KR20090029797A - Compounds for the treatment of periodontal disease - Google Patents

Abstract

Compounds, compositions and methods are provided which are useful in the treatment of periodontal disease.

Description

Compound for the treatment of periodontal disease {COMPOUNDS FOR THE TREATMENT OF PERIODONTAL DISEASE}

Cross-Reference to the Related Application

This application claims priority to US Provisional Patent Application No. 60 / 823,893, filed August 9, 2006 and No. 60 / 804,504, filed June 12, 2006, which is incorporated by reference in its entirety for all purposes. do.

Bacterial infections of the oral cavity include gingivitis, which is an inflammation of the gums, and periodontitis, which is an inflammation of the periodontal. Plaque bacteria and bacterial toxins that accumulate below the gingival gland can cause inflammation of the gum called gingivitis. Inflammation of the gingiva includes the influx of lymphocytes and macrophages into the gum tissue and the release of their proinflammatory cytokines (TNFa and IL 1b) and matrix metalloproteases (MMPs). Periodontitis or pyrrhea is a disease that involves chronic inflammation of the gums (gingiva) that persists for years or decades in a patient and causes loss of connective tissue and / or bone that supports the teeth. What distinguishes these two oral inflammatory diseases is the loss of bone around the teeth. Loss of surrounding bone that holds the teeth in the jaw can cause the teeth to loosen and fall out over the years. Gingivitis can be reversible by antimicrobial and / or anti-inflammatory treatment and good oral hygiene, while periodontitis is irreversible. However, progression can be stopped or slowed down by appropriate treatment. Periodontitis is the second most important cause of tooth loss after tooth decay.

The development of new compounds and methods for treating oral infections, such as those involving bacteria, viruses, fungi and / or parasites, represents a significant advance in the art. Such development and the like have been examined by the present invention.

Summary of the Invention

In a first aspect, the present invention provides an oral care composition comprising the compounds described herein. In an exemplary embodiment, the oral care composition comprises a hydrous, dentifrice, liquid whitening agent, chewing gum, soluble, partially soluble, non-soluble film or strip, wipe or towelette, implant First, the member selected from dental floss. In an exemplary embodiment, the oral care composition comprises a toothpaste, a prophylactic paste, a tooth polish, a gel, a professional gel, and other related products applied by a dentist, as well as water soluble agents, mouthwashes, floss, chewing Selected from gums, lozenges, tablets, edible food products, and the like. In an exemplary embodiment, the toothpaste is a member selected from powders, cream toothpastes and dental gels. In an exemplary embodiment, the compound is present in a therapeutically effective amount. In an exemplary embodiment, the compound is present in an amount of about 0.1% wgt compound per wgt of the oral care composition to about 5% wgt compound per wgt of the oral care composition. In an exemplary embodiment, the compound is present in an amount of about 0.3% wgt per wgt of the oral care composition to about 0.6% wgt per wgt of the oral care composition. In an exemplary embodiment, the compound comprises about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, and the like. About (all percentages are expressed as wgt of compound per wgt of the oral care composition) in the range of 0.3% to about 5%. In an exemplary embodiment, the compound is present in the range of about 2% to about 10%. In an exemplary embodiment, the compound is present in the range of about 2% to about 4%. In an exemplary embodiment, the compound is present in the range of about 2.5% to about 6%. In an exemplary embodiment, the compound is present in the range of about 0.1% to about 1%.

In another exemplary embodiment, the compound has a structure according to one of formulas 1, 2a, 2b, 2c, and 2d, including salts thereof:

From here,

B is boron;

O is oxygen;

R ^* and R ^** are each independently substituted or unsubstituted alkyl (C ₁ -C ₄ ), substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ), substituted or unsubstituted alkenyl, substituted or unsubstituted Ring alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl;

z is 0 or 1 and when z is 1, A is CH, CR ¹⁰ or N;

D is N, CH or CR ¹² ;

E is H, OH, alkoxy or 2- (morpholino) ethoxy, CO ₂ H or CO ₂ alkyl;

m is 0-2;

r is 1 or 2, wherein when r is 1 G is = O (double-bonded oxygen), and when r is 2 each G is independently H, methyl, ethyl or propyl;

R ¹² is (CH ₂ ) _k OH, where k is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN , Halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ and CONH ₂ ;

J is CR ¹⁰ or N;

R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl, cycloalkyl, (CH ₂ ) _n OH (n is 2 to 3), CH ₂ NH ₂ , CH ₂ NHalkyl, CH ₂ N (alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , NH ₂ , alkoxy, CF ₃ , SCF ₃ , NO ₂ , SO ₃ H and OH.

In another exemplary embodiment, the compound has a structure according to the formula:

Where m is zero. In another exemplary embodiment, the compound has a structure according to the formula:

In another exemplary embodiment, E is OH, R ⁹ is H, and R ^* and R ^** are independently selected from substituted or unsubstituted phenyl. In another exemplary embodiment, R ^* and R ^** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. In another exemplary embodiment, R ^* and R ^*** are 4-methyl, 3-chloro phenyl. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane or (bis (3-chloro-4-methylphenyl) borinic acid 3- Hydroxypicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and 5- (4-cyanophenoxy) -1,3-di It is a member selected from hydro-1-hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane and the compound is about 0.1% wgt / wgt to about 5% wgt / present in an amount of wgt. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane and the compound is about 0.3% wgt / wgt to about 0.6% wgt / present in an amount of wgt.

In an exemplary embodiment, the compounds described herein have antiviral properties. In another exemplary embodiment, the compounds described herein have anti-inflammatory properties. In an exemplary embodiment, the compounds described herein have both antiviral and anti-inflammatory properties. In an exemplary embodiment, the compounds described herein have both antibacterial and anti-inflammatory properties and are 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane.

In a second aspect, the present invention provides a method of killing or inhibiting the growth of a microorganism, including killing or inhibiting the growth of the microorganism by contacting the microorganism with a therapeutically effective amount of a compound described herein. do. In an exemplary embodiment, the microorganism is Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Treponema ( Treponema ), Bulleidia species, Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptococcus species , pepto Streptococcus (Pepto -streptococcus) species, the CAP nosayi topa (Capnocytophaga) species, earthy Pu Te Leeum (Fusobacterium) species, Pseudomonas Fort fatigue (Porphyromonas) is a member selected from the species, and the night teroyi death (Bacteroides) species . In another exemplary embodiment, the microorganism is Actinobacillus actinomy -cetemcomitans ), Porphyromonas gingivalis ), Tannerella forsythesis forsythensis ), Prevotella intermedia , Eubacterium nodatum ), Treponema denticola ), Bulleidia extructa , Mosquitobacterium thymidum timidum ), Slackia exigua , Campylobacter rectus ), Eikenella corrodens ), Peptostrep- tococcus micros , Peptostreptococcus anaerobius , Capnocytophaga okrasea ochracea ), Fusobacterium nucleatum ), Porphyromonas asaccharolytica ) and Bacteroides forsythus .

In another exemplary embodiment, the compound used in the method of the present invention has the structure described above. In another exemplary embodiment, the compound used in the process of the invention is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane or (bis (3-chloro-4) -Methylphenyl) borinic acid 3-hydroxypicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and 5- (4-cyanophenoxy ) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound used in the process of the invention is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane.

In a third embodiment, the present invention provides a method of treating or preventing periodontal disease in a human or animal, comprising treating or preventing periodontal disease by administering to the human or animal a therapeutically effective amount of a compound described herein. to provide. In an exemplary embodiment, the periodontal disease is a member selected from gingivitis, periodontitis and juvenile / acute periodontitis.

In another exemplary embodiment, the compound used in the method of the present invention has the structure described above. In another exemplary embodiment, the compound used in the process of the invention is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane or (bis (3-chloro-4) -Methylphenyl) borinic acid 3-hydroxypicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and 5- (4-cyanophenoxy C) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound used in the process of the invention is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane.

In an exemplary embodiment, the compounds used in the compositions and methods described herein have a structure according to Formula I:

Where B is boron. R ^1a is negatively charged, salt counterion, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl. M is a member selected from oxygen, sulfur and NR ^2a . R ^2a is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted Member selected from heteroaryl. J is a member selected from (CR ^3a R ^4a ) _n1 and CR ^5a . R ^3a , R ^4a and R ^5a are H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl. The index n1 is an integer selected from 0-2. W is a member selected from _C═O (carbonyl), (CR ^6a R ^7a ) m 1 and CR ^8a . R ^6a , R ^7a and R ^8a are H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl. The index m1 is an integer selected from 0 and 1. A is a member selected from CR ^9a and N. D is a member selected from CR ^10a and N. E is a member selected from CR ^11a and N. G is a member selected from CR ^12a and N. R ^9a , R ^10a , R ^11a and R ^12a are H, OR ^{* a} , NR ^{* a} R ^{** a} , SR ^{* a} , -S (O) R ^{* a} , -S (O) ₂ R ^{* a} ,- S (O) ₂ NR ^{* a} R ^{** a} , -C (O) R ^{* a} , -C (O) OR ^{* a} , -C (O) NR ^{* a} R ^{** a} , nitro, halogen, cyano Independent from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl Is the member selected. Each of R ^{* a} and R ^{** a} is H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclo It is a member independently selected from alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The combination of nitrogen (A + D + E + G) is an integer selected from 0-3. The member selected from R ^3a , R ^4a and R ^5a and the member selected from R ^6a , R ^7a and R ^8a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^3a and R ^4a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^6a and R ^7a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^9a and R ^10a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^10a and R ^11a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^11a and R ^12a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring.

In an exemplary embodiment, the compound for use in the compositions and methods described herein has a structure according to formula (IX):

Here, variables A, D, E and G are described elsewhere herein. R ²⁰ , R ²¹ and R ²² are negatively charged, salt counterions, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted Or an unsubstituted aryl, and a substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound for use in the compositions and methods described herein has a structure according to formula (XI):

Here, the variables R ¹ , A, D, E, G, J, W and M are described elsewhere herein.

In an exemplary embodiment, the microorganism is involved in periodontal disease. In another exemplary embodiment, the microorganism is a member selected from a virus, bacterium, fungus, yeast or parasite. In another exemplary embodiment, the bacterium is Actinobacillus species, Porphyromonas species, Tannerella species, Prebotella species, Eubacterium species, Treponema species, Bullidia species, Mosquitobacterium species, Slash Chia species, Campylobacter species, Echinella species, Peptostreptococcus species, Peptostreptococcus species, Capnocytopa species, Fusobacterium species, Porphyromonas species, and Bacteroides species. In another exemplary embodiment, the bacterium is Actinobacillus actinomycetemcomitans ), Porphyromonas gingivalis ), Tannerella forsythensis , Prevotella intermedia ), Eubacterium nodatum ), Treponema denticola ), Bulleidia extructa , Mosquitobacterium thymidum timidum ), Slackia exigua , Campylobacter rectus ), Eikenella corrodens ), Peptostreptococcus micros ), Peptostreptococcus anerobius anaerobius ), Capnocytophaga ( Capnocytophaga) ochracea ), Fusobacterium nucleatum , Porphyromonas ascarolica ( Porphyromonas) asaccharolytica) and Park City Fort Des teroyi tooth (Bacteroides forsythus ).

In a second aspect, the present invention provides a method of treating or preventing periodontal disease in an animal, comprising administering to the animal a therapeutically effective amount of the boron-containing compound described herein. In an exemplary embodiment, the animal is a human. In another exemplary embodiment, the periodontal disease is a member selected from gingivitis, periodontitis, and juvenile / acute periodontitis.

In a third aspect, the present invention provides an oral care composition comprising the boron-containing compound described herein. This oral care composition can be used to treat periodontal disease.

Further aspects, advantages and objects of the present invention will become apparent from the following detailed description.

Figure 1 shows the results of testing some of the boron-containing compounds of the present invention for some bacteria involved in periodontal disease.

2 shows exemplary compounds of the invention.

3 shows exemplary compounds of the invention.

Definition and abbreviations

Abbreviations used herein generally have their usual meaning in the chemical and biological arts.

"Compounds of the present invention" and "exemplary compounds for use in the methods of the present invention" are used interchangeably and refer to the compounds mentioned herein, and pharmaceutically acceptable salts and prodrugs of these compounds. .

Where substituent groups are specified in their usual formula from left to right, they include chemically identical substituents having the structure from right to left equivalents, for example -CH ₂ O- to -OCH _2- I would like to quote.

As used herein, the term "poly" means at least two. For example, polyvalent metal anions are metal ions having a valence of at least two.

"Part" means the radical of a molecule attached to another part.

The symbol (marker of page 9 / paragraph) indicates the point at which the indicated portion is attached to the rest of the molecule, whether used as a bond or showing a perpendicular to the bond.

The term “alkyl” by itself or as part of another substituent, unless stated otherwise, may be fully saturated, mono- or polyunsaturated, and includes a specified number of carbons, including divalent and polyvalent radicals. A straight chain or branched chain, or cyclic hydrocarbon radical, or a combination thereof, having an atom (ie C ₁ -C ₁₀ means 1 to 10 carbons). Examples of saturated hydrocarbon radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, for example, Homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl and the like are included, but are not limited to these. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl) , Ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers are included, but are not limited to these. The term "alkyl" also means including derivatives of alkyl as defined in more detail below, such as "heteroalkyl", unless stated otherwise. Alkyl groups limited to hydrocarbon groups are referred to as "homoalkyl".

The term "alkylene", by itself or as part of another substituent, is a divalent radical derived from an alkane, such as, but not limited to, -CH ₂ ^C H ₂ CH ₂ CH _2- . And also include groups described below as "heteroalkylene". In general, alkyl (or alkylene) groups can have from 1 to 24 carbon atoms, with those groups having 10 or less carbon atoms being preferred in the present invention. "Lower alkyl" or "lower alkylene" is generally a shorter chain alkyl or alkylene group having 8 or less fewer carbon atoms.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense and refer to an alkyl group attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Indicates.

The term "heteroalkyl", by itself or in combination with another term, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, consisting of the stated number of carbon atoms and at least one heteroatom, Or a combination thereof In an exemplary embodiment, the heteroatom can be selected from the group consisting of B, O, N and S, wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatoms May be optionally quaternized The heteroatom (s) B, O, N and S may be placed at any internal position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule. ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -S (O) -CH ₃ , -CH ₂ -CH ₂ -S (O) ₂ -CH ₃ , -CH = CH-O-CH ₃ , -CH ₂ -CH = N-OCH ₃ and -CH = CH-N (CH ₃ ) -CH ₃ , but these Up to two heteroatoms may be present in series such as, for example, —CH ₂ —NH—OCH _3. Likewise, the term “heteroalkylene” is used on its own or as a substitute for another substituent. As part, but not limited to, as illustrated by —CH ₂ —CH ₂ —S—CH ₂ —CH ₂ — and —CH ₂ —S—CH ₂ —CH ₂ —NH—CH ₂ —. Divalent radicals derived from heteroalkyl In the case of a heteroalkylene group, the heteroatom may also occupy one or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, Alkyleneamino, alkylenediamino, etc.) Also, in the case of alkylene and heteroalkylene bond groups, the orientation of the bond groups is not indicated in the direction in which the formula of the bond group is described, e.g. (O) ₂ R'- represents both -C (O) ₂ R'- and -R'C (O) _2- .

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with another term, refer to cyclic forms of "alkyl" and "heteroalkyl", respectively, unless stated otherwise. In addition, in the case of heterocycloalkyls, the heteroatoms may occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morph Polyyl, tetrahydrofuran-2-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like, but are not limited to these.

The term "halo" or "halogen", by itself or as part of another substituent, means a fluorine, chlorine, bromine or iodine atom, unless stated otherwise. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C ₁ -C ₄ ) alkyl” means including trifluoromeric, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. However, they are not limited thereto.

The term "aryl" means a polyunsaturated aromatic substituent, which may be a single ring or a plurality of rings (preferably 1 to 3 rings), unless otherwise stated. The term "heteroaryl" means an aryl group (or ring) containing 1 to 4 heteroatoms. In an exemplary embodiment, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom (s) are optionally quaternized. Heteroaryl groups may be attached to the rest of the molecule through heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2 Imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 -Pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinol Salinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the aforementioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

Briefly, the term “aryl” when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl as defined above. Thus, the term "arylalkyl" refers to alkyl groups (eg, phenoxymethyl, 2-pyridyloxymethyl, in which the aryl group is substituted by a carbon atom (eg methylene group), for example by an oxygen atom) It is meant to include radicals attached to alkyl groups (eg, benzyl, phenethyl, pyridylmethyl, etc.), including 3- (1-naphthyloxy) propyl, and the like.

The terms (eg, "alkyl", "heteroalkyl", "aryl" and "heteroaryl") are meant to include both substituted and unsubstituted forms of the radicals mentioned, respectively. Preferred substituents for each type of radical are given below.

Substituents for alkyl and heteroalkyl radicals (often including groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) Generally referred to as "alkyl group substituents", they are present in a number from 0 to (2m '+ 1), where m' is the total number of carbon atoms in these radicals, one of a variety of groups selected from the following groups Or more, but not limited to: -OR ', = O, = NR', = N-OR ', -NR'R ", -SR', -halogen, -OC (O) R ' , -C (O) R ', -CO ₂ R', -CONR'R ", -OC (O) NR'R", -NR "C (O) R ', -NR'-C (O) NR "R"', -NR "C (O) ₂ R', -NR-C (NR'R" R "') = NR"", -NR-C (NR'R") = NR "',- S (O) R ′, —S (O) ₂ R ′, —S (O) ₂ NR′R ″, —NRSO ₂ R ′, —CN and NO ₂ . R ', R ", R"' and R "" each is preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, for example substituted by 1-3 halogens Aryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. Where the compounds of the invention comprise one or more R groups, for example, each R group may be combined with each of these groups in which one or more R ', R ", R"' and R "" groups are present; Are independently selected. When R 'and R "are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R" is 1-blooded. It includes but is not limited to rolidinyl and 4-morpholinyl. From the above description of substituents, those skilled in the art will appreciate that the term "alkyl" refers to haloalkyl (eg, -CF ₃ and -CH ₂ CF ₃ ) and acyl (eg, -C (O) It will be understood that the term includes groups containing carbon atoms bonded to groups other than hydrogen atoms, such as CH ₃ , -C (O) CF ₃ , -C (O) CH ₂ OCH _3, etc.). .

Like substituents described for alkyl radicals, substituents for aryl and heteroaryl groups are generally referred to as "aryl group substituents". Substituents range from 0 to the total number of open valences on the aromatic ring system, for example halogen, -OR ', = O, = NR', = N-OR ', -NR'R ". , -SR ', -halogen, -OC (O) R', -C (O) R ', -CO ₂ R', -CONR'R ", -OC (O) NR'R", -NR "C (O) R ', -NR'-C (O) NR "R"', -NR "C (O) ₂ R ', -NR-C (NR'R" R "') = NR"",- NR-C (NR'R ") = NR"', -S (O) R', -S (O) ₂ R ', -S (O) ₂ NR'R ", -NRSO ₂ R', -CN And NO ₂ , -R ', -N ₃ , -CH (Ph) ₂ , fluoro (C ₁ -C ₄ ) alkoxy and fluoro (C ₁ -C ₄ ) alkyl; Wherein R ′, R ″, R ″ ′ and R ″ ″ are preferably independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted Heteroaryl. Where the compounds of the invention comprise one or more R groups, for example, each R group may be combined with each of these groups in which one or more R ', R ", R"' and R "" groups are present; Are independently selected.

Two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with substituents of the formula -TC (O)-(CRR ') _q -U-, wherein T and U are independently -NR-, -O -, -CRR'- or a single bond, q is an integer of 0-3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A- (CH ₂ ) _r -B-, wherein A and B are independently -CRR'-,- O-, -NR-, -S-, -S (O)-, -S (O) _2- , -S (O) ₂ NR'- or a single bond, r is an integer from 1 to 4. One of the single bonds of the new ring thus formed may be optionally substituted by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with substituents of the formula-(CRR ') _s -X- (CR "R"') _d- , wherein s and d are independent , An integer of 0 to 3, and X is -O-, -NR'-, -S-, -S (O)-, -S (O) _2-, or -S (O) ₂ NR'-. The substituents R, R ', R "and R"' are preferably independently hydrogen or is selected from substituted or unsubstituted (C ₁ -C ₆₎ alkyl.

As used herein, "ring" means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The ring includes a fused ring portion. The number of atoms in a ring is generally defined by the number of members in the ring. For example, "5- to 7-membered ring" means that there are 5 to 7 atoms in the enclosing arrangement. The ring optionally includes heteroatoms. Thus, the term "5- to 7-membered ring" includes, for example, pyridinyl and piperidinyl. The term "ring" also includes a ring system comprising more than one ring, wherein each "ring" is independently as defined above.

As used herein, the term "heteroatom" includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

The symbol "R" represents substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclo. General abbreviation for a substituent group selected from alkyl groups.

An “effective” amount of drug, agent or permeant means a sufficient amount of active agent that provides the desired local or systemic effect. A “locally effective”, “aesthetically effective”, “pharmaceutically effective” or “therapeutically effective” amount indicates the amount of drug needed to provide the desired therapeutic result.

"Locally effective" means that when applied to skin, nails, hair, toenails or hoofs, it produces a desired pharmacological result locally or systemically at the site of application as a result of the transdermal passage of the active ingredient in the substance. Means a substance.

By "cosmetically effective" is meant a substance which, when applied to skin, nails, hair, toenails or hooves, produces a locally desired cosmetic result at the site of application of the active ingredient in the substance.

The term "pharmaceutically acceptable salts" is meant to include salts of the compounds of the invention prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. If the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, as is, or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. If the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, as is, or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid. As well as salts, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suveric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfate Salts derived from relatively nontoxic organic acids such as phonic acid and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic acid or galacturonic acid. See, eg, Berge et al., Journal of Pharmaceutical Science 66 : 1-19 (1977). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compound to be converted to either base or acid addition salts.

The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The form of the parent compound differs from various salts with certain physical properties such as solubility in polar solvents.

In addition to salt forms, the present invention provides compounds in prodrug form. The prodrugs of the compounds or complexes described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. In addition, prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo or ex vivo environment.

Certain compounds of the present invention may exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are included within the scope of the present invention.

Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds; Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

Compounds of the invention may also contain non-natural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, the compounds may be radiolabeled by radioisotopes such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Isotope modifications of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" provides for the proper delivery of an effective amount of an active agent as defined herein and does not impair the effectiveness of the biological activity of the active agent, All agents or carrier media that are sufficiently non-toxic to the patient are shown. Representative carriers include water, vegetable oils and mineral oils, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulations are well known to those skilled in the art of cosmetic and topical medications. Additional information regarding the carrier may be found in Remington: The , incorporated herein by reference. Science and Practice of Pharmacy , 21st Ed., Lippincott, Williams & Wilkins (2005).

"Pharmaceutically acceptable topical carrier" and equivalent terms refer to pharmaceutically acceptable carriers as described herein above, suitable for topical application. Topical pharmaceutically acceptable or inert liquids or cream vehicles that can suspend or dissolve the active agent (s) and have nontoxic and non-inflammatory properties when applied to skin nails, hair, toenails or hoofs. An example of a carrier. The term is also intended to include carrier materials which are specifically approved for use in topical cosmetics.

The term “pharmaceutically acceptable additive” is known or used in the field of drug formulation and is a preservative, antioxidant, fragrance that is sufficiently non-toxic to the host or patient without excessively inhibiting the effectiveness of the biological activity of the active agent. , Emulsifiers, dyes and excipients. Additives for topical preparations are well known in the art and may be added to topical compositions as long as they are pharmaceutically acceptable and are not detrimental to epithelial cells or their function. In addition, they should not cause a decrease in the stability of the composition. For example, inert fillers, emollients, tackifiers, excipients, fragrances, whitening agents, antioxidants, gelling agents, stabilizers, surfactants, emollients, colorants, preservatives, buffers, other permeation enhancers, and the present bone Other conventional ingredients of topical or transdermal delivery formulations such as are known in the art are included.

The term "enhancing", "enhancing penetration" or "enhancing penetration" refers to the permeability of the skin, nails, hair, toenails or hooves to the drug to increase the rate at which the drug penetrates through the skin, nails, hair, toenails or hooves. It is about increasing. Enhanced permeation through the use of such enhancers can be observed, for example, by measuring the diffusion rate of the drug through the skin, nails, hair, toenails or hooves of an animal or human using a diffusion cell apparatus. have. Diffusion cells are described in Merittt et. al ., J of Controlled Release , 1 : 161-162 (1984). The term "permeation enhancer" or "penetration enhancer", alone or in combination, means a component or mixture of ingredients that acts to increase the permeability of the skin, nails, hair, toenails or hooves to the drug.

The term “excipient” is commonly known to mean a carrier, diluent and / or vehicle used to formulate a drug composition effective for the desired use.

The term “topical administration” refers to the application of a medicament to the outer surface of the skin, nails, hair, toenails or hooves such that the agent enters the underlying tissue across the outer surface of the skin, nails, hair, toenails or hooves. Indicates. Topical administration includes applying the composition to intact skin, nails, hair, toenails or hooves, or to damaged, wounded or open wounds, nails, hair, toenails or hooves. Topical administration of the medicament may provide a limited distribution of the medicament to the skin or surrounding tissue, or may provide a systemic distribution of the medicament if the medicament is removed from the treatment area by the blood stream.

The term "transdermal delivery" refers to the diffusion of a medicament across the barrier of skin, nails, hair, toenails or hooves due to topical administration or other application of the composition. The stratum corneum acts as a barrier, and several drugs can penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutes, and therefore absorption of the drug occurs more easily through the skin, nails, hair, toenails or hooves where the stratum corneum has been exfoliated to expose the epidermis. Percutaneous delivery includes injection through any part of the skin, nails, hair, toenails or hooves or mucous membranes or absorption or permeation through other delivery and the rest. Absorption through intact skin, nails, hair, toenails or hooves can be enhanced by placing the active agent in a suitable pharmaceutically acceptable vehicle before applying it to the skin, nails, hair, toenails or hooves. Passive topical administration consists of applying the active agent directly to the treatment site with an emollient or penetration enhancer. As used herein, percutaneous delivery includes delivery by permeation through or through the skin, ie skin, nails, hair, toenails or hooves.

The term “microbial infection” refers to all infections of host tissues by infectious components, including but not limited to viruses, bacteria, mycobacteria, fungi and parasites. Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al ., eds., 12th ed. 1991); Williams et al ., J of Medicinal Chem . 42 : 1481-1485 (1990).

The term “microbial infection” refers to all infections of host tissues by infectious components, including but not limited to viruses, bacteria, mycobacteria, fungi and parasites. Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al ., eds., 12th ed. 1991); Williams et al ., J of Medicinal Chem . 42 : 1481-1485 (1990).

As used herein, "biological medium" refers to both in vitro and in vivo biological environments. Exemplary in vitro “biological media” include, but are not limited to, cell cultures, tissue cultures, equivalents, plasma and blood. In vivo application is generally carried out in mammals, preferably in the human body.

MIC or minimum inhibitory concentration is the point at which the compound arrests at least 90% of cell growth compared to the untreated control.

Also used herein are compounds that are multivalent or polyatomic species, including species such as, for example, dimers, trimers, tetramers and higher homologs, or reactive analogs of the compounds used in the present invention. Multivalent and polyvalent species may be assembled from a single species or more than one species of the invention. For example, the dimer structure can be "homo-dimeric" or "heterodimeric". Moreover, polyvalent and polyvalent structures, in which a compound of the present invention or a reactive analog thereof is attached to an oligomeric or polymeric framework (eg, polylysine, dextran, hydroxyethyl starch, etc.) are also included within the scope of the present invention. do. The framework is preferably multifunctional (ie has an array of reactive sites for attaching the compounds used in the present invention). In addition, the framework may be derivatized by a single species of the invention or one or more species of the invention.

The invention also encompasses the use of compounds functionalized to provide compounds with enhanced water-solubility over similar compounds that are not similarly functionalized within the motifs set forth in the formulas included herein. Thus, any substituents presented herein can be replaced by similar radicals with enhanced water-solubility. For example, within the scope of the present invention, hydroxyl groups are replaced with diols or amines with quaternary amines, hydroxy amines or similar more water soluble moieties. In a preferred embodiment, additional water-solubility is imparted by substituting moieties that enhance the water-solubility of the parent compound at sites towards the editing domain that are not essential for activity. Methods of enhancing the water-solubility of organic compounds are known in the art. Such methods include functionalizing the organic nucleus with permanently charged moieties such as quaternary ammonium, or charged groups at physiological pH such as carboxylic acids, amines. Other methods include adding hydroxyl- or amine-containing groups such as alcohols, polyols, polyethers and the like to the organic nucleus. Representative examples include, but are not limited to, polylysine, polyethyleneimine, poly (ethyleneglycol) and poly (propyleneglycol). Suitable functionalization chemistries and strategies for these compounds are known in the art. See, eg, Dunn, R.L., et al., Eds. POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACS Symposium Series Vol. 469, American Chemical Society, Washington, D.C. 1991].

Description of Embodiment

I. Boron-containing compounds

The present invention provides boron-containing compounds useful for the treatment of microorganisms located in the oral cavity of an animal. The compound is also useful for treating periodontal disease.

I. a) Borin acid  ester

The present invention includes compounds having a structure according to formulas 1, 2a, 2b, 2c, and 2d, including salts thereof:

Wherein B is boron; O is oxygen; R ^* and R ^** are each independently substituted or unsubstituted alkyl (C ₁ -C ₄ ), substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ), substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl. The index z is 0 or 1, and when z is 1, A is CH, CR ¹⁰ or N. D is N, CH or CR ¹² . E is H, OH, alkoxy or 2- (morpholino) ethoxy, CO ₂ H or CO ₂ alkyl. The index m is 0-2, the index r is 1 or 2, where G is = O (double-bonded oxygen) when r is 1, and when r is 2, each G is independently H , Methyl, ethyl or propyl. R ¹² is (CH ₂ ) _k OH, where k is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN , Halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ and CONH ₂ , where J is CR ¹⁰ or N. R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl, cycloalkyl, (CH ₂ ) _n OH (n is 2 to 3), CH ₂ NH ₂ , CH ₂ NHalkyl, CH ₂ N (alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , NH ₂ , alkoxy, CF ₃ , SCF ₃ , NO ₂ , SO ₃ H and OH.

In a preferred embodiment of the formulas described herein, such as formulas 1, 2a, 2b, 2c or 2d, R ^* and / or R ^** are the same or different, preferably wherein R ^* and R ^** One is substituted or unsubstituted alkyl (C ₁ -C ₄ ), or R ^* and R ^** are each substituted or unsubstituted alkyl (C ₁ -C ₄ ).

In a preferred embodiment of the formulas described herein, such as formulas 1, 2a, 2b, 2c or 2d, R ^* and / or R ^** are the same or different, preferably wherein R ^* and R ^** One is substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ), or R ^* and R ^** are each substituted or unsubstituted alkyl (C ₃ -C ₇ ).

In a preferred embodiment of the formulas described herein, such as formulas 1, 2a, 2b, 2c or 2d, R ^* and / or R ^** are the same or different, preferably wherein R ^* and R ^** One is substituted or unsubstituted alkenyl, or R ^* and R ^** are each substituted or unsubstituted alkenyl. In a more preferred embodiment thereof, alkenyl has the structure of Formula 2:

Wherein R ¹ , R ² and R ³ are each independently hydrogen, alkyl, aryl, cycloalkyl, substituted aryl, aralkyl, substituted aralkyl, (CH ₂ ) _k OH where k is 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , and NO ₂ .

In a preferred embodiment of the formulas described herein, such as formulas 1, 2a, 2b, 2c or 2d, R ^* and / or R ^** are the same or different, preferably wherein R ^* and R ^** One is substituted or unsubstituted alkynyl, or R ^* and R ^** are each substituted or unsubstituted alkynyl. In a more preferred embodiment thereof, the alkynyl has the structure of formula

Wherein R ¹ is hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH ₂ ) _k OH (where k is 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₂ N (alkyl) ₂ , SO ₂ NH Alkyl, SO ₂ NH ₂ , SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , and NO ₂ .

In a preferred embodiment of the formulas described herein, such as formulas 1, 2a, 2b, 2c or 2d, R ^* and / or R ^** are the same or different, preferably wherein R ^* and R ^** One is substituted or unsubstituted phenyl, or R ^* and R ^** are each substituted or unsubstituted phenyl, provided that z is 1, A is CR ¹⁰ , D is CR ¹² , and J is CR ¹⁰ And compounds of formula 2 wherein z is 1, A is CR ¹⁰ , D is CR ¹² , m is 2, and G is H or methyl or ethyl. In the separate embodiments described above, G is also not propyl. However, in certain embodiments such excluded compounds are not claimed to be novel, but in one or more methods of the invention, preferably for the treatment of infection, most preferably for the fungal infection It may have a use in. In a preferred embodiment, only novel compounds of the invention are contemplated for this use.

The novel compounds of the present invention do not include quinaldine derivatives such as 2-methylquinoline, wherein R ⁹ is methyl, A _z is CH, D is CH, J is CH, and R ¹¹ is hydrogen. However, such compounds may be useful in the methods of the present invention.

Preferred embodiments are compounds of the formulas described in the invention, such as formulas 1, 2a, 2b, 2c or 2d, wherein R ^* and R ^** are not phenyl or substituted phenyl, respectively.

Another preferred embodiment is a compound of the formula described herein, such as Formula 1, 2a, 2b, 2c or 2d, wherein one of R ^* and R ^** is benzyl or substituted benzyl.

Further preferred embodiments are compounds of the formulas described in the invention, such as formula 1, 2a, 2b, 2c or 2d, wherein r is 1, G is = 0, m is 0 and E is OH.

Preferred embodiments also include z is 1, R ⁹ is alkyl (C ₄ or greater), (CH ₂ ) _n OH, where n is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NHalkyl , CH ₂ N (alkyl) ₂ , CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, alkoxy (C ₄ or higher), SCF ₃ , and NO ₂ And a compound of formula as described herein, such as formula 1, 2a, 2b, 2c or 2d.

In one preferred embodiment the compound is z is 1 and R ¹⁰ is alkyl (C ₄ or higher), (CH ₂ ) _n OH where n is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH Alkyl, CH ₂ N (alkyl) ₂ , CHO, CH═NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, alkoxy (C ₄ or higher), SCF ₃ , and NO Has the formula described in the present invention, such as formula 1, 2a, 2b, 2c or 2d selected from ₂ .

In another preferred embodiment the compound is z is 1 and D is CR ¹² , wherein R ¹² is (CH ₂ ) _k OH where k is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy (C ₄ or higher), aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, Has the formula described in the present invention, such as formula 1, 2a, 2b, 2c or 2d selected from SO ₃ H, SCF ₃ , CN, NO ₂ , NH ₂ SO ₂ and CONH ₂ .

In a further preferred embodiment the compound has a formula described in the present invention such as formula 1, 2a, 2b, 2c or 2d wherein z is 1 and E is N- (morpholinyl) ethoxy or C ₄ or more alkoxy. .

In another preferred embodiment the compound has a formula described in the present invention, such as Formula 1, 2a, 2b, 2c or 2d, wherein A or D is nitrogen or m is 2.

In another preferred embodiment the compound is one of R ^* or R ^** , each of alkyl (C ₆ or higher), aryl, substituted aryl, benzyl, substituted benzyl, (CH ₂ ) _k OH, wherein k is 1 , 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy ( C ₆ or higher), aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH ₂ A substituted phenyl substituted by 1 to 5 substituents selected from alkyl, having the formula described in the present invention as Formula 1, 2a, 2b, 2c or 2d. .

In a further preferred embodiment thereof the phenyl has the structure of formula

Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH ₂ ) _k OH (here K is 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₃ H, SCF ₃ , CN, halogen , CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NHalkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxa Zolidin-2-yl, or alkyl substituted oxazolidin-2-yl.

One very preferred embodiment is that R ^* is 3-fluorophenyl, R ^** is 4-chlorophenyl, R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, J Is a compound of the formula described herein, such as Formula 1, 2a, 2b, 2c, or 2d, which is CH, and may be called (3-fluorophenyl) (4-chlorophenyl) borinic acid 8-hydroxyquinoline ester .

Another preferred embodiment is that R ^* and R ^** are each 3- (4,4-dimethyloxazolidin-2-yl) phenyl, R ⁹ is H, R ¹¹ is H, A _z is CH , D is CH, J is CH, a compound of the formula described in the present invention, such as Formula 1, 2a, 2b, 2c or 2d, and bis (3- (4,4-dimethyloxazolidin-2-yl) Phenyl) borinic acid 8-hydroxyquinoline ester.

A further preferred embodiment is that R ^* is 3-fluorophenyl, R ^** is cyclopropyl, R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, J is CH Phosphorus is a compound of the formula described herein, such as Formula 1, 2a, 2b, 2c or 2d, and may be called (3-fluorophenyl) (cyclopropyl) borinic acid 8-hydroxyquinoline ester.

Very preferred embodiments are those in which R ^* is 4- (N, N-dimethyl) -aminomethylphenyl, R ^** is 4-cyanophenyl, R ⁹ is H, R ¹¹ is H, A _z is CH , D is CH, J is CH and is a compound of the formula described in the present invention, such as Formula 1, 2a, 2b, 2c or 2d, wherein (4- (N, N-dimethyl) -aminomethylphenyl) (4-sia Nophenyl) borinic acid 8-hydroxyquinoline ester.

Another very preferred embodiment is that R ^* is the same as R ^** and is 3-chloro-4-methylphenyl, R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, and E is OH, m is 0, r is 1, G is ═O (double bonded oxygen) and is a compound of the formula described in the present invention, such as Formula 1, 2a, 2b, 2c or 2d, and bis (3- Chloro-4-methylphenyl) borinic acid 3-hydroxypicolinate ester.

A further very preferred embodiment is that R ^* is the same as R ^** and is 2-methyl-4-chlorophenyl, R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, E Is OH, m is 0, r is 1, G is = O (double bonded oxygen) and is a compound of the formula described in the present invention, such as Formula 1, 2a, 2b, 2c or 2d, -Methyl-4-chlorophenyl) borinic acid 8-hydroxypicolinate ester.

In a preferred embodiment of the formulas described herein, such as Formulas 1, 2a, 2b, 2c or 2d, R ^* and / or R ^** are the same or different and preferably here in R ^* and R ^** One is substituted or unsubstituted benzyl, or R ^* and R ^** are each substituted or unsubstituted benzyl. In a further preferred embodiment thereof, benzyl has the structure of formula (5):

Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH ₂ ) _k OH (here, k is 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH , Alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH _2- , OCH ₂ CH ₂ NHalkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazoli Din-2-yl, or alkyl substituted oxazolidin-2-yl.

One preferred embodiment wherein R ^* and / or R ^** are the same or different, preferably wherein one of R ^* and R ^** is a substituted or unsubstituted heterocycle, or R ^* and R ^** are each A compound of formula as described herein, such as formula 1, 2a, 2b, 2c or 2d, which is a substituted or unsubstituted heterocycle. In a further preferred embodiment thereof, the heterocycle has the structure of formula

Wherein X is CH═CH, N═CH, NR ¹³ (where R ¹³ is H, alkyl, aryl or aralkyl), O or S, and Y is CH or N. R ¹ , R ² and R ³ are each independently hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH ₂ ) _k OH where k is 1, 2 or 3 CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₂ N (alkyl ) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl Is selected from the group.

A very preferred embodiment is that R ^* is pyrid-3-yl, R ^** is 4-chlorophenyl, R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, J Is a compound of the formula as described herein ((pyrid-3-yl) (4-chlorophenyl) borinic acid 8-hydroxyquinoline ester) as CH 1, 2a, 2b, 2c or 2d .

Very preferred embodiments are those in which R ^* is 5-cyanopyrid-3-yl, R ^** is vinyl, R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, J Is a compound of the formula ((5-cyanopyrid-3-yl) (vinyl) borinic acid 8-hydroxyquinoline ester) described in the present invention, such as Formula 1, 2a, 2b, 2c or 2d, which is CH .

One preferred embodiment wherein R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, J is CH and the formulas described in the present invention such as Formula 1, 2a, 2b, 2c or 2d Compound.

Another preferred embodiment is R ⁹ is H, R ¹¹ is H, A _z is CH, D is CH, E is OH, m is 0, r is 1, G is = O (double Bound oxygen), a compound of formula as described herein, such as Formula 1, 2a, 2b, 2c or 2d.

The structures of the present invention also allow solvent interactions that can provide structures (such as Formulas 1b and 2e) comprising atoms derived from solvents encountered by the compounds of the present invention during synthesis and therapeutic use. do:

Thus, such solvent structures can in particular intercalate themselves into at least a portion of the compounds of the invention, in particular between boron and nitrogen atoms, to increase the ring size of such compounds by one or two atoms. For example, when the boron ring of the structure of the present invention contains 5 atoms including, for example, boron, nitrogen, oxygen and two carbons, a solvent atom is interrupted between boron and nitrogen to obtain a 7-membered ring. Can be. As one example, the use of hydroxyl and amino solvents can increase the size of the ring to provide a structure containing oxygen or nitrogen between the ring boron and nitrogen atoms. This structure is explicitly contemplated by the present invention, preferably when R ^*** is H or alkyl.

Preparation of Compound

The synthesis of the compounds of the present invention is carried out in several forms. Scheme A illustrates the synthesis of intermediate borin acids and their subsequent conversion to the desired borin acid complex. If R ^* and R ^** are the same, the desired borin acid 5 is obtained by reaction of two equivalents of arylmagnesium halide (or aryllithium) with trialkyl borate followed by acidic hydrolysis. If R ^* and R ^** are not the same, one equivalent of arylmagnesium halide (or aryllithium) and the appropriate aryl (dialkoxy) borane (4), heteroaryl (dialkoxy) borane or alkyl (dialkoxy) borane The reaction with (alkoxy group consisting of methoxy, ethoxy, isopropoxy or propoxy moiety) followed by acidic hydrolysis yields asymmetric borinic acid 6 in excellent yield. Where applicable, the reaction of alkylene esters (3, T = none, CH ₂ , C (CH ₃ ) ₂ ) with appropriate organocerium, organolithium, organomagnesium or equivalent reactants is convenient.

As shown in Scheme A, the borinic acid complex is equivalent to 1 equivalent in a suitable solvent (ie ethanol, isopropanol, dioxane, ether, toluene, dimethylformamide, N-methylpyrrolidone, or tetrahydrofuran) from the precursor borin acid. Obtained by reaction with a desired heterocyclic ligand.

Scheme A

In certain circumstances, the compounds of the present invention may contain one or more asymmetric carbon atoms so that the compounds may exist in various stereoisomeric forms. These compounds may be, for example, in racemate or optically active form. In these situations, single enantiomers, ie optically active forms, can be obtained by asymmetric synthesis or by cleavage of racemates. The cleavage of racemates can be carried out by conventional methods such as, for example, crystallization in the presence of a splitting agent, or chromatography using, for example, a chiral HPLC column.

I. b) Boronic acid  ester

In a first aspect, the present invention provides a compound having a structure according to formula (I)

Where B is boron. R ^1a is negatively charged, salt counterion, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl. M is a member selected from oxygen, sulfur and NR ^2a . R ^2a is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted Member selected from heteroaryl. J is a member selected from (CR ^3a R ^4a ) _n1 and CR ^5a . R ^3a , R ^4a and R ^5a are H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl. The index n1 is an integer selected from 0-2. W is a member selected from _C═O (carbonyl), (CR ^6a R ^7a ) m 1 and CR ^8a . R ^6a , R ^7a and R ^8a are H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl. The index m1 is an integer selected from 0 and 1. A is a member selected from CR ^9a and N. D is a member selected from CR ^10a and N. E is a member selected from CR ^11a and N. G is a member selected from CR ^12a and N. R ^9a , R ^10a , R ^11a and R ^12a are H, OR ^{* a} , NR ^{* a} R ^{** a} , SR ^{* a} , -S (O) R ^{* a} , -S (O) ₂ R ^{* a} ,- S (O) ₂ NR ^{* a} R ^{** a} , -C (O) R ^{* a} , -C (O) OR ^{* a} , -C (O) NR ^{* a} R ^{** a} , nitro, halogen, cyano Independent from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl Is the member selected. Each of R ^{* a} and R ^{** a} is H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclo It is a member independently selected from alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The combination of nitrogen (A + D + E + G) is an integer selected from 0-3. The member selected from R ^3a , R ^4a and R ^5a and the member selected from R ^6a , R ^7a and R ^8a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^3a and R ^4a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^6a and R ^7a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^9a and R ^10a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^10a and R ^11a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring. R ^11a and R ^12a optionally combine with the atoms to which they are attached to form a 4 to 7 membered ring.

In an exemplary embodiment, the compound has a structure according to formula la:

In another exemplary embodiment, each of R ^3a and R ^4a is H, cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted Substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted mercaptomethyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted aminomethyl, substituted And unsubstituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted indolyl, and substituted or unsubstituted amido. In another exemplary embodiment, each of R ^3a and R ^4a is cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted Substituted hydroxyalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted mercaptomethyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted aminomethyl, substituted or unsubstituted Substituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted indolyl, and substituted or unsubstituted amido.

In another exemplary embodiment, each of R ^3a and R ^4a is H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted Independently selected from substituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl. In another exemplary embodiment, R ^3a and R ^4a are members selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl. In another exemplary embodiment, R ^3a is H and R ^4a is a member selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl. In another exemplary embodiment, R ^3a is H and R ^4a is H.

In another exemplary embodiment, each of R ^9a , R ^10a , R ^11a and R ^12a is H, OR ^{* a} , NR ^{* a} R ^{** a} , SR ^{* a} , -S (O) R ^{* a} ,- S (O) ₂ R ^{* a} , -S (O) ₂ NR ^{* a} R ^{** a} , -C (O) R ^{* a} , -C (O) OR ^{* a} , -C (O) NR ^{* a} R ^{** a} , halogen, cyano, nitro, substituted or unsubstituted methoxy, substituted or unsubstituted methyl, substituted or unsubstituted ethoxy, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted Hydroxymethyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyloxy, substituted or unsubstituted phenyl methoxy, substituted or unsubstituted Thiophenyloxy, substituted or unsubstituted pyridinyloxy, substituted or unsubstituted pyrimidinyloxy, substituted or unsubstituted benzylfuran, substituted or unsubstituted methylthio, substituted or unsubstituted mercaptomethyl, substituted Beech ring Mercaptoalkyl, substituted or unsubstituted phenylthio, substituted or unsubstituted thiophenylthio, substituted or unsubstituted phenyl methylthio, substituted or unsubstituted pyridinylthio, substituted or unsubstituted pyrimidinylthio, substituted Or unsubstituted benzylthiofuranyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted benzylsulfonyl, substituted or unsubstituted phenylmethylsulfonyl, substituted or unsubstituted thiophenylsulfonyl, substituted or unsubstituted Substituted pyridinylsulfonyl, substituted or unsubstituted pyrimidinylsulfonyl, substituted or unsubstituted sulfonamidyl, substituted or unsubstituted phenylsulfinyl, substituted or unsubstituted benzylsulfinyl, substituted or unsubstituted phenyl Methylsulfinyl, substituted or unsubstituted thiophenylsulfinyl, substituted or unsubstituted pyridinylsulfinyl, substituted or unsubstituted pyrimidinylsulfinyl, substituted or unsubstituted sub Furnace, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted trifluoromethylamino, substituted or unsubstituted aminomethyl, substituted or unsubstituted alkylaminomethyl, substituted or unsubstituted Substituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted benzylamino, substituted or unsubstituted phenylamino, substituted or unsubstituted thiophenylamino, substituted or unsubstituted pyridinylamino, Substituted or unsubstituted pyrimidinylamino, substituted or unsubstituted indolyl, substituted or unsubstituted morpholino, substituted or unsubstituted alkylamido, substituted or unsubstituted arylamido, substituted or unsubstituted Ureido is a member independently selected from substituted or unsubstituted carbamoyl, and substituted or unsubstituted piperizinyl. In an exemplary embodiment, R ^9a , R ^10a , R ^11a and R ^12a exclude -C (O) R ^{* a} , -C (O) OR ^{* a} , -C (O) NR ^{* a} R ^{** a} And from the list of substituents described above.

In another exemplary embodiment, R ^9a , R ^10a , R ^11a and R ^12a are fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxymethyl, trifluoromethyl, methoxy, tri Fluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperidinyl Carbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl), phenylmethoxy, 1H-tetrazol-5-yl, 1-ethoxy Carbonylmethyloxy, 1-ethoxycarbonylmethyl, 1-ethoxycarbonyl, carboxymethoxy, thiophen-2-yl, thiophen-2-ylthio, thiophen-3-yl, thiophen-3 -Ylthio, 4-fluorophenylthio, butylcarbonylphenylmethoxy, butylcarbonylphenylmethyl, butylcarbonylmethyl, 1- (piperidin-1-yl) carbonyl) methyl, 1- (piperi Din-1-yl) carbonyl) methoxy, 1- (piperidin-2-yl) carbonyl) methoxy , 1- (piperidin-3-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl) methoxy, 1- (4- ( Pyrimidin-2-yl) piperazin-1-yl) carbonyl) methyl, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl, 1-4- (pyrimidin- 2-yl) piperazin-1-yl, 1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl, 1- (4- (pyridin-2-yl) piperazin-1- Yl) carbonylmethyl, (1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl) -methoxy), 1- (4- (pyridin-2-yl) piperazin-1 -Yl, 1H-indol-1-yl, morpholino, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3- (phenylthio)- 1H-indol-1-yl, 3- (2-cyanoethylthio) -1H-indol-1-yl, benzylamino, 5-methoxy-3- (phenylthio) -1H-indol-1-yl, 5-methoxy-3- (2-cyanoethylthio) -1H-indol-1-yl, 5-chloro-1H-indol-1-yl, 5-chloro-3- (2-cyanoethylthio) -1H-indol-1-yl, dibenzylamino, benzylamino, 5-chloro-3- (phenylthio ) -1H-indol-1-yl, 4- (1H-tetrazol-5-yl) phenoxy, 4- (1H-tetrazol-5-yl) phenyl, 4- (1H-tetrazol-5-yl ) Phenylthio, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio, 4-cyanophenylthio, 2-chlorophenoxy C, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4 Cyanobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, 4-fluorobenzyloxy, unsubstituted phenyl, Independently selected from unsubstituted benzyl. In an exemplary embodiment, R ^9a is H and R ^12a is H.

In an exemplary embodiment, the compound according to Formula I or Formula Ia is a member selected from the following compounds:

In an exemplary embodiment, the compound has a structure according to one of formulas I-Io, wherein the substituent selection for R ^9a , R ^10a , R ^11a and R ^12a includes all possibilities contained in paragraph 90 above except H Has In an exemplary embodiment, the compound has a structure according to one of formulas Ib-Io, wherein the selection of substituents for R ^9a , R ^10a , R ^11a and R ^12a includes all possibilities contained in paragraph 91 above except H Has

In an exemplary embodiment, the compound is a member where R ^1a is selected from H, negatively charged and salt counterions and the remaining R groups (R ^{9a in} Ib, R ^{10a in} Ic, R ^{11a in} Id and R ^{12a in} Ie) are fluorine Chloro, bromo, nitro, cyano, amino, methyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridine-3- Il, pyridin-4-yl, pyrimidinyl, piperizino, piperidinyl, piperizinocarbonyl, piperidinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy , Thiophenyl, 3- (butylcarbonyl), phenylmethoxy, 1H-tetrazol-5-yl, 1-ethoxycarbonylmethyloxy, 1-ethoxycarbonylmethyl, 1-ethoxycarbonyl, carboxy Methoxy, thiophen-2-yl, thiophen-2-ylthio, thiophen-3-yl, thiophen-3-ylthio, 4-fluorophenylthio, butylcarbonylphenylmethoxy, butylcarbonyl Phenylmethyl, part Tylcarbonylmethyl, 1- (piperidin-1-yl) carbonyl) methyl, 1- (piperidin-1-yl) carbonyl) methoxy, 1- (piperidin-2-yl) carbon Yl) methoxy, 1- (piperidin-3-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl) methyl, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl, 1-4- (Pyrimidin-2-yl) piperazin-1-yl, 1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl, 1- (4- (pyridin-2-yl) pipe Razin-1-yl) carbonylmethyl, (1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl) -methoxy), 1- (4- (pyridin-2-yl) Piperazin-1-yl, 1H-indol-1-yl, morpholino, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3- ( Phenylthio) -1H-indol-1-yl, 3- (2-cyanoethylthio) -1H-indol-1-yl, benzylamino, 5-methoxy-3- (phenylthio) -1H-indole- 1-yl, 5-methoxy-3- (2-cyanoethylthio) -1H-indol-1-yl, 5-cle Rho-1H-indol-1-yl, 5-chloro-3- (2-cyanoethylthio) -1H-indol-1-yl, dibenzylamino, benzylamino, 5-chloro-3- (phenylthio) -1H-indol-1-yl, 4- (1H-tetrazol-5-yl) phenoxy, 4- (1H-tetrazol-5-yl) phenyl, 4- (1H-tetrazol-5-yl) Phenylthio, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio, 4-cyanophenylthio, 2-chlorophenoxy , 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4- Formula Ib- which is a member selected from cyanobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy and 4-fluorobenzyloxy Have the formula according to Ie.

In an exemplary embodiment, the compound is a member wherein R ^1a is selected from H, negatively charged and salt counterions and each of the remaining two R groups (R ^9a and R ^{10a in If} , R ^9a and R ^11a in Ig, R in Ih) ^9a and R ^12a, in the R ^10a and R ^11a, Ij in Ii R ^10a and R ^12a, in Ik R ^11a and R ^12a) is fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxymethyl , Trifluoromethyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperidinyl , Piperidinocarbonyl, piperidinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl), phenylmethoxy, 1H-tetra Sol-5-yl, 1-ethoxycarbonylmethyloxy, 1-ethoxycarbonylmethyl, 1-ethoxycarbonyl, carboxymethoxy, thiophen-2-yl, thiophen-2-ylthio, thi Offen-3-yl, thio 3-ylthio, 4-fluorophenylthio, butylcarbonylphenylmethoxy, butylcarbonylphenylmethyl, butylcarbonylmethyl, 1- (piperidin-1-yl) carbonyl) methyl, 1- ( Piperidin-1-yl) carbonyl) methoxy, 1- (piperidin-2-yl) carbonyl) methoxy, 1- (piperidin-3-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl) methyl, 1 -(4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl, 1-4- (pyrimidin-2-yl) piperazin-1-yl, 1- (4- (pyridine-2 -Yl) piperazin-1-yl) carbonyl, 1- (4- (pyridin-2-yl) piperazin-1-yl) carbonylmethyl, (1- (4- (pyridin-2-yl) pipepe Razin-1-yl) carbonyl) -methoxy), 1- (4- (pyridin-2-yl) piperazin-1-yl, 1H-indol-1-yl, morpholino, morpholinyl, mor Polynocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3- (phenylthio) -1H-indol-1-yl, 3- (2-cyanoethylthio) -1H -Indol-1-yl, benzylamino, 5 -Methoxy-3- (phenylthio) -1H-indol-1-yl, 5-methoxy-3- (2-cyanoethylthio) -1H-indol-1-yl, 5-chloro-1H-indole -1-yl, 5-chloro-3- (2-cyanoethylthio) -1H-indol-1-yl, dibenzylamino, benzylamino, 5-chloro-3- (phenylthio) -1H-indole- 1-yl, 4- (1H-tetrazol-5-yl) phenoxy, 4- (1H-tetrazol-5-yl) phenyl, 4- (1H-tetrazol-5-yl) phenylthio, 2- Cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio, 4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy , 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, Formulas according to formula If-Ik which are members selected from 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy and 4-fluorobenzyloxy Have

In an exemplary embodiment, the compound is a member wherein R ^1a is selected from H, negatively charged and salt counterions, and each of the remaining three R groups (R ^9a , R ^10a , R ^11a , Im in R ^9a , R ^10a , R ^12a , R ^9a , R ^11a , R ^12a , R ^12a , Io R ^10a , R ^11a , R ^12a ) is fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxymethyl, trifluoro Methyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizino Carbonyl, piperidinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl), phenylmethoxy, 1H-tetrazol-5- 1, ethoxycarbonylmethyloxy, 1-ethoxycarbonylmethyl, 1-ethoxycarbonyl, carboxymethoxy, thiophen-2-yl, thiophen-2-ylthio, thiophen-3- 1, thiophen-3-ylthio, 4-fluoro Nylthio, Butylcarbonylphenylmethoxy, Butylcarbonylphenylmethyl, Butylcarbonylmethyl, 1- (piperidin-1-yl) carbonyl) methyl, 1- (piperidin-1-yl) carbonyl ) Methoxy, 1- (piperidin-2-yl) carbonyl) methoxy, 1- (piperidin-3-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl ) Piperazin-1-yl) carbonyl) methoxy, 1- (4- (pyrimidin-2-yl) piperazin-1-yl) carbonyl) methyl, 1- (4- (pyrimidin-2- Yl) piperazin-1-yl) carbonyl, 1-4- (pyrimidin-2-yl) piperazin-1-yl, 1- (4- (pyridin-2-yl) piperazin-1-yl) Carbonyl, 1- (4- (pyridin-2-yl) piperazin-1-yl) carbonylmethyl, (1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl)- Methoxy), 1- (4- (pyridin-2-yl) piperazin-1-yl, 1H-indol-1-yl, morpholino, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl , Phenylureido, phenylcarbamoyl, acetamido, 3- (phenylthio) -1H-indol-1-yl, 3- (2-cyanoethylthio) -1H-indol-1-yl, benzylamino, 5-methoxy-3- (phenylthio) -1H- Dol-1-yl, 5-methoxy-3- (2-cyanoethylthio) -1H-indol-1-yl, 5-chloro-1H-indol-1-yl, 5-chloro-3- (2 -Cyanoethylthio) -1H-indol-1-yl, dibenzylamino, benzylamino, 5-chloro-3-((Žylthio) -1H-indol-1-yl, 4- (1H-tetrazol-5 -Yl) phenoxy, 4- (1H-tetrazol-5-yl) phenyl, 4- (1H-tetrazol-5-yl) phenylthio, 2-cyanophenoxy, 3-cyanophenoxy, 4 -Cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio, 4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy C, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4 It has a formula according to formula Il-Io which is a member selected from -chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy and 4-fluorobenzyloxy.

In another exemplary embodiment, the clue is that the compound may not be a member selected from C1-C40.

In another exemplary embodiment, the clue exists that the compound may not have a structure according to Formula Ix:

^Wherein R ^7b is a member selected from H, methyl, ethyl and phenyl. R ^10b is a member selected from H, OH, NH ₂ , SH, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio to be. R ^11b is a member selected from H, OH, NH ₂ , SH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio to be. In another exemplary embodiment, there is a clue that the compound may not have a structure according to formula (Ix) wherein R ^1b is a member selected from negative charges, H and salt counterions. In another exemplary embodiment, the clue exists that the compound may not have a structure according to Formula (Ix) wherein R ^10b and R ^11b are H. In another exemplary embodiment, the compound is H wherein one member selected from R ^10b and R ^11b is H and the other member selected from R ^10b and R ^11b is halo, methyl, cyano, methoxy, hydroxymethyl and p-cya The clue exists that it cannot have a structure according to formula (Ix) which is a member selected from nophenyloxy. In another exemplary embodiment, the compound has a structure according to Formula Ix, wherein R ^10b and R ^11b are members independently selected from fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl There is a clue that it can't have. In another exemplary embodiment, the compound is a member wherein R ^1b is selected from negatively charged, H and salt counterions; R ^7b is H; There is a clue that R ^10b is F and R ^11b is H and has no structure according to formula (Ix). In another exemplary embodiment, there is a clue that the compounds may not have a structure according to formula (Ix) in which R ^11b and R ^12b combine with the atoms to which they are attached to form a phenyl group. In another exemplary embodiment, the compound is a compound wherein R ^1b is a member selected from negatively charged, H and salt counterions; R ^7b is H; R ^10b is 4-cyanophenoxy; There is a clue that R ^11b may not have a structure according to formula (Ix) in which H is H.

In another exemplary embodiment, the clue exists that the compound may not have a structure according to Formula Iy:

Where R ^10b is a member selected from H, halogen, CN and substituted or unsubstituted C _{1 -4} alkyl.

In another exemplary embodiment, the structure has at least one member selected from R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^11a and R ^12a Or there is a clue that it does not have a structure which is a member selected from formulas (I) to (Io) which are halogen. In another exemplary embodiment, when M is oxygen, W is a member selected from (CR ^3a R ^4a ) _n1 , where n1 is 0, J is a member selected from (CR ^6a R ^7a ) _m1 , Wherein m1 is 1, A is CR ^9a , D is CR ^10a , E is CR ^11a , G is CR ^12a , and R ^9a is not halogen, methyl, ethyl, or optionally combines with R ^10a To form a phenyl ring; R ^10a is not unsubstituted phenoxy, C (CH ₃ ) ₃ , halogen, CF ₃ , methoxy, ethoxy or optionally combines with R ^9a to form a phenyl ring; R ^11a is not halogen or optionally combines with R ^10a to form a phenyl ring; There is a clue that R ^12a is not halogen. In another exemplary embodiment, when M is oxygen, W is a member selected from (CR ^3a R ^4a ) _n1 , where n1 is 0, J is a member selected from (CR ^6a R ^7a ) _m1 , M1 is 1, A is CR ^9a , D is CR ^10a , E is CR ^11a , G is CR ^12a , and R ^6a and R ^7a are not halophenyl. In another exemplary embodiment, M is oxygen, W is a member selected from (CR ^3a R ^4a ) _n1 , where n1 is 0, J is a member selected from (CR ^6a R ^7a ) _m1 , wherein m 1 is 1, A is CR ^9a , D is CR ^10a , E is CR ^11a , G is CR ^12a , and R ^9a , R ^10a and R ^{11a are} H, R ^6a , R ^7a and R There is a clue that ^12a is not H. In another exemplary embodiment, M is oxygen, where n1 is 1, J is a member selected from (CR ^6a R ^7a ) _m1 , wherein m1 is 0, A is CR ^9a , and D is CR ^10a , E is CR ^11a , G is CR ^12a , R ^9a is H, R ^10a is H, R ^11a is H, R ^6a is H, R ^7a is H, and R ^12a is H In the case there is a clue that W is not C═O (carbonyl). In another exemplary embodiment, M is oxygen, W is CR ^5a , J is CR ^8a , A is CR ^9a , D is CR ^10a , E is CR ^11a , G is CR ^12a , and R ^{When 6a} , R ^7a , R ^9a , R ^10a , R ^11a and R ^12a are H, there is a clue that R ^5a and R ^8a together with the atoms to which they are attached do not form a phenyl ring.

In an exemplary embodiment, the compound of the invention has a structure that is a member selected from the formulas Iab, Iac, Iad, Ia and Iaf:

Where q is a number from 0 to 1. R ⁸ is halogen. R ^a , R ^b , R ^c , R ^d and R ^e are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted Or an unsubstituted aryl and a substituted or unsubstituted heteroaryl. In an exemplary embodiment, the clue exists that the compound is not a member selected from the following compounds:

In an exemplary embodiment, the compound has a structure that is a member selected from formulas Iag, Iah, Iai, Iaj and Iak:

In an exemplary embodiment, R ^a , R ^d and R ^e are each independently selected from the following groups:

In an exemplary embodiment, R ^b and R ^c are independently selected from H, methyl, and the following groups:

로부터 선택된 구성원이다. 또 다른 예시적 구체예에서, R^b 및 R^c는 이들이 부착된 질소와 함께 임의로 결합하여 하기의 그룹들로부터 선택된 구성원을 형성한다:In another exemplary embodiment, R ^b is H, R ^c is H, methyl,

Member selected from. In another exemplary embodiment, R ^b and R ^c optionally combine with the nitrogen to which they are attached to form a member selected from the following groups:

In an exemplary embodiment, R ^a is a member selected from the following groups:

In an exemplary embodiment, R ^d is a member selected from the following groups:

In an exemplary embodiment, R ^c is a member selected from the following groups:

In an exemplary embodiment, the compound is a member selected from the following compounds:

In an exemplary embodiment, the compound has the structure shown in FIG. 2. In an exemplary embodiment, the compound has the structure shown in FIG. 3.

In an exemplary embodiment, the compound is of formula Ib, wherein the remaining R groups (R ^{9a for} Ib, R ^{10a for} Ic, R ^{11a for} Id, and R ^{12a for} Ie) are carboxymethoxy , Ic, Id and Ie.

In an exemplary embodiment, the compound is R ^9a or R ^10a for Formula If, R ^9a or R ^11a for Formula Ig, R ^9a or R ^12a for Formula Ih, R ^10a or R for Formula Ii ^11a , R ^10a or R ^12a for Formula Ij, R ^11a or R ^12a for Formula Ik is halogen, and other substituents in the pairing (e.g., if R ^9a in Formula If is F, R ^10a Is selected from the following substituent list) has a structure which is a member selected from the formula If-Ik which is a member selected from NH ₂ , N (CH ₃ ) H and N (CH ₃ ) ₂ .

In another exemplary embodiment, the compound has a structure that is a member selected from the following compounds:

Wherein R ^* and R ^** are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, And substituted or unsubstituted heteroaryl. In an exemplary embodiment, the compound is a member selected from the following compounds:

Wherein R ^1a is a member selected from negative charges, H and salt counterions.

In another exemplary embodiment, the compound has a structure that is a member selected from formula Iak:

(Iak), 여기에서 q는 1이고, R^g는 플루오로, 클로로 및 브로모로부터 선택된 구성원이다.

(Iak) wherein q is 1 and R ^g is a member selected from fluoro, chloro and bromo.

In another exemplary embodiment, the compounds and embodiments described by Formulas I-Io include hydrates with water, solvates with alcohols (eg, methanol, ethanol, propanol); Adducts with amino compounds (eg, ammonia, methylamine, ethylamine); Adducts with acids (eg, formic acid, acetic acid); Complexes with ethanolamine, quinoline, amino acids, and the like.

In another exemplary embodiment, the compound has a structure according to formula Ip:

^Wherein R ^x2 is a member selected from substituted or unsubstituted C ₁ -C ₅ alkyl and substituted or unsubstituted C ₁ -C ₅ heteroalkyl. R ^y2 and R ^z2 are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or Independently selected from unsubstituted heteroaryl. ^** A1-M1 is not defined?

In another exemplary embodiment, the compound has a structure according to formula Iq:

Where B is boron. R ^x2 is a member selected from substituted or unsubstituted C ₁ -C ₅ alkyl and substituted or unsubstituted C ₁ -C ₅ heteroalkyl. R ^y2 and R ^z2 are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or Independently selected from unsubstituted heteroaryl. In another exemplary embodiment, at least one member selected from R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^11a and R ^12a is nitro, cyano and halogen Member selected from.

In another exemplary embodiment, the compound has a structure that is a member selected from formulas Ir, Is, It, Iu, Iv, Iw and Iz:

In another exemplary embodiment, the compound is at least one member selected from R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^11a and R ^12a . , Fluoro, chloro, bromo and cyanophenoxy, having the formula according to formula Ib-Ie. In another exemplary embodiment, the compound is a member selected from the following compounds:

In another exemplary embodiment, the compound is a member selected from the following compounds:

In another exemplary embodiment, there is a clue that the compound may not have a structure according to Formula Iaa:

Wherein R ^6b , R ^9b , R ^10b , R ^11b and R ^12b have the same substituent list as described for Formulas Ix and Iy above.

In another exemplary embodiment, the present invention provides multivalent or polyvalent species of the compounds of the present invention. In an exemplary embodiment, the present invention provides dimers of the compounds described herein. In an exemplary embodiment, the present invention provides dimers of the compounds described herein. In an exemplary embodiment, the present invention provides dimers of compounds that are members selected from C1-C96. In an exemplary embodiment, the dimer is a member selected from the following compounds:

In an exemplary embodiment, the present invention provides anhydrides of the compounds described herein. In an exemplary embodiment, the present invention provides anhydrides of the compounds described herein. In an exemplary embodiment, the present invention provides anhydrides of compounds that are members selected from C1-C96. In an exemplary embodiment, the anhydride is a member selected from the following compounds:

In an exemplary embodiment, the present invention provides trimers of the compounds described herein. In an exemplary embodiment, the present invention provides trimers of the compounds described herein. In an exemplary embodiment, the present invention provides a trimer of a compound that is a member selected from C1-C96. In an exemplary embodiment, the trimer is a member selected from the following compounds:

In another exemplary embodiment, R ^10a is a member selected from the following groups:

로부터 선택된 구성원이다. R¹⁶ 및 R¹⁷은 H, 치환되거나 비치환된 알킬, 치환되거나 비치환된 헤테로알킬, 치환되거나 비치환된 사이클로알킬, 치환되거나 비치환된헤테로사이클로알킬, 치환되거나 비치환된 아릴 및 치환되거나 비치환된 헤테로아릴로부터 독립적으로 선택된 구성원이다. 지수 p는 1 내지 5로부터 선택된 정수이다. 지수 z는 1 내지 8로부터 선택된 정수이다. X는 S 및 O로부터 선택된 구성원이다.Where R ¹⁵ is CN, COOH and

Member selected from. R ¹⁶ and R ¹⁷ are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted It is a member independently selected from cyclic heteroaryl. The index p is an integer selected from 1 to 5. The index z is an integer selected from 1-8. X is a member selected from S and O.

In another exemplary embodiment, the compound has a structure according to formula VIII:

Wherein R ^4a is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl. R ^10a is a member selected from H, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted arylthio and substituted or unsubstituted arylalkylthio .

In another exemplary embodiment, the compound has a structure of a compound that is a member selected from the following compounds:

In another exemplary embodiment, the compound is a compound of:

In another aspect, the present invention provides a compound useful in the process of the present invention having a structure according to formula (IX):

Variables A, D, E and G are described elsewhere herein. R ²⁰ , R ²¹ and R ²² are negatively charged, salt counterions, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted Or an unsubstituted aryl and a substituted or unsubstituted heteroaryl.

In another exemplary embodiment, the compound has a structure according to formula (X):

In another exemplary embodiment, the compound is a member selected from the following compounds:

Compounds of the invention include hydrates with water, solvates with alcohols such as methanol, ethanol, propanol and the like; Adducts with amino compounds such as ammonia, methylamine, ethylamine and the like; Adducts with acids such as formic acid, acetic acid and the like; Complexes with ethanolamine, quinoline, amino acids, and the like.

In an exemplary embodiment, the compound is 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C1), 1,3-dihydro-1-hydroxy-2,1 Benzoxaborole (C2), 5-fluoro-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole (C3), 6-fluoro-1-hydroxy- 1,2,3,4-tetrahydro-2,1-benzoxaboroline (C4), 5,6-difluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole ( C5), 5-cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C6), 1,3-dihydro-1-hydroxy-5-methoxy-2, 1-benzoxaborole (C7), 1,3-dihydro-1-hydroxy-5-methyl-2,1-benzoxaborole (C8), 1,3-dihydro-1-hydroxy-5- Hydroxymethyl-2,1-benzoxaborole (C9), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10), 1,3-dihydro- 2-oxa-1-cyclopenta [α] naphthalene (C11), 7-hydroxy-2,1-oxaborolan [5,4-c] pyridine (C12), 1,3-dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborole (C13), 3-benzyl-1,3-dihydro-1-hydroxy-3-methyl-2, 1-benzoxaborole (C14), 3-benzyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C15), 1,3-dihydro-4-fluoro-1- Hydroxy-2,1-benzoxaborole (C16), 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C17), 6- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C18), 6- (3-cyanophenoxy) -1,3-dihydro- 1-hydroxy-2,1-benzoxaborole (C19), 6- (4-chlorophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C20), 6 -Phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C21), 5- (4-cyanobenzyloxy) -1,3-dihydro-1-hydroxy- 2,1-benzoxaborole (C22), 5- (2-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C23), 5-phenoxy- 1,3-dihydro -1-hydroxy-2,1-benzoxaborole (C24), 5- [4- (N, N-diethylcarbamoyl) phenoxy] -1,3-dihydro-1-hydroxy-2, 1-benzoxaborole (C25), 1,3-dihydro-1-hydroxy-5- [4- (morpholinocarbonyl) phenoxy] -2,1-benzoxaborole (C26), 5- (3,4-dicyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C27), 6-phenylthio-1,3-dihydro-1-hydroxy -2,1-benzoxaborole (C28), 6- (4-trifluoromethoxyphenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C29), 5- (N-methyl-N-phenylsulfonylamino) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C30), 6- (4-methoxyphenoxy) -1,3 -Dihydro-1-hydroxy-2,1-benzoxaborole (C31), 6- (4-methoxyphenylthio) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C32), 6- (4-methoxyphenylsulfonyl) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C33), 6- (4-methoxyphenylsulfinyl) -1,3-diha Draw-1-hydroxy-2,1-benzoxaborole (C34), 5-trifluoromethyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C35), 4- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C36), 5- (3-cyanophenoxy) -1,3-dihydro- 1-hydroxy-2,1-benzoxaborole (C37), 5- (4-carboxyphenoxy) -1-hydroxy-2,1-benzoxaborole (C38), 1-hydroxy-5- [ 4- (tetrazol-1-yl) phenoxy] -2,1-benzoxaborole (C39), 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 1 , 3-dihydro-1-hydroxy-2,1-benzoxaborole, 5-fluoro-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole, 6- Fluoro-1-hydroxy-1,2,3,4-tetrahydro-2,1-benzoxaborin, 5,6-difluoro-1,3-dihydro-1-hydroxy-2,1 Benzoxaborole, 5-cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 1,3-dihydro-1-hydroxy-5- Oxy-2,1-benzoxaborole, 1,3-dihydro-1-hydroxy-5-methyl-2,1-benzoxaborole, 1,3-dihydro-1-hydroxy-5-hydroxy Methyl-2,1-benzoxaborole, 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, 1,3-dihydro-2-oxa-1-cyclopenta [α] naphthalene, 7-hydroxy-2,1-oxaborolan [5,4-c] pyridine, 1,3-dihydro-6-fluoro-1-hydroxy-2,1-benzoxa Borol, 3-benzyl-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole, 3-benzyl-1,3-dihydro-1-hydroxy-2,1- Benzoxaborole, 1,3-dihydro-4-fluoro-1-hydroxy-2,1-benzoxaborole, 5- (4-cyanophenoxy) -1,3-dihydro-1-hydro Roxy-2,1-benzoxaborole, 6- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6- (3-cyanophenoxy ) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6- (4-chlorophenoxy) -1,3-dihydro -1-hydroxy-2,1-benzoxaborole, 6-phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5- (4-cyanobenzyloxy)- 1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5- (2-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole , 5-phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5- [4- (N, N-diethylcarbamoyl) phenoxy] -1,3-di Hydro-1-hydroxy-2,1-benzoxaborole, 1,3-dihydro-1-hydroxy-5- [4- (morpholinocarbonyl) phenoxy] -2,1-benzoxaborole , 5- (3,4-dicyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6-phenylthio-1,3-dihydro-1-hydroxy -2,1-benzoxaborole, 6- (4-trifluoromethoxyphenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5- (N-methyl-N -Phenylsulfonylamino) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6- (4-methoxyphenoxy) -1,3-dihydro- 1-hydroxy-2,1-benzoxaborole, 6- (4-methoxyphenylthio) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6- (4-meth Methoxyphenylsulfonyl) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6- (4-methoxyphenylsulfinyl) -1,3-dihydro-1-hydroxy- 2,1-benzoxaborole, 5-trifluoromethyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 4- (4-cyanophenoxy) -1,3- Dihydro-1-hydroxy-2,1-benzoxaborole, 5- (3-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5- ( 4-carboxyphenoxy) -1-hydroxy-2,1-benzoxaborole, 1-hydroxy-5- [4- (tetrazol-1-yl) phenoxy] -2,1-benzoxaborole, A structure selected from 4- (4-cyanophenoxy) phenylboronic acid, 3- (4-cyanophenoxy) phenylboronic acid, and 4- (4-cyanophenoxy) -2-methylphenylboronic acid Has

In an exemplary embodiment, the compound has a structure that is a member selected from the following compounds:

Preparation of Compound

In one aspect, the present invention provides compounds useful in the methods of the present invention.

Preparation of Boron-Containing Editing Zone Inhibitors

The compounds used in the present invention can be prepared by using commercially available starting materials, known intermediates, or by using synthetic methods disclosed in the literature described herein and incorporated by reference.

Boronic acid  ester

The following exemplary scheme illustrates the process for preparing the boron-containing molecules of the present invention. These methods are not limited to producing the compounds shown and can be used to prepare various molecules such as the compounds and complexes described herein. The compounds of the present invention may also be synthesized by methods well known within the skill of those skilled in the art, although not explicitly described in the schemes. Compounds can be prepared using readily available materials of known intermediates.

In the following schemes, the symbol X represents bromo or iodo. Symbol Y is selected from H, lower alkyl, and arylalkyl. Symbol Z is selected from H, alkyl and aryl. The symbol PG represents a protection group. Symbols A, D, E, G, R ^x , R ^y , R ^z , R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^10a , R ^11a And R ^12a may be used as mentioned for the corresponding symbol in the compounds described in the present invention.

Boronic acid  Manufacturing Method # 1

In steps 1 and 2 of Scheme 1, compound 1 or 2 is converted to alcohol 3. In step 1, compound 1 is treated with a reducing agent in a suitable solvent. Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof and the like. Lithium aluminum hydride, or sodium borohydride may be used as the reducing agent. The reducing agent can be used in amounts ranging from 0.5 to 5 equivalents relative to compound 1 or 2. Suitable solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, combinations thereof, and the like. The reaction temperature ranges from 0 ° C. to the boiling point of the solvent used; The reaction completion time is in the range of 1 to 24 hours.

In step 2, the carbonyl group of compound 2 is treated with a reducing agent in a suitable solvent. Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof and the like. Lithium aluminum hydride, or sodium borohydride may be used as the reducing agent. The reducing agent can be used in amounts ranging from 0.5 to 5 equivalents relative to compound 2. Suitable solvents include lower alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, combinations thereof, and the like. The reaction temperature ranges from 0 ° C. to the boiling point of the solvent used; The reaction completion time is in the range of 1 to 24 hours.

In step 3, the hydroxyl groups of compound 3 are protected by stable protecting groups under neutral or basic conditions. The protecting group is generally selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethylsilyl, tert-butyldimethylsilyl, tributylsilyl, combinations thereof and the like. In the case of methoxymethyl, compound 3 is treated with 1 to 3 equivalents of chloromethyl methyl ether in the presence of a base. Suitable bases include sodium hydride, potassium tert-butoxide, tertiary amines such as diisopropylethylamine, triethylamine, 1,8-diazabicyclo [5,4,0] undec-7- Yen, and inorganic bases such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, combinations thereof, and the like. The base can be used in amounts ranging from 1 to 3 equivalents relative to compound 3. The reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably 0 to 40 ° C .; The reaction completion time ranges from 1 hour to 5 days.

In the case of tetrahydropyran-2-yl, compound 3 is treated with 1 to 3 equivalents of 3,4-dihydro-2H-pyran in the presence of 1 to 10 mol% acid catalyst. Suitable acid catalysts include pyridinium p-toluenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, hydrogen chloride, sulfuric acid, combinations thereof, and the like. Suitable solvents include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene and acetonitrile, combinations thereof, and the like. The reaction temperature is in the range of 0 ° C to the boiling point of the solvent used, preferably 0 to 60 ° C; The reaction is completed within 1 hour to 5 days.

In the case of trialkylsilyl, compound 3 is treated with 1 to 3 equivalents of chlorotrialkylsilane in the presence of 1 to 3 equivalents of base. Suitable bases include tertiary amines such as imidazole, diisopropylethylamine, triethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene, combinations thereof, and the like. Included. The reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably 0 to 40 ° C .; The reaction completion time is in the range of 1 to 48 hours.

In step 4, compound 4 is converted to boronic acid 5 via halogen metal exchange. Compound 4 is substituted with 1 to 3 equivalents of n-butyllithium, sec-butyllithium, tert-butyllithium, isopropylmagnesium chloride relative to compound 4 in the presence or absence of an initiator such as diisobutylaluminum hydride (DiBAl) or Treatment with alkylmetal reagents such as Mg turnings is followed by addition of 1 to 3 equivalents of trialkyl borate such as trimethyl borate, triisopropyl borate or tributyl borate for compound 4. Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexane, combinations thereof, and the like. Alkylmetal reagents may also be added in the presence of trialkyl borate. The addition of butyllithium is carried out at -100 to 0 ° C, preferably at -80 to -40 ° C. The addition of isopropylmagnesium chloride is carried out at -80 to 40 ° C, preferably at -20 to 30 ° C. The addition of Mg turning with or without the addition of DiBAl is carried out at -80 to 40 ° C, preferably at -35 to 30 ° C. Addition of trialkyl borate is carried out at -100 to 20 ° C. After addition of the trialkyl borate, the reaction solution is warmed to room temperature, which is generally -30 to 30 ° C. If the alkylmetal reagent is added in the presence of trialkyl borate, the reaction mixture is added and then warmed to room temperature. The reaction completion time is in the range of 1 to 12 hours. Compound 5 may not be isolated and may be used for the next step without purification or in a single pot.

In step 5, the protecting group of compound 5 is removed under acidic conditions to provide a compound of the present invention. Suitable acids include acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid and the like. This acid can be used in amounts ranging from 0.1 to 20 equivalents relative to compound 5. If the protecting group is trialkylsilyl, basic reagents such as tetrabutylammonium fluoride may also be used. Suitable solvents include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, acetonitrile, acetone, combinations thereof, and the like. The reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably 10 ° C. to the reflux temperature of the solvent; The reaction completion time is in the range of 0.5 to 48 hours. The product can be purified by methods known to those skilled in the art.

Scheme 1

In another aspect, the present invention provides a process for preparing tetrahydropyran-containing boronic acid esters having a structure according to the formula:

Wherein R ¹ and R ² are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and It is a member independently selected from substituted or unsubstituted heteroaryl. R ¹ and R ² may optionally combine with the atoms to which they are attached to form a 4- to 7-membered ring. R ^9a , R ^10a , R ^11a and R ^12a are H, OR ^* , NR ^* R ^** , SR ^* , -S (O) R ^* , -S (O) ₂ R ^* , -S (O) ₂ NR ^* R ^** , nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl , And substituted or unsubstituted heteroaryl. R ^* and R ^** are H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted Or a member selected from unsubstituted heteroaryl. This method a) applies a first compound having a structure according to the following formula to Grignard or organolithium conditions:

b) contacting the product of step a) with a borate ester to form said tetrahydropyran-containing boronic acid ester. In an exemplary embodiment, the halogen is a member selected from iodo and bromo. In another exemplary embodiment, the borate ester is a member selected from B (OR ¹ ) ₂ (OR ² ), wherein R ¹ and R ² are each H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl , A member selected independently from substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl to be. R ¹ and R ² together with the atoms to which they are attached may form a member optionally selected from substituted or unsubstituted dioxabolol, substituted or unsubstituted dioxaborinane and substituted or unsubstituted dioxaborepan. have. In another exemplary embodiment, the borate ester is a member selected from B (OR ¹ ) ₂ (OR ² ), wherein R ¹ and R ² together with the atom to which they are attached are dioxaborolane, substituted or unsubstituted Forms a member selected from tetramethyldioxaborolane, substituted or unsubstituted phenyldioxaborolane, dioxaborinane, dimethyldiooxaborinane and dioxaborepan. In another exemplary embodiment, the Grignard or organolithium conditions further comprise diisobutyl aluminum hydride. In another exemplary embodiment, the temperature of the Grignard reaction does not exceed about 35 ° C. In another exemplary embodiment, the temperature of the Grignard reaction does not exceed about 40 ° C. In another exemplary embodiment, the temperature of the Grignard reaction does not exceed about 45 ° C. In an exemplary embodiment, step (b) is performed at a temperature of about -30 ° C to about -20 ° C. In another exemplary embodiment, step (b) is performed at a temperature of about -35 ° C to about -25 ° C. In another exemplary embodiment, step (b) is performed at a temperature of about −50 ° C. to about −0 ° C. In another exemplary embodiment, step (b) is performed at a temperature of about −40 ° C. to about −20 ° C. In another exemplary embodiment, the tetrahydropyran-containing boronic acid ester is a compound of:

In another aspect, the present invention provides a) subjecting a first compound having a structure according to the following formula to Grignard or organolithium conditions:

b) quenching the reaction solution with water and an organic acid to form a compound having the formula:

In an exemplary embodiment, the organic acid is a member selected from acetic acid. In another exemplary embodiment, the deactivation step is not essentially in contact with a strong acid. In another exemplary embodiment, the compound is 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is purified by recrystallization from a recrystallization solvent, wherein the recrystallization solvent is essentially free of acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 2% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 1% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 0.5% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains less than 0.1% acetonitrile. In an exemplary embodiment, the recrystallization solvent contains toluene and a hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 1: 1 toluene: hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 2: 1 toluene: hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 3: 1 toluene: hydrocarbon solvent. In an exemplary embodiment, the recrystallization solvent contains about 4: 1 toluene: hydrocarbon solvent. In an exemplary embodiment, the hydrocarbon solvent is a member selected from heptane, octane, hexane, pentane and nonane. In an exemplary embodiment, the recrystallization solvent is 3: 1 toluene: heptane.

Borin acid  Manufacturing Method # 2

In step 6 of Scheme 2, compound 2 is converted to boronic acid 6 via a transition metal catalyzed cross-coupling reaction. Compound 2 is optionally substituted with 1 to 3 equivalents of bis (pinacolato) diboron or 4,4,5,5-tetramethyl-1,3,2 in the presence of a transition metal catalyst, using appropriate ligands and bases Treat with dioxaborolane. Suitable transition metal catalysts include palladium (II) acetate, palladium (II) acetoacetonate, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosph) Pino) ferrocene] dichloropalladium (II), combinations thereof, and the like. The catalyst can be used in amounts ranging from 1 to 5 mol% relative to compound 2. Suitable ligands include triphenylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, combinations thereof, and the like. Ligands can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable bases include sodium carbonate, potassium carbonate, potassium phenoxide, triethylamine, combinations thereof, and the like. Bases can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable solvents include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, combinations thereof, and the like. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 150 ° C .; The reaction completion time is in the range of 1 to 72 hours.

The pinacol ester is then oxidatively degraded to afford compound 6. The pinacol esters are treated with sodium periodate followed by acid. Sodium periodate can be used in amounts ranging from 2 to 5 equivalents relative to compound 6. Suitable solvents include tetrahydrofuran, 1,4-dioxane, acetonitrile, methanol, ethanol, combinations thereof, and the like. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, combinations thereof, and the like. The reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably 0 to 50 ° C .; The reaction completion time is in the range of 1 to 72 hours.

In step 7, the carbonyl group of compound 6 is treated with a reducing agent in an appropriate solvent to provide a compound of the present invention. Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof and the like. Lithium aluminum hydride or sodium borohydride may also be used as reducing agent. The reducing agent can be used in amounts ranging from 0.5 to 5 equivalents relative to compound 6. Suitable solvents include lower alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, combinations thereof, and the like. The reaction temperature ranges from 0 ° C. to the boiling point of the solvent used; The reaction completion time is in the range of 1 to 24 hours.

Scheme 2

Boronic acid  Manufacturing Method # 3

In step 8 of Scheme 3, the compound of the present invention may be prepared in one step from compound 3. Compound 3 is mixed with trialkyl borate and then treated with alkylmetal reagents. Suitable alkylmetal reagents include n-butyllithium, sec-butyllithium, tert-butyllithium, combinations thereof, and the like. Suitable trialkyl borates include trimethyl borate, triisopropyl borate, tributyl borate, combinations thereof, and the like. The addition of butyllithium is carried out at -100 to 10 占 폚, preferably at -80 to -40 占 폚. After addition the reaction mixture is allowed to warm to room temperature. The reaction completion time is in the range of 1 to 12 hours. Trialkyl borate can be used in amounts ranging from 1 to 5 equivalents relative to compound 3. Alkylmetal reagents can be used in amounts ranging from 1 to 2 equivalents relative to compound 3. Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexane, combinations thereof, and the like. The reaction completion time is in the range of 1 to 12 hours. Alternatively, the mixture of compound 3 and trialkyl borate can be refluxed for 1 to 3 hours and the alkylmetal reagent can be added after distilling off the alcohol molecules formed by transesterification.

Scheme 3

Boronic acid  Manufacturing Method # 4

In step 10 of Scheme 4, the methyl group of compound 7 is brominated with N-bromosuccinimide. N-bromosuccinimide can be used in amounts ranging from 0.9 to 1.2 equivalents relative to compound 7. Suitable solvents include carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, chlorobenzene, combinations thereof, and the like. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 150 ° C .; The reaction completion time is in the range of 1 to 12 hours.

In step 11, the bromomethylene group of compound 8 is converted to benzyl alcohol 3. Compound 8 is treated with sodium acetate or potassium acetate. These acetates can be used in amounts ranging from 1 to 10 equivalents relative to compound 8. Suitable solvents include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, combinations thereof, and the like. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 100 ° C .; The reaction completion time is in the range of 1 to 12 hours. The resulting acetate is hydrolyzed to compound 3 under basic conditions. Suitable bases include sodium hydroxide, lithium hydroxide, potassium hydroxide, combinations thereof, and the like. Bases can be used in amounts ranging from 1 to 5 equivalents relative to compound 8. Suitable solvents include methanol, ethanol, tetrahydrofuran, water, combinations thereof, and the like. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 100 ° C .; The reaction completion time is in the range of 1 to 12 hours. Alternatively, compound 8 can be converted directly to compound 3 under similar conditions as described above.

Over steps 3 to 5 compound 3 is converted to the compound of the invention.

Scheme 4

Boronic acid  Manufacturing Method # 4

In step 12 of Scheme 5, compound 2 is treated with (methoxymethyl) triphenylphosphonium chloride or (methoxymethyl) triphenylphosphonium bromide in the presence of a base, followed by acid hydrolysis to give compound 9. . Suitable bases include sodium hydride, potassium tert-butoxide, lithium diisopropylamide, butyllithium, lithium hexamethyldisilazane, combinations thereof, and the like. The (methoxymethyl) triphenylphosphonium salt can be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, ether, toluene, hexane, N, N-dimethylformamide, combinations thereof, and the like. The reaction temperature is in the range of 0 ° C to the boiling point of the solvent used, preferably 0 to 30 ° C; The reaction completion time is in the range of 1 to 12 hours. The enolether formed is hydrolyzed under acidic conditions. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methanol, ethanol, combinations thereof, and the like. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 100 ° C .; The reaction completion time is in the range of 1 to 12 hours.

Over steps 2 to 5 compound 9 is converted to the compound of the invention.

Scheme 5

Boronic acid  Manufacturing Method # 6

In Scheme 6, compound I wherein R ¹ is H is converted to compound I where R ¹ is alkyl by mixing with the corresponding alcohol R ¹ OH. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, combinations thereof, and the like. Alcohols (R ¹ OH) can also be used as solvents. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 100 ° C .; The reaction completion time is in the range of 1 to 12 hours.

Scheme 6

Boronic acid  Manufacturing Method # 7

In Scheme 7, compound Ia is converted into its aminoalcohol complex Ib. Compound Ia is treated with HOR ¹ NR ^1a R ^1b . Aminoalcohols can be used in amounts ranging from 1 to 10 equivalents relative to compound la. Suitable solvents include methanol, ethanol, propanol, tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, water, combinations thereof, and the like. Included. The reaction temperature is in the range of 20 ° C. to the boiling point of the solvent used, preferably 50 to 100 ° C .; The reaction completion time is in the range of 1 to 24 hours.

Scheme 7

The compounds of the present invention can be converted to hydrates and solvates by methods similar to those described above.

I. c) Borin acid  ester

In one aspect, the present invention provides compounds useful in the methods of the present invention having a structure according to formula (XI):

^Wherein variables R ^1c , A, D, E, G, J, W and M are as described elsewhere herein.

In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted alkyl (C ₁ -C ₄ ). In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted alkyloxy. In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ). In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted alkenyl. In further exemplary embodiments thereof, the substituted alkyl has the structure of Formula XII:

^Wherein R ^23c , R ^24c and R ^25c are each H, haloalkyl, aralkyl, substituted aralkyl, (CH ₂ ) _r OH (where r is 1 to 3), CH ₂ NR ^26c R ^27c (here R ^26c and R ^27c are independently selected from hydrogen and alkyl), CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen , CF ₃ , NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted It is a member independently selected from cyclic heteroaryl.

In another exemplary embodiment of Formula (XI), R ^1c is substituted or unsubstituted alkynyl. In further exemplary embodiments thereof, the substituted alkynyl has the structure of Formula XIII:

^Wherein R ^23c is defined as above.

In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted aryl. In further exemplary embodiments thereof, the substituted aryl has the structure of Formula XIV:

^Wherein R ^28c , R ^29c , R ^30c , R ^31c and R ^32c are each H, aralkyl, substituted aralkyl, (CH ₂ ) _s OH (where s is 1 to 3), CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , (CH ₂ ) _t NR ²⁶ R ²⁷ where R ²⁶ and R ²⁷ are independently selected from hydrogen, alkyl and alkanoyl (t = 0 to 2), SO ₂ NH ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NHalkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl, alkyl substituted oxazolidin-2-yl, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted aralkyl. In further exemplary embodiments thereof, the substituted aralkyl has the structure of Formula XV:

^Wherein R ^28c , R ^29c , R ^30c , R ^31c and R ^32c are defined as above and n1 is an integer selected from 1 to 15.

In an exemplary embodiment of formula (XI), R ^1c is substituted or unsubstituted heteroaryl. In further exemplary embodiments thereof, the heteroaryl has the structure of Formula XVIa or XVIb:

Wherein X is a member selected from ^CH═CH , N═CH, NR ^35c where R ^35c is H, alkyl, aryl or benzyl, O or S. R ^33c and R ^34c are each H, haloalkyl, aralkyl, substituted aralkyl, (CH ₂ ) _u OH (where u is 1, 2 or 3), (CH ₂ ) _v NR ^26c R ^27c (here R ^26c and R ^27c are independently selected from hydrogen, alkyl and alkanoyl) (v = 0 to 3), CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted Or an unsubstituted aryl and a substituted or unsubstituted heteroaryl.

The structures of the present invention also allow solvent interactions that can provide structures (Formula XVII) comprising atoms derived from the solvents encountered by the compounds of the present invention during synthesis and therapeutic use. Structure XVII results from the formation of a coordinating bond between the solvent (s) and the boric Lewis center. Thus, such solvent complexes can be stable objects with significant bioactivity. This structure is clearly contemplated by the present invention when R ^40c is H or alkyl.

In an exemplary embodiment, the present invention provides a structure that is a member selected from formulas Ic, IIc, and IIIc:

Where B is boron. q1 and q2 are integers independently selected from 1 to 3. q3 is an integer selected from 0-4. M is a member selected from H, halogen, -OCH ₃ , and -CH ₂ -O-CH ₂ -O-CH ₃ . M ¹ is a member selected from halogen, —CH ₂ OH, and —OCH ₃ . X is a member selected from O, S and NR ^xc . R ^xc is a member selected from H and substituted or unsubstituted alkyl. R ^1c , R ^3c , R ^4c , R ^2c and R ^5c are H, OH, NH ₂ , SH, CN, NO ₂ , SO ₂ , OSO ₂ OH, OSO ₂ NH ₂ , substituted or unsubstituted alkyl, substituted or And independently selected from unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R ^41c is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted vinyl.

Compounds of the invention include hydrates with water, solvates with alcohols such as methanol, ethanol, propanol and the like; Adducts with amino compounds such as ammonia, methylamine, ethylamine and the like; Adducts with acids such as formic acid, acetic acid and the like; Complexes with ethanolamine, quinoline, amino acids, and the like.

In an exemplary embodiment, the compound is 2- (3-chlorophenyl)-[1,3,2] -dioxaborolane, (3-chlorophenyl) (4'-fluoro- (2 '-(methoxy) Methoxy) -methyl) -phenyl) -borinic acid, 1- (3-chlorophenyl) -5-fluoro-1,3-dihydrobenzo [c] [1,2] oxaborole, 1- (3- Chlorophenyl) -6-fluoro-1,3-dihydrobenzo [c] [1,2] oxaborole, 1- (3-chlorophenyl) -1,3-dihydrobenzo [c] [1,2 ] Oxaborole, 5-chloro-1- (3-fluorophenyl) -1,3-dihydrobenzo [c] [1,2] oxaborole, 2- (3-fluorophenyl)-[1,3 , 2] -dioxaborolane, 3- (benzo [c] [1,2] oxaborole-1 (3H) -yl) benzonitrile, 2- (3-cyanophenyl)-[1,3,2 ] -Dioxaborolane, (3-chlorophenyl) (5'-fluoro- (2 '-(methoxymethoxy) methyl) -phenyl) -borinic acid, 1- (3-chlorophenyl) -1, 3-dihydro-3,3-dimethylbenzo [c] [1,2] oxaborole, (3-chlorophenyl) (2- (2- (methoxymethoxy) propan-2-yl) phenylborinic acid, 1- (3-chlorophenyl) -1,3-dihydro-3,3-dimethylbenzo [c] [1,2] oxaborole, 1- (4-clo Lophenyl) -1,3-dihydrobenzo [c] [1,2] oxaborole, 2- (4-chlorophenyl)-[1,3,2] -dioxaborolane, 4- (benzo [c ] [1,2] oxaborole-1 (3H) -yl) benzonitrile, 2- (4-cyanophenyl)-[1,3,2] -dioxaborolane, 4- (5-fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) benzonitrile, 2- (4-cyanophenyl)-[1,3,2] -dioxaborolan, 3- (5-fluoro Robenzo [c] [1,2] oxaborole-1 (3H) -yl) benzonitrile, 2- (3-cyanophenyl)-[1,3,2] -dioxaborolane, 3- (6 -Fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) benzonitrile, 2- (3-cyanophenyl)-[1,3,2] -dioxaborolane, 1- (3-cyanophenyl) -5,6-dimethoxy-1,3-dihydrobenzo [c] [1,2] oxaborole, 2- (3-chlorophenyl)-[1,3,2]- Dioxaborolane, (4- (5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenylmethanamine, 5-fluoro-2- (methoxymethoxymethyl ) Phenyl]-[1,3,2] -dioxaborolan, 4- (5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenylmethanamine, (3 -(5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl ) Phenylmethanamine, (4- (5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl) methanol, (3- (5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl) methanol, 3- (6- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenol, 3- (5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) pyridine, (2- (benzo [c] [1,2] oxaborole-1 (3H) -yl) Phenyl) methanol, 2-[(methoxymethoxy) methyl] phenyl boronic acid, 2-[(methoxymethoxymethyl) phenyl]-[1,3,2] -dioxaborolan, bis [2- ( Methoxymethoxymethyl) phenyl] borinic acid, (2- (benzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl) methanol, (2- (benzo [c] [1,2 ] Oxaborole-1 (3H) -yl) phenyl) -N, N-dimethylmethanamine, (2- (benzo [c] [1,2] oxaborole-1 (3H) -yl) -5-chlorophenyl ) -N, N-dimethylmethanamine, (2- (benzo [c] [1,2] oxaborole-1 (3H) -yl) -5-chlorophenyl) methanol, (2- (benzo [c] [ 1,2] oxaborole-1 (3H) -yl) -5-chlorophenyl) methanol, (5-chloro-2- (5-chlorobenzo [c] [1,2] oxaborole-1 (3H)- Yl) phenyl) methanol, bis [4-chloro-2- (methok) Methoxymethyl) phenyl] borinic acid, (5-chloro-2- (5-chlorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl) methanol, (5-chloro-2- (5-chlorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl-N, N-dimethylmethanamine, 1- (4-chloro-2-methoxyphenyl) -1,3 -Dihydrobenzo [c] [1,2] benzoxaborole, 4-chloro-2-methoxyphenylboronic acid ethylene glycol ester, 1- (4-chloro-2-methoxyphenyl) -1,3-di Hydrobenzo [c] [1,2] bansoxabolol, 2- (benzo [c] [1,2] oxaboral-1 (3H) -yl) -5-chlorophenol, 2- (3- (benzo [ c] [1,2] oxaborole-1 (3H) -yl) phenoxy) -5-chlorophenol, 2- (3- (benzo [c] [1,2] oxaborole-1 (3H) -yl ) Phenoxy) -5-chlorophenol, 4-((3- (5-fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl) methyl) morpholine, 3- ( 5- (fluorobenzo [c] [1,2] oxaborole-1 (3H) -yl) phenyl) -methyl-8-hydroxy-quinolin-2-carboxylate, 1- (3-chlorophenyl)- 2,3-dihydro-2- (methoxymethyl) -1H-benzo [c] [1,2] azaborole, 3-chlorophenyl 2- [N, N-bis ( Methoxymethyl) aminomethyl] phenylborinic acid, 1- (3-chlorophenyl) -2,3-dihydro-2- (methoxymethyl) -1H-benzo [c] [1,2] azaborole, 1- (3-chlorophenyl) -1,3,4,5-tetrahydrobenzo- [c] [1,2] -oxaborepine, 1- (3-chlorophenyl) -1,3,4,5-tetra Hydrobenzo [c] [1,2] oxaborepine, 1- (3-chlorophenyl) -3,4-dihydro-1H-benzo [c] [1,2] -oxavorinine, 2- (3 -Chlorophenyl)-[1,3,2] dioxaborolane, (3-chlorophenyl) (2 '-(2- (methoxymethoxy) ethyl) phenyl) borinic acid, and 1- (3-chloro Phenyl) -3,4-dihydro-1H-benzo [c] [1,2] oxavorinine.

I. d) Preparation of Boron-Containing Compounds

The compounds used in the present invention can be prepared by using commercially available starting materials, known intermediates, or by using synthetic methods disclosed in the literature described herein and incorporated by reference.

I. e) Boronic acid  ester

Methods of preparing boronic acid esters are known in the art and use these methods to prepare the boronic acid esters described in the present invention within the knowledge of those skilled in the art. Examples include US Pat. Nos. 10 / 740,304, 10 / 867,465, 11 / 152,959, 11 / 153,765, 11 / 153,010, 11 / 389,605, 11 / 357,687, 11 / 357,687 and US Provisional Patent Application, incorporated herein by reference. 60 / 754,750, 60 / 774,532 and 60 / 746,361. Another example of a synthetic route for the preparation of the compounds used in the present invention is represented as follows:

I. f) Borin acid  ester

Methods of preparing boric acid esters are known in the art and use these methods to prepare the boronic acid esters described herein within the knowledge of those skilled in the art. Examples include US Pat. Nos. 10 / 868,268 and 11 / 743,665, which are incorporated herein by reference.

II . Test for periodontal disease inhibition

Techniques recognized in the art of genetics and molecular / cell biology are used to identify compounds suitable for inhibiting periodontal disease. Examples of test methods used for this measurement are provided in the present invention.

III . Oral care compositions

In another aspect, the present invention provides an oral care composition comprising a compound of the present invention. In an exemplary embodiment, the compound is a boron-containing compound described herein. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4-methylphenyl) borinic acid 3-hydroxy Oxypicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and 5- (4-cyanophenoxy) -1,3-dihydro -1-hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4-methylphenyl) borinic acid 3-hydroxy Oxypicolinate ester). These oral care compositions are used in the methods of the present invention.

The oral care composition of the present invention may take any physical form suitable for application to the oral surface. In various descriptive embodiments, the composition comprises a liquid solution suitable for irrigation, cleaning or spraying; Toothpastes such as powders, cream toothpastes or dental gels; Liquids suitable for painting tooth surfaces (eg liquid whitening agents); Chewing gum; Soluble, partially soluble or non-soluble films or strips (eg, whitening strips); wafer; Wipes or towellets; Implants; dental floss; Hydrations, mouthwashes, dental floss, chewing gums, lozenges, tablets, edible food products, periodontal sacs, as well as cream toothpastes, preventive paysheets, tooth polishes, gels, professional gels and other related products applied by dentists Periochips (made of a material such as chlorhexidine gluconate) for insertion into the cells, and the like. The composition may contain active and / or carrier components in addition to those recited above.

In certain embodiments of the invention, the compounds described herein in the oral care composition may be encapsulated in a material called microspheres. This substance may act as a slow release mechanism for the compound. In an exemplary embodiment, the microspheres are at least partially constructed from chitosan. In an exemplary embodiment, 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane is encapsulated in an oral care composition in microspheres. Further descriptions of microencapsulated materials can be found in Govender et al., Journal , incorporated herein by reference. of Microencapsulation , 23 (7): Nov. 2006, pp 750-761.

In certain embodiments, the composition is suitable for application to the oral surfaces of small livestock, such as cats or dogs. Such compositions can generally be eaten or chewed by animals, and can take the form of, for example, cat or dog food, treatments or toys.

Illustratively, the composition in any of the above-described embodiments is a hydrous or cleaning agent, oral spray, toothpaste, oral strip, liquid whitening agent or chewing gum. Detergents include liquids suitable for irrigation with devices such as high pressure water jets. Toothpastes include, but are not limited to, cream toothpaste, gels and powders. As used herein, "liquid whitening agent" includes flowable liquids as well as semi-liquid compositions, such as gels, as long as they can be applied to the tooth surface by painting the composition with a brush or other suitable device. "Painting" in this context means applying a thin layer of the composition to the tooth surface. In one embodiment, the composition is a cream toothpaste or a gel toothpaste.

The compositions of the present invention may comprise, in addition to the boron-containing compounds described herein, vitamins or vitamin derivatives or antioxidant components or one or more active agents (“active agents”).

Useful active agents include the treatment of appearance and structural changes in teeth, plaques, tartar, dental caries, caries, abscesses, inflammation and / or bleeding gums, gingivitis, general oral infectious and / or inflammatory conditions, tooth sensitivity, bad breath, and There is a focus on prevention. Thus, the compositions of the present invention may be used in combination with whitening agents, fluoride ion sources, antimicrobial agents other than the boron-containing compounds described herein, tin ion sources, zinc ion sources, saliva promoters, breath-freshening agents, It may contain one or more active agents such as anti-plaque agents, anti-inflammatory agents other than all boron-containing compounds with anti-inflammatory properties, periodontal agents, analgesics and nutrients. The active agent should be selected according to compatibility with each other and with the other components of the composition.

Active agents useful in the present invention are typically selected in such a way as to be safe and effective, i.e., when the desired benefit is repeated, for example, when the composition is used repeatedly as described herein, toxicity, corresponding to the ideal effect / risk ratio, It is present in the composition in an amount sufficient to provide a therapeutic, prophylactic, nutritional or cosmetic effect without undue side effects such as irritant or allergic reactions. Such safe and effective amounts are usually within the range approved by the appropriate regulatory body, but this is not necessarily the case. The safe and effective amount in a particular case depends on a number of factors, including the particular effect desired or the condition desired to be treated or prevented, the particular subject using the composition or the composition is administered, the frequency and duration of use, and the like. The active agent is generally in a total amount of about 0.01% to about 80%, for example about 0.05% to about 60%, about 0.1% to about 50%, or about 0.5% to about 40% by weight of the composition. exist.

One or more active agents, including the boron-containing compounds described herein, may optionally be present in the composition in encapsulated form. For example, beads containing one or more active agents may be suitable for rupturing during brushing or chewing to release the active agent (s) on the oral surface.

In addition, the compositions of the present invention may include any ingredient conventionally present or desirable in oral care compositions. For example, the composition may comprise a whitening agent such as a peroxy compound, chlorine dioxide, chlorite and hypochlorite, polymer-peroxide complex, polyvinylpyrrolidone-hydrogen peroxide (PVP-H ₂ O ₂ ) complex; Sources of fluoride ions (monofluorophosphate and fluorosilicate salts), antibacterial agents. Active agents such as antibacterial agents can include, for example, those listed in US Pat. No. 5,776,435 to Gaffar et al., The contents of which are incorporated herein by reference. The composition may further comprise a tooth anti-sensitizer, a salivary stimulant (saliva stimulant), a respiratory-cooling agent, an antiplaque agent or a plaque decay agent.

Useful carriers for optional inclusion in the compositions of the present invention include diluents, abrasives, bicarbonate salts, pH modifiers, surfactants, foam regulators, thickeners, viscosity modifiers, wetting agents, sweeteners, fragrances and colorants. One carrier material, or one or more carrier materials of the same or different classes may optionally be present. Water is the preferred diluent and in some compositions such as water solubles and whitening liquids may involve additional solvents such as alcohols, for example ethanol.

The composition may contain abrasives, pH modifiers, surfactants, foam modifiers, thickeners, viscosity modifiers, wetting agents, sweeteners, fragrances and colorants.

The present invention further provides an oral care method comprising applying the composition described herein to the oral surface of a subject. In one embodiment, the composition is a cream toothpaste or gel toothpaste and the applying step consists of brushing the surface, for example the tooth surface and the periodontal surface adjacent thereto, with the toothpaste.

According to embodiments of the present invention, there is also provided a method of inhibiting inflammation in oral tissue of a subject. The method of this embodiment includes applying a compound of the present invention to the oral surface in proximity to the tissue. In an exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4-methylphenyl) borinic acid 3-hydroxypi Collinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, and 5- (4-cyanophenoxy) -1,3-dihydro-1 -Hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane. In another embodiment, a method of enhancing oral health in a subject is provided. The method of this embodiment includes applying a compound of the invention to the oral surface of a subject.

Implementation of the method of the present invention may enhance oral health from any aspect or aspects. As one example, such methods can enhance periodontal and / or gingival health, for example, by reducing bacterial infections and / or inflammation. As another example, such methods may provide a respiratory-cooling effect, for example, through antibacterial and / or antioxidant activity. As another example, such methods can enhance tooth preservation, for example, by reducing or preventing dental caries and preventing the destruction of the bone matrix that keeps the teeth in place. As another example, this method may provide an anti-plaque effect. As another example, this method may reduce damage to oral tissue due to free radicals, including those resulting from contact with tobacco smoke or contaminated air.

It is well known that enhanced oral health, particularly improved periodontal and / or gingival health, associated with reduced bacterial infections and / or inflammation can induce systemic or systemic health effects. Delivery of vitamins through the oral surface as provided herein can further enhance overall health by replenishing vitamins ingested by food.

Systemic conditions that can be improved as a result of improved oral health by practicing the methods of the present invention include cardiovascular diseases including atherosclerosis, coronary heart disease (CHD) and stroke; diabetes; Respiratory infections, including bacterial pneumonia; Premature low birth weight; Stomach ulcers; Bacteremia; Infective endocarditis; Prosthetic infection; Chronic obstructive pulmonary disease (COPD); And brain abscesses.

Execution of the method may consist of a single application as described herein or may include repetition of such an application. In one embodiment, the method as described herein is performed at regular intervals, for example once or twice a day, for example, in a program or regimen performed at home and / or professional or clinical settings. Repeat twice or once a week, twice or once a month.

In any of the above methods, the subject may be a human or non-human mammal, eg, a dog, cat, horse or exotic mammal. In certain embodiments, the subject is a small livestock, such as a cat or a dog, and the composition, in the form of a food, treatment, or toy, is provided for chewing on an animal.

Oral care compositions of the present invention are organic, including, but not limited to, hydrophilic liquid vehicles, including, but not limited to, glycerin, propylene glycol, polyethylene glycol, and triglycerides, diglycerides, and mineral oils, essential oils, and fatty vegetable oils. It may further comprise various other components including hydrophobic liquid vehicles such as oils. These hydrophilic and hydrophobic liquid vehicles can be used alone or in combination, preferably from about 2 to about 50 wt.% (For compositions comprising liquid vehicles), in particular from about 10 to about 35, based on the total composition It can be added at a ratio of wt.%. Compositions of the present invention for oral cavity using one or more of these liquid vehicles may be formulated preferably in the form of use, such as gels, liquids or pastes.

Oral care compositions of the present invention may also contain flavoring ingredients, generally in the form of natural flavoring or aroma oils and / or herbal extracts and oils. These fragrance ingredients may not only serve to provide a delicious aroma to the oral care composition, but may also act simultaneously as natural antibacterial and preservatives. Oils suitable for use in the present invention include citric oil, lemon oil, lime oil, lemongrass oil, orange oil, sweet orange oil, grapefruit oil, pomegranate oil, apricot seed oil extract, tangerine extract, Tangelo oil, peppermint oil, spearmint oil, sage oil, rosemary oil, cinnamon oil, wintergreen oil, cloves oil, eucalyptus oil, ginger oil, sasafrase oil, menthol, avensis mint oil, synthetic mint fragrance and oil, carr Bon, Eugenol, Methyl Eugenol, Methyl Salicylate, Methyl Eugenol, Timol, Anetol, Milletfolium Extract, Chamomile, Lavender Oil, Myrrh, Eugenol, Tea Tree Oil, Sage Oil, Mallow, Limonene, ocymen, n-decyl alcohol, citronellol, α-terpineol, linarol, ethylrinalol, timene, almond oil, nutmeg, and vanillin, including but not limited to Do not. One of these perfumes, or a mixture of two or more of these perfumes may be used in the toothpaste composition. Their content ranges from about 3% to about 20% by weight, for example from about 4% to about 15% by weight based on the total composition.

Silica abrasives may also be incorporated into the oral care compositions of the present invention without departing from the scope of the present invention. Certain silica abrasives suitable for use in the present invention include, but are not limited to, silica gel, precipitated silica, silicates and hydrated silica. Suitable silica gels for use in the present invention are known in the art and are hydrogels, hydrogels, xerogels, and aerogels, such as those described in US Pat. No. 6,440,397. Precipitated silica is known in the art, such as suitable oral care-type precipitated silica, such as described in US Pat. No. 5,589,160. Suitable silicates may be any of naturally occurring or synthesized silicas suitable for use in oral care compositions. These silica abrasives may be used alone or in combination. Exemplary silica abrasives for use in the present invention include silica gel. Silica abrasives can be used with or in place of calcium salt components.

Water may optionally be incorporated into the oral care compositions of the present invention, such as cream toothpastes and water solubles. The water used to prepare commercially suitable oral care compositions should preferably be deionized and free of organic impurities. Water may generally comprise from about 0% to about 40% by weight of the cream dentifrice composition in the present invention.

In addition to the components described above, the oral care compositions of the present invention may further contain various optional ingredients and vehicles commonly used in formulations for use in the oral cavity, such as cream toothpastes and water solubles. These optional ingredients include, but are not limited to, abrasives, surfactants, thickeners, buffers, wetting agents, preservatives and ingredients such as antibiotics and anti-caries agents. All of these additives, described in more detail below, are generally customary and are known to those skilled in the art.

Dental abrasives useful in the toothpaste compositions of the invention include a variety of different materials known in the art. Preferably, the abrasive material should be one that is compatible with the composition of interest and does not excessively polish the dentin. Suitable abrasives include silica, including gels and precipitates; Dendritic abrasives such as insoluble polymethaphosphate, hydrated alumina, polymerized resins (eg, urea, melamine, cross-linked epoxides, phenolic resins, and the like), and mixtures thereof.

Another optional ingredient of the oral care composition of the present invention is a humectant. Wetting agents act to prevent a composition, such as a cream toothpaste, from curing upon exposure to air, and to provide the moisturizer and cream toothpaste composition with a moist feeling in the oral cavity. Certain humectants can also impart the desired sweetness of the perfume to the cream toothpaste and the hydrous composition. Wetting agents suitable for use in the compositions of the present invention include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, polyethylene glycol and propylene glycol.

Oral care compositions of the present invention may also optionally contain sweetening agents such as sodium saccharin, acesulfame potassium, glycyrrhizin, perilatin, taumartin, aspartylphenylalanyl methyl ester and xylitol.

The buffer is another optional ingredient of the oral care composition of the present invention. The buffer serves to keep the pH of the composition within the desired range. Suitable buffers for use in the dentifrice compositions of the invention include soluble phosphate salts.

 Other optional ingredients of the oral care composition of the present invention are preservatives such as preventing microbial growth in the oral care composition. Suitable preservatives include alcohols such as methylparaben, propylparaben, benzoate, and ethanol.

Binders and thickeners may also be used in the oral care compositions of the invention, especially in cream toothpaste compositions. Preferred binders and thickeners include carrageenan (eg, Viscarin, Irish moss, etc.); Cellulose derivatives such as hydroxyethyl cellulose, sodium carboxymethyl cellulose and sodium carboxymethyl hydroxypropyl cellulose, carboxyvinyl polymers; Natural rubbers such as karaya rubber, gum arabic and tragacanth; Polysaccharide rubbers such as xanthan rubber; Fumed silica; And colloidal magnesium aluminum silicates.

The composition of the oral care composition of the present invention may optionally contain a surfactant. Suitable surfactants are reasonably stable and preferably are those that form bubbles (foams) throughout the pH range of the dentifrice composition. Surfactants may also be added to act as solubilizers to help maintain poorly soluble components in solution or mixture. Surfactants useful as sudsing agents in dentifrice compositions can be soaps, polysorbates, poloxamers, and synthetic detergents that are anionic, nonionic, cationic, amphoteric or amphoteric, and mixtures thereof.

The oral care composition of the present invention may also optionally include an anticarious agent. Preferred anticarious agents are water soluble fluoride ion sources. The number of such fluoride ion sources is large and well known in the art and includes those described in US Pat. No. 3,535,421. Exemplary fluoride ion source materials include sodium fluoride, potassium fluoride, sodium monofluorophosphate, and mixtures thereof.

Antimicrobials and antiplaques may also optionally be present in the oral care compositions of the present invention. Such components may include the following materials: triclosan (5-chloro-2- (2,4-dichlorophenoxy) -phenol); Chlorhexidine; Chlorhexidine digluconate (CHX); Alexidine, hexetidine (HEX); Sanguinarine (SNG); Benzalkonium chloride; Salicylicanilide; Domiphene bromide; Cetylpyridinium chloride (CPC); Tetradecylpyridinium chloride (TPC); N-tetra-decyl-4-ethylpyridinium chloride (TDEPC); Octenidine; Delmofinol; Octapinol, and other piperidino derivatives; Niacin preparations; Zinc / tin ionic component; Antibiotics such as ogumentin, amoxicillin, tetracycline, deoxycycline, minocycline and metronidazole; Peroxides such as silium peroxide, hydrogen peroxide and magnesium monopertalate and analogs thereof; And analogs and salts of the antimicrobial and antiplaque agents listed above.

The oral care composition of the present invention may also optionally comprise one or more tartar formation inhibitors (ant-tartar agents). Tartar formation inhibitors that may be useful in the dentifrice compositions of the present invention include antimicrobial agents such as chlorhexidine, niidamycin and triclosan, metals and metal salts such as zinc citrate, vitamin C, bisphosphonates, triclosanpyrophosphate, pyrophosphates, polyphosphates, Polyacrylates and other polycarboxylates, polyepoxysuccinates, ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid and related compounds, polyphosphonates, and polypyrophosphates such as sodium hexametaphosphate, as well as literature [KJ Fairbrother et al., "Anticalculus agents", Journal of Clinical Periodontology Vol. 27, pp. 285 301 (2000), including other calculus inhibitors known to those skilled in the art.

Nutrients and vitamins may also be added to the oral care compositions of the present invention. These ingredients include folate, retinoid (vitamin A), vitamin B (B ₁ -thiamine, B ₂ -riboflavin, B ₃ -niacin, B ₅ -pantothenic acid, B ₆ -pyridoxine, B ₇ -biotin, B ₈ / B ₉ / Bc-folic acid, B ₁₂ -cyanocobalamin), vitamin C (ascorbic acid, sodium ascorbate), vitamin E, vitamin E analogs (dl-α-tocopherol acetate, tocopherol succinate, tocopherol nicotinate) and Zinc may be included.

Tooth desensitizers (e.g., potassium and strontium salts), condensed tartar inhibitors such as sodium and potassium tetrapyrophosphate, whitening agents such as aluminum oxide and calcium peroxide, necrotic debriding agents such as sodium bicarbonate, blue ( Blue) Mica as well as pigments and dyes such as 15-CI74160, Green 7-CI74260, Reds 4-CI12085 and 40 CI16035, Yellow 115 CI47005 and 5 CI19140, and Carmine 5 CI16035 And various other additives, such as additives such as sparkles, may also optionally be formulated into the oral care compositions of the present invention.

As with any other oral care additive, one or a mixture of two or more of these ingredients may be used in an appropriate amount for the oral care composition.

IV . How to inhibit microbial growth or kill microbes

In a further aspect, the present invention provides a method of inhibiting or killing the growth of microorganisms, preferably bacteria, fungi, viruses, yeasts or parasites, including contacting an organism with a compound of the invention. In an exemplary embodiment, the compound is a boron-containing compound described herein. In an exemplary embodiment, the microorganism is human, cow, deer, reindeer, goat, bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, It is present in the oral cavity of animals that are members selected from otters, chickens, ducks, geese, guinea fowls, pigeons, swans, and turkeys. In another exemplary embodiment, the animal is a human. Instead, this method is used in vitro, for example, to remove microbial contamination in cell culture. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4-methylphenyl) borinic acid 3-hydroxy Sipicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole and 5- (4-cyanophenoxy) -1,3-dihydro-1 -Hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane.

IV .a) Methods involving fungi or yeast

In an exemplary embodiment, the microorganism is a member selected from fungi and yeasts. In another exemplary embodiment, the fungus or yeast is a Candida (Candida) species, tricot python (Trichophyton) species, micro spokes Solarium (Microsporium) species, Aspergillus (Aspergillus) species, Cryptococcus Rhodococcus (Cryptococcus) species, Blas Sat Blastomyces species, Cocciodiodes species, Histoplasma species, Paracoccidiodes species, Phycomycetes species, Malassezia species, Fusarium (Fusarium) species, epi Dermo python (Epidermophyton) species, sital lithium (Scytalidium) species, Scoring pool La options sheath (Scopulariopsis) species, altereuna Liao (Alternaria) species, Penny room Solarium (Penicillium) species, Fora to PR ( Phialophora ) species, Rhizopus species, Scedosporium species and Zygomycetes rivers. In another exemplary embodiment, the fungus or yeast is A. fumigatus , Blastomyces dermatitidis , Candida albicans ( C. albicans , fluconazole susceptibility and resistance strains) ), C. glabrata , C. krusei , C. neoformans , C. parapsilosis , C. parapsilosis , C. tropicalis ), Cocciodiodes immitis ), Epidermophyton Flocosum ( E. floccosum ), Fusarium soni ( F. solani ), Histoplasma capsulatum , Malassezia purpur furfur ), M. pachydermatis , M. sympodialis , M. audouinii , M. canis , M. canis , M. gypseum , Paracoccidiodes brasiliensis) and pie My nose three tests (Phycomycetes) species, a tricot Python menta selected him from the Pie Test (T. mentagrophytes), Tricot Python Lu Broome (T. rubrum), Tricot Python tonnage Lance (T. tonsurans) members. In another exemplary embodiment, the fungus or yeast is a tricot python outlet rikum (T. concentricum), tricot python whilst erecting (T. violaceum), tricot python syoen Raney (T. schoenleinii), tricot python beru koseom (T. verrucosum ), tricot Python sew the nenseu (T. soudanense), My cross Forum erecting houses (M. gypseum), kwinum to My cross Forum (M. equinum), Candida gwil hormone de Liege (C. guilliermondii), dry years global Jia M. globosa , M. obtuse , M. restricta , M. slooffiae , and Aspergillus flavus ( A) . it is a member selected from flavus). In another exemplary embodiment, the fungus or yeast is dermatophyte, tricophyton, microsporum, epidermophyton, aspergillus, blastomyces, Candida, coccidiodes, cryptococcus, Hendersonula , Histoplasma , Paecilomyces , paracoccidioides , Pneumocystis , Trichosporium and yeast-yang fungi.

IV .b) How to contain bacteria

In an exemplary embodiment, the microorganism is a bacterium. In an exemplary embodiment, the bacterium is a Gram-positive bacterium. In another exemplary embodiment, the gram-positive bacterium is Staphylococcus (Staphylococcus) species, Streptococcus (Streptococcus) species, Bacillus (Bacillus) species, Mycobacterium (Mycobacterium) species, Corynebacterium (Corynebacterium) species (Propionibacterium sludge tumefaciens (Propionibacterium) species), Clostridium (Clostridium) species, liquid Martino My process (Actinomyces) species, Enterococcus (Enterococcus) is a member selected from the species, and Streptomyces (Streptomyces) species. In another exemplary embodiment, the bacterium is a gram-negative bacterium. In another exemplary embodiment, the gram-negative bacteria are Acinetobacter (Acinetobacter) species, Neisseria (Neisseria) species, Pseudomonas (Pseudomonas) species, brucellosis (Brucella) species, Agrobacterium (Agrobacterium) species, Bor having telra (Bordetella) species, Escherichia (Escherichia) species, Shigella (Shigella) species, Yersinia (Yersinia) species, Salmonella (Salmonella) species, keulrep when Ella (Klebsiella) species, Enterobacter (Enterobacter) species, Haemophilus (Haemophilus) species, paseuturel La (Pasteurella) species, Streptococcus, Bacillus (Streptobacillus) species, RY location deionized (spirochetal) species, Campylobacter (Campylobacter) species, Vibrio (Vibrio) species and Helicobacter a member selected from (Helicobacter) species to be. In another exemplary embodiment, the bacterium is Propionibacterium acnes ); Staphylococcus epidermidis (Staphylococcus epidermidis ); Staphylococcus ( Staphylococcus) saprophyticus ); Streptococcus pyogenes ); Streptococcus agalactiae ; Streptococcus pneumoniae (Streptococcus pneumoniae ); Enterococcus faecalis ); Enterococcus faecium ; Bacillus anthraquinone system (Bacillus anthracis ); Mycobacterium avium -intracellaré ( Mycobacterium avium - intracellulare ); Mycobacterium tuberculosis tuberculosis ); Acinetobacter Amantobacter baumanii ); Corynebacterium diphtheria ; Clostridium perfringens (Clostridium perfringens ); Clostridium botulinum (Clostridium botulinum ); Clostridium tetani ; Neisseria gonorrhoeae ); Neisseria Meningitidis meningitidis ); Nozawa rugi Pseudomonas (Pseudomonas aeruginosa); Legionella pneumophila (Legionella pneumophila ); Escherichia coli (Escherichia coli ); Yersinia pestis ; Haemophilus influenzae (Haemophilus influenzae ); Helicobacter pylori ); Campylobacter fetus ); Campylobacter jejuni jejuni ); Vibrio cholerae ; Vibrio parahemoritis ( Vibrio parahemolyticus ); Treponema pallidum ); Actinomyces israelii ; Rickettsia probazeki prowazekii ); Rickettsia rickettsii ; Chlamydia trachomatis ); Chlamydia psittaci ); Brucella abortus ; Agrobacterium tumefaciens tumefaciens ); And Francisella Toularensis tularensis ).

In an exemplary embodiment, the bacterium is an acidic bacterium, including mycobacterium species; Bacillus, including Bacillus species, Corynebacterium species (also Propionibacterium), and Clostridium species; Filamentous bacteria, including actinomyces species and streptomyces species; Pseudomonas, Brucella, Agrobacterium, Bordetella, Escherichia, Shigella, Yersinia, Salmonella, Klebsiella, Enterobacter, Haemophilus, Pasteurella and Strepto Bacilli, such as Bacillus spp .; Spiroketal species, campylobacter species, vibrio species; And intracellular bacteria, including Rickettsia spp. And chlamydia spp.

Compounds used in the present invention are active against a variety of bacterial organisms. These include Staphylococcus, for example Staphylococcus aureus ; Enterococcus, for example enterococcus paecalis; Streptococcus, for example Streptococcus pneumoniae; Haemophilus, for example Haemophilus influenza; Moraxella, for example M. catarrhalis ; And gram positive and gram negative aerobic and anaerobic bacteria, including Escherichia coli, for example Escherichia coli. The compounds used in the present invention are also active against mycobacterium, for example mycobacterium tuberculosis. The compounds used in the present invention are also active against intracellular microorganisms such as chlamydia and rickettsia. The compound used in the present invention may also, Mycoplasma (mycoplasma), for example, even for the active Mycoplasma pneumoniae (M. pneumoniae).

In addition, the compounds used in the present invention are resistant to β-lactam antibiotics such as Staphylococcus aureus, and other antibacterial agents such as methicillin, acrolides, aminoglycosides and lincosamide (multiple It is active against Staphylococcus coagulase negative strains such as Staphylococcus epidermidis. Thus, the compounds used in the present invention are useful for the treatment of MRSA, MRCNS, and MRSE. The compounds used in the present invention are also active against vancomycin resistant strains in the strains of Enterococcus paecalis, and are therefore used to treat infections associated with VRE organisms. In addition, the compounds used in the present invention are useful for the treatment of Staphylococcus organisms resistant to mupirocin.

In another exemplary embodiment, the bacterium is Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Tre Treponema species, Bulleidia species, Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptococcus ( Peptostreptococcus species, Peptostreptococcus species, Capnocytophaga species, Fusobacterium species, Porphyromonas species, and Bacteroides species. . In another exemplary embodiment, the bacterium is Actinobacillus actinomy -cetemcomitans ), Porphyromonas gingivalis ), Tannerella forsythesis forsythensis ), Prevotella intermedia , Eubacterium nodatum ), Treponema denticola ), Bulleidia extructa , Mosquitobacterium thymidum timidum ), Slackia exigua , Campylobacter rectus ), Eikenella corrodens corrodens ), Peptostrep- tococcus micros , Peptostreptococcus anaerobius , Capnocytophaga okrasea ochracea ), Fusobacterium nucleatum ), Porphyromonas asaccharolytica ) and Bacteroides forsythus . In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4-methylphenyl) borinic acid 3-hydroxy Sipicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole and 5- (4-cyanophenoxy) -1,3-dihydro-1 -Hydroxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane.

IV .c) How to include a virus

The compounds of the present invention are useful for treating diseases of both animals and humans, including viruses. In an exemplary embodiment, the microorganism is a virus. In an exemplary embodiment, the virus is ABC-type virus, human rhinovirus, yellow fever virus, human respiratory coronavirus, severe acute respiratory syndrome (SARS), respiratory syncytial virus, influenza virus, parainfluenza virus 1-4, human immunodeficiency Virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human cytomegalovirus (HCMV), varicella zoster Virus, Epstein-Barr (EBV), poliovirus, coxsackievirus, ecovirus, rubella virus, neuroderma-tropic virus, variola virus, papovirus, rabies virus, Dengue virus, West Nile virus. In another exemplary embodiment, the virus is picornaviridae , flaviviridae , coronaviridae , paramyxoviridae , orthomyxoviridae ), the retro birida (retroviridae), is a member selected from the herpes birida (herpesviridae) and Hepa and out the birida (hepadnaviridae). In another exemplary embodiment, the virus is a member selected from the viruses included in the table below.

virus Virus category Applicable Human Infection RNA  virus Picomaviridae Polio Hepatitis A Human Renovirus Togaviridae and Flaviviridae Lou Bella (Rubella) - Rubella Yellow Fever Coronaviridae Rhabdoviridae Human Respiratory Coronavirus (HCV) Severe Acute Respiratory Syndrome (SARS) Lyssavirus -Rabies Paramyxoviridae Orthomyxoviridae Paramyxovirus -Mumps Morbillvirus -Measles Pneumovirus -Respiratory syncytial virus Influenza AC Bunyaviridae Part Catania virus (Bunyavirus) - sounded yum Vera (Bunyamwera) (BUN) hantavirus (Hantavirus) - lament (Hantaan) (HTN) Age les virus (Nairevirus) - Crimean Congo haemorrhagic fever (CCHF) player Bo virus (Phlebovirus) - Sand Paris heat (SFN) Boo greater virus (Uukuvirus) - Boo Province Emmy (Uukuniemi) (UUK) Rift Valley heat (Rift Valley Fever ) (RVFN) Arena birida (Arenaviridae) Jyunin (Junin) - Argentine hemorrhagic fever Matthew Nkufo (Machupo) - Bolivian hemorrhagic fever Lhasa (Lassa) - Lhasa column (Lassa fever) LCM -Aseptic Lymphoblastic Choroiditis Leobiridae ( Reoviridae ) Rotovirus Reovirus Orbivirus Retroviridae Human Immunodeficiency Virus 1 (HIV-1) Human Immunodeficiency Virus 2 (HIV-2) Simian Immunodeficiency Virus (SIV) DNA  virus Papovaviridae Adenoviridae Parvoviridae Pediatric Virus in the Kidney Human Respiratory Distress and Some Heart Ophthalmological Infections Human Gastrointestinal Distress (Norwalk Virus) Herpesviridae ( Herpesviridae ) Foxviridae ( Poxviridae ) Herpes simplex virus 1 (HSV-1) Herpes simplex virus 2 (HSV-2) Human cytomegalovirus (HCMV) Varicella zoster virus (VZV) Epstein-Barr virus (EBV) Human herpes virus 6 (HHV6) Orthopox virus It is a child of smallpox. Hepadnaviridae Hepatitis B Virus (HBV) Hepatitis C Virus (HCV)

IV .d) How to treat a disease that includes parasites

The compounds of the present invention are useful for treating diseases of both animals and humans with parasites, including protozoa and worms. Examples of such parasitic species include in particular ent amoeba (Entamoeba), Lai sh mania (Leishmania), toxoplasmosis (Toxoplasma), tree key Nella (Trichinella) and ski testosterone dressage (Schistosoma). In an exemplary embodiment, the parasite flasks modium arm Shifa room (Plasmodium falciparum), non-plasminogen modium box (P. vivax), plasminogen modium Ovalle (P. ovale), plasminogen modium malaria (P. malariae), plasminogen modium P. berghei, Leishmania donovani ), Leishmania Inpantum ( L. infantum ), Leishmania Chagasi ( L. chagasi ), Leishmania Mexicana ( L. mexicana ), Leishmania amazonensis ( L. amazonensis ) Shimanian Venezuelensis ( L. venezuelensis ), Leishmania Tropics ( L. tropics ), Leishmania Major ( L. major ), Leishmania Minor ( L. minor ), Leishmania Ethiopica ( L . aethiopica), Lai sh mania Viana Brazil Li N-Sys (Biana L. braziliensis), Lai sh mania (V) guya norbornene system (L. (V.) guyanensis), Lai sh mania (V) wave or filament sheath (L. ( V.) panamensis ), Laishmania (V) Peruviana ( L. (V.) peruviana ), Tripanosoma brucei rhodesiens ( Tripanosoma brucei) rhodesiense ), T. brucei gambiense , T. cruzi , T. cruzi , Giardia intestinalis intestinalis ), Girard lambda ( G. lambda ), Toxoplasma gondii ), Entamoeba histolytica ), Trichomonas vaginalis ), Pneumocystis carinii , and Cryptosporidium parvum ). In an exemplary embodiment, the diseases caused by the parasites are malaria, Chagas' disease, lysmaniasis, African sleeping sickness (African human tripanosoma), flagellosis, toxoplasmosis, amoebiasis and cryptospores Member selected from iridiumosis.

V. How to treat or prevent periodontal disease

In another aspect, the present invention relates to a method of treating or preventing periodontal disease, or both. The method comprises administering to the animal a therapeutically effective amount of a compound of the invention. In an exemplary embodiment, the compound is a member selected from the boron-containing compounds described herein that are sufficient to treat or prevent the disease. In an exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4-methylphenyl) borinic acid 3-hydroxypicoli Nate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydro Is a member selected from Roxy-2,1-benzoxaborole. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane. In another exemplary embodiment, the animal is human, cow, deer, reindeer, goat, bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, Ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. In another exemplary embodiment, the animal is a human. In another exemplary embodiment, the animal is a member selected from humans, cows, goats, pigs, sheep, horses, cows, bulls, dogs, guinea pigs, gerbils, rabbits, cats, chickens, and turkeys. In another exemplary embodiment, the infection is a member selected from gingivitis, periodontitis or juvenile / acute periodontitis.

The invention is further illustrated by the following examples. These examples are not intended to define or limit the scope of the invention.

General : Melting points were obtained using Mel-Temp-II melting point apparatus and are not calibrated. ¹ H NMR spectra were recorded on an Oxford 300 (300 MHz) spectrometer (Varian). Mass spectra were measured on API 3000 (Applied Bio-systems). Purity (relative area) by HPLC was performed on ProStar Model 330 (PDA detector, Varian), Model 210 (pump, Varian) and BetaBasic-18 4.6 × 150 mm column (Thermo Electron Corporation). Using, measured at 220 nm using a linear gradient of 0-100% MeCN in 0.01% H ₃ PO ₄ over 10 minutes followed by 100% MeCN for an additional 10 minutes.

Example  One

Preparation of 3 from 1

1.1 Carboxylic acid  restoration

To a solution of 1 (23.3 mmol) in dry THF (70 mL) under nitrogen was added dropwise BH ₃ THF solution (1.0 M, 55 mL, 55 mmol) at 0 ° C. and the reaction mixture was stirred at rt overnight. The mixture was then cooled again using an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH ₃ . The resulting mixture was stirred until no foam was released, then 10% NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue after rotary evaporation was purified by flash column chromatography on silica gel to give 20.7 mmol of 3 .

1.2 result

Exemplary compounds of formula 3 prepared by the above methods are given below.

1.2.a 2- Bromo -5- Chlorobenzyl Alcohol

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.57 (d, J = 8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J = 6.0 Hz, 1H) and 4.46 (d, J = 6.0 Hz, 2H) ppm.

1.2.b 2- Bromo -5-methoxybenzyl Alcohol

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.42 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.77 (dd, J ₁ = 3 Hz, J ₂ = 3 Hz, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.44 (d, J = 5.1 Hz, 2H), 3.76 (s, 3H).

Example  2

Preparation of 2 from 3

2.1 Reduction of aldehydes

To a solution of 2 (Z = H, 10.7 mmol) in methanol (30 mL) was added sodium borohydride (5.40 mol) and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 9.9 mmol 3 .

2.2 result

Exemplary compounds of formula 3 prepared by the above methods are given below.

2.2.a 2- Bromo -5- (4- Cyanophenoxy )benzyl Alcohol

¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) 2.00 (br s, 1H), 4.75 (s, 2H), 6.88 (dd, J = 8.5, 2.9 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H).

2.2.b 2- Bromo -4- (4- Cyanophenoxy )benzyl Alcohol

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.83 (d, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 7.18 (dd, 1H), 7.11 (d, 2H), 5.48 (t, 1H) and 4.50 (d, 2H) ppm.

2.2.c 5- (4- Cyanophenoxy )-One- Indanol

Mp 50-53 ° C. MS (ESI < + >): m / z = 252 (M + l). HPLC: 99.7% purity at 254 nm and 99.0% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.80 (d, 2H), 7.37 (d, 1H), 7.04 (d, 2H), 6.98-6.93 (m, 2H), 5.27 (d, 1H) , 5.03 (q, 1H), 2.95-2.85 (m, 1H), 2.75-2.64 (m, 1H), 2.39-2.29 (m, 1H) and 1.85-1.74 (m, 1H) ppm.

2.2.d 2- Bromo -5- ( tert - Butyldimethylsiloxy )benzyl Alcohol

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s, 1H), 6.65 (dd, J = 8.2, 2.6 Hz, 1H) , 6.98 (d, J = 2.9 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H).

Further examples of compounds that can be produced by this method include 2-bromo-4- (3-cyanophenoxy) benzyl alcohol; 2-bromo-4- (4-chlorophenoxy) benzyl alcohol; 2-bromo-4-phenoxybenzyl alcohol; 2-bromo-5- (3,4-dicyanophenoxy) benzyl alcohol; 2- (2-bromo-5-fluorophenyl) ethyl alcohol; 2-bromo-5-fluorobenzyl alcohol; And 1-bromo-2-naphthalenemethanol.

Example  3

Preparation of 3 to 4

3.1 Protective  Alkylation

Compound 3 (20.7 mmol) was dissolved in CH ₂ Cl ₂ (150 mL) and cooled to 0 ° C. using an ice bath. To this solution was added sequentially N, N-diisopropyl ethyl amine (5.4 mL, 31.02 mmol, 1.5 eq) and chloromethyl methyl ether (2 mL, 25.85 mmol, 1.25 eq) under nitrogen. The reaction mixture was stirred at rt overnight, washed with NaHCO ₃ -saturated water and then with NaCl-saturated water. The residue after rotary evaporation was purified by flash column chromatography on silica gel to give 17.6 mmol of 4 .

3.2 result

Exemplary compounds of formula 4 prepared by the above methods are given below.

3.2.a 2- Bromo -5- Chloro -One-( Methoxy methoxymethyl )benzene

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.63 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 2.4 and 0.6 Hz, 1H), 7.32 (dd, J = 8.4 and 2.4 Hz , 1H), 4.71 (s, 2H), 4.53 (s, 2H) and 3.30 (s, 3H) ppm.

3.2.b 2- Bromo -5- Fluoro -1- [1- ( Methoxy methoxy ) Ethyl] benzene

¹ H-NMR (300.058 MHz, CDCl ₃ ) δ ppm 1.43 (d, J = 6.5 Hz, 3H), 3.38 (s, 3H), 4.55 (d, J = 6.5 Hz, 1H), 4.63 (d, J = 6.5 Hz, 1H), 5.07 (q, J = 6.5 Hz, 1H), 6.85 (m, 1H), 7.25 (dd, J = 9.7, 2.6 Hz, 1H), 7.46 (dd, J = 8.8, 5.3 Hz, 1H).

3.2.c 2- Bromo -5- Fluoro -1- [2- ( Methoxy methoxy ) Ethyl] benzene

¹ H-NMR (300.058 MHz, CDCl ₃ ) δ ppm 3.04 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 4.62 (s, 2H) , 6.82 (td, J = 8.2, 3.2 Hz, 1H), 7.04 (dd, J = 9.4, 2.9 Hz, 1H), 7.48 (dd, J = 8.8, 5.3 Hz, 1H).

3.2.d 2- Bromo -4,5- Difluoro -One-( Methoxy methoxymethyl )benzene

¹ H-NMR (300.058 MHz, CDCl ₃ ) δ ppm 3.42 (s, 3H), 4.57 (d, J = 1.2 Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H).

3.2.e 2- Bromo -5- Cyano -One-( Methoxy methoxymethyl )benzene

¹ H-NMR (300.058 MHz, CDCl ₃ ) δ ppm 3.43 (s, 3H), 4.65 (s, 2H), 4.80 (s, 2H), 7.43 (dd, J = 8.2, 4.1 Hz, 1H), 7.66 ( d, J = 8.2 Hz, 1H), 7.82 (d, J = 4.1 Hz, 1H).

3.2.f 2- Bromo -5- Methoxy -One-( Methoxy methoxymethyl )benzene

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.48 (dd, J ₁ = 1.2 Hz, J ₂ = 1.2 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.83 (dd, J ₁ = 3 Hz, J ₂ = 3 Hz, 1H), 4.69 (d, J = 1.2 Hz, 2H), 4.5 (s, 2H), 3.74 (d, J = 1.5 Hz, 1H), 3.32 (d, J = 2.1 Hz, 3H) ppm.

3.2.g 1-benzyl-1- (2- Bromophenyl )-One-( Methoxy methoxy )ethane

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.70-7.67 (m, 1H), 7.25-7.09 (m, 6H), 6.96-6.93 (m, 2H), 4.61 (d, 1H), 4.48 ( d, 1H), 3.36-3.26 (m, 2H), 3.22 (s, 3H) and 1.63 (s, 3H) ppm.

3.2.h 2- Bromo -6- Fluoro -One-( Methoxy methoxymethyl )benzene

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.43 (s, 3H), 4.74 (s, 2H), 4.76 (d, J = 2.1 Hz, 2H), 7.05 (t, J = 9.1 Hz, 1H), 7.18 (td, J = 8.2, 5.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H).

3.2.i 2- Bromo -4- (4- Cyanophenoxy )-One-( Methoxy methoxymethyl )benzene

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.84 (d, 2H), 7.56 (d, 1H), 7.44 (d, 1H), 7.19-7.12 (m, 3H), 4.69 (s, 2H) , 4.56 (s, 2H) and 3.31 (s, 3H) ppm.

3.2.j 2- Bromo -5- ( tert - Butyldimethylsiloxy )-One-( Methoxy methoxymethyl )benzene

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.19 (s, 6H), 0.98 (s, 9H), 3.43 (s, 3H), 4.59 (s, 2H), 4.75 (s, 2H), 6.64 (dd, J = 8.5, 2.9 Hz, 1H), 6.98 (d, J = 2.9 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H).

3.2.k 2- Bromo -5- (2- Cyanophenoxy )-One-( Methoxy methoxymethyl )benzene

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.41 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J = 7.6, 0.9 Hz, 1H), 7.28 (d, J = 2.9 Hz, 1H), 7.49 (ddd, J = 8.8, 7.6, 1.8 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 7.9, 1.8 Hz, 1H).

3.2.l 2- Bromo -5- Phenoxy -One-( Methoxy methoxymethyl )benzene

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.40 (s, 3H), 4.62 (s, 2H), 4.74 (s, 2H), 6.80 (dd, J = 8.8, 2.9 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 7.12 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.48 ( d, J = 8.5 Hz, 1H).

Further examples of compounds that can be produced by this method include 2-bromo-1- (methoxymethoxymethyl) benzene; 2-bromo-5-methyl-1- (methoxymethoxymethyl) benzene; 2-bromo-5- (methoxymethoxymethyl) -1- (methoxymethoxymethyl) benzene; 2-bromo-5-fluoro-1- (methoxymethoxymethyl) benzene; 1-bromo-2- (methoxymethoxymethyl) naphthalene; 2-bromo-4-fluoro-1- (methoxymethoxymethyl) benzene; 2-phenyl-1- (2-bromophenyl) -1- (methoxymethoxy) ethane; 2-bromo-5- (4-cyanophenoxy) -1- (methoxymethoxymethyl) benzene; 2-bromo-4- (3-cyanophenoxy) -1- (methoxymethoxymethyl) benzene; 2-bromo-4- (4-chlorophenoxy) -1- (methoxymethoxymethyl) benzene; 2-bromo-4-phenoxy-1- (methoxymethoxymethyl) benzene; 2-bromo-5- (3,4-dicyanophenoxy) -1- (methoxymethoxymethyl) benzene is included.

Example  4

Preparation of I via 4 to 5

4.1. Metallization  And Voronylation

To a solution of 4 (17.4 mmol) in anhydrous THF (80 mL) was added dropwise tert-BuLi or n-BuLi (11.7 mL) at −78 ° C. under nitrogen and the solution turned brown. Then B (OMe) ₃ (1.93 mL, 17.3 mmol) was injected at once and the cooling bath was removed. The mixture was allowed to warm slowly with stirring for 30 minutes and then stirred for 2 hours in a water bath. After addition of 6 N HCl (6 mL), the mixture was stirred at rt overnight and about 50% hydrolysis occurred as indicated by TLC analysis. The solution was rotary evaporated and the residue was dissolved in MeOH (50 mL) and 6 N HCl (4 mL). The solution was refluxed for 1 hour and the hydrolysis was complete as indicated by TLC analysis. Rotary evaporation gave a residue, which was dissolved in EtOAc, washed with water and then evaporated. The crude product was purified by flash column chromatography on silica gel to give a solid with 80% purity. The solid was further purified by washing with hexanes to give 7.2 mmol of I.

4.2 result

Analytical data for exemplary compounds of Formula I are provided below.

4.2.a 5- Chloro -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

5-Chlorobenzo [c] [1,2] oxaborole-1 (3H) -ol ( C1 )

Mp 142-150 ° C. MS (ESI): m / z = 169 (M + 1, positive) and 167 (M-1, negative). HPLC (220 nm): 99% purity. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.30 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H ) And 4.96 (s, 2H) ppm.

4.2.b 1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

Benzo [c] [1,2] oxaborole-1 (3H) -ol ( C2 )

Mp 83-86 ° C. MS (ESI): m / z = 135 (M + 1, positive) and 133 (M-1, negative). HPLC (220 nm): 95.4% purity. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.14 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H) and 4.97 (s, 2H) ppm.

4.2.c 5- Chloro -3- Methylbenzo [c] [1,2] oxaborole -1 (3H) -ol ( C3 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.37 (d, J = 6.4 Hz, 3H), 5.17 (q, J = 6.4 Hz, 1H), 7.14 (m, 1H), 7.25 (dd, J = 9.7, 2.3 Hz, 1H), 7.70 (dd, J = 8.2, 5.9 Hz, 1H), 9.14 (s, 1H).

4.2.d 6- Fluoro -One- Hydroxy -1,2,3,4- Tetrahydro -2,1- Benzoxaborin

6-fluoro-3,4-dihydrobenzo [c] [1,2] oxavorinin-1-ol ( C4 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.86 (t, J = 5.9 Hz, 2H), 4.04 (t, J = 5.9 Hz, 2H), 7.0-7.1 (m, 2H), 7.69 ( dd, J = 8.2, 7.2 Hz, 1H), 8.47 (s, 1H).

4.2.e 5,6- Difluoro -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

5,6-difluorobenzo [c] [1,2] oxaborole-1 (3H) -ol ( C5 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm 4.94 (s, 2H), 7.50 (dd, J = 10.7, 6.8 Hz, 1H), 7.62 (dd, J = 9.7, 8.2 Hz, 1H), 9.34 (s, 1 H).

4.2.f 5- Cyano -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-carbonitrile ( C6 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm 5.03 (s, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 9.53 (s, 1H).

4.2.g 1,3- Dehydro -One- Hydroxy -5- Methoxy -2,1- Benzoxaborole

5-methoxybenzo [c] [1,2] oxaborole-1 (3H) -ol ( C7 )

Mp 102-104 ° C. MS ESI: m / z = 165.3 (M + 1) and 162.9 (M-1). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.95 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H ), 4.91 (s, 2H), 3.77 (s, 3H) ppm.

4.2.h 1,3- Dehydro -One- Hydroxy -5- methyl -2,1- Benzoxaborole

5-Methylbenzo [c] [1,2] oxaborole-1 (3H) -ol ( C8 )

Mp 124-128 ° C. MS ESI: m / z = 148.9 (M + 1) and 146.9 (M-1). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.05 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 7.2 Hz, 2H ), 4.91 (s, 2H), 2.33 (s, 3H) ppm.

4.2.i 1,3- Dehydro -One- Hydroxy -5- Hydroxymethyl -2,1- Benzoxaborole

5- (hydroxymethyl) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C9 )

MS: m / z = 163 (M-1, ESI-). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.08 (s, 1H), 7.64 (d, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 5.23 (t, 1H), 4.96 (s, 2H), 4.53 (d, 2H) ppm.

4.2.j 1,3- Dehydro -5- Fluoro -One- Hydroxy -2,1- Benzoxaborole

5-fluorobenzo [c] [1,2] oxaborole-1 (3H) -ol ( C10 )

Mp 110-114 ° C. MS ESI: m / z = 150.9 (M-1). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.20 (s, 1H), 7.73 (dd, J ₁ = 6 Hz, J ₂ = 6 Hz, 1H), 7.21 (m, 1H), 7.14 (m , 1H), 4.95 (s, 2H) ppm.

4.2.k 1,3- Dehydro -2-oxa-1- Cyclopenta [α] naphthalene

Naphtho [1,2-c] [1,2] oxaborole-1 (3H) -ol ( C11 )

Mp 139-143 ° C. MS ESI: m / z = 184.9 (M + l). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.21 (s, 1H), 8.28 (dd, J ₁ = 6.9 Hz, J ₂ = 0.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H ), 7.95 (d, J = 7.5 Hz, 1H), 7.59-7.47 (m, 3H), 5.09 (s, 2H) ppm.

4.2.m 1,3- Dehydro -6- Fluoro -One- Hydroxy -2,1- Benzoxaborole

6-fluorobenzo [c] [1,2] oxaborole-1 (3H) -ol ( C13 )

Mp 110-117.5 ° C. MS (ESI): m / z = 151 (M-1, negative). HPLC (220 nm): 100% purity. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.29 (s, 1H), 7.46-7.41 (m, 2H), 7.29 (td, 1H) and 4.95 (s, 2H) ppm.

4.2.n 3-benzyl-1,3- Dehydro -One- Hydroxy -3- methyl -2,1- Benzoxaborole

3-benzyl-3-methylbenzo [c] [1,2] oxaborole-1 (3H) -ol ( C14 )

MS (ESI): m / z = 169 (M + l, positive). HPLC: 99.5% purity at 220 nm and 95.9% at 254 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.89 (s, 1H), 7.49-7.40 (m, 3H), 7.25-7.19 (m, 1H), 7.09-7.05 (m, 3H), 6.96- 6.94 (m, 2H), 3.10 (d, 1H), 3.00 (d, 1H) and 1.44 (s, 3H) ppm.

4.2.o 3-benzyl-1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

3-benzylbenzo [c] [1,2] oxaborole-1 (3H) -ol ( C15 )

MS (ESI < + >): m / z = 225 (M + l). HPLC: 93.4% purity at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.08 (s, 1H), 7.63 (dd, 1H), 7.43 (t, 1H), 7.35-7.14 (m, 7H), 5.38 (dd, 1H) , 3.21 (dd, 1H) and 2.77 (dd, 1H) ppm.

4.2.p 1,3- Dehydro -4- Fluoro -One- Hydroxy -2,1- Benzoxaborole

4-fluorobenzo [c] [1,2] oxaborole-1 (3H) -ol ( C16 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.06 (s, 2H), 7.26 (ddd, J = 9.7, 7.9, 0.6 Hz, 1H), 7.40 (td, J = 8.2, 4.7 Hz , 1H), 7.55 (d, J = 7.0 Hz, 1H), 9.41 (s, 1H).

4.2.q 5 -(4- Cyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) benzonitrile ( C17 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.95 (s, 2H), 7.08 (dd, J = 7.9, 2.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 9.1 Hz, 2H), 9.22 (s, 1H).

4.2.r 6- (4- Cyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-6-yloxy) benzonitrile ( C18 )

Mp 148-151 ° C. MS: m / z = 252 (M + 1) (ESI < + >) and m / z = 250 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.7% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.26 (s, 1H), 7.82 (d, 2H), 7.50 (d, 1H), 7.39 (d, 1H), 7.26 (dd, 1H), 7.08 (d, 2H) and 4.99 (s, 2H) ppm.

4.2.s 6- (3- Cyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

3- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-6-yloxy) benzonitrile ( C19 )

Mp 146-149 ° C. MS: m / z = 252 (M + 1) (ESI < + >) and m / z = 250 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 97.9% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.21 (s, 1H), 7.60-7.54 (m, 2H), 7.50-7.45 (m, 2H), 7.34-7.30 (m, 2H), 7.23 ( dd, 1H) and 4.98 (s, 2H) ppm.

4.2.t 6- (4- Chlorophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6- (4-chlorophenoxy) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C20 )

Mp 119-130 ° C. MS: m / z = 261 (M + 1) (ESI < + >) and m / z = 259 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.9% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.18 (s, 1H), 7.45-7.41 (m, 3H), 7.29 (d, 1H), 7.19 (dd, 1H), 7.01 (d, 2H) And 4.96 (s, 2H) ppm.

4.2.u 6- Phenoxy -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6-phenoxybenzo [c] [1,2] oxaborole-1 (3H) -ol ( C21 )

Mp 95-99 ° C. MS: m / z = 227 (M + 1) (ESI < + >) and m / z = 225 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.4% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.17 (s, 1H), 7.43-7.35 (m, 3H), 7.28 (s, 1H), 7.19-7.09 (m, 2H), 6.99 (d, 2H) and 4.96 (s, 2H) ppm.

4.2.v 5- (4- Cyanobenzyloxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

4-((1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) methyl) benzonitrile ( C22 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.90 (s, 2H), 5.25 (s, 2H), 6.98 (dd, J = 7.9, 2.1 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 9.01 (s, 1H).

4.2.w 5- (2- Cyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

2- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) benzonitrile ( C23 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.95 (s, 2H), 7.0-7.2 (m, 3H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.68 (ddd , J = 9.1, 7.6, 1.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.91 (dd, J = 7.9, 1.8 Hz, 1H).

4.2.x 5- Phenoxy -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

5-phenoxybenzo [c] [1,2] oxaborole-1 (3H) -ol ( C24 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.91 (s, 2H), 6.94 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 7.6 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H), 7.70 (d, J = 8.5 Hz, 1H), 9.11 (s, 1H).

4.2.y 5- [4- (N, N- Diethylcarbonyl ) Phenoxy ] -1,3- Dehydro -One- Hydroxy -2,1-ben Zoksa Borol

N, N-diethyl-4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) benzonitrile ( C25 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.08 (br s, 6H), 3.1-3.5 (m, 4H), 4.93 (s, 2H), 7.0-7.1 (m, 4H), 7.37 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.9 Hz, 1H), 9.15 (s, 1H).

4.2.z 1,3- Dehydro -One- Hydroxy -5- [4- ( Morpholinocarbonyl ) Phenoxy ] -2,1-ben Zoksa Borol

(4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) phenyl) (morpholino) methanone ( C26 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.3-3.7 (m, 8H), 4.93 (s, 2H), 7.0-7.1 (m, 4H), 7.44 (d, J = 8.8 Hz , 2H), 7.73 (d, J = 7.9 Hz, 1H), 9.16 (s, 1H).

4.2. aa 5- (3,4- Dicyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) phthalonitrile ( C27 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.97 (s, 2H), 7.13 (dd, J = 7.9, 2.1 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 7.43 (dd, J = 8.8, 2.6 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 9.26 (s, 1 H).

4.2. ab 6- Phenylthio -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6- (phenylthio) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C28 )

Mp 121-124 ° C. MS: m / z = 243 (M + l) (ESI < + >) and m / z = 241 (M-1) (ESI-). HPLC: 99.6% purity at 254 nm and 99.6% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.25 (s, 1H), 7.72 (dd, 1H), 7.48 (dd, 1H), 7.43 (dd, 1H), 7.37-7.31 (m, 2H) , 7.29-7.23 (m, 3H) and 4.98 (s, 2H) ppm.

4.2. ac 6- (4- Trifluoromethoxyphenoxy ) -1,3- Dehydro -One- Hydroxy -2,1-ben Zoksa Borol

6- (4- (trifluoromethoxy) phenoxy) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C29 )

Mp 97-101 ° C. MS: m / z = 311 (M + l) (ESI < + >) and m / z = 309 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 100% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.20 (s, 1H), 7.45 (d, 1H), 7.37 (d, 2H), 7.33 (d, 1H), 7.21 (dd, 1H), 7.08 (d, 2H) and 4.97 (s, 2H) ppm.

4.2. ad 5- (N- methyl -N- Phenylsulfonylamino ) -1,3- Dehydro -One- Hydroxy -2,1-ben Zoksa Borol

N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxabolol-5-yl) -N-methylbenzenesulfonamide ( C30 )

Mp 85-95 ° C. MS: m / z = 304 (M + l) (ESI < + >) and m / z = 302 (M-1) (ESI-). HPLC: 96.6% purity at 254 nm and 89.8% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.23 (s, 1H), 7.72-7.63 (m, 2H), 7.56 (t, 2H), 7.50 (d, 2H), 7.16 (s, 1H) , 7.03 (d, 1H), 4.91 (s, 2H) and 3.14 (s, 3H) ppm.

4.2. ae 6- (4- Methoxyphenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6- (4-methoxyphenoxy) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C31 )

Mp 126-129 ° C. MS: m / z = 257 (M + 1) (ESI < + >) and m / z = 255 (M-1) (ESI-). HPLC: 98.4% purity at 254 nm and 98.4% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.14 (s, 1H), 7.36 (d, 1H), 7.19 (s, 1H), 7.12 (d, 1H), 6.98 (d, 2H), 6.95 (d, 2H), 4.93 (s, 2H) and 3.73 (s, 3H) ppm.

4.2. af 6- (4- Methoxyphenylthio ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6- (4-methoxyphenylthio) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C32 )

Mp 95-100 ° C. MS: m / z = 272 (M < + >), 273 (M + 1) (ESI < + >) and m / z = 271 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 99.2% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.20 (s, 1H), 7.51 (d, 1H), 7.39-7.28 (m, 4H), 6.98 (d, 2H), 4.93 (s, 2H) And 3.76 (s, 3 H) ppm.

4.2. ag 6- (4- Methoxyphenylsulfonyl ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6- (4-methoxyphenylsulfonyl) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C33 )

Mp 180-192 ° C. MS: m / z = 305 (M + 1) (ESI < + >) and m / z = 303 (M-1) (ESI-). HPLC: 96.8% purity at 254 nm and 95.5% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.46 (s, 1H), 8.28 (s, 1H), 7.99 (d, 1H), 7.85 (d, 2H), 7.61 (d, 1H), 7.11 (d, 2H), 5.02 (s, 2H) and 3.80 (s, 3H) ppm.

4.2. ah 6- (4- Methoxyphenylsulfinyl ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

6- (4-methoxyphenylsulfinyl) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C34 )

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.37 (s, 1H), 8.02 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 2H), 7.53 (d, 1H), 7.07 (d, 2H), 5.00 (s, 2H) and 3.76 (s, 3H) ppm.

4.2. ai 5- Trifluoromethyl -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

5- (trifluoromethyl) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C35 )

Mp 113-118 ° C. MS: m / z = 203 (M + 1) (ESI < + >) and m / z = 201 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 100% at 220 nm. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.48 (s, 1H), 7.92 (d, 1H), 7.78 (s, 1H), 7.67 (d, 1H) and 5.06 (s, 2H) ppm.

4.2. aj 4- (4- Cyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxabolol-4-yloxy) benzonitrile ( C36 )

For coupling reactions between 4-fluorobenzonitrile and substituted phenols to provide starting material 2 , see Igarashi, S. et. al ., Chemical & Pharmaceutical Bulletin (2000), 48 (11), 1689-1697.

¹ H-NMR (300 MHz, DMSO-d ₆ ) (ppm) 4.84 (s, 2H), 7.08 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 7.9 Hz, 1H), 7.45 (t , J = 7.3 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.5 Hz, 2H).

4.2. ak 5- (3- Cyanophenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

3- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) benzonitrile ( C37 )

For coupling reactions between 3-fluorobenzonitrile and substituted phenols to provide starting material 2 , see Li, F. et. al ., Organic Letters (2003), 5 (12), 2169-2171.

¹ H-NMR (300 MHz, DMSO-d ₆ ) (ppm) 4.93 (s, 2H), 7.0-7.1 (m, 2H), 7.3-7.4 (m, 1H), 7.5-7.7 (m, 3H), 7.75 (d, J = 8.2 Hz, 1H).

4.2. al 5- (4- Carboxyphenoxy ) -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole

4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-5-yloxy) benzoic acid ( C38 )

To a solution of 5- (4-cyanophenoxy) -1-hydroxy-2,1-benzoxaborole (430 mg, 1.71 mmol) obtained at C17 in ethanol (10 mL), 6 mol / L sodium hydroxide ( 2 ml) was added and the mixture was refluxed for 3 hours. Hydrochloric acid (6 mol / L, 3 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) and then triturated with diisopropyl ether to give the target compound (37 mg, 8%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.94 (s, 2H), 7.0-7.1 (m, 4H), 7.76 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 9.19 (s, 1H), 12.8 (br s, 1H).

4.2. am One- Hydroxy -1,3- Dehydro -5- [4- ( Tetrazole -1 day) Phenoxy ] -2,1-benzoxaborole

5- (4- (1H-tetrazol-5-yl) phenoxy) benzo [c] [1,2] oxaborole-1 (3H) -ol ( C39 )

5- (4-cyanophenoxy) -1-hydroxy-2,1-benzoxaborole (200 mg, 0.797 mmol) in N, N-dimethylformamide (5 mL), sodium azide (103 mg, 1.59 mmol) and ammonium chloride (85 mg, 1.6 mmol) were stirred at 80 ° C. for 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) and then triturated with ethyl acetate to give the target compound (55 mg, 23%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.95 (s, 2H), 7.0-7.1 (m, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 9.18 (br s, 1H).

Example  5

Preparation of I via 2 to 6

5.1 Catalytic Voronylation , Reduction and Closure

2 (10.0 mmol) in 1,4-dioxane (40 mL), bis (pinacolato) diboron (2.79 g, 11.0 mmol), PdCl ₂ (dppf) (250 mg, 3 mol%) and potassium acetate ( 2.94 g, 30.0 mmol) was stirred at 80 ° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was dissolved in tetrahydrofuran (80 mL) and then sodium periodate (5.56 g, 26.0 mmol) was added. After stirring for 30 minutes at room temperature, 2 N HCl (10 mL) was added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ether to yield 6.3 mmol of the corresponding boronic acid. To a solution of boronic acid (0.595 mmol) obtained in methanol (5 mL) was added sodium borohydride (11 mg, 0.30 mmol) and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 0.217 mmol of I.

5.2 result

Analytical data for exemplary compounds of Formula I are presented below.

5.2.a 1,3- Dehydro -5- Fluoro -One- Hydroxy -2,1- Benzoxaborole ( C10 )

Analytical data for this compound is presented in 4.2.j.

Example  6

Preparation of I from 3

6.1 Single-container ( one - pot ) Voronylation  And Closure

To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35 mL, 5.86 mmol) in tetrahydrofuran (10 mL) n-butyllithium (1.6 mol / L in hexane over 15 minutes at -78 ° C under nitrogen atmosphere) , 6.7 mL, 10.7 mmol) was added dropwise and the mixture was stirred for 2 hours while warming to room temperature. The reaction was deactivated with 2 N HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography and treated with pentane to give 0.41 mmol of I.

6.2 result

Analytical data for exemplary compounds of Formula I are presented below.

6.2.a 1,3- Dehydro -5- Fluoro -One- Hydroxy -2,1- Benzoxaborole ( C10 )

Analytical data for this compound is presented in 4.2.j.

Example  7

Preparation of I from 3

7.1 Single-vessel by distillation Voronylation  And Closure

To a solution of 3 (4.88 mmol) in toluene (20 mL) was added triisopropyl borate (2.2 mL, 9.8 mmol) and the mixture was heated at reflux for 1 h. Solvent, resulting isopropyl alcohol and excess triisopropyl borate were removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and cooled to -78 ° C. n-butyllithium (3.2 mL, 5.1 mmol) was added dropwise over 10 minutes and the mixture was stirred for 1 hour while warming to room temperature. The reaction was deactivated with 2 N HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 1.54 mmol of I.

7.2 result

Analytical data for exemplary compounds of Formula I are presented below.

7.2.a 1,3- Dehydro -5- Fluoro -One- Hydroxy -2,1- Benzoxaborole ( C10 )

Analytical data for this compound is presented in 4.2.j.

Example  8

Preparation of 7 to 8

8.1 Bromination

To a solution of 7 (49.5 mmol) in carbon tetrachloride (200 mL) was added N-bromosuccinimide (8.81 g, 49.5 mmol) and N, N-azoisobutylonitrile (414 mg, 5 mol%), The mixture was heated at reflux for 3 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford crude methyl-brominated intermediate 8 .

Example  9

Preparation of 3 from 8

9.1 Hydroxylation

To crude 8 (49.5 mmol) was added dimethylformamide (150 mL) and sodium acetate (20.5 g, 250 mmol) and the mixture was stirred at 80 ° C. overnight. Water was added and the mixture was extracted with ether. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added methanol (150 mL) and 1 N sodium hydroxide (50 mL) and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated to about 1/3 the volume under reduced pressure. Water and hydrochloric acid were added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography and triturated with dichloromethane to give 21.8 mmol of 3 .

9.2 result

Exemplary compounds of formula 3 prepared by the above methods are given below.

9.2.a 2- Bromo -5- Cyanobenzyl Alcohol

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ ppm 4.51 (d, J = 5.9 Hz, 2H), 5.67 (t, J = 5.6 Hz, 1H), 7.67 (dd, J = 8.2, 2.0 Hz, 1H), 7.80 (s, J = 8.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H).

Further examples of compounds that can be produced by this method include 2-bromo-5- (4-cyanophenoxy) benzyl alcohol.

Example  10

Preparation of 2 to 9

10.1 reaction

A mixture of 2 (20.0 mmol), (methoxymethyl) triphenylphosphonium chloride (8.49 g, 24.0 mmol) and potassium tert-butoxide (2.83 g, 24.0 mol) in N, N-dimethylformamide (50 mL) Was stirred at rt overnight. The reaction was deactivated with 6 N HCl and the mixture was extracted with ethyl acetate. The organic layer was washed with water (× 2) and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Tetrahydrofuran (60 mL) and 6 N HCl were added to the residue and the mixture was heated under reflux for 8 h. Water was added and the mixture was extracted with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 16.6 mmol of 9 .

Example  11

Manufacturing method of step 13

11.1 reaction

A solution of I in a suitable alcohol solvent (R ¹ -OH) was refluxed under a nitrogen atmosphere and then distilled to remove the alcohol and to yield the corresponding ester.

Example  12

Ia from Ib Manufacture

12.1 reaction

Amino alcohol was added to a solution of Ia in toluene and the precipitated solid was collected to give Ib .

12.2 result

(500 mg, 3.3 mmol) was dissolved in toluene (37 mL) at 80 ° C. Ethanolamine (0.20 mL, 3.3 mmol) was added. The mixture was cooled to room temperature in an ice bath and then filtered to give C40 as a white powder (600.5 mg, 94%).

12.2.a 1,3- Dehydro -5- Fluoro -One- Hydroxy -2,1- Benzoxaborole Ethanolamine  Adjunct ( C40 )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.88 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.66 (s, 2H), 5.77 ( br, 2H), 6.85-6.91 (m, 2H), 7.31 (td, J = 7.2, 1.2 Hz, 1H).

Example  13

Pyridinyloxaborole  Produce

14a. Metallization  And Voronylation

To a solution of 3-bromo-4-hydroxymethylpyridine (10.7 mmol) and B (OMe) ₃ (2.73 mL, 11.9 mmol) in anhydrous THF (20 mL) n-butyllithium (13.6) at -78 ° C under nitrogen Ml, 21.8 mmol) was added dropwise. Thereafter, the cooling bath was removed. The mixture was slowly warmed up with stirring for 30 minutes and then stirred for 2 hours by water bath. After that, brine was added and the pH was adjusted to 7 with 6 N HCl. The mixture was washed with THF (× 2) and the aqueous layer (containing product) was evaporated to dryness. The residue was washed with THF and the product extracted with ethanol (× 2). Ethanol was removed in vacuo, water was added to the residue and removed in vacuo. Toluene was added and removed in vacuo. The resulting residue was triturated with diethyl ether and the product was collected by filtration to give C12 .

14b. 7- Hydroxy -2,1- Oxaborolano [5,4-c] pyridine  [[1,2] Oxaborolo [ 3,4-c] pyridine -1 (3H) -ol] ( C12 )

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ ppm 5.00 (s, 2H), 7.45 (d, J = 5.0 Hz, 1H), 8.57 (d, J = 5.3 Hz, 1H), 8.91 (s , 1H), 9.57 (s, 1H). ESI-MS m / z 134 (M ⁻ H ⁻⁻ ), C ₆ H ₆ BNO ₂ = 135.

Example  14

Cyclic Borin acid  ester

Additional compounds may be produced by the methods described herein. The following compounds can be prepared using Examples 1-7 by selecting appropriate starting materials such as 1 or 3 . Where available, melting point characterization is provided for these compounds.

14. result

Analytical data for exemplary compounds of Formula I are presented below.

14a. Ethyl 2- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- Iloxy )acetate ( C41 )

M.P. 134-137 ° C. Exemplary starting materials: ethyl 2- (4-bromo-3- (hydroxymethyl) phenoxy) acetate.

14b. 2- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- Iloxy Acetic acid ( C42 )

M.P. 163-166 ° C. Exemplary starting materials: ethyl 2- (4-bromo-3- (hydroxymethyl) phenoxy) acetate. The title compound is obtained after saponification of the corresponding ester.

14c. 6- (thiophene-2- Ilthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C43 )

M.P. 99-104 ° C. Exemplary starting materials: (2-bromo-4- (thiophen-2-ylthio) phenyl) methanol.

14d. 6- (4- Fluorophenylthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C44 )

M.P. 135-138 ° C. Exemplary starting materials: (2-bromo-4- (4-fluorophenylthio) phenyl) methanol.

14e. 1- (3-((1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- Iloxy ) methyl ) Phenyl Pentane-1-one ( C45 )

M.P. 96-98 ° C. Exemplary starting materials: 1- (3-((4-bromo-3- (hydroxymethyl) phenoxy) methyl) phenyl) pentan-1-one.

14f. 2- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- Iloxy ) -1- (piperidin-1-yl) Ethanon ( C46 )

M.P. 158-163 ° C. Exemplary starting materials: 2- (4-bromo-3- (hydroxymethyl) phenoxy) -1- (piperidin-1-yl) ethanone.

14g. 2- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- Iloxy ) -1- (4-pyrimidin-2-yl) piperazin-1-yl) Ethanon ( C47 )

M.P. 190-195 ° C. Exemplary starting materials: 2- (4-bromo-3- (hydroxymethyl) phenoxy) -1- (4-pyrimidin-2-yl) piperazin-1-yl) ethanone.

14h. 6- (4- (pyridin-2-yl) piperazin-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C48 )

M.P. 135-138 ° C. Exemplary starting materials: (2-bromo-4- (4- (pyridin-2-yl) piperazin-1-yl) phenyl) methanol.

14i. 6- Nitrobenzo [c] [1,2] oxaborole -1 (3H) -ol ( C49 )

M.P. 163-171 ° C. Exemplary starting materials: benzo [c] [1,2] oxaborole-1 (3H) -ol. For preparation see JACS 82, 2172, 1960.

14j. 6- Aminobenzo [c] [1,2] oxaborole -1 (3H) -ol ( C50 )

M.P. 145-148 ° C. Exemplary starting materials: 6-nitrobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14k. 6- (dimethylamino) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C51 )

M.P. 120-123 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14l. N- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6- days) Benzamide ( C52 )

M.P. 186-193 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14 m. 6- (4- Phenylpiperazine -1 day) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C53 )

M.P. 159-161 ° C. Exemplary starting materials: (2-bromo-4- (4-phenylpiperazin-1-yl) phenyl) methanol.

14o. 6- (1H-indol-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C55 )

M.P. 135-140 ° C. Exemplary starting materials: (2-bromo-4- (1H-indol-1-yl) phenyl) methanol.

14p. 6- morpholinobenzo [c] [1,2] oxaborole- 1 (3H) -ol ( C56 )

M.P. 128-132 ° C. Exemplary starting materials: (2-bromo-4-morpholinophenyl) methanol.

14q. 6- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- Iloxy ) Nicotinonitrile ( C57 )

M.P. 193-198 ° C. Exemplary starting materials: 6- (4-bromo-3- (hydroxymethyl) phenoxy) nicotinonitrile.

14r. 5- Fluoro -6- Nitrobenzo [c] [1,2] oxaborole -1 (3H) -ol ( C58 )

M.P. 162-167 ° C. Exemplary starting materials: 5-fluorobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14s. 5- Bromo -6- ( Hydroxymethyl ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C59 )

M.P. > 257 ° C. Exemplary starting materials: (2,5-dibromo-4- (methoxymethyl) phenyl) methanol.

14t. 3,7- Dehydro -1,5- Dihydroxy -1H, 3H-benzo [1,2-c: 4,5- c ' ] Vis [ 1,2] oxaborol ( C60 )

M.P. > 250 ° C. Exemplary starting materials: (2,5-dibromo-1,4-phenylene) dimethanol.

14u. 1- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6-day) -3- Fe Neilurea ( C61 )

M.P. 213-215 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14v. N- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6- days) Benzenesulfonamide ( C62 )

M.P. 175-184 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14w. N- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6- days) Acet amides ( C63 )

M.P. 176-185 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14x. 7- ( Hydroxymethyl ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C64 )

M.P. 241-250 ° C. Exemplary starting materials: (2-bromo-1,3-phenylene) dimethanol.

14y. 7- Methylbenzo [c] [1,2] oxaborole -1 (3H) -ol ( C65 )

M.P. 107-111 ° C. Exemplary starting materials: (2-bromo-3-methylphenyl) methanol.

14z. 6- (3- ( Phenylthio ) -1H-indol-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C66 )

M.P. 159-163 ° C. Exemplary starting materials: (2-bromo-4- (3-phenylthio) -1 H-indol-1-yl) phenyl) methanol.

14 aa . 3- (1- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6-yl) -1H-indole-3- Ilthio ) Propanenitrile ( C67 )

M.P. 135-141 ° C. Exemplary starting materials: 3- (1- (3-bromo-4- (hydroxymethyl) phenyl) -1H-indol-3-ylthio) propanenitrile.

14 bb . 6- (5- Methoxy -1H-indol-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C68 )

M.P. 120-124 ° C. Exemplary starting materials: (2-bromo-4- (5-methoxy-1 H-indol-1-yl) phenyl) methanol.

14 cc . 5,6- Methylenedioxybenzo [c] [1,2] oxaborole -1 (3H) -ol ( C69 )

M.P. 185-189 ° C. Exemplary starting materials: (6-bromobenzo [d] [1,3] dioxol-5-yl) methanol.

14 dd . 6-amino-5- Fluorobenzo [c] [1,2] oxaborole -1 (3H) -ol ( C70 )

M.P. 142-145 ° C. Exemplary starting materials: 6-nitro-5-fluorobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14 ee . 6- ( Benzylamino ) -5- Fluorobenzo [c] [1,2] oxaborole -1 (3H) -ol ( C71 )

M.P. 159-164 ° C. Exemplary starting materials: 6-amino-5-fluorobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14 ff . 6- (5- Methoxy -3- ( Phenylthio ) -1H-indol-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C72 )

M.P. 135-141 ° C. Exemplary starting materials: (2-bromo-4- (5-methoxy-3- (phenylthio) -1 H-indol-1-yl) phenyl) methanol.

14 gg . 3- (1- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6-day) -5- Methoxy -1H-indole-3- Ilthio ) Propanenitrile ( C73 )

M.P. 149-154 ° C. Exemplary starting materials: 3- (1- (3-bromo-4- (hydroxymethyl) phenyl) -5-methoxy-1H-indol-3-ylthio) propanenitrile.

14 hh . 4- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -7- Iloxy Benzonitrile ( C74 )

M.P. 148-153 ° C. Exemplary starting materials: 4- (2-bromo-3- (hydroxymethyl) phenoxy) benzonitrile.

14 ii . 6- (5- Chloro -1H-indol-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C75 )

M.P. 149-154 ° C. Exemplary starting materials: (2-bromo-4- (5-chloro-lH-indol-1-yl) phenyl) methanol.

14 jj . 3- (5- Chloro -1- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxabo Roll-6-yl) -1H-indole-3- Ilthio ) Propanenitrile ( C76 )

M.P. > 225 ° C. Exemplary starting materials: 3- (1- (3-bromo-4- (hydroxymethyl) phenyl) -5-chloro-1H-indol-3-ylthio) propanenitrile.

14 kk . 6- ( Benzylamino ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C77 )

M.P. 126-133 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14 ll . 6- ( Dibenzylamino ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C78 )

M.P. 115-123 ° C. Exemplary starting materials: 6-aminobenzo [c] [1,2] oxaborole-1 (3H) -ol.

14 mm . 7- (4- (1H- Tetrazole -5 days) Phenoxy ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C79 )

M.P. Decompose at 215 ° C. Exemplary starting materials: 4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborole-7-yloxy) benzonitrile.

14 nn . 6- (5- Chloro -3- ( Phenylthio ) -1H-indol-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C80 )

M.P. 145-151 ° C. Exemplary starting materials: (2-bromo-4- (5-chloro-3- (phenylthio) -1 H-indol-1-yl) phenyl) methanol.

14 pp . 6- (4- (pyrimidin-2-yl) piperazin-1-yl) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C82 )

M.P. NA ° C. Exemplary starting materials: (2-bromo-4- (4-pyrimidin-2-yl) piperazin-1-yl) phenyl) methanol.

14 qq . 7- ( Benzyloxy ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C83 )

M.P. NA ° C. Exemplary starting materials: (3- (benzyloxy) -2-bromophenyl) methanol.

14 rr . 4- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -6- Ilthio Pyridinium chloride ( C84 )

M.P. NA ° C. Exemplary starting materials: (2-bromo-4- (pyridin-4-ylthio) phenyl) methanol.

14 ss . 6- (pyridine-2- Ilthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C85 )

M.P. NA ° C. Exemplary starting materials: (2-bromo-4- (pyridin-2-ylthio) phenyl) methanol.

14 tt . 7- Fluorobenzo [c] [1,2] oxaborole -1 (3H) -ol ( C86 )

M.P. 120-124 ° C. Exemplary starting materials: (2-bromo-3-fluorophenyl) methanol.

14 uu . 6- (4- Trifluoromethyl ) Phenoxy ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C87 )

M.P. 98-105 ° C. Exemplary starting materials: (2-bromo-4- (4- (trifluoromethyl) phenoxy) phenyl) methanol.

14 vv . 6- (4- Chlorophenylthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C88 )

M.P. 157-161 ° C. Exemplary starting materials: (2-bromo-4- (4-chlorophenylthio) phenyl) methanol.

14 ww . 6- (4- Chlorophenylsulfinyl ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C89 )

M.P. 154-161 ° C. Exemplary starting materials: 6- (4-chlorophenylthio) benzo [c] [1,2] oxaborole-1 (3H) -ol.

14 xx . 6- (4- Chlorophenylsulfonyl ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C90 )

M.P. 157-163 ° C. Exemplary starting materials: 6- (4-chlorophenylthio) benzo [c] [1,2] oxaborole-1 (3H) -ol.

14 yy . N- (1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5-day) -N- (fe Nilsulfonyl ) Benzenesulfonamide ( C91 )

M.P. 142-152 ° C. Exemplary starting materials: N- (4-bromo-3- (hydroxymethyl) phenyl) -N- (phenylsulfonyl) benzenesulfonamide.

14 zz . 6- (4- ( Trifluoromethyl ) Phenylthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C92 )

M.P. 111-113 ° C. Exemplary starting materials: (2-bromo-4- (4- (trifluoromethyl) phenylthio) phenyl) methanol.

14 aaa . 6- (4- ( Trifluoromethyl ) Phenylsulfinyl ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C93 )

M.P. 79-88 ° C. Exemplary starting materials: 6- (4- (trifluoromethyl) phenylthio) benzo [c] [1,2] oxaborole-1 (3H) -ol.

14 bbb . 6- (4- ( Methylthio ) Phenylthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol ( C94 )

M.P. 117-120 ° C. Exemplary starting materials: (2-bromo-4- (4- (methylthio) phenylthio) phenyl) methanol.

14 ccc . 6- (p- Tolylthio ) Benzo [c] [1,2] Oxabolol -1 (3H) -ol  ( C95 )

M.P. 139-144 ° C. Exemplary starting materials: (2-bromo-4- (p-tolylthio) phenyl) methanol.

14 ddd . 3-((1- Hydroxy -1,3- Dihydrobenzo [c] [1,2] oxaborole -5- One-jade city) Methyl ) Benzonitrile ( C96 )

M.P. 147-150 ° C. Exemplary starting materials: 3-((4-bromo-3- (hydroxymethyl) phenoxy) methyl) benzonitrile.

Example  15

CBOs  And CBEs Precursor to

15.1 2- Bromo -5- Fluoro -[One-( Methoxy methoxy ) methyl ]benzene (5b)

To a solution of 3 (62.0 g, 293 mmol) in MeOH (400 mL) was added NaBH ₄ (5.57 g, 147 mmol) in portions at 0 ° C. and the mixture was stirred at rt for 1 h. Water was added and the solvent removed under reduced pressure to approximately half the volume. The mixture was poured into EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 4b , which was used for the next step without purification. To a solution of 4b (60.8 g, 293 mmol) and i-Pr ₂ NEt (61 mL, 0.35 mol) in CH ₂ Cl ₂ was added chloromethyl methyl ether (27 mL, 0.35 mmol) at 0 ° C. and the mixture was cooled to room temperature. Stir overnight at. Water was added and the mixture was extracted with CHCl ₃ . The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 5b (73.2 g, quantitative). ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.43 (s, 3H), 4.62 (s, 2H), 4.78 (s, 2H), 6.88 (td, J = 8.5, 3.2 Hz, 1H), 7.25 (dd, J = 9.6, 3.1 Hz, 1H), 7.48 (dd, J = 8.8, 5.3 Hz, 1H).

15.2 2- Bromo -[One-( Methoxy methoxy ) methyl ]benzene (5a)

This compound was prepared from 2-bromobenzyl alcohol in the same manner as compound 5b and used in the next step without further purification.

15.3 2- [4- Fluoro -2-[( Methoxy methoxy ) methyl ] Phenyl ]-[1,3,2] Dioxaborolan (6)

To a solution of 5b (16.2 g, 65.1 mmol) in THF (130 mL) was added sec-BuLi (1.4 M, 56 mL) and (MeO) ₃ B (14.5 mL, 130 mmol) at −78 ° C. under a nitrogen atmosphere and The mixture was allowed to warm to rt and stirred for 2 h. Water and 1 N NaOH were added to the mixture, which was washed with Et ₂ O. Then the pH was adjusted to 4 with 1 N HCl and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . Thereafter, the solvent was removed under reduced pressure to yield boronic acid, which was used for the next step without further purification. Ethylene glycol (3.29 g, 53 mmol) was added to a solution of boronic acid in toluene (300 mL) and the mixture was refluxed for 3 hours by Dean-Stark trap. The solvent was removed under reduced pressure to give 6 (12.1 g, 77%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.42 (s, 3H), 4.36 (s, 4H), 4.76 (s, 2H), 4.87 (s, 2H), 6.96 (td, J = 8.2 , 2.6 Hz, 1H), 7.26 (dd, J = 10.6, 2.6 Hz, 1H), 7.83 (dd, J = 8.2, 6.4 Hz, 1H).

15.4 2- (3- Chlorophenyl ) [1,3,2] Dioxaborolan (7b; R ⁱⁱⁱ = 3- Cl - Ph )

3-chlorophenylboronic acid (3.041 g, 19.4 mmol) was dissolved in 75 mL of anhydrous THF under nitrogen atmosphere. Ethylene glycol (1.32 g, 21.3 mmol) was added and the solution was refluxed for 18 hours. The solution was cooled and the THF was removed under reduced pressure to afford 7b (3.55 g, 100%) as a brown solid which solidified on cooling in the freezer. ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.39 (s, 4H), 7.32 (t, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.2, 1.2 Hz, 1H), 7.67 (d , J = 7.0 Hz, 1 H), 7.78 (br s, 1 H).

Compounds 7a and 7c-k were synthesized in a similar manner to 7b .

15.5 2- Phenyl [1,3,2] dioxaborolane (7a; R ⁱⁱⁱ = Ph )

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.30 (s, 4H), 7.35-7.41 (t, J = 8.2 Hz, 2H), 7.46-7.52 (m, 1H), 7.68-7.72 ( dd, J = 6.2, 2.6 Hz, 2H).

15.6 2- (4- Chlorophenyl ) [1,3,2] Dioxaborolan (7c; R ⁱⁱⁱ = 4- Cl - Ph )

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.38 (s, 4H), 7.36 (d, J = 6.7 Hz, 2H), 7.74 (d, J = 7.0 Hz, 2H).

15.7 2- (3- Fluorophenyl ) [1,3,2] Dioxaborolan (7d; R ⁱⁱⁱ = 3-F- Ph )

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.39 (s, 4H), 7.1-7.2 (m, 1H), 7.36 (td, J = 8.2, 5.6 Hz, 1H), 7.48 (dd, J = 9.1, 2.6 Hz, 1H), 7.58 (d, J = 7.0 Hz, 1H).

15.8 2- (4- Fluorophenyl ) [1,3,2] Dioxaborolan (7e; R ⁱⁱⁱ = 4-F- Ph )

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.29 (s, 4H), 7.17-7.23 (t, J = 8.5 Hz, 2H), 7.71-7.76 (dd, J = 8.5, 6.1 Hz, 2H).

15.9 2- (3- Methylphenyl ) [1,3,2] Dioxaborolan (7f; R ⁱⁱⁱ = 3- Me - Ph )

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3H), 4.31 (s, 4H), 7.29-7.32 (m, 2H), 7.50-7.53 (m, 2H).

15.10 2- Styryl [1,3,2] dioxaborolane (7b; R ⁱⁱⁱ = Styryl )

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.20 (s, 4H), 6.15 (d, J = 18.5 Hz, 1H), 7.31-7.39 (m, 4H), 7.56 (dd, J = 1.5, 7.6 Hz, 2H).

15.11 2- (thiophen-3-yl) [1,3,2] Dioxaborolan (7j; R ⁱⁱⁱ = Thiophen-3-yl)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.27 (s, 4H), 7.30 (dd, J = 4.8, 0.9 Hz, 1H), 7.58 (dd, J = 4.5, 2.4 Hz, 1H) , 8.03 (dd, J = 2.7, 1.2 Hz, 1H).

15.12 2- (4- Methylthiophene -3- days) [1,3,2] Dioxaborolan (7k; R ⁱⁱⁱ = 4- Methylthiophene -3 days)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3H), 4.25 (s, 4H), 7.13-7.14 (m, 1H), 7.93 (d, J = 3.0 Hz, 1H) .

Example  16

CBEs

16.1 1- (3- Chlorophenyl ) -1,3- Dehydro -5- Fluoro -2,1- Benzoxaborole (9f)

Compound 5b (1.06 g, 4.20 mmol) was dissolved in 50 mL of anhydrous THF under nitrogen atmosphere and cooled to -78 ° C. To the solution was added tert-BuLi (1.7 M in pentane, 5.3 mL) slowly. After stirring at −78 ° C. for 10 min, compound 7b (764 mg, 4.20 mmol) in 10 mL of dry THF was added and the solution was stirred for an additional 0.5 h. The solution was then warmed to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between 40 mL of H ₂ O and 80 mL of diethyl ether. The solution was stirred vigorously for several minutes and then neutralized with 6 N HCl (pH 7). The organic layer was separated and the aqueous solution was extracted again with ether (2 × 80 mL). The combined ether extracts were dried over MgSO ₄ , filtered and evaporated to afford crude 8f (1.22 g) as a yellow oil which was used for the next step without purification. Compound 8f (700 mg, 2.30 mmol) was dissolved in 46 ml THF and 4 ml concentrated HCl. The solution was stirred at rt for 12 h. Then water (10 mL) was added and THF was removed under reduced pressure. This gave a suspension. The precipitate was filtered under vacuum, washed with water (10 mL), then hexanes (5 mL), and dried to afford compound 9f (334 mg, 59%) as a white solid: mp 112-114 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.15 (s, 2H), 7.02-7.08 (t, J = 8.8 Hz, 1H), 7.14-7.17 (d, J = 8.8 Hz, 1H) , 7.23-7.33 (m, 2 H), 7.65-7.72 (m, 3 H); ESI-MS m / z 247.08, 249.03 (M ⁻ H) ⁻ ; HPLC purity: 97.1%; Assay (C ₁₃ H ₉ BClFO) C, H.

Compounds 9a-e , 9g-j , 10a, b and 12-15 were synthesized in a similar manner to 9f .

16.1 1,3- Dehydro -One- Phenyl -2,1- Benzoxaborole (9a)

Colorless oil; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.41 (s, 2H), 7.43-7.61 (m, 6H), 8.11 (d, J = 9.4 Hz, 2H), 8.18 (d, J = 8.2 Hz, 1H); ESI-MS m / z not observed; HPLC purity: 95.5%.

16.2 1,3- Dehydro -5- Fluoro -One- Phenyl -2,1- Benzoxaborole (9b)

mp 90-99 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.37 (s, 2H), 7.22 (dt, J = 2.3, 8.9 Hz, 1H), 7.38 (dd, J = 2.1, 9.4 Hz, 1H) , 7.45-7.57 (m, 3H), 8.06 (dd, J = 1.8, 7.9 Hz, 2H), 8.16 (dd, J = 5.9, 8.2 Hz, 1H); ESI-MS m / z 213 (M + H) ⁺ ; HPLC purity: 95.1%.

16.3 1- (3- Chlorophenyl ) -1,3- Dehydro -2,1- Benzoxaborole (9c)

Colorless oil; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.26 (s, 2H), 7.29-7.45 (m, 5H), 7.77-7.86 (m, 3H); ESI-MS m / z not observed; HPLC purity: 96.0%; Assay (C ₁₃ H ₁₀ BClO) C, H.

16.4 1,3- Dehydro -1- (3- Fluorophenyl ) -2,1- Benzoxaborole (9d)

Colorless oil; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.28 (s, 2H), 7.23 (m, 1H), 7.43 (m, 1H), 7.41-7.48 (m, 3H), 7.57-7.61 ( dd, J = 9.6, 2.6 Hz, 1H), 7.74-7.77 (d, J = 7.3 Hz, 1H), 7.93-7.95 (d, J = 7.3 Hz, 1H); ESI-MS m / z not observed; HPLC purity: 98.3%; Assay (C ₁₃ H ₁₀ BFO) C, H.

16.5 1,3- Dehydro -1- (4- Fluorophenyl ) -2,1- Benzoxaborole (9e)

mp 53-55 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.37 (s, 2H), 7.26-7.32 (m, 2H), 7.42 (m, 1H), 7.53-7.55 (m, 2H), 8.11- 8.16 (m, 3 H); ESI-MS m / z not observed; HPLC purity: 99.3%; Assay (C ₁₃ H ₁₀ BFO) C, H.

16.6 1,3- Dehydro -5- Fluoro -1- (3- Fluorophenyl ) -2,1- Benzoxaborole (9g)

mp 80-82 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.20 (s, 2H), 7.06-7.18 (m, 2H), 7.22 (dd, J = 9.6, 1.8 Hz, 1H), 7.39 (td, J = 7.8, 5.4 Hz, 1H), 7.49 (dd, J = 9.9, 2.7 Hz, 1H), 7.63 (dd, J = 6.9, 0.9 Hz, 1H), 7.83 (dd, J = 8.1, 5.7 Hz, 1H ); ESI-MS m / z not observed; HPLC purity: 98.5%; Assay (C ₁₃ H ₉ BF ₂ O) C, H.

16.7 1,3- Dehydro -5- Fluoro -1- (4- Fluorophenyl ) -2,1- Benzoxaborole (9h)

mp 75-77 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.33 (s, 2H), 7.19-7.30 (m, 3H), 7.36 (dd, J = 9.9, 2.1 Hz, 1H), 8.05-8.14 ( m, 3H); ESI-MS m / z not observed; HPLC purity: 99.0%; Assay (C ₁₃ H ₉ BF ₂ O) C, H.

16.8 1,3- Dehydro -5- Fluoro -1- (3- Methylphenyl ) -2,1- Benzoxaborole (9i)

mp 48-49 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.37 (s, 3H), 5.36 (s, 2H), 7.25 (m, 1H), 7.3-7.5 (m, 3H), 7.8-7.9 ( m, 2H), 8.20 (dd, J = 7.9, 5.9 Hz, 1H); ESI-MS m / z 227 (M + H) ⁺ ; HPLC purity: 99.8%; Assay (C ₁₄ H ₁₂ BFO) C, H.

16.9 1,3- Dehydro -5- Fluoro -1- (4- Methylphenyl ) -2,1- Benzoxaborole (9j)

mp 48-49 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.36 (s, 3H), 5.35 (s, 2H), 7.25 (m, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.40 (dd, J = 9.4, 1.5 Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H), 8.20 (dd, J = 7.9, 5.6 Hz, 1H); ESI-MS m / z 227 (M + H) ⁺ ; HPLC purity: 98.9%; Assay (C ₁₄ H ₁₂ BFO) C, H.

16.10 1,3- Dehydro -One- Styryl -2,1- Benzoxaborole (10a)

mp 57-59 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.33 (s, 2H), 6.85 (d, J = 18.8 Hz, 1H), 7.38-7.46 (m, 4H), 7.56 (d, J = 4.7 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.83 (d, J = 18.8 Hz, 1H), 8.14 (d, J = 7.3 Hz, 1H); ESI-MS m / z 221 (M + H) ⁺ ; HPLC purity: 98.5%; Anal (C ₁₃ H ₁₀ BFO.0.1H ₂ O) C, H.

16.11 1,3- Dehydro -5- Fluoro -One- Styryl -2,1- Benzoxaborole (10b)

mp 84-86 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.32 (s, 2H), 6.86 (d, J = 18.8 Hz, 1H), 7.24 (td, J = 2.3, 10.6 Hz, 1H), 7.38 -7.47 (m, 4H), 7.74 (d, J = 7.0 Hz, 2H), 7.83 (d, J = 18.8 Hz, 1H), 8.19 (dd, J = 5.9, 8.2 Hz, 1H); ESI-MS m / z 239 (M + H) ⁺ ; HPLC purity: 99.1%; Assay (C ₁₃ H ₁₀ BFO) C, H.

16.12 1,3- Dehydro -5- Fluoro -1- (furan-3-yl) -2,1- Benzoxaborole (12)

Colorless oil; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.34 (s, 2H), 6.84 (m, 1H), 7.24 (m, 1H), 7.37-7.40 (d, J = 9.4 Hz, 1H) , 7.83 (m, 1 H), 8.14-8.18 (dd, J = 8.2, 5.9 Hz, 1 H), 8.49 (m, 1 H); ESI-MS m / z 203 (M + H) ⁺ ; HPLC purity: 96.9%; Assay (C ₁₁ H ₈ BFO ₂ ) C, H.

16.13 1,3- Dehydro -5- Fluoro -1- (thiophen-3-yl) -2,1- Benzoxaborole (13)

mp 33-35 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.33 (s, 2H), 7.24 (m, 1H), 7.35-7.38 (d, J = 9.3 Hz, 1H), 7.65 (m, 2H) , 8.17-8.22 (dd, J = 8.4, 6.3 Hz, 1H), 8.48 (m, 1H); ESI-MS m / z 219 (M + H) ⁺ ; HPLC purity: 97.8%; Assay (C ₁₁ H ₈ BFOS) C, H.

16.14 1,3- Dehydro -5- Fluoro -1- (4- Methylthiophene -3-yl) -2,1- Benzoxaborole (14)

mp 51-53 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.46 (s, 3H), 5.36 (s, 2H), 7.20-7.27 (m, 2H), 7.37-7.40 (dd, J = 9.4, 2.1 Hz, 1H), 8.14-8.19 (dd, J = 8.2, 5.9 Hz, 1H), 8.48-8.49 (d, J = 2.6 Hz, 1H); ESI-MS m / z 233 (M + H) ⁺ ; HPLC purity: 100%; Assay (C ₁₂ H ₁₀ BFOS) C, H.

16.15 1,3- Dehydro -5- Fluoro -1-vinyl-2,1- Benzoxaborole (11)

Compound 5b (2.0 g, 8.0 mmol) in THF (30 mL) was cooled to −78 ° C. and tert-butyllithium (9.9 mL, 16.8 mmol) was added slowly as a 1.7 M solution in pentane. After stirring at −78 ° C. for 30 minutes, dibutyl ester of vinyl boronic acid was added dropwise. The mixture was stirred at -78 ° C for 1 hour, then warmed to room temperature and stirred overnight. Conc. HCl (4 mL) was added or stirred at rt for 4 h. Water (10 mL) was added and THF was removed under reduced pressure. The residue was extracted with ethyl ether, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (9: 1 hexanes / ethyl acetate) to give 11 (383 mg, 30%) as a yellowish oil. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.27 (s, 2H), 6.25 (t, J = 8.5 Hz, 1H), 6.50 (d, J = 9.4 Hz, 1H), 7.06-7.15 (m, 2H), 7.89 (dd, J = 5.6, 7.9 Hz, 1H); ESI-MS m / z (M + H) ⁺ ; HPLC purity: 98.7%; Anal (C ₉ H ₈ BFO.0.1H ₂ O) C, H.

16.16 3- (1,3- Dehydro -5- Fluoro -2,1- Benzoxaborole -1-yl) pyridine (15)

To a solution of 3-bromopyridine (731 mg, 4.63 mmol) in THF (5 mL) was added isopropylmagnesium chloride (1 M in THF; 2.3 mL) at room temperature under a nitrogen atmosphere and the mixture was stirred for 1 hour. . To the mixture was added compound 6 (1.11 g, 4.63 mmol) in THF (4 mL) and the mixture was stirred at rt overnight. Water was added and pH was adjusted to 7 with 1 N HCl. Then the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was dissolved in THF (30 mL). 1 N HCl (10 mL) was added to the mixture and the mixture was refluxed overnight. The pH was adjusted to 7 with aqueous NaHCO ₃ and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was recrystallized from i-Pr ₂ O to give compound 15 (76 mg, 7.7%): mp 210-212 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.94 (s, 2H), 6.9-7.1 (m, 2H), 7.36 (br s, 1H), 7.66 (dd, J = 6.7, 5.3 Hz, 1H) , 8.19 (d, J = 6.7 Hz, 1H), 8.24 (br s, 1H), 8.64 (d, J = 5.3 Hz, 2H); ESI-MS m / z 214 (M + H) ⁺ ; Anal (C ₁₂ H ₉ BFNO.0.6H ₂ O) C, H, N.

Example  17

CBOs Precursor to

17.1 2- Bromo -5- Fluoro -[One-( Methoxy methoxy ) Ethyl] benzene (18c)

To a solution of compound 3 (4.23 g, 20.0 mmol) in THF (30 mL) was added MeMgBr (1.4 mol / L in THF; 18 mL) at −78 ° C. under a nitrogen atmosphere and the mixture was warmed to room temperature for 2 hours. Stirred. The reaction was deactivated with 2 N HCl and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. To a solution of the residue (4.62 g) in CH ₂ Cl ₂ (100 mL) was added i-Pr ₂ NEt (5.2 mL, 30 mmol) and chloromethyl methyl ether (2.0 mL, 26 mmol) at 0 ° C. and reaction The mixture was stirred at rt overnight. Water was added and the mixture was extracted with CHCl ₃ . The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (15: 1 hexanes / ethyl acetate) to give 18c (4.97 g, 2 steps 94%): ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.43 ( d, J = 6.5 Hz, 3H), 3.38 (s, 3H), 4.55 (d, J = 6.5 Hz, 1H), 4.63 (d, J = 6.5 Hz, 1H), 5.07 (q, J = 6.5 Hz, 1H), 6.85 (m, 1H), 7.25 (dd, J = 9.7, 2.6 Hz, 1H), 7.46 (dd, J = 8.8, 5.3 Hz, 1H).

17.2 2- Bromo -5- Chloro -One-( Methoxy methoxymethyl )benzene (18d)

To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in dry THF (70 mL) under nitrogen was added dropwise BH ₃ THF solution (1.0 M, 55 mL) at 0 ° C. and the reaction mixture was allowed to stand at room temperature. Stir overnight at. The mixture was then cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH ₃ . The resulting mixture was stirred until no more foam was released and then 10% NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue after rotary evaporation was purified by silica gel column chromatography (5: 1 hexanes / EtOAc) to give 2-bromo-5-chlorobenzyl alcohol (4.58 g, 88%) as a white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ): δ (ppm) 7.57 (d, J = 8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H).

2-bromo-5-chlorobenzyl alcohol obtained above was dissolved in CH ₂ Cl ₂ (150 mL) and cooled to 0 ° C. on an ice bath. To this solution was added sequentially i-Pr ₂ NEt (5.4 mL, 31 mmol) and chloromethyl methyl ether (2.0 mL, 26 mmol) under nitrogen. The reaction mixture was stirred at rt overnight and washed with NaHCO ₃ -saturated water and then brine. The residue after rotary evaporation was purified by silica gel column chromatography (5: 1 hexanes / EtOAc) to give 18d (4.67 g, 85%) as colorless oil: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.30 (s, 3H), 4.53 (s, 2H), 4.71 (s, 2H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (dd, J = 2.4, 0.6 Hz , 1H), 7.63 (d, J = 8.7 Hz, 1H).

17.3 4- Bromo -3- ( Methoxy methoxymethyl )toluene (18e)

This compound was prepared from 2-bromo-5-methylbenzoic acid in the same manner as compound 18d : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.27 (s, 3H), 3.30 (s, 3H ), 4.51 (s, 2H), 4.68 (s, 2H), 7.05 (dd, J = 7.9, 2.3 Hz, 1H), 7.30 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 8.2 Hz , 1H).

17.4 2- Bromo -5- Methoxy -One-( Methoxy methoxymethyl )benzene (18 g)

This compound was prepared from 2-bromo-5-methoxybenzoic acid in the same manner as compound 18d : ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.30 (s, 1H), 3.74 (s, 3H) , 4.50 (s, 2H), 4.69 (s, 2H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 7.40 (d, J = 2.9 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H).

17.5 2- Bromo -1,5- Bis (methoxymethoxymethyl) benzene (18h)

This compound was prepared from 4-bromo-1,3-phthalic acid in the same manner as compound 18d : ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.28 (s, 3H), 3.30 (s, 3H) , 4.50 (s, 2H), 4.54 (s, 2H), 4.64 (s, 2H), 4.69 (s, 2H), 7.20 (dd, J = 8.8, 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H).

17.6 2- Bromo -4,5- Difluoro -One-( Methoxy methoxymethyl )benzene (18k)

This compound was prepared from 2-bromo-4,5-difluorobenzoic acid in the same manner as compound 18d : ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.42 (s, 3H), 4.57 (d , J = 1.2 Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H).

17.7 2- Bromo -6- Fluoro -One-( Methoxy methoxymethyl )benzene (18l)

This compound was prepared from 2-bromo-6-fluorobenzoic acid in the same manner as compound 18d : ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.43 (s, 3H), 4.74 (s, 2H) , 4.76 (d, J = 2.1 Hz, 2H), 7.05 (t, J = 9.1 Hz, 1H), 7.18 (td, J = 8.2, 5.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H) .

17.8 2- Bromo -4- Fluoro -One-( Methoxy methoxymethyl )benzene (18m)

This compound was prepared from 2-bromo-4-fluorobenzoic acid in the same manner as compound 18d and used for the next step without purification.

17.9 4- Bromo -3- ( Methoxy methoxymethyl ) Benzonitrile (18f)

To a solution of 17 (10.0 g, 49.5 mmol) in carbon tetrachloride (200 mL) N-bromosuccinimide (8.81 g, 49.5 mmol) and 2,2'-azobis (isobutyronitrile) (414 mg, 5 mol%) was added and the mixture was refluxed for 3 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added dimethylformamide (150 mL) and sodium acetate (20.5 g, 250 mmol) and the mixture was stirred at 80 ° C. overnight. Water was added and the mixture was extracted with ether. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added methanol (150 mL) and 1 mol / L sodium hydroxide (50 mL) and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated to approximately 1/3 volume under reduced pressure. Water and hydrochloric acid were added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography (3: 1 hexanes / ethyl acetate), and then triturated with dichloromethane to give 2-bromo-5-cyanobenzyl alcohol (4.63 g, 44% overall yield): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.51 (d, J = 5.9 Hz, 2H), 5.67 (t, J = 5.6 Hz, 1H), 7.67 (dd, J = 8.2, 2.0 Hz, 1H), 7.80 (s, J = 8.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H).

To a solution of 2-bromo-5-cyanobenzyl alcohol (4.59 g, 21.7 mmol) in dichloromethane (80 mL) at 0 ° C. diisopropylethylamine (5.6 mL, 32 mmol) and chloromethyl methyl ether (2.3 ML, 30 mmol) was added and the reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (6: 1 hexanes / ethyl acetate) to give 18f (4.08 g, 71%): ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.43 (s, 3H), 4.65 (s, 2H), 4.80 (s, 2H), 7.43 (dd, J = 8.2, 4.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 4.1 Hz, 1H).

17.10 2- Bromo -5- Trifluoromethyl -One-( Methoxy methoxymethyl )benzene (18i)

This compound was prepared from 2-bromo-5-trifluoromethylbenzaldehyde in the same manner as compound 5b and used for the next step without purification.

17.11 One- Bromo -2-( Methoxy methoxymethyl )naphthalene (18j)

This compound was prepared in the same manner from 1-bromonaftaldehyde to compound 5b : ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.42 (s, 3H), 4.75 (s, 2H), 4.81 (s , 2H), 7.5-7.7 (m, 3H), 7.99 (d, J = 7.7 Hz, 2H), 8.22 (d, J = 7.7 Hz, 1H).

17.12 1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole (19a)

This compound was purchased from Lancaster Synthessi.

17.13 1,3- Dehydro -5- Fluoro -One- Hydroxy -2,1- Benzoxaborole (19b)

To a solution of 5b (73.2 g, 293 mmol) in anhydrous THF (400 mL) was added n-butyllithium (1.6 M in hexane, 200 mL) over 45 minutes at −78 ° C. under a nitrogen atmosphere. Anions precipitated out. After 5 minutes, (i-PrO) ₃ B (76.0 mL, 330 mmol) was added over 10 minutes and the mixture was allowed to warm to room temperature over 1.5 hours. Water and 6N HCl (55 mL) were added and the solvent was removed under reduced pressure to make approximately half the volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. To the solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL) and the mixture was stirred at 30 ° C. overnight. The solvent was removed under reduced pressure to make approximately half the volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was treated with i-Pr ₂ O / hexanes to give 19b (26.9 g, 60%) as a white powder: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm ) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J = 9.7, 1.8 Hz, 1H), 7.74 (dd, J = 8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m / z 151 (M ⁻ H) ⁻ ; HPLC purity 97.8%; Assay (C ₇ H ₆ BFO ₂ ) C, H.

17.14 1,3- Dehydro -5- Fluoro -One- Hydroxy -3- methyl -2,1- Benzoxaborolan (19c)

This compound was prepared from 18c in the same manner as compound 19b : mp 72-76 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.37 (d, J = 6.4 Hz, 3H), 5.17 (q, J = 6.4 Hz, 1H), 7.14 (m, 1H), 7.25 (dd , J = 9.7, 2.3 Hz, 1H), 7.70 (dd, J = 8.2, 5.9 Hz, 1H), 9.14 (s, 1H). ESI-MS m / z 165 (M ⁻ H) ⁻ ; HPLC purity 95.2%; Assay (C ₈ H ₉ BO ₂ ) C, H.

17.15 5- Chloro -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborole (19d)

This compound was prepared from 18d in the same manner as compound 19b : mp 142-144 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.96 (s, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.71 (d, J = 7.8 Hz , 1H), 9.30 (s, 1 H); ESI-MS m / z 167 (M ⁻ H) ⁻ ; HPLC purity 99.0%; Assay (C ₇ H ₆ BClO ₂ .0.1H ₂ O) C, H.

17.16 1,3- Dehydro -One- Hydroxy -5- methyl -2,1- Benzoxaborole (19e)

This compound was prepared from 18e in the same manner as compound 19b : mp 124-128 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.33 (s, 3H), 4.91 (s, 2H), 7.13 (d, J = 7.2 Hz, 1H), 7.18 (s, 1H), 7.58 (d, J = 7.2 Hz, 1 H), 9.05 (s, 1 H); ESI-MS m / z 147 (M ⁻ H) ⁻ ; HPLC purity 99.0%; Assay (C ₈ H ₉ BO ₂ ) C, H.

17.17 1,3- Dehydro -One- Hydroxy -5- Methoxy -2,1- Benzoxaborole (19 g)

This compound was prepared from 18 g in the same manner as compound 19b : mp 102-104 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.77 (s, 3H), 4.91 (s, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 7.60 (d, J = 8.1 Hz, 1 H), 8.95 (s, 1 H); ESI-MS m / z 163 (M ⁻ H) ⁻ ; HPLC purity 100%; Assay (C ₈ H ₉ BO ₃ ) C, H.

17.18 1,3- Dehydro -One- Hydroxy -5- Hydroxymethyl -2,1- Benzoxaborole (19h)

This compound was prepared from 18h in the same manner as compound 19b : mp 124-128 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.53 (d, 2H), 4.94 (s, 2H), 5.24 (t, 1H), 7.26 (d, 1H), 7.33 (s, 1H) , 7.64 (d, 1 H), 9.08 (s, 1 H); ESI-MS m / z 163 (M ⁻ H) ⁻ ; HPLC purity 100%.

17.19 1,3- Dehydro -One- Hydroxy -5- Trifluoromethoxy - Benzoxaborole (19i)

This compound was prepared from 18i in the same manner as compound 19b : mp 113-118 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.05 (s, 2H), 7.65-7.68 (d, J = 7.5 Hz, 1H), 7.78 (s, 1H), 7.90-7.93 (d, J = 7.8 Hz, 1 H), 9.47 (s, 1 H); ESI-MS m / z 201 (M ⁻ H) ⁻ ; HPLC purity 100%.

17.20 1,3- Dehydro -One- Hydroxy -2,1- Naphtho [2,1-d] oxaborole (19j)

This compound was prepared from 18j in the same manner as compound 19b : mp 139-143 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.09 (s, 2H), 7.59-7.47 (m, 3H), 7.95 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 8.28 (dd, J = 6.9, 0.6 Hz, 1H), 9.21 (s, 1H); ESI-MS m / z 185 (M + H) ⁺ ; Anal (C ₁₁ H ₉ BO ₂ ) C, H.

17.21 1,3- Dehydro -4- Fluoro -One- Hydroxy -2,1- Benzoxaborole (19l)

This compound was prepared from 18 l in the same manner as compound 19b : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.06 (s, 2H), 7.26 (ddd, J = 9.7, 7.9, 0.6 Hz, 1H), 7.40 (td, J = 8.2, 4.7 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 9.41 (s, 1H); ESI-MS m / z 151 (M ⁻ H) ⁻ ; HPLC purity 98.7%; Assay (C ₇ H ₆ BFO ₂ ) C, H.

17.22 1,3- Dehydro -6- Fluoro -One- Hydroxy -2,1- Benzoxaborole (19m)

This compound was prepared from 18m in the same manner as compound 19b : ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.95 (s, 2H), 7.29 (td, J = 9.0, 2.7 Hz, 1H) , 7.41-7.46 (m, 2 H), 9.29 (s, 1 H); ESI-MS m / z 151 (M ⁻ H) ⁻ ; HPLC purity 100%; Assay (C ₇ H ₆ BFO ₂ ) C, H.

17.23 5,6- Difluoro -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborolan (19k)

To a solution of 18k (2.97 g, 11.1 mmol) and (i-PrO) ₃ B (2.8 mL, 12 mmol) in THF (30 mL) over n-BuLi (1.6 in hexane over 30 minutes at -78 ° C) under nitrogen atmosphere mol / L, 7.5 ml) was added and the mixture was stirred for 2 hours while warming to room temperature. The reaction was deactivated with 2 N HCl and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. To a solution of the residue in THF (25 mL) was added 6 N HCl (5 mL) and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. Recrystallization from EtOAc / i-Pr ₂ O gave 19k (1.14 g, 60%) as a white powder: mp 134-140 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.94 (s, 2H), 7.50 (dd, J = 10.7, 6.8 Hz, 1H), 7.62 (dd, J = 9.7, 8.2 Hz, 1H) , 9.34 (s, 1 H); ESI-MS m / z 169 (M ⁻ H) ⁻ ; HPLC purity 96.6%; Assay (C ₇ H ₅ BF ₂ O ₂ ) C, H.

17.24 5- Cyano -1,3- Dehydro -One- Hydroxy -2,1- Benzoxaborolan (19f)

This compound was prepared from 18f in the same manner as compound 19k : mp 98-101 ° C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.03 (s, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.90 ( s, 1 H), 9.53 (s, 1 H); ESI-MS m / z 158 (M ⁻ H) ⁻ ; HPLC purity 97.7%.

17.25 1,3- Dehydro -7- Fluoro -One- Hydroxy -2,1- Benzoxaborolan (19n)

To a solution of 20 (2.00 g, 15.9 mmol) and TMEDA (5.70 mL, 38.0 mmol) in THF (100 mL) was added sec-butyllithium (25 mL, 35.0 mmol) as a 1.4 M solution at -78 ° C. The mixture was stirred at -78 ° C for 1 h, then (i-PrO) ₃ B (8.10 mL, 35.0 mmol) was added. The reaction was allowed to warm to room temperature very slowly and then stirred overnight. Water was added and pH was adjusted to 12, which was then washed with ethyl ether. The aqueous layer was acidified to pH 2 with 6 N HCl, then extracted with ethyl ether, washed with brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was purified by flash column chromatography (2: 1 hexanes / ethyl acetate) to give 19n (270 mg) as a white solid: mp 120-124 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.99 (s, 2H), 7.00 (t, J = 8.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.48 (td , J = 5.1, 7.8 Hz, 1H), 9.25 (s, 1H); ESI-MS m / z 151 (M ⁻ H) ⁻ ; HPLC purity 97.4%; Assay (C ₈ H ₆ BNO ₂ ) C, H.

Example  18

Benzoxaborin

18.1 2- Bromo -5- Fluorophenylacetaldehyde (21a)

Compound 3 (4.23 g, 20.0 mmol), (methoxymethyl) triphenylphosphonium chloride (8.49 g, 24.0 mmol) and potassium tert-butoxide (2.83 g, 24.0) in N, N-dimethylformamide (50 mL) mol) mixture was stirred overnight at room temperature. The reaction was deactivated with 6 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Tetrahydrofuran (60 mL) and 6 N hydrochloric acid were added to the residue, and the mixture was heated under reflux for 8 hours. Water was added and the mixture was extracted with ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 21a (3.60 g, 83%): ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.86 (d, J = 1.5 Hz, 2H), 6.9-7.1 (m, 2H), 7.57 (dd, J = 8.8, 5.3 Hz, 1H), 9.76 (t, J = 1.5 Hz, 1H).

18.2 One- Bromo -4- Fluoro -2- [2- ( Methoxy methoxy ) Ethyl] benzene (22a)

To a solution of 21a (3.60 g, 16.6 mmol) in methanol (40 mL) was added sodium borohydride (640 mg, 16.6 mmol) at 0 ° C. and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added dichloromethane (50 mL), diisopropylethylamine (3.5 mL, 20 mmol) and chloromethyl methyl ether (1.5 mL, 20 mmol) at 0 ° C. and the reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (15: 1 hexanes / ethyl acetate) to give 22a (2.99 g, 2 steps 68%) as colorless oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm ) 3.04 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 4.62 (s, 2H), 6.82 (td, J = 8.2, 3.2 Hz, 1H), 7.04 (dd, J = 9.4, 2.9 Hz, 1H), 7.48 (dd, J = 8.8, 5.3 Hz, 1H).

18.3 One- Bromo -2- [2- ( Methoxy methoxy ) Ethyl] benzene (22b)

This compound was synthesized in a similar manner from 21b to 22a and used for the next step without purification.

18.4 6- Fluoro -One- Phenyl -1,2,3,4- Tetrahydro -2,1- Benzoxaborin (23a)

This compound was synthesized in a similar manner to compound 9f from 22a and 7a : colorless oil; ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.02 (t, J = 6.1 Hz, 2H), 4.34 (t, J = 6.1 Hz, 2H), 6.9-7.1 (m, 2H), 7.4-7.6 (m, 3H), 7.8-7.9 (m, 3H); ESI-MS m / z 227 (M + H) ⁺ ; HPLC purity 95.3%; Anal (C ₁₄ H ₁₂ BFO.0.1H ₂ O) C, H.

18.5 One- Phenyl -1,2,3,4- Tetrahydro -2,1- Benzoxaborin (23b)

This compound was synthesized in a similar manner to compound 9f from 22b and 7a : colorless oil; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.94 (t, J = 5.9 Hz, 2H), 4.21 (t, J = 5.9 Hz, 2H), 7.28 (t, J = 7.9 Hz, 2H ), 7.3-7.5 (m, 4H), 7.66 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H); ESI-MS m / z not observed; HPLC purity 96.0%; Assay (C ₁₄ H ₁₃ BO) C, H.

18.6 6- Fluoro -One- Hydroxy -1,2,3,4- Tetrahydro -2,1- Benzoxaborin (24)

This compound was synthesized from 22a in a similar manner to compound 19b . Silicagel column chromatography (2: 1 hexanes / ethyl acetate) followed by trituration with pentane gave 24 as white powder: mp 77-82 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.86 (t, J = 5.9 Hz, 2H), 4.04 (t, J = 5.9 Hz, 2H), 7.0-7.1 (m, 2H), 7.69 (dd, J = 8.2, 7.2 Hz, 1 H), 8.47 (s, 1 H); ESI-MS m / z 165 (M ⁻ H) ⁻ ; HPLC purity 99.0%; Assay (C ₈ H ₈ BFO ₂ ) C, H.

Example  19

Ethylene glycol Boronate  Formation of esters (3, no T =)

General procedure

Boronic acid was dissolved in anhydrous THF, anhydrous toluene or anhydrous diethyl ether (about 10 mL / g) under nitrogen. Ethylene glycol (1 molar equivalent) was added to the reaction solution and the reaction solution was heated to reflux for 1 to 4 hours. The reaction solution was cooled to room temperature and the solvent was removed under reduced pressure to leave ethylene glycol ester as oil or solid. In the case of an oil obtained or a solid dissolved in hexane, anhydrous hexane was added and removed under reduced pressure. The product was then placed under high vacuum for several hours. If a solid was obtained that did not dissolve in hexane, the solid was collected by filtration and washed with cold hexane.

3- Cyanophenylboronic acid  Ethylene glycol ester (3a)

3-cyanophenyl boronic acid (1 g, 6.8 mmol) was dissolved in dry THF (10 mL) under nitrogen. Ethylene glycol (379 μl, 422 mg, 6.8 mmol) was added and the reaction was heated to reflux for 4 hours and then cooled to room temperature. THF was removed by rotary evaporator to yield a white solid. Cold hexanes were added and the product was collected by filtration to give a white solid (1.18 g, quantitative yield). ¹ H NMR (300.058 MHz, DMSO-d ₆ ) δ ppm 7.92-8.01 (3H, m), 7.50-7.64 (1H, m), 4.35 (4H, s).

Thiophene 3- Boronic acid  Ethylene glycol ester (3b)

Thiophen-3-boronic acid (1 g, 7.8 mmol) was dissolved in dry THF (10 mL) under nitrogen. Ethylene glycol (435 μl, 484 mg, 7.8 mmol) was added and the reaction was heated to reflux for 1 hour and then cooled to room temperature. THF was removed by rotary evaporator to yield a white solid. Hexane was added to dissolve the solid and removed by rotary evaporation. The product was placed under high vacuum to give a tan solid (1.17 g, 97%). ¹ H NMR (300.058 MHz, CDCl ₃ ) δ ppm 7.93 (1H, s), 7.3-7.4 (2H, m), 4.35 (4H, s).

3- Fluorophenylboronic acid  Ethylene glycol ester (3c)

A mixture of 3-fluorophenylboronic acid (7.00 g, 50.0 mmol) and ethylene glycol (2.8 mL, 50 mmol) in toluene (200 mL) was heated to reflux for 3 hours under Dean-Stark conditions. . The solvent was removed under reduced pressure to give 3-fluorophenylboronic acid ethylene glycol ester (7.57 g, 91%).

Boronic acid  Asymmetry from Ethylene Glycol Ester Borin acid  (6) formation

General Procedure A: Grignard  Way

Boronic ethylene glycol ester was dissolved in dry THF (10-20 mL / g) under nitrogen. The solution was cooled to −78 ° C. in an acetone / dry ice bath or to 0 ° C. in an ice / water bath. Grignard reagent (0.95-1.2 molar equivalents) was added dropwise to the cooled solution. The reaction was allowed to warm to room temperature and stirred for 3-18 hours. 6 N HCl (2 mL / g) was added and the solvent was removed under reduced pressure. The product was extracted with diethyl ether (40 mL / g) and washed with water (3 times in the same volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed by rotary evaporation to afford the crude product, which was purified by column chromatography or used in the next step without purification. Alternative workup method: If the borinic acid product contained basic groups such as amines or pyridine, after stirring at room temperature for 3-18 hours, water (2 mL / g) was added and the pH was adjusted to 5-8. The product was extracted up to 3 times with diethyl ether or ethyl acetate or THF (40 mL / g). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed by rotary evaporation to afford the crude product, which was purified by column chromatography or used in the next step without purification.

(4- Cyanophenyl ) (3- Fluorophenyl ) Borin acid (6a)

4-cyanophenyl boronic acid ethylene glycol ester (500 mg, 2.89 mmol) was dissolved in dry THF under nitrogen. The solution was cooled to −78 ° C. in an acetone / dry ice bath and 3-fluorophenylmagnesium bromide (1 M in THF) (2.74 mL, 2.74 mmol, 0.95 molar equivalents) was added dropwise to the cold solution. The reaction was slowly warmed to room temperature and stirred for 18 hours. 6 N HCl (1 mL) was added to the reaction solution to cloud the appearance and the solvent was removed using a rotary evaporator. The product was extracted with diethyl ether (20 mL) and washed with water (3 × 20 mL). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed using a rotary evaporator to afford the crude product as an oily solid. This was used for next step without purification.

General procedure B: (hetero) aryl-lithium method

(Hetero) aryl-bromide or iodide was dissolved in dry THF (20-30 mL / g) under nitrogen and degassed. The solution was cooled to −78 ° C. in an acetone / dry ice bath and n-, sec- or tert-butyllithium (1.2-2.4 molar equivalents) in THF or other solvent was added drop wise to the cold solution (generally dark yellow in solution). To change to Boronic ethylene glycol ester (1 molar equivalent) was dissolved in dry THF or diethyl ether (2-10 mL / g) under nitrogen. Boronic acid ethylene glycol ester in THF was added dropwise to the cooled aryl-lithium solution (generally causing the solution to turn pale yellow). The reaction was allowed to warm to room temperature and stirred for 1-18 hours. 6 N HCl (2-4 mL / g) was added and the solvent was removed under reduced pressure. The product was extracted with diethyl ether (40 mL / g) and washed with water (3 times in the same volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed by rotary evaporation to afford the crude product, which was purified by column chromatography or used in the next step without purification. Alternative workup method: If the borinic acid product contained basic groups such as amines or pyridine, after stirring at room temperature for 3-18 hours, water (2 mL / g) was added and the pH was adjusted to 5-8. The product was extracted up to 3 times with diethyl ether or ethyl acetate or THF (40 mL / g) and washed with water (3 times in the same volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed by rotary evaporation to afford the crude product, which was purified by column chromatography or used in the next step without purification.

(3- Thienyl ) (3- Chlorophenyl ) Borin acid (6b)

3-Chloro-bromobenzene (447 μl, 728 mg, 3.8 mmol) was dissolved in dry THF (15 mL) under nitrogen. The solution was degassed and cooled to −78 ° C. in an acetone / dry ice bath. tert-butyllithium (1.7 M in THF) (4.47 mL, 7.6 mmol, 2 molar equivalents) was added dropwise to the cold solution to induce the solution to turn dark yellow. 3-thiophenboronic acid ethylene glycol ester (586 mg) was dissolved in anhydrous diethyl ether (1 mL) while the solution was stirred at -78 ° C. Thereafter, the boronic acid ester solution was added dropwise to the cold solution to induce the color to turn pale yellow. The reaction was allowed to warm to room temperature and stirred for 18 hours. 6 N HCl (2 mL) was added and the reaction stirred for 1 hour. Solvent was removed using a rotary evaporator. The product was extracted with diethyl ether (10 mL) and washed with water (2 × 10 mL). The organic layer was dried (MgSO ₄ ), filtered and the solvent removed using a rotary evaporator to afford the crude product as an orange oil. The product was purified by column chromatography using hexane: ethyl acetate 5: 1 as silica gel and eluent to afford the pure product (614 mg, 73%) as a clear oil.

(3- Chlorophenyl ) Vinyl boric acid (6c)

It was prepared by a method similar to that described for 6b by reaction of 3-cyanophenyl boronic acid ethylene glycol ester with vinyllithium.

(3- Fluoro -5- Chlorophenyl ) Ethynylborinic acid (6d)

It was prepared by a method similar to that described for 6b by reaction of 3-fluoro-5-chlorophenyl boronic acid ethylene glycol ester with ethynyl lithium.

(4- methyl -3- Chlorophenyl )(2- Thienyl ) Borin acid (6e)

It was prepared by a method similar to that described for 6b by the reaction of 2-thienylboronic acid ethylene glycol ester with 4-methyl-3-chlorophenyllithium.

(4- Cyanophenyl ) Ethynylborinic acid (6f)

It was prepared by a method similar to that described for 6b by reaction of 4-cyanophenylboronic acid ethylene glycol ester with ethynyl lithium.

(3- Fluorophenyl ) Cyclopropylborinic acid (6 g)

It was prepared by a method similar to that described for 6b by reaction of 3-fluorophenylboronic acid ethylene glycol ester with cyclopropyllithium.

(3- Thienyl ) Methylborinic acid (6h)

It was prepared by a method similar to that described for 6b by reaction of 3-thienylboronic acid ethylene glycol ester with methyllithium.

(4- Pyridyl ) Phenylborinic Acid (6i)

It was prepared by a method similar to that described for 6b by reaction of phenylboronic acid ethylene glycol esters with 4-pyridylithium.

(3- Cyanophenyl )(2- Fluorophenyl ) Borin acid (6j)

It was prepared by a method similar to that described for 6b by reaction of 3-cyanophenylboronic acid ethylene glycol ester with 2-fluorophenyllithium.

4-( Dimethylaminomethyl ) Phenyl  3- Fluorophenyl Borin acid (6k)

sec-butyllithium (1.4 M in cyclohexane, 6.0 mL) was added to a solution of N, N-dimethyl-4-bromobenzylamine (1.50 g, 7.00 mmol) in THF (14 mL) at −78 ° C. under a nitrogen atmosphere. Was added and the mixture was stirred for 15 minutes. 3-fluorophenylboronic acid ethylene glycol ester (1.16 g, 7.00 mmol) in THF (7 mL) was added to the mixture. The reaction was allowed to warm to room temperature and stirred for 1 hour. Water was added and the mixture was washed with ether. The pH was adjusted to 8 with 1 M hydrochloric acid. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give borin acid (890 mg, 49%).

With organic metals Trialkyl Borate  Symmetry by Reaction Borin acid  (5) formation

Bis (4-chlorophenyl) borinic acid (5a) ( procedure C )

A cold solution (-78 ° C.) of trimethyl borate (0.37 mL) in anhydrous tetrahydrofuran (THF, 25 mL) was treated by dropwise addition of 4-chlorophenylmagnesium bromide (6.75 mL, 1 M solution in ether). The reaction mixture was stirred at -78 ° C for 1 hour and then at room temperature for 18 hours. The solvent was removed under reduced pressure. The resulting residue was stirred with 100 ml of ether and 15 ml of 6 N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ether (2 × 100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed to give a pale yellow solid. The product was chromatographed on silica gel (hexane: ether = 1: 1) to give 420 mg of boric acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 5.84 (s, OH), 7.46 (d, 4H, Ar—H), 7.72 (d, 4H, Ar—H).

Bis (3-chloro-4-methylphenyl) borinic acid (5b)

In a similar manner to that for 5a, the title compound was obtained from the reaction of 3-chloro-4-methylphenylmagnesium bromide with trimethyl borate. The product was obtained by chromatography on silica gel.

Bis (3-fluoro-4-methylphenyl) borinic acid (5c)

In a similar manner to that for 5a, the title compound was obtained from the reaction of 3-fluoro-4-methylphenyllithium with trimethyl borate. The product was obtained by chromatography on silica gel.

Bis (3-chloro-4-methoxyphenyl) borinic acid (5d)

In a similar manner to that for 5a, the title compound was obtained from the reaction of 3-chloro-4-methoxyphenyllithium with trimethyl borate. The product was obtained by chromatography on silica gel.

Bis (3-fluoro-4-methoxyphenyl) borinic acid (5e)

In a similar manner to that for 5a, the title compound was obtained from the reaction of 3-fluoro-4-methoxyphenyllithium with trimethyl borate. The product was obtained by chromatography on silica gel.

With organic metals Alkyl  (Or aryl or Alkenyl ) Dialkoxyborane  Asymmetry by Reaction Borin acid  (6) formation

(4 -Chloro - phenyl ) methyl - borinic acid (6m) ( procedure D )

Di (isopropoxy) methylborane (1 mL, 0.78 g) was added dropwise via syringe to 4-chlorophenylmagnesium bromide (5.5 mL, 1 M solution in ether) at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour and then at ambient temperature overnight. The reaction mixture was treated dropwise with 100 ml of ether and 15 ml of 6 N hydrochloric acid and stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with ether (2 × 100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.1 g of oil. ¹ H NMR of the product was consistent with (4-chlorophenyl) methyl borin acid.

(4- Fluorophenyl ) Methylborinic acid (6n)

In a similar manner to that for 6m, the title compound was obtained from the reaction of 4-fluorophenylmagnesium bromide with di (isopropoxy) methylborane. The product was obtained by chromatography on silica gel.

(4-biphenyl) Methylborinic acid (6o)

In a similar manner to that for 6m, the title compound was obtained from the reaction of 4-biphenyllithium with di (isopropoxy) methylborane. The product was obtained by chromatography on silica gel.

(3- Chloro -4- Methylphenyl ) Methylborinic acid (6p)

In a similar manner to that for 6m, the title compound was obtained from the reaction of 3-chloro-4-methylphenyllithium with di (isopropoxy) methylborane. The product was obtained by chromatography on silica gel.

(3- Chloro -4- Methoxyphenyl ) Methylborinic acid (6q)

In a similar manner to that for 6m, the title compound was obtained from the reaction of 3-chloro-4-methoxyphenyllithium with di (isopropoxy) methylborane. The product was obtained by chromatography on silica gel.

(4- Dimethylaminophenyl ) Methylborinic acid (6r)

In a similar manner to that for 6m, the title compound was obtained from the reaction of 4-dimethylaminophenyllithium with di (isopropoxy) methylborane. The product was obtained by chromatography on silica gel.

(3- Pyridyl ) Vinyl boric acid (6s)

Isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) is added to a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) at room temperature under a nitrogen atmosphere, and the mixture is 1 Stir for hours. Vinylboronic acid dibutyl ester (3.4 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 18 hours. Water was added and pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).

(3- Chloro -4- Dimethylaminophenyl ) Vinyl boric acid (6t)

In a similar manner to that for 6s, the title compound was obtained from the reaction of 3-chloro-4-dimethylaminophenyllithium with vinylboronic acid dibutyl ester. The product was obtained by chromatography on silica gel.

Borin acid - Alkyl alcohol  derivative

Bis (3-chlorophenyl) borinic acid  4- (hydroxyethyl) Imidazole  ester (121)

To a solution of bis (3-chlorophenyl) borinic acid (0.4 g, 1.428 mmol) in ethanol (10 mL) 4- (hydroxyethyl) imidazole hydrochloride (0.191 g, 1.428 mmol), sodium bicarbonate (0.180 g, 2.143 mmol) was added and the reaction mixture was stirred at rt for 18 h. Salt was removed by filtration. The filtrate was concentrated and treated with hexanes to give the product as a solid and collected by filtration (450 mg, 84.9% yield). ¹ H NMR (CD ₃ OD) δ (ppm) 2.92 (t, 2H), 3.82 (t, 2H), 7.0-7,2 (m, 9H), 7.90 (s, 1H); (ES ⁻ ) (m / z) 343.11, MF C ₁₇ H ₁₅ BCl ₂ N ₂ O.

Bis (4-chlorophenyl) borinic acid  4-( Hydroxymethyl ) Imidazole  ester (126)

In a similar manner as in Example 121, the title compound was obtained from the reaction of bis (4-chlorophenyl) borinic acid and 4- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals. (ES ⁻ ) (m / z) 328.79, MF C ₁₆ H ₁₃ BCl ₂ N ₂ O.

Bis (3-chloro-4-methylphenyl) borinic acid  1-benzyl-4- ( Hydroxymethyl ) Imidazole  ester (127)

To bis (3-chloro-4-methylphenyl) borinic acid (121 mg, 0.521 mmol) was added to a solution of 1-benzyl-4- (hydroxymethyl) imidazole (96 mg, 0.521 mmol) in methanol (5 mL). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was treated with hexane to give a solid. The product was isolated by filtration and washed with hexane to give the product (193 mg, 83%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.3 (s, 6H, 2 × CH ₃ ), 4.8 (brs, 2H, CH ₂ ), 5.1 (brs, 2H, CH ₂ ), 6.9-7.4 (complex, 13H, Ar-H); MS (ES ⁺ ) (m / z) 448.78, MF C ₂₅ H ₂₃ BCl ₂ N ₂ O.

Bis (3-chloro-4-methylphenyl) borinic acid  One- methyl -2-( Hydroxymethyl ) Imidazole  ester (128)

In a similar manner as in Example 127, the title compound was obtained from the reaction of bis (3-chloro-4-methylphenyl) borinic acid with 1-methyl-2- (hydroxy-methyl) imidazole hydrochloride. The product was obtained as white crystals. (ES ⁺ ) (m / z) 372.82, MF C ₁₉ H ₂₁ BCl ₂ N ₂ O.

Bis (3-chloro-4-methylphenyl) borinic acid  1-ethyl-2- ( Hydroxymethyl ) Imidazole  ester (129)

In a similar manner as in Example 127, the title compound was obtained from the reaction of bis (3-chloro-4-methylphenyl) borinic acid with 1-ethyl-2- (hydroxy-methyl) imidazole hydrochloride. The product was obtained as white crystals. (ES ⁺ ) (m / z) 386.83, MF C ₂₀ H ₂₃ BCl ₂ N ₂ O.

Bis (3-chloro-4-methylphenyl) borinic acid  One- methyl -4-( Hydroxymethyl ) Imidazole  ester (130)

In a similar manner as in Example 127, the title compound was obtained from the reaction of bis (3-chloro-4-methylphenyl) borinic acid with 1-methyl-4- (hydroxy-methyl) imidazole hydrochloride. The product was obtained as white crystals. (ES ⁺ ) (m / z) 372.88, MF C ₁₉ H ₂₁ BCl ₂ N ₂ O.

Bis (3-chloro-4-methylphenyl) borinic acid  2- Pyridylethanol (131)

In a similar manner as in Example 121, the title compound was obtained from the reaction of bis (3-chloro-4-methylphenyl) borinic acid and 2-pyridylethanol. The product was obtained as white crystals. (ES ⁺ ) (m / z) 383.84, MF C ₂₁ H ₂₀ BCl ₂ NO.

Hydroxyquinoline  derivative

Bis (3-chlorophenyl) borinic acid  5- Cyano -8- Hydroxyquinoline  ester  (19)

To a solution of bis (3-chlorophenyl) borinic acid (0.25 g) in ethanol (5 mL) and water (2 mL) was added 5-cyano-8-hydroxyquinoline (0.15 g). The solution was stirred at rt for 21 h. A yellow solid precipitate formed which was collected by filtration and washed with cold ethanol. The product was obtained as yellow crystals. ¹ H NMR (DMSO) δ: (ppm) 7.24-7.35 (m, 8H), 7.38 (d, 1H), 8.18 (dd, 1H), 8.40 (d, 1H), 8.86 (d, 1H), 9.50 ( d, 1H).

(3- Chlorophenyl )(2- Thienyl ) Borin acid  8- Hydroxyquinoline  ester (36)

To a solution of (3-chlorophenyl) (2-thienyl) borinic acid (1.5 g) in ethanol (2 mL) was added 8-hydroxyquinoline (0.77 g) in hot ethanol (2 mL). The reaction solution was heated to reflux and cooled to room temperature. A yellow solid precipitated out. The mixture was cooled in ice, the solids were collected by filtration and washed with cold ethanol. The product was obtained as a yellow solid (1.01 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ: (ppm) 6.98-7.06 (m, 2H), 7.19-7.26 (m, 3H), 7.38-7.50 (m, 4H), 7.71 (t, 1H), 7.91 (dd, 1H), 8.80 (d, 1H), 9.18 (d, 1H); (ESI ⁺ ) (m / z) 350.1, MF C ₁₉ H ₁₃ BClNOS.

(2- Thienyl ) Methylborinic acid  8- Hydroxyquinoline  ester (26)

In a similar manner as in Example 36, the title compound was obtained from the reaction of (2-thienyl) borinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals.

(3- Cyanophenyl ) Vinyl boric acid  8- Hydroxyquinoline  ester 40

In a similar manner as in Example 36, the title compound was obtained from the reaction of (3-cyanophenyl) vinylborinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals. (ESI ⁺ ) (m / z) 285.1, MF C ₁₈ H ₁₃ BN ₂ O.

(2- Chlorophenyl ) Ethynylborinic acid  8- Hydroxyquinoline  ester (43)

In a similar manner as in Example 36, the title compound was obtained from the reaction of (2-chlorophenyl) ethynylborinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals. (ESI ⁺ ) (m / z) 292.1, MF C ₁₇ H ₁₁ BClNO.

Bis (ethynyl) borinic acid  8- Hydroxyquinoline (44)

In a similar manner as in Example 36, the title compound was obtained from the reaction of bis (ethynyl) borinic acid with 8-hydroxyquinoline. The product was obtained as pale yellow crystals. (ESI ⁺ ) (m / z) 206.1, MF C ₁₃ H ₈ BNO.

(3- Fluorophenyl ) Cyclopropylborinic acid  8- Hydroxyquinoline  ester (70)

In a similar manner as in Example 36, the title compound was obtained from the reaction of (3-fluorophenyl) cyclopropylborinic acid with 8-hydroxyquinoline. The product was obtained as pale yellow crystals. (ES ⁻ ) (m / z) 291.05, MF C ₁₈ H ₁₅ BFNO.

(3- Pyridyl ) Vinyl boric acid  8- Hydroxyquinoline  ester (99)

A solution of (3-pyridyl) vinyl borin acid (1.04 g, 7.82 mmol) and 8-hydroxyquinoline (961 mg, 6.63 mmol) in ethanol was stirred at 40 ° C. for 20 minutes. The solvent was removed under reduced pressure and the residue was crystallized from diethyl ether / diisopropyl ether / hexanes to give the title product (99) as a pale yellow powder (355 mg, 21%). ¹ H NMR (DMSO ₆ ) δ: (ppm) 5.23 (dd, 1H), 5.46 (dd, 1H), 6.43 (dd, 1H), 7.14 (d, 1H), 7.19 (dd, 1H), 7.41 (d , 1H), 7.6-7.8 (m, 2H), 7.88 (dd, 1H), 8.35 (dd, 1H), 8.57 (s, 1H), 8.76 (d, 1H), 9.00 (d, 1H); ESI ⁺ (m / z) 261, MF C ₁₆ H ₁₃ BN ₂ O.

(4-( Dimethylaminomethyl ) Phenyl ) (3- Fluorophenyl ) Borin acid  8- Hydroxyquinoline  ester (100)

In a similar manner as in Example 99, the title compound was obtained from the reaction of (4- (dimethylaminomethyl) phenyl) (3-fluorophenyl) borinic acid with 8-hydroxyquinoline. The product was obtained as pale yellow crystals. ESI ⁺ (m / z) 385, MF C ₂₄ H ₂₂ BFN ₂ O.

3- Hydroxypicolinic acid  derivative

Bis (3-chloro-4-methylphenyl) borinic acid  3- Hydroxypicolinate  ester (111)

Bis (3-chloro-4-methylphenyl) borinic acid (14.6 g) was dissolved in ethanol (120 mL) and heated to reflux. 3-hydroxypicolinic acid (5.83 g) was added portionwise to the hot solution. After addition of the last portion of 3-hydroxypicolinic acid, the reaction was stirred under reflux for 15 minutes and then cooled to room temperature. Part of the ethanol was removed to concentrate the reaction solution. The solid was removed by filtration. Recrystallization from ethanol gave the title product as white crystals (13.4 g). MP = 165.0-166.5 ° C.

Example  20

Anti-inflammatory activity data for 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane

Proinflammatory Cytokines : THP -1 cell, LPS  @ 1mg / ml, 24 hours

TNF-α: 2.7 μΜ; IL-1β: 1.0 μM; IL-6: 5.3 μΜ; IL-8: 9.6 μM

TH1 Cytokines : PBMC , PHA  @ 20 mg / ml, 24 hours

IFN-g:> 25 μM; IL-2:> 25 μM

TH2 Cytokines : PBMC , PHA  @ 20 mg / ml, 24 hours

IL-4:> 25 μM; IL-5: 9.3 μΜ; IL-10: 14.5 μM; IL-13:> 10 μM

Adjustability Cytokines : PBMC , PHA  @ 10 mg / ml, 24 hours

IL-3:> 10 μM

Example  21

Calcium sulfate Dihydrate  And about 0.5 wt .% 3- Hydroxypyridine -2- Carbonyl -Bis (3- Claw Low-4- Methylphenyl )-Boran ( Bis (3-chloro-4-methylphenyl) boronic acid  3- Hydroxypicoline Cream dentifrice composition)

Cream toothpaste formulations according to the invention are prepared as follows.

To a suitable metering container 6 ml grapefruit oil, 2 ml citric oil, 2 ml sweet orange oil, 2 ml peppermint oil and 2 ml eucalyptus oil are added and the fragrance oil is mixed at ambient temperature. Thereafter, concentrated liquid paraffin [food grade] (also known as mineral oil) is added in an amount sufficient to bring the total volume of the mixture to 100 ml. The oil components are mixed to form a homogeneous solution. This is the basic aromatic oil component for use in the cream toothpaste described in the present invention.

To 30 g fine powdered gypsum (calcium sulfate dihydrate, pure for food production industry) 0.2 g 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3- Chloro-4-methylphenyl) boronic acid 3-hydroxypicolinate ester) is added as a dry solid powder. The two solids are mixed to form a homogeneous solid and then 12 g of the aromatic oil component obtained above are added. The composition of powder and oil are mixed together to form a smooth paste. After that, the paste is filled into the tube.

Example  22

Calcium sulfate Dihydrate  And about 5.0 wt .% 3- Hydroxypyridine -2- Carbonyl -Bis (3- Chloro 4-M Tilfe Neil) -borane ( Bis (3-chloro-4-methylphenyl) boronic acid  3- Hydroxypicolinate  Cream toothpaste composition)

The paste composition of Example 21 was reformed, wherein 2.2 g of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro) was used in the same manner as described. 4-methylphenyl) boronic acid 3-hydroxypicolinate ester) is used. The paste is formed into a smooth paste as described above and filled into the tube.

Example  23

Calcium sulfate Dihydrate , About 5.0 wt .% 3- Hydroxypyridine -2- Carbonyl -Bis (3- Chloro 4-M Tilfe Neil) -borane ( Bis (3-chloro-4-methylphenyl) boronic acid  3- Hydroxypicolinine Cream and toothpaste composition containing glycerin)

To 60 g of fine powdery gypsum (as in Example 21) 1.2 g of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4- Methylphenyl) boronic acid 3-hydroxypicolinate ester) is added as a dry solid powder and the two solids are mixed together to form a homogeneous powder. This solid powder is then mixed with 32 g of oil component (prepared as in Example 21) for 30 minutes. A smooth semi-liquid paste is produced. To this paste 4 g of glycerin (available from many commercial sources) is added and the mixing is continued for an additional 30 minutes. The product paste is filled into aluminum tubes and prepared for use.

Example  24

About 0.5 wt .% 3- Hydroxypyridine -2- Carbonyl - Vis (3- Chloro -4- Methylphenyl ) -Borane (bis (3- Chloro-4-methylphenyl) Boronic Acid 3- Hydroxypicolinate  Esters) Waterborne

Water-soluble agents are prepared in the following manner in the following manner:

% w / w

Sorbitol 70% Solution (Non-crystalline) 5

Ethanol 96% BP (volume%) 7

Sodium Saccharin BP Crystals (76% Sac) 0.02

Polyethylene Glycol-40 Hydrogenated Castor Oil 0.15

(Brand name Croduret 40 ET 0080

Available as DF)

Sodium Fluoride BP 0.05

Sodium Benzoate BP 0.1

Blue 12401 Anst 0.0006

Yellow 2G Anst 0.00055

Bentonite BP 1 Oral Mouth Flavor Flavor (Volume%) 0.1

Boron-containing compound (3-hydroxypyridine-2-carbonyl-0.5

Bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-

4-methylphenyl) boronic acid 3-hydroxypicolinate ester)

100.0% of the total purified water

The water soluble agent is first mixed with ethanol and water at room temperature, and then the additional components in the formulation, surfactants, flavoring agents, wetting agents, copolymers and boron-containing compounds, are mixed with the aqueous alcoholic medium. Thereafter, the processed hydrous is filtered as necessary.

Example  25

About 0.3 wt .% 3- Hydroxypyridine -2- Carbonyl - Vis (3- Chloro -4- Methylphenyl ) -Borane (bis (3- Chloro-4-methylphenyl) boronic acid  3- Hydroxypicolinate  Cream toothpaste)

Cream toothpaste is prepared in the usual manner with the following composition:

% wt

Precipitated Silica 25.0

Gelled Silica 2.0

Sorbitol 20.0

Propylene Glycol 2.5

Sodium Carboxymethyl Cellulose 1.0

Lauryl diethanol amide 1.0

Sodium Lauryl Sulfate 1.5

Sodium Lauroyl Sarcosinate 0.3

Sodium saccharin 0.1

Boron-containing compound (3-hydroxypyridine-2-carbonyl- 0.3

Bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-

4-methylphenyl) boronic acid 3-hydroxypicolinate ester)

Stanus Gluconate 0.3

Gelatin 0.2

Spices 0.8

100.0% of the total purified water

The components are mixed at room temperature to form a homogeneous smooth paste. After that, the paste is filled into the tube.

Example  26

MIC  exam

All MIC tests were conducted on Malassezia species grown in urea gravy [Nakamura et. al ., Antimicrobial Agents and Chemotherapy , 2000 , 44 (8) p. 2185-2186 except yeast (M27-A2 NCCLS) and filamentous fungi [Pfaller et al ., NCCLS publication M38-A-Reference Method for Broth Dilution Antifungal Susceptibility Testing of filamentous Fungi; Approved Standard. Wayne, PA: NCCLS; 2002 (Vol 22, No. 16)], according to the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS) for antimicrobial testing. The results of the MIC test are shown in FIG.

Compounds of the invention are evaluated for their antimicrobial activity according to the instructions and procedures directed by the National Committee for Clinical Laboratory Standards (NCCLS). NCCLS Document M7-A #, 1993-Antimicrobial Susceptibility Resting.

MIC  Protocol for Measurement

Useful protocols for MIC measurements include:

1. About 2.5 mg of the compound to be tested was weighed into cryovials.

2. A 5 mg / ml stock solution was prepared by correspondingly adding DMSO to the sample.

3. A 256 μg / ml working solution was prepared by using a 5 mg / ml stock solution and correspondingly adding sterile distilled water.

4. The Beckman 2000 Automated Workstation was programmed to mount 96 well plates with gravy and compound as follows:

100 μl of appropriate broth was added to columns 1-11;

200 μl of appropriate broth was added to column 12;

100 μl of compound was added to column 1 with 256 μg / ml working solution (one compound per column);

2-fold series dilution was performed in columns 1 to 10;

Column 11 served as a growth control.

5. 10 organism panels were plated from storage vials stored at −80 ° C. and incubated at 34 ° C. for 24 hours. The organisms were then subcultured and incubated at 34 ° C. for 24 hours.

Inoculum was first prepared in sterile distilled water with a target of 0.09-0.11 absorbance at 620 nm wavelength.

{Fraction (1/100)} Dilution was made in appropriate broth.

100 μl of broth with organisms was added to columns 1-11.

Column 12 served as a blank control.

6. The completed 96 well plates were incubated at 34 ° C. for 24 hours. 96 well plates were then read using a Beckman Automated Plate Reader at 650 nm wavelength. MIC was determined through calculations involving growth control (column 11) and empty control (column 12).

In vitro  Antifungal MIC  Protocol for Measurement

Protocols useful for measuring antifungal activity are described below.

Produce:

Medium is prepared 1-2 weeks before the start of the experiment. Medium is stored in the refrigerator (4 ° C.) before use.

Sabouraud Dextrose Agar Plate:

1. Dextrose agar medium was added to 1 L of dH ₂ O with gentle stirring with 65 g of powdered sand.

2. Autoclaved at 121 ° C. and 22 psi for 15 minutes;

3. The medium was cooled to about 50 ° C;

4. The medium was poured into a 100 x 15 mm sterile Petri dish in a 20 ml aliquot.

RPMI 1640 + MOPS Juicy:

1. 1 packet of powdered RPMI medium was added to 1 L of dH ₂ O (15 ° C.-30 ° C.) with gentle stirring;

2. 2 g of NaHCO ₃ was added;

3. 34.5 g MOPS was added;

4. Adjust pH to 7.0 with NaOH or HCl;

5. Sterilized by membrane filtration (0.22 micron cellulose acetate filter).

Sterile Saline (0.9%):

1. 9 g of NaCl was dissolved in 1 L of dH ₂ O;

2. Autoclaved at 121 ° C. and 22 psi for 15 minutes.

Sterile dH ₂ O:

1. dH ₂ O was autoclaved at 121 ° C. and 22 psi for 15 minutes.

step:

1.Plate 10 panels of organisms from storage vials stored at −80 ° C. (suspend in juice with 20% glycerin) and incubate at 37 ° C. for 24 hours. Subsequently, the organism is passage-cultured and incubated at 37 ° C. for 24 hours. These can be used to prepare fresh inoculum for step 6.

2. Add about 2.5 mg of the compound to be tested to a 2 ml cryovial. Fluconazole, amphotericin B and itraconazole are tested as reference compounds.

3. Prepare 5 mg / ml stock solutions by correspondingly adding DMSO to the samples. Compounds that are insoluble only by vortexing are sonicated.

4. A 256 μg / ml working solution is prepared by using a 5 mg / ml stock solution and correspondingly adding sterile distilled water.

5. Use 96-well plates for MIC measurements. Each of the eight columns can be used to test different compounds. Compounds are loaded into the first column and 2-fold dilutions take place in columns 1-10. Column 11 is a growth control (no compound) and column 12 is a blank control (no compound or organism). Manual addition of broth and compound is carried out as follows:

100 μl of RPMI + MOPS broth is added to columns 1-11;

200 μl of RPMI + MOPS broth is added to column 12;

100 μl of compound is added to column 1 with 256 μg / ml working solution (one compound per column);

2-fold series dilution takes place in columns 1 to 10;

Column 11 serves as a growth control (only medium + organic).

6. Prepare fresh inoculum for testing on 96-well plates using passage-cultured organisms. Each 96-well plate will test different organisms.

Inoculum is prepared by sterile saline using colonies from the passage-culture organism (step 1). The target is to adjust to 70-75% transmittance at 530 nm wavelength using Novospec II spectrophotometer.

{Fraction (1/100)} Dilution takes place in RPMI + MOPS gravy.

Add 100 μl of this broth with organisms to columns 1-11 (column 12 serves as a co-control).

7. Incubate the completed 96-well plate at 37 ° C. for 24 hours. 96 well plates are then read using a Biomek automated plate reader for absorbance at 650 nm wavelength.

Calculation:

Absorbance readings from the biomex automated plate reader are used to determine the inhibition rate for each test well. The equation used is:

Inhibition% = [1- (ABS _{Test Group} -ABS _{Air Control} ) / (ABS _{Average Growth} -ABS _{Air Control} )] × 100%

ABS _{test group} : absorbance of test well

ABS _{ball control:} Absorbance of the ball control wells on the same column (column 12) and the test wells

ABS _{Average Growth} : Average Absorbance of Growth Control Wells (Column 11)

The minimum inhibitory concentration (MIC) is identified as the lowest concentration of the compound when the inhibition rate is 80% or higher.

Accordingly, the present invention is generally referred to as borin acid complex and most preferably provides antibiotics derived from disubstituted borin acid.

All patents, patent applications, and other documents cited in this application are incorporated by reference in their entirety.

Claims (24)

An oral care composition comprising a compound having a structure according to one of Formulas 1, 2a, 2b, 2c, and 2d, including salts:

From here, B is boron; O is oxygen; R ^* and R ^** are each independently substituted or unsubstituted alkyl (C ₁ -C ₄ ), substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ), substituted or unsubstituted alkenyl, substituted or unsubstituted Ring alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; z is 0 or 1 and when z is 1, A is CH, CR ¹⁰ or N; D is N, CH or CR ¹² ; E is H, OH, alkoxy or 2- (morpholino) ethoxy, CO ₂ H or CO ₂ alkyl; m is 0-2; r is 1 or 2, wherein when r is 1 G is = O (double-bonded oxygen), and when r is 2 each G is independently H, methyl, ethyl or propyl; R ¹² is (CH ₂ ) _k OH, where k is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN , Halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ and CONH ₂ ; J is CR ¹⁰ or N; R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl, cycloalkyl, (CH ₂ ) _n OH (n is 2 to 3), CH ₂ NH ₂ , CH ₂ NHalkyl, CH ₂ N (alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , NH ₂ , alkoxy, CF ₃ , SCF ₃ , NO ₂ , SO ₃ H and OH. The oral care composition of claim 1, which is a member selected from a water soluble agent, toothpaste, liquid whitening agent, chewing gum, soluble, partially soluble, non-soluble film or strip, wipe or towelette, implant and floss. The oral care composition of claim 2, wherein the toothpaste is a member selected from powders, cream toothpastes and dental gels. The oral care composition of claim 1, wherein the compound is present in a therapeutically effective amount. The oral care composition of claim 1, wherein the compound is present in an amount from about 0.1% wgt / wgt to about 5% wgt / wgt. The oral care composition of claim 1, wherein the compound is present in an amount from about 0.3% wgt / wgt to about 0.6% wgt / wgt. The oral care composition according to claim 2, wherein the compound has a structure according to the formula:

Where m is zero. The oral care composition of claim 2, wherein the compound has a structure according to the formula:

8. The oral care composition of claim 7, wherein E is OH, R ⁹ is H, and R ^* and R ^** are independently selected from substituted or unsubstituted phenyl. 10. The oral care composition of claim 9, wherein R ^* and R ^** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. 11. The oral care composition of claim 10, wherein R ^* and R ^** are 4-methyl, 3-chloro phenyl. The oral care composition of claim 11, wherein the compound is present in an amount from about 0.3% wgt / wgt to about 0.6% wgt / wgt. Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Treponema species, Buleydia ( Bulleidia ), Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptococcus species, Peptostreptococcus species , A microorganism selected from Capnocytophaga species, Fusobacterium species, Porphyromonas species, and Bacteroides species in a therapeutically effective amount of Killing or inhibiting growth of the microorganism, including contacting a compound having a structure according to one of 2a, 2b, 2c and 2d (including salts) Methods:

From here, B is boron; O is oxygen; R ^* and R ^** are each independently substituted or unsubstituted alkyl (C ₁ -C ₄ ), substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ), substituted or unsubstituted alkenyl, substituted or unsubstituted Ring alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; z is 0 or 1 and when z is 1, A is CH, CR ¹⁰ or N; D is N, CH or CR ¹² ; E is H, OH, alkoxy or 2- (morpholino) ethoxy, CO ₂ H or CO ₂ alkyl; m is 0-2; r is 1 or 2, wherein when r is 1 G is = O (double-bonded oxygen), and when r is 2 each G is independently H, methyl, ethyl or propyl; R ¹² is (CH ₂ ) _k OH, where k is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN , Halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ and CONH ₂ ; J is CR ¹⁰ or N; R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl, cycloalkyl, (CH ₂ ) _n OH (n is 2 to 3), CH ₂ NH ₂ , CH ₂ NHalkyl, CH ₂ N (alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , NH ₂ , alkoxy, CF ₃ , SCF ₃ , NO ₂ , SO ₃ H and OH. The method of claim 13, wherein the microorganism is Actinobacillus ( Actinobacillus) actinomycetemcomitans ), Porphyromonas gingivalis , Tannerella forsythensis ), Prevotella intermedia intermedia ), Eubacterium nodatum ), Treponema denticola , Bulleidia extructa ), Mosquitobacterium Timidum ( Mogibacterium) timidum ), Slackia exigua ), Campylobacter rectus ), Eikenella corrodens , Peptostreptococcus micros ), Peptostreptococcus anerobius anaerobius ), Capnocytophaga ( Capnocytophaga) ochracea ), Fusobacterium nucleatum , Porphyromonas ascarolica ( Porphyromonas) asaccharolytica) and Park City Fort Des teroyi tooth (Bacteroides forsythus ). The method of claim 13, wherein the compound has a structure according to the formula:

Where m is zero. The method of claim 15, wherein E is OH, R ⁹ is H, and R ^* and R ^** are independently selected from substituted or unsubstituted phenyl. The method of claim 16, wherein R ^* and R ^** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. 18. The method of claim 17, wherein R ^* and R ^** are 4-methyl, 3-chloro phenyl. Treating or preventing periodontal disease in a human or animal, comprising administering to the human or animal a therapeutically effective amount of a compound having a structure according to one of the following Formulas 1, 2a, 2b, 2c, and 2d, including salts: Way:

From here, B is boron; O is oxygen; R ^* and R ^** are each independently substituted or unsubstituted alkyl (C ₁ -C ₄ ), substituted or unsubstituted cycloalkyl (C ₃ -C ₇ ), substituted or unsubstituted alkenyl, substituted or unsubstituted Ring alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; z is 0 or 1 and when z is 1, A is CH, CR ¹⁰ or N; D is N, CH or CR ¹² ; E is H, OH, alkoxy or 2- (morpholino) ethoxy, CO ₂ H or CO ₂ alkyl; m is 0-2; r is 1 or 2, wherein when r is 1 G is = O (double-bonded oxygen), and when r is 2 each G is independently H, methyl, ethyl or propyl; R ¹² is (CH ₂ ) _k OH, where k is 1, 2 or 3, CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN , Halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° -amino, 3 ° -amino, NH ₂ SO ₂ and CONH ₂ ; J is CR ¹⁰ or N; R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl, cycloalkyl, (CH ₂ ) _n OH (n is 2 to 3), CH ₂ NH ₂ , CH ₂ NHalkyl, CH ₂ N (alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, SO ₂ N (alkyl) ₂ , SO ₂ NHalkyl, SO ₂ NH ₂ , NH ₂ , alkoxy, CF ₃ , SCF ₃ , NO ₂ , SO ₃ H and OH. The method of claim 19, wherein the compound has a structure according to the formula:

Where m is zero. The method of claim 20, wherein E is OH, R ⁹ is H, and R ^* and R ^** are independently selected from substituted or unsubstituted phenyl. The method of claim 21, wherein R ^* and R ^** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. The method of claim 22, wherein R ^* and R ^** are 4-methyl, 3-chloro phenyl. 20. The method of claim 19, wherein said periodontal disease is a member selected from gingivitis, periodontitis and juvenile / acute periodontitis.

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