the trademarks used in the examples are non-limiting and are not intended to be limiting, but are merely examples of how those skilled in the art might choose to perform one or more of the embodiments of the invention.

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

[0174] The following example schemes are presented for the guidance of the reader and collectively represent exemplary ways of making the compounds provided herein. Further, 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 variable groups are as defined above. (Example 1) 2-Hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 1)

Chem.

[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 Boc 2 O (37.8 g, 173 mmol, 1.5 equiv), and the resulting solution was stirred at room temperature for 1 hour. 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 pale 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 dropwise LDA (75 mL, 150 mmol, 1.2 equiv) at -78 °C. The resulting solution was slowly warmed to room temperature and stirred for 16 hours. 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 pale 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 hours 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, and then acetone (50.6 mL) and TFAA (65 mL) were slowly added simultaneously. After 16 h at 100 °C under a nitrogen atmosphere, this 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) was added B 2 ((+)-Pinanediol) 2 (10.5 g, 29.30 mmol, 1.5 equiv), PdCl 2 (dppf) (797 mg, 0.98 mmol, 0.05 equiv) and KOAc (3.8 g, 39.06 mmol, 2.0 equiv). Under a nitrogen atmosphere, this mixture was stirred at 95 °C overnight. This mixture was filtered, and the filtrate was diluted with EA and water. The organic layer was washed with brine, dried over Na 2 SO 4 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(PPh 3 ) 4 (162 mg, 0.14 mmol, 0.05 equiv) and 2N Na 2 CO 3 (7.0 mL, 14.0 mmol, 5 equiv). Under a nitrogen atmosphere, this mixture was stirred at 80 °C overnight. Next, this mixture was diluted with EA, washed with water and brine, and dried over Na 2 SO 4It was dehydrated and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 1:0 to 10:1), and Compound 1G (715 mg, 78%) was obtained. Step 7: Synthesis of 1H

[0181] 2M BH 3 -S(Me) 2 (1.2 mL, 2.47 mmol, 2.0 equiv) in dry THF (10 mL) was slowly added to 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 and dried over Na 2 SO 4 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. Then, the reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 30:1 to 10:1), and Compound 1H (106 mg, 19%) was obtained. Step 8: Synthesis of 1I

[0182] To a solution of Compound 1H (120 mg, 0.266 mmol, 1.0 equiv) in H 2 O / 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. Then, the mixture was purified by preparative HPLC (under neutral conditions), and Compound 1I (50 mg, 60%) was obtained. 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 under H 2It was stirred at room temperature for 4 hours. After filtration through a Celite® pad, the filtrate was purified by preparative HPLC (under acidic conditions) to give Compound 1 (20 mg, 26%). LC-MS: 221 [M-H] - [Chemical Structure] (Example 2) Disodium 4-(benzyloxymethyl)-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylate (Compound 2) [Chemical Structure] Step 1: Synthesis of 2B

[0184] CH 2 Cl 2 A solution of bromine (14.06 mL, 274 mmol, 1 equiv) in CH 2 Cl 2 (20 mL) was slowly added dropwise over 8 hours to a suspension of 2,6-dimethoxybenzoic acid (2A) (50 g, 274 mmol) in CH 2 Cl 2 (200 mL). After stirring overnight at room temperature, the clear orange slurry was heated to remove some of the solvent (methyl bromide, hydrogen bromide, and CH 2 Cl 2 ) by distillation at atmospheric pressure (total volume of 100 mL distilled). Ethanol (150 mL) was added, and the remaining CH Step 2: Synthesis of 2C

[0185] The contents of a 10 mL syringe filled with trifluoroacetic anhydride (11.25 mL, 81 mmol, 2 equiv) and a 20 mL syringe filled with acetone (17 mL, 232 mmol, 5.7 equiv) were simultaneously dispensed by a 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. The addition of TFA (5 mL) gave a clear solution. After an additional 1 h at 70 °C, the solution became slightly heterogeneous. Upon completion of the addition, HPLC indicated that the product to starting material ratio was 89:11. After stirring overnight at 70 °C, this ratio was 92:8. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), filtered through Celite® and a pad, and the flask was washed with ethyl acetate (2 × 10 mL). The clear black filtrate was concentrated to dryness. The solid was dissolved in ethyl acetate (50 mL) and CH 2 Cl 2 (10 mL, to improve the solubility of the product ) and washed twice with saturated solutions of NaHCO 3 (50 and 30 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 x 10 mL) was added and the mixture was refluxed (the product began to crystallize after the last addition of heptane). The heterogeneous mixture was refluxed for 15 min and cooled to room temperature. After stirring at room temperature for 2 h and at 0 °C for 2 h, the solid was collected by filtration. The filtrate was recycled and the flask was washed. The solid was washed with 3:1 heptane / ethyl acetate at 0 °C (2 x 10 mL) and air dried, then dried under high vacuum to give compound 2C (8.83 g, 76%) as an off-white powder. Step 3: Synthesis of 2D

[0186] To a mixture of compound 2C (10.0 g, 3.5 mmol, 1.0 equiv) in dioxane (300 mL) was added B 2 ((+)-pinanediol) 2 (18.8 g, 52.5 mmol, 1.5 equiv), PdCl 2(dppf) (2.8 g, 3.5 mmol, 0.1 eq) and KOAc (6.86 g, 70 mmol, 2.0 eq) were added. Under a nitrogen atmosphere, the mixture was stirred at 96 °C overnight. Next, the mixture was filtered, the filtrate was diluted with EA, washed with water and brine, and dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 30:1 to 5:1), and powdered 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 eq) in THF (120 mL) was added Bromide 1F’ (5.6 g, 24.8 mmol, 1.3 eq), Pd(PPh 3 ) 4 (1.1 g, 0.95 mmol, 0.05 eq) and 2N Na 2 CO 3 (48 mL, 95 mmol, 5.0 eq). Under a nitrogen atmosphere, the mixture was stirred at 80 °C for 12 hours. The mixture was filtered, the filtrate was extracted with EA and H 2 O to separate the organic layer, washed with brine, and dried over Na 2 SO 4 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%, containing some pinanediol). Step 5: Synthesis of 2F

[0188] To a dry THF (300 mL) solution of 2M BH 3 -S(Me) 2 (32 mL, 63.56 mmol, 1.5 eq) was slowly added a dry THF (50 mL) solution of Compound 2E (15 g, 42.37 mmol, 1.0 eq) at -15 °C under a nitrogen atmosphere. Next, the mixture was removed from the water bath and stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with EA. The organic layer was washed with brine and dried over Na 2 SO4 It was dehydrated and concentrated in vacuo. This 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 mixture 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 H 2 O / ACN (7 mL / 15 mL) was added 3M 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] +

Chemical formula

Chemical formula

[0190] To a solution of Compound 2 (2.0 g, 5.85 mmol, 1.0 equiv) in methanol (20 mL) were added 1N HCl (to adjust the solution to pH 5 - 6) and Pd / C (200 mg, 10% W / W). The mixture was stirred under H 2 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] +

Chemical formula

Chem.

[0191] When 2-Hydroxy-4-(hydroxymethyl)-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 3) (1.03 g) was separated by a chiral column (Superchiral S-AD, hexane / EtOH / MeOH / formic acid = 60 / 13 / 27 / 0.01, v / v / v / v), Compound 4 (344 mg, 33%) and Compound 5 (410 mg, 39%) were obtained. Compounds 4 and 5 are illustrated as stereoisomers in the above scheme, but the absolute stereochemistry of the individual isomers has not yet been determined. Compound 4: LC-MS: 251 [M-H] -

Chem.

Chem.

Chem.

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

[0193] To a mixture of bromide Compound 6A (20.0 g, 72.99 mmol, 1.0 eq) in dioxane (200 mL) was added B 2 ((+)-Pinanediol) 2 (39.2 g, 109.5 mmol, 1.5 eq), PdCl 2 (dppf) (3.0 g, 3.65 mmol, 0.05 eq) and KOAc (14.3 g, 145.9 mmol, 2.0 eq). Under a nitrogen atmosphere, the mixture was stirred at 95 °C overnight. The mixture was filtered, the filtrate was diluted with EtOAc, washed with water and brine, dehydrated with Na 2 SO 4 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 eq) in THF (90 mL) was added 1F’ (12.2 g, 54.14 mmol, 1.5 eq), Pd(PPh 3 ) 4 (2.1 g, 1.80 mmol, 0.05 eq) and 2N Na 2 CO 3 (90 mL, 180.5 mmol, 5.0 eq). Under a nitrogen atmosphere, the mixture was stirred at 80 °C overnight. Next, 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 and brine, and Na 2 SO 4It was dehydrated 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] 2M BH 3 -S(Me) 2 (1.5 mL, 2.92 mmol, 2.0 equiv) in dry THF (10 mL) was slowly added to 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 h, quenched with water, and extracted with EA. The organic layer was washed with brine and dried over Na 2 SO 4 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 H 2 O / 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). Under H 2 the mixture was stirred 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 [M-H] - [Chemistry] (Example 6) (4R)-7-Fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinin-8-carboxylic acid and (4S)-7-fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinin-8-carboxylic acid (Compounds 7 and 8) [Chemistry]

[0198] When 7-fluoro-2-hydroxy-4-(hydroxymethyl)-3,4-dihydro-1,2-benzoxaborinin-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)), Compound 7 (40.8 mg, 16%) and Compound 8 (33.0 mg, 13%) were obtained. Compounds 7 and 8 are illustrated as stereoisomers in the above scheme, but the absolute stereochemistry of each isomer has not yet been determined. Compound 7: LC-MS: 239 [M-H] - [Chemistry] Compound 8: LC-MS: 239 [M-H] - [Chemistry] (Example 7) 2-Hydroxy-4-(hydroxymethyl)-3,4-dihydrooxaborinino[6,5-c]pyridine-8-carboxylic acid (Compound 9) [Chemistry] Step 1: Synthesis of Compound 9B

[0199] To a mixture of Compound 9A (Tetrahedron, 2011, 67, 8757 - 8762) ( 1.0 g, 3.12 mmol, 1.0 equiv) in dioxane (10 mL), B 2 ((+)-Pinanediol) 2 (1.67 g, 4.67 mmol, 1.5 equiv), PdCl 2 (dppf) (255 mg, 0.31 mmol, 0.1 equiv) and KOAc (916 mg, 9.35 mmol, 3.0 equiv) were 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 H 2 O to separate the organic layer, washed with brine, dehydrated with Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA / DCM = 30:1:0~5:1:1) 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), 1F’ (1.18 g, 5.22 mmol, 2.0 equiv), Pd(PPh 3 ) 4 (151 mg, 0.13 mmol, 0.05 equiv) and 2N Na 2 CO 3 (6.5 mL, 13.0 mmol, 5 equiv) were added. Under a nitrogen atmosphere, the mixture was stirred at 80 °C overnight. Next, the reaction mixture was filtered, and the filtrate was washed with ethyl acetate. The organic layer was washed with water and brine, dehydrated with Na 2 SO 4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EA = 20:1~5:1) 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) was added B 2 ((+)-Pinanediol) 2 (370 mg, 1.03 mmol, 1.15 equiv), Cu 2 O (10 mg, 0.072 mmol, 0.08 equiv), PPh 3 (26 mg, 0.099 mmol, 0.11 equiv) and KH 2 PO 4 (188 mg, 1.079 mmol, 1.2 equiv). Under a nitrogen atmosphere, the mixture was stirred at 40 °C for 2.5 h. Next, the mixture was filtered, the filtrate was washed with EA, the organic layer was washed with brine, dehydrated over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA = 20:1~2:1) 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 BBr 3 (1.3 mL, 1.30 mmol, 5 equiv). The mixture was stirred at room temperature for 1 h and then purified by preparative HPLC (under acidic conditions) to give Compound 9 (5.5 mg). LC-MS: 224 [M+H] +

Chemical Structure

Chemical Structure

[0203] A mixture consisting 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 at H 2 room temperature for 2 days under. The resulting mixture was filtered and purified by preparative TLC to obtain 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 H 2 O / ACN (0.5 mL / 0.5 mL), TFA (0.01 mL, 0.125 mmol, 2 equiv), TES (0.05 mL) and i-BuB(OH) 2 (13 mg, 0.125 mmol, 2 equiv) were added. The mixture was stirred at 25 °C overnight and adjusted to pH 10 - 11 with 0.5 N NaOH (0.25 mL). The resulting mixture was stirred at room temperature for 2 hours and purified by preparative HPLC (under neutral conditions) to obtain compound 10 (3.4 mg). LC-MS: 314 [M+H] +

Chemical formula

Chemical formula

[0205] BH 3 -S(Me) 2 (28.2 mL, 56.4 mmol, 2.0 equiv) in dry THF (60 mL) was added with compound 2E (10 g, 28.2 mmol, 1 equiv) at -15 °C. The mixture was warmed to room temperature and stirred for 3.5 hours. TLC showed that compound 2E was not remaining. The mixture was diluted with water (30 mL) and extracted with EA (2 x 60 mL). The organic phase was washed with Na 2 SO4 When dehydrated and concentrated, a residue was obtained and 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 equiv). The mixture was stirred overnight at room temperature and concentrated. The residue was purified by flash column chromatography (PE / EA = 5:1) to give compound 11A (11 g, not pure). 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. Under a hydrogen atmosphere (balloon), 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) were added trimethyloxonium tetrafluoroborate (167 mg, 1.13 mmol, 2.0 equiv) and Cs 2 CO 3 (183.5 mg, 0.563 mmol, 1.0 equiv). Under a nitrogen atmosphere, the mixture was stirred at 25 °C overnight. 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] Compound 11C (155 mg, 0.34 mmol, 1.0 equiv) in H 23N NaOH (0.34 mL, 1.02 mmol, 3 eq) was added to the O / ACN (1.5 mL / 1.5 mL) solution. The mixture was stirred at 25 °C overnight. TFA (0.06 mL), TES (0.06 mL) and i-BuB(OH) 2 (68 mg, 0.68 mmol, 2 eq) were added to this mixture. The resulting mixture was stirred at 25 °C for 1 h and purified by preparative HPLC (under acidic conditions) to give compound 11 (57 mg, 63%). LC-MS: 267 [M+H] +

Chemical formula

Chemical formula

[0210] At room temperature, PBr 3 (10.5 mL, 110 mmol) was added dropwise to water (6.0 mL, 330 mmol) to generate HBr gas. The generated HBr gas was bubbled into a solution of Et 4 N + Br - (97.0 g, 0.3 mol, 1.2 eq) in DCM (300 mL) at 0 °C. 3-Butyn-1-ol (12A, 19.0 mL, 0.25 mol, 1.0 eq) was added to this HBr solution and the solution was heated at 40 °C for 5 h. The solvent was removed and then distilled to give 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) were 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 mixture was stirred at room temperature for 3 h, filtered, washed with brine, dehydrated with MgSO 4 and concentrated, and purified by FCC (SiO 2 , 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) were added alkene 12C (688 mg, 2.60 mmol, 2.0 equiv), and then a 2 M solution of K 2 CO 3 (1.6 mL, 3.2 mmol, 2.5 equiv). The solution was bubbled with N 2 for 10 min, then Pd(PPh 3 ) 4 (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 3 (saturated aq.), extracted with EtOAc (twice), dehydrated with Na 2 SO 4 , concentrated and purified by FCC (SiO 2 , 10% EtOAc / hexane) to give 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) was added BH 3 -S(Me) 2(1.2 equivalents, 0.42 mL, 2 M in THF, 0.84 mmol, 1.2 equivalents) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. (+)-Pinanediol (291 mg, 1.7 mmol, 2.4 equivalents) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with H 2 O and extracted with EtOAc (3 times), dried over Na 2 SO 4 and concentrated. The residue was purified by FCC (SiO 2 , 40% EtOAc / hexane) 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 h. 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] +

Chemical Structure

[0215] Compound 3 (described in Example 3) was also prepared using the following alternative synthetic procedure.

Chemical Structure

[0216] Compound 3A (J. Org. Chem., 2016, 81, 4269-4279) (26 g, 0.123 mo l, 1.5 equiv), triisopropylsilyl propargyl ether (3B) (24 g, 0.082 mol, 1.0 equiv) and bis(1,5-cyclooctadiene)dirhodium(I) dichloride (0.826 g, 1.23 mmol, 0.015 equiv) in toluene (260 mL) were heated to 80 °C and stirred overnight under N 2 2. 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) were added compound 2C (2.57 g, 8.983 mmol, 1.0 equiv), PdCl 2 (dppf) (368 mg, 0.494 mmol, 0.05 equiv), water (1.625 g, 98.81 mmol, 10 equiv) and K 3 PO 4 ·3H 2 2O (7.175 g, 29.644 mmol, 3.0 equiv). Under a nitrogen atmosphere, the mixture was stirred at 80 °C overnight. The mixture was filtered and the filtrate was diluted with EA and H 2 2O. The layers were separated and the organic layer was washed with brine, dried over Na 2 2SO 4 4 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 h and TLC indicated that no compound 3D remained. The resulting mixture was diluted with water (150 mL) and extracted with EA (2 x 300 mL) The organic phase was dehydrated with Na 2 SO 4 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 2 (1.6 g, 10% w / w) under N 2 and then the mixture was replaced with hydrogen. The mixture was stirred at room temperature for 6 h. 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 indicated that 10% of Compound 3F remained. Then, additional 3N HCl (20.7 mL, 61.02 mmol, 2.0 equiv) was added. The mixture was stirred at room temperature for 3 h, at which point LC-MS indicated 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 x 75 mL). The organic phase was washed with water (75 mL), brine (75 mL), dried over sodium sulfate and concentrated. The crude product 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 Compound 3G (7.0 g, 23.9 mmol, 1.0 equiv) in H 2 O / CH 3To the CN (35 mL / 35 mL) solution, 3N NaOH (16 mL, 47.8 mmol, 2.0 eq) was added at room temperature. The mixture was stirred at room temperature for 1.5 h, and TLC showed that no 3G remained. Next, 3N HCl was added to adjust the solution to pH about 2. The resulting solution was stirred at room temperature overnight and lyophilized. This solid was dissolved in water (20 mL) and extracted with EA (5 x 20 mL). Drying and concentration of the organic layer gave crude compound 3 (5.4 g). Further purification of this compound by preparative HPLC (under acidic conditions) gave pure compound 3. LC-MS: 253 [M+H] +

Chemical formula

Chemical formula

[0222] To a mixture of Compound 11B (1.5 g, 3.38 mmol, 1.0 eq) in DCM (10 mL), CBr 4 (1.68 g, 5.07 mmol, 1.5 eq) and PPh 3 (1.33 g, 5.07 mmol, 1.5 eq) were added. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 h. Next, the mixture was concentrated in vacuo. Purification of the residue by column chromatography on silica gel (PE / EA = 30:1 to 5:1) gave 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 eq) in DMF (8 mL), NaN 3(108 mg, 1.66 mmol, 3.0 equiv) was added. Under a nitrogen atmosphere, this mixture was stirred at 48 °C for 19 h. Next, this mixture was filtered and the filtrate was diluted with EA. The organic layer was washed with water and brine, dehydrated with Na 2 SO 4 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. This mixture was stirred at room temperature for 2 days. Next, this mixture was 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) was added 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) under N 2 2. This mixture was stirred at room temperature for 4 h. Next, the resulting mixture was 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 H 2 2O / ACN (1 mL / 1 mL) was added 3N NaOH (0.17 mL, 0.509 mmol, 2 equiv) and this mixture was stirred at room temperature for 2 h. To this reaction mixture was added TFA (0.06 mL) and TES (0.06 mL), then i-BuB(OH) 2(52 mg, 0.509 mmol, 2 eq) was slowly added. The resulting mixture was stirred at room temperature for 1 h, concentrated, and purified by preparative HPLC (under acidic conditions) to obtain the compound 13 in its acid form (25 mg).

[0227] To a solution of the compound 13 in its acid form (25 mg, 0.089 mmol, 1.0 eq) in H 2 O / ACN (0.2 mL / 0.2 mL), 3N NaOH (0.06 mL, 0.18 mmol, 2 eq) was added. The mixture was stirred at room temperature for 0.5 h and purified by preparative HPLC (under neutral conditions) to obtain the compound 13 (17 mg, 55%). LC-MS: 280 [M+H] + ; 278 [M-H] -

Chemical formula

Chemical formula

[0228] To a solution of Compound 13C (180 mg, 0.406 mmol, 1.0 eq) in H 2 O / ACN (1 mL / 1 mL), TFA (0.2 mL) and TES (0.2 mL) were added, followed by i-BuB(OH) 2 (83 mg, 0.812 mmol, 2 eq). The mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in CH 3 CN / H 2 O, and the pH of this solution was adjusted to about 10 with 3N NaOH. The mixture was purified by preparative HPLC (under neutral conditions) to obtain Compound 14 (30 mg, 29%). LC-MS: 252 [M+H] +

Chemical formula

[0229] To a solution of Compound 13B (200 mg, 0.255 mmol, 1.0 equivalent) in H 2 O / ACN (0.5 mL / 0.5 mL) were added TFA (0.06 mL) and TES (0.06 mL), and then i-BuB(OH) 2 (87 mg, 0.853 mmol, 2 equivalents). The mixture was stirred at 27 °C for 8 hours. Then, the reaction mixture was concentrated at room temperature, and 3N NaOH (0.28 mL, 0.84 mmol, 2 equivalents) was added to the crude product. The mixture was stirred at room temperature overnight and concentrated, and purified by preparative HPLC (under neutral conditions) to obtain Compound 15 (39 mg, 33%). LC-MS: 278 [M+H] + and 555 [2M+H] + and 535 [2M-H] - [Chemical formula] (Example 15) Disodium salt of 2-hydroxy-4-[[4-(hydroxymethyl)-1,2,3-triazol-1-yl]methyl]-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (Compound 16) [Chemical formula] 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-ynyloxy)silane (127 mg, 0.60 mmol, 2.0 equiv). Under a nitrogen atmosphere, the reaction mixture was stirred at 120 °C overnight. The resulting mixture was concentrated under vacuum. 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 H 2 O / ACN (1 mL / 1 mL) was added 3N NaOH (0.12 mL, 0.36 mmol, 3 equiv). The mixture was stirred at room temperature overnight, then TFA (1 mL), TES (1 mL) and i-BuB(OH) 2 (23 mg, 0.235 mmol, 2 equiv) were slowly added. The reaction mixture was stirred at room temperature for an additional 1 hour and concentrated, then purified by preparative HPLC (under acidic conditions) to give compound 16B (27 mg) in its acid form. To a solution of the acid of compound 16B (27 mg, 0.081 mmol, 1.0 equiv) in H 2 O / 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 minutes, then triturated with H 2 O / acetone (1:20) to give compound 16 (17 mg, 53%). LC-MS: 334 [M+H] +

Chemical formula

Chemical formula

[0232] To a mixture of compound 13C (150 mg, 0.34 mmol, 1.0 equiv) in DCM (5 mL), acetyl chloride (52 mg, 0.68 mmol, 2.0 equiv) and triethylamine (0.14 mL, 1.02 mmol, 3.0 equiv) were added under N 2 2. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with DCM and washed with water to afford 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 H 2 2O / 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 h, then TFA (1.5 mL) and TES (1.5 mL), and then i-BuB(OH) 2 (62 mg, 0.62 mmol, 2 equiv) were added slowly. The resulting mixture was stirred at room temperature for 1 h and then purified by preparative HPLC (under acidic conditions) to afford 17 in its acid form. To a solution of 17 in its acid form (62 mg, 0.21 mmol, 1.0 equiv) in H 2 2O / 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 30 min and lyophilized. The solid was triturated with a solution of water and acetone (1:20) to afford compound 17 (40 mg, 22%). LC-MS: 294 [M+H] + , 292 [M-H] -

Chemical Structure

[0234] Using various bacterial strains resistant to aztreonam due to the expression of various β-lactamases, the efficacy and spectrum of these inhibitors were determined by evaluating the aztreonam-enhancing activity of β-lactamase inhibitors (BLIs) in a dose-titration enhancement assay. Aztreonam is a monobactam antibiotic and is hydrolyzed by most β-lactamases belonging to class A or C (but not class B or D). The enhancing effect was observed as the ability of the BLI compound to inhibit growth in the presence of aztreonam below the inhibitory concentration. The MICs of the test strains varied from 64 μg / mL to concentrations higher than 128 μg / mL. Aztreonam was present in the test medium at 4 μg / mL. The compounds were tested at concentrations up to 20 μg / mL. In this assay, the efficacy of the compound was reported as the minimum concentration of BLI required to inhibit the growth of bacteria in the presence of 4 μg / mL of aztreonam (MPC @4 ). Table 1 summarizes the BLI efficacy of aztreonam enhancement (MPC @4 ) against various strains overexpressing class A (ESBL and KPC) and class C β-lactamases. The aztreonam MIC for each strain is also shown. Table 1. BLI that enhances aztreonam against strains expressing class A and class C enzymes Activity

Table 1

[0235] The selected β-lactamase inhibitors were also tested for their ability to enhance tigemonam, which is a monobactam. The enhancement effect was observed as the ability of the BLI compound to inhibit growth in the presence of tigemonam at concentrations below the inhibitory concentration. The MIC of the test strains varied from 16 μg / mL to concentrations higher than 64 μg / mL. Tigemonam was present in the test medium at 4 μg / mL. The compounds were tested at concentrations up to 20 μg / mL. In this assay, the potency of the compound was reported as the minimum concentration of BLI required to inhibit the growth of bacteria in the presence of 4 μg / mL of tigemonam (MPC @4 ). Table 2 summarizes the BLI potency for tigemonam enhancement (MPC @4 ) against various strains overexpressing class A (ESBL) and class C β-lactamases. The tigemonam MIC for each strain is also shown. Table 2. Activity of BLI that enhances tigemonam against strains expressing class A and class C enzymes

Table 2-1

Table 2-2

[0236] The ability of β-lactamase inhibitors to enhance biapenem, where the carbapenem is biapenem, was also tested against strains producing carbapenemases of class A (KPC), class D (OXA-48), and class B (metallo-β-lactamases, NDM-1 and VIM-1). The enhancement effect was observed as the ability of the BLI compound to inhibit growth in the presence of biapenem below the inhibitory concentration. The biapenem MIC of the test strains was 16 - 32 μg / mL. Biapenem was present at 1 μg / mL in the test medium. The compounds were tested at concentrations up to 20 μg / mL. In this assay, the potency of the compounds was reported as the minimum concentration of BLI required to inhibit the growth of bacteria in the presence of 1 μg / mL of biapenem (MPC @1 ). Table 3 summarizes the BLI potency for biapenem enhancement (MPC @1 ) against four strains overexpressing class A (KPC), class D (OXA-48), and class B (NDM-1 and VIM-1) carbapenemases. The biapenem MIC for each strain is also shown . Table 3. Activity of BLI enhancing 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

[0237] For strains of Acinetobacter baumannii that produce carbapenemases of class D (OXA-23 and OXA-72), the ability of β-lactamase inhibitors to enhance meropenem, which is a carbapenem, was also tested. The enhancement effect was observed as the ability of the BLI compound to inhibit growth in the presence of meropenem at concentrations below the inhibitory concentration. The meropenem MIC of the test strains was from 32 to higher than 64 μg / mL. Meropenem was present in the test medium at 8 μg / mL. The compounds were tested at concentrations up to 20 μg / mL. In this assay, the potency of the compound was reported as the minimum concentration of BLI required to inhibit bacterial growth in the presence of 8 μg / mL of meropenem (MPC @8 ). Table 4 summarizes the BLI potency for meropenem enhancement (MPC @8 ) against two strains overexpressing carbapenemases of OXA-72 and OXA-23. The meropenem MIC for each strain is also shown. Table 4. Activity of BLI enhancing meropenem against strains expressing class D carbapenemases derived from Acinetobacter baumannii [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 are provided. (Item 1) A compound having the structure of formula (I) or formula (II): [Chemical formula] 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) 2 R 1 、 Optionally substituted C 1~10 alkyl, optionally substituted C 2~10 alkenyl, optionally substituted C 2~10 alkynyl, optionally substituted C 3~7 carbocyclic, optionally substituted 5 - 10 membered heterocyclic, optionally substituted C 6~10 aryl, optionally substituted 5 - 10 membered heteroaryl, optionally substituted C 3~7 carbocyclic - C 1~6Alkyl, 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 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- to 10-membered heteroaryl, J is selected from the group consisting of CR 5 and N, L is selected from the group consisting of CR 6 and N, M is selected from the group consisting of CR 7 and N, R 5 、R 6 and R 7 are each independently -H, -OR 8 、halogen, -CF 3 、optionally substituted C 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 C 6~10 Aryl, optionally substituted 5- to 10-membered heteroaryl, cyano, C1 ~C 6 alkoxy(C 1 ~C 6 )alkyl, aryloxy and sulfhydryl (mercapto), selected from the group consisting of R 8 is hydrogen, optionally substituted C 1~4 alkyl, optionally substituted C 3~7 carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted C 6~10 aryl and optionally substituted 5- to 10-membered heteroaryl, selected from the group consisting of 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,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

[Claim 1] The invention described in the specification.

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