BRPI0713010A2 - compounds for the treatment of periodontal disease - Google Patents

Abstract

COMPOUNDS FOR THE TREATMENT OF PERIODONTAL DISEASE. Compounds, compositions and methods are provided that are useful in the treatment of periodontal disease.

Description

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COMPOSIENTS FOR TREATMENT OF PERIODONTAL DISEASE

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I Cross-reference to related orders

This application claims priority for Serial Provisional Patent Application No. 60 / 823,893, filed August 29, 2006, and 60 / 804,504 filed June 12, 2006, which are hereby incorporated in their entirety for all purposes by reference. Background of the invention

Bacterial infections of the mouth include gum inflammation, gingivitis, and periodontal inflammation, periodontitis. Bacterial plaque and bacterial toxins that accumulate below the gum line can cause gum inflammation called gingivitis. Inflammation of the gums involves the influx of lymphocytes and macrophages into the gum tissue and their release of proinflammatory cytokines (TNFα and IL1b) and matrix metalloproteases (MMPs). Periodontitis, or pyorrhea, is a condition that involves chronic inflammation of the gums, often persisting unnoticed for years or decades in a patient, which results in the loss of connective tissue and / or bone that supports the tooth. It is a bone loss around the tooth that differentiates these two oral inflammatory diseases. The loss of the surrounding bone, which supports the tooth in the jaw, can result in "loose" teeth over the years, and so they fall out. Although gingivitis is reversible with antibacterial and / or anti-inflammatory treatments and good oral hygiene, periodontitis is irreversible. However, progression can be significantly impeded or retarded with appropriate treatment. Periodontitis is the second most important cause, after tooth decay, of tooth loss.

The development of new compounds and methods for treating mouth infections, such as those involving bacteria, viruses, fungi and / or parasites, should represent a significant advance in the technique. This development, and others, are focused on by the present invention. Summary of the invention

In a first aspect, the invention provides an oral hygiene composition comprising a compound described herein. In an exemplary embodiment, the oral hygiene composition is a selected member of an oral rinse, dentifrice, liquid whitener, chewing gum, partially dissolvable or non-dissolvable dissolvable strip or film, handkerchief, implant, dental floss. In an exemplary embodiment, the oral care composition is a selected member of a toothpaste, prophylactic paste, tooth polish, gel, professional gel, and other related dentist-applied products, as well as mouthwash, dental floss, chewing gum. , lozenge, tablet, edible food product and others. In an exemplary embodiment, the toothpaste is a selected member of a powder, toothpaste and dental gel. In one exemplary embodiment, the compound is present in a therapeutically effective amount. In one exemplary embodiment, the compound is present in an amount from about 0.1 wt% compound / weight of the oral hygiene composition to about 5 wt% compound / weight of the oral hygiene composition. In one exemplary embodiment, the compound is present in an amount from about 0.3 wt% compound / weight of the oral hygiene composition to about 0.6 wt% compound / weight of the oral hygiene composition. In one exemplary embodiment, the compound is present in the range of about (all percentages are by weight of compound / weight of oral hygiene composition) .0.3% to about 5%, including 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 others. In exemplary embodiments, the compound is present in the range from about 2% to about 10%. In exemplary embodiments, the compound is present in the range from about 2% to about 4%. In exemplary embodiments, the compound is present in the range of from about 2.5% to about 6%. In exemplary embodiments, the compound is present in the range of from about 0.1% to about 1%. In another example embodiment, the compound has a structure according to one of the following formulas:

<formula> formula see original document page 4 </formula>

wherein B is boron, O is oxygen, R * and R ** are independently selected from substituted or unsubstituted (C1-C4) alkyl, substituted or unsubstituted (C3-C7) cycloalkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; ζ is 0 or 1, and when ζ is 1, A is CH, CR10 or N; D is N, CH or CR12; E is Η, OH, alkoxy or 2- (morpholino) ethoxy, CO2H or CO2 alkyl; m = 0-2; rélou2, and wherein when r is 1, G is = 0 (double bonded oxygen), and when r is 2, each G is independently H, methyl, ethyl or propyl; R 12 is selected from (CH 2) kOH (where k = 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 NH alkyl, 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, and where J is CR10 or N; R9, R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, (CH2) nOH (n = 2 to 3), CH2NH2, CH2NHalkyl, CH2N (alkyl) 2, halogen, CHO, CH = NOH, CO2H CO2-alkyl, S-alkyl, SO2-alkyl, S-aryl, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, NH2, alkoxy, CF3, SCF3, NO2, SO3H and OH, including salts thereof.

In another example embodiment, the compound has a structure according to

<formula> formula see original document page 5 </formula>

where m is 0. In another example embodiment, the compound has a structure according to <formula> formula see original document page 6 </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 A-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 a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane or bis (3-chloro-4-acid) ester methylphenyl) borinic), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol. 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 present in an amount of about 0.1% w / w to about 5% w / w In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane and the compound is present in an amount of about 0.3% w / w to about 0.6% w / w.

In one exemplary embodiment, the compound described herein has antibacterial properties. In another exemplary embodiment, the compound described herein has antiinflammatory properties. In one example embodiment, the compound

described herein has both antibacterial and anti-inflammatory properties. In one exemplary embodiment, the compound described herein has both antibacterial and anti-inflammatory properties, and is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane.

In a second aspect, the invention provides a method for killing a microorganism or inhibiting the growth of a microorganism comprising contacting said microorganism with a therapeutically effective amount of a compound described herein, thereby killing or inhibiting the growth of the microorganism. In one example embodiment, the microorganism is a selected member of the Actinobacillus species, Porphyromonas species, Tannerella species, Prevotellal species Eubacteriuml species Treponema species, Bulleidial species

Mogibacterium, Slackia species, Campylobacter species, Eikenella species, Peptostreptoeoecus species, Peptostreptoeoeeus species, Capnoeytophaga species, Fusobaeterium species, Porphyromonas species and Baeteroides species. In another exemplary embodiment, the microorganism is a selected member of AetinobaeiIlus aetinomyeetemeomitans, Porphyromonas gingivalis, Tannerella forsythensis,

Prevotella intermedia, Eubaeterium nodatum, Treponema dentieola, Bulleidia extrueta, Mogibacterium timidum, Slaekia exigua, Campylobaeter reetus, Eikenella eorrodens, Peptostreptoeoecus anaerobius, Capnocytophaga ochriumphorephus Bacteriumpheatonas nuchrolphus

In another exemplary embodiment, the compound for use in the method has the structure described above. In another exemplary embodiment, the compound for use in the method is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane or ((3-hydroxypicolinate) bis (3- chloro-4-methylphenyl) boronic), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2, 1-benzoxaborol. In another exemplary embodiment, the compound for use in the method is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane.

In a third aspect, the invention provides a method for treating or preventing periodontal disease in a human or animal comprising administering to the human or animal a therapeutically effective amount of a compound described herein, thereby treating or preventing said disease. periodontal. In one exemplary embodiment, periodontal disease is a selected member of gingivitis, periodontitis, and juvenile / acute periodontitis.

In another exemplary embodiment, the compound for use in the method has the structure described above. In another exemplary embodiment, the compound for use in the method is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane or ((3-hydroxypicolinate) bis (3- chloro-4-methylphenyl) boronic), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2, 1-benzoxaborol. In another exemplary embodiment, the compound for use in the method is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane.

In one exemplary embodiment, a compound for use in the compositions and methods described herein has a structure according to Formula I:

<formula> formula see original document page 9 </formula>

where B is boron. R1a is a member selected from a negative charge, a counterion of salt, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl , and substituted or unsubstituted heteroaryl. M is a selected member of oxygen, sulfur and NR2a. R 2a is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl. J is a member selected from (CR3aR4a) n1, and CR5a, R3a, R4a and R5a are independently selected members of H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. Index n1 is an integer selected from 0 to 2. W is a member selected from C = O (carbonyl), (CR6aR7a) rai, and CR8ai R6a, R7a, K and R8a are independently selected members of H, cyano, alkyl substituted or unsubstituted, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The index ml is a selected integer from 0 and 1. A is a selected member of CR9a and N. D is a selected member of CR10a and Ν. E is a selected member of CRlla and N. G is a selected member of CR12a and N. R9a, R10a, Rlla and R12a are independently selected members of H, 0R * a, NR * aR * * a, SR * a, - S (O) R * a, -S (O) 2R * 3, -S (O) 2NR * aR ** a, -C (O) R * 3, -C (0) 0R * a, -C ( O) NR * aR ** a, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl substituted. Each R * a and R ** a is a member independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl , and substituted or unsubstituted heteroaryl. The nitrogen combination (A + D + E + G) is an integer selected from 0 to 3. A selected member of R3a, R4a and R5a and a selected member of R6a, R7a and R8a, together with the atoms to which they are present. are attached, are optionally joined to form a 4- to 7-membered ring. R3a and R4a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring. R 6a and R 7a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring. R 9a and R 10a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring. R10a and R11a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring. R11a and R12a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring.

In one exemplary embodiment, a compound for use in the compositions and methods described herein has a structure according to Formula IX: <formula> formula see original document page 11 </formula>

wherein the variables A, D, EeG are described elsewhere in this specification. R20, R21 and R22 are independently selected members of a negative charge, a counterion of salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl. unsubstituted, and substituted or unsubstituted heteroaryl.

In one exemplary embodiment, a compound for use in the compositions and methods described herein has a structure according to Formula XI:

<formula> formula see original document page 12 </formula>

wherein the variables R1, A, D, E, G, J, W and M are described elsewhere in this specification.

In one exemplary embodiment, the microorganism is involved in periodontal disease. In another exemplary embodiment, the microorganism is a selected member of a virus, bacteria, fungus, yeast or parasite. In another exemplary embodiment, the bacterium is a selected member of the Actinobacillus species, Porphyromonasl species Tannerellal species Prevotella species, Eubacterium species, Treponema species, Bulleidia species, Mogibacterium species, Slackia species, Campylobacter species, Eikenella species, Peptostreptoctoeo species and Peptostreptoeo species , Capnoeytophaga species, Fusobaeterium species, Porphyromonas species and Bacteroides species. In yet another exemplary embodiment, the bacterium is a selected member of Actinobacillus actinomyeetemeomitans, Porphyromonas gingivalis, Tannerella forsythensis, Prevotella intermedia, Eubacterium nodatum, Treponema dentieola, Bulleidia extrueta, Mogibacterium timidum, Slackia rectus, Campylaeusus, Campylobacteria , Peptostreptoeoeeus anaerobius, Capnocytophaga ochracea, Fusobacterium nucleatum, Porphyromonas asaccharolytica and Bacteroides forsythus.

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

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

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

Brief Description of Drawings

FIG. 1 presents the test results of various boron-containing compounds of the invention against various bacteria that are involved in periodontal disease.

FIG. 2 shows the examples of compounds of the invention.

FIG. 3 shows the examples of compounds of the invention.

Detailed Description of the Invention Definitions and Abbreviations

The abbreviations used in this specification generally have their conventional meaning within the chemical and biological technique.

"Compound of the invention" and "exemplary compounds of use in the methods of the invention" are used interchangeably and refer to compounds discussed herein, and pharmaceutically acceptable salts and prodrugs of such compounds. When substituent groups are specified by their conventional left-to-right chemical formula, they also include chemically identical substituents, which should result from writing the right-to-left structure, for example -CH2O- should also refer to to -OCH2-.

The term "poly" as used herein means at least 2. For example, a polyvalent metal ion is a metal ion that has a valence of at least 2.

"Portion" refers to the radical of a molecule that is attached to another moiety.

The symbol jwv, used as a bond or shown perpendicular to a bond, indicates the point at which the portion shown is attached to the remainder of the molecule.

The term "alkyl" by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- - or polyunsaturated and may include di and multivalent radicals having the designated number of carbon atoms (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, without limitation, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologues and isomers of for example n-pentyl, n-hexyl, n-heptyl, n-octyl, and others. An unsaturated alkyl group is one that has one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, without limitation, 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. The term "alkyl", unless otherwise indicated, should also include those alkyl derivatives defined in more detail below as "heteroalkyl". Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl".

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified but not limited by -CH 2 CH 2 CH 2 CH 2 -, and also includes those groups described below as "heteroalkylene". Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or less carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter alkyl chain or alkylene group, generally having eight or fewer carbon atoms.

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

The term "heteroalkyl", alone or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the determined number of carbon atoms and at least one heteroatom. In one exemplary embodiment, the heteroatoms may be selected from the group consisting of B, O, NeS, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms B, O, NeS may be located at any position within the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Examples include, without limitation, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, CH2-CH2-N (CH3) -CH3, -CH2-SCH2-CH3, -CH2-CH2i-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. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited to, by -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -. S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylene groups, heteroatoms may also occupy each or both of the chain termini (e.g. alkyleneoxy, alkylenedioxy, alkylene amino, alkylenediamine, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is indicated by the direction in which the linking group formula is written. For example, the formula -C (O) 2R'- represents both -C (O) 2R'- and -R 1C (O) 2-.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, without limitation, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and others. Examples of heterocycloalkyl include, without limitation, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and others.

The terms "halo" or "halogen", by themselves or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" should include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C1 -C4) alkyl" should include, without limitation, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term "aryl" means, unless otherwise stated, an aromatic polyunsaturated substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings), which are covalently fused or bonded. The term "heteroaryl" refers to aryl groups (or rings) containing from one to four heteroatoms. In one exemplary embodiment, the heteroatom is selected from Β, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. 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-pyrimididyl, 4-pyriraidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl,? 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substitutes for each of the above 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 (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Therefore, the term "arylalkyl" should include those radicals wherein an aryl group is attached to an alkyl group (e.g. benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups wherein a carbon atom (e.g. methylene) was replaced, for example, by an oxygen atom (e.g. phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and others).

Each of the above terms (e.g. "alkyl", "heteroalkyl", "aryl" and "heteroaryl") must include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Alkyl and heteroalkyl radical substituents (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) are generally referred to as "alkyl group substituents", and they may be one or more from several groups selected from, but not limited to: -OR ', = 0, = NR', = N-OR ', -NR'R ", -SR', - halogen, OC (O) R ', -C (O) R ', -CO 2 R', -CONR'R ", -0C (0) NR'R", NR "C (O) R ', -NR'-C (O) NR" R "', - NRwC (O) 2R ', -NR-C (NR'R "R'") = NR ", -NR-C (NR'R") = NR '", -S (O) R', -S ( O) 2R ', S (O) 2NR' R ", -NRSO2R ', -CN and -NO2 in a number ranging from zero to (2m' + 1), where m 'is the total number of carbon atoms in such a radical. R ', R ", R"' and R "" each preferably preferably refers to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, for example 1-3 halogen substituted aryl, alkyl substituted or unsubstituted alkoxy groups or thioalkoxy groups or arylalkyl. When a compound of the invention includes more than one group R, for example, each of the groups R is independently selected as are each group R ', R ", R"' and R "" when more than one of these groups is present. When R 'and R "are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7- membered ring. For example, -NR'R" must include, but It is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one skilled in the art will understand that the term "alkyl" should include groups that include carbon atoms attached to groups other than hydrogen groups, such as haloalkyl (e.g. -CF3 and -CH2CF3) and acyl (e.g. -C (O) CH 3, -C (O) CF 3, -C (O) CH 2 OCH 3, and others).

Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are generally referred to as "aryl group substituents". The substituents are selected, for example, from: halogen, -OR ', = 0, = 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) 2R ', -NR-C (NR'R" R' ") = NR", -NR-C (NR'R ") = NR '", -S (O) R', -S (O) 2R ', S (O) 2NR' R ", -NRSO2R ', -CN and -NO2, -R', -N3, -CH (Ph) 2, (C1 -C4) fluorine and fluorine (C 1 -C 4) alkyl, in a number ranging from zero to the total number of open valences in the aromatic ring system, and when R ', R ", R"' and R "" are preferably independently selected from hydrogen, substituted alkyl or unsubstituted, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R ', R ", R"' and R "" groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -TC (O) - (CRR ') qU-, wherein TeU are independently —NR-, -0-, -CRR'- or a single bond, eq is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A- (CH 2) r B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S (O) -, -S (O) 2-, -S (O) 2NR'- or a single bond, er is a number from 1 to 4. One of the unique bonds of the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula - (CRR ') SX- (CR "R'") d-, wherein sed are independently integers from 0 to 3 and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2- or -S (O) 2NR'-. The substituents R, R ', R "and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (C1 -C6) alkyl.

"Ring" as used herein means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A ring includes fused ring portions. The number of atoms in a ring is typically defined by the number of members in the ring. For example, a "5-7 membered" ring means that there are 5 to 7 atoms in the surrounding arrangement. The ring optionally included a heteroatom. Therefore, 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 defined as above.

As used herein, the term "heteroatom" includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (0), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

"R" is a general abbreviation for a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted heterocycloalkyl.

By "effective amount" of a medicament, formulation, or permeant is meant a sufficient amount of an active agent to provide at the desired site the systemic effect. A "topically effective", "cosmetically effective", "pharmaceutically effective" or "therapeutically effective" amount refers to the amount of medicament required to effect the desired therapeutic result.

"Topically effective" refers to a material which, when applied to the skin, nail, hair, claw or hoof, produces a desired pharmacological result locally at the site of application or systemically as a result of transdermal passage of an active ingredient in the material.

"Cosmetically effective" refers to a material which, when applied to the skin, nail, hair, claw or hoof, produces a desired cosmetic result locally at the site of application of an active ingredient to the material.

The term "pharmaceutically acceptable salts" shall include salts of the compounds of the invention which are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acid functionality, basic addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable basic addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or a similar salt. Where the compounds of the present invention contain relatively basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired pure acid or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbon, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydrochloric, or phosphorus acids and others, as well as salts thereof Relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, submeric, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic and others. Also included are amino acid salts such as arginate and others, and organic acid salts such as glucuronic or galacturonic acids and others (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acid functionalities that allow the compounds to be converted to basic or acid addition salts.

Neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

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

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are 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 to the uses contemplated by the present invention and are within the scope of the present invention.

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

The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, should be encompassed within the scope of the present invention.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that provides for the adequate release of an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the active agent's biological activity. , and that is sufficiently non-toxic to the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases and others. Such bases include suspending agents, thickeners, penetration enhancers, and others. Its formulation is well known to those skilled in the cosmetic and topical pharmaceutical technique. Additional information about carriers can be found at Remington ·. The Science and Practice of Pharmacyl 21st Ed., Lippincott, Williams & Wilkins (2005), which is incorporated herein by reference. "Pharmaceutically acceptable topical carrier" and

equivalent terms refer to pharmaceutically acceptable carriers, as described hereinabove, suitable for topical application. An inactive liquid or cream carrier capable of suspending or dissolving the active agent (s), and having the properties of being non-toxic and non-inflammatory when applied to skin, nail, hair, claw or hoof, is an example of a topical carrier. pharmaceutically acceptable. This term specifically encompasses materials

Conveyors approved for use in cosmetics as well. The term "pharmaceutically acceptable additive" refers to preservatives, antioxidants, fragrances, emulsifiers, dyes and excipients known or used in the field of drug formulation and which do not interfere with the effectiveness of the biological activity of the active agent, and which are sufficiently non-active. toxic to the host or patient. Additives for topical formulations are well known in the art, and may be added to the topical composition as long as they are pharmaceutically acceptable and not detrimental to epithelial cells or their function. In addition, they should not cause deterioration in composition stability. For example, inert fillers, anti-irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactant, emollients, coloring agents, preservatives, buffering agents, other permeation enhancers, and other conventional components. of topical or transdermal release formulations as are known in the art.

The terms "enhancement", "penetration enhancement" or "permeation enhancement" refer to an increase in the permeability of the skin, nail, hair, claw or hoof to a drug to increase the rate at which the drug permeates through the skin, nail, hair, claw, or hoof. Increased permeation effected through the use of such enhancers can be observed, for example, by measuring the diffusion rate of the drug through the animal or human skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al, J of Controlled Release, 1: 161-162 (1984). The term "permeation enhancer" or "penetration enhancer" refers to an agent or mixture of agents which alone or in combination acts to increase the skin, nail, hair or hoof permeability of a medicament.

The term "excipients" is conventionally known to mean carriers, diluents and / or carriers used in the formulation of effective drug compositions for the intended use.

The term "topical administration" refers to the application of a pharmaceutical agent to the outer surface of the skin, nail, hair, claw or hoof such that the agent crosses the outer surface of the skin, nail, hair, claw or hoof and between in the underlying tissues. Topical administration includes applying a composition to intact skin, nail, hair, claw or hoof, or to an open crack or injury to the skin, nail, hair, claw or hoof. Topical administration of a pharmaceutical agent may result in limited distribution of the agent to surrounding skin and tissues, or, when the agent is removed from the treatment area by the bloodstream, may result in systemic distribution of the agent.

The term "transdermal release" refers to the diffusion of an agent through the barrier of the skin, nail, hair, claw or hoof that results from topical administration or other application of a composition. The stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to various solutes, and drug absorption occurs therefore more easily through the skin, nail, hair, claw or hoof that is excoriated or devoid of the stratum corneum to expose the epidermis. Transdermal release includes injection or other release through any portion of the skin, nail, hair, claw or hoof or mucous membrane and absorption or permeation through the remaining portion. Absorption through intact skin, nail, hair, claw or hoof may be increased by placing the active agent in a suitable pharmaceutically acceptable carrier prior to application to the skin, nail, hair, claw or hoof. Passive topical administration may consist of the application of the active agent directly to the treatment site in combination with penetration enhancers or emollients. As used herein, transdermal release should include permeation release through or beyond the integument, i.e. skin, nail, hair, claw or hoof.

The term "microbial infection" refers to any infection of a host tissue by an infectious agent that includes, but is not limited to, viruses, bacteria, mycobacteria, fungi, and parasites (see, for example, Harrison's Principles of International Medicine, p. 93-98 (Wilson et al., Eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem. 42: 1,481-1,485 (1999), incorporated herein in their entirety by reference).

The term "microbial infection" refers to any infection of a host tissue by an infectious agent that includes, without limitation, viruses, bacteria, mycobacteria, fungi, and parasites (see, for example, Harrison's Principles of International Medicine, pp. 24-30). 93-98 (Wilson et al., Eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem. 42: 1,481-1,485 (1999), incorporated herein in their entirety by reference).

"Biological environment" as used herein refers to biological environments in vitro and in vivo. Examples of in vitro "biological media" include, without limitation, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed on mammals, preferably humans.

MIC, or minimal inhibitory concentration, is the point at which the compound disrupts more than 90% of cell growth relative to an untreated control.

Also of use in the present invention are compounds which are poly or multivalent species, including, for example, species such as dimers, trimers, tetramers and higher homologues of the compounds of use in the invention or reactive analogs thereof. Poly and multivalent species may be assembled from a single species or more than one species of the invention. For example, a dimeric construct may be "homodimeric" or "heterodimeric". In addition, poly and multivalent constructs wherein a compound of the invention or a reactive analog thereof is attached to an oligomeric or polymeric structure (e.g., polylysine, dextran, hydroxyethyl starch and others) are within the scope of the present invention. The structure is preferably polyfunctional (i.e. having an arrangement of reactive sites for attachment of the compounds of use in the invention). In addition, the structure may be derivatized with a single species of the invention or more than one species of the invention.

Further, the present invention includes the use of compounds in the motif set forth in the formulas herein which are functionalized to generate compounds which have increased water solubility over analogous compounds which are not similarly functionalized. Therefore, any of the substituents presented herein may be substituted with analogous radicals having increased water solubility. For example, it is within the scope of the invention to replace a hydroxyl group with a diol, or an amine with a quaternary amine, hydroxy amine or similar, more water soluble moiety. In a preferred embodiment, additional water solubility is transmitted by substitution at a site not essential for activity toward the editing domain of the compounds presented herein with a portion that increases the water solubility of the parent compounds. Methods of increasing the water solubility of organic compounds are known in the art. Such methods include, without limitation, the functionalization of an organic nucleus with a permanently charged moiety, for example quaternary ammonium, or a group that is charged at a physiologically relevant pH, for example carboxylic acid, amine. Other methods include attachment to the organic core of hydroxyl or amine containing groups, for example alcohols, polyols, polyethers, and the like. Representative examples include, without limitation, polylysine, polyethyleneimine, poly (ethylene glycol) and poly (propylene glycol). Suitable chemistry and functionalization strategies for these compounds are known in the art. See, for example, 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 Modalities I. Boron Containing Compounds

This invention provides boron containing compounds which are useful in the treatment of microorganisms located in the oral cavities of animals. The compounds are also useful in treating periodontal disease.

I. a.) Borinic esters

The invention comprises a compound having the structure according to the following formulas: <formula> formula see original document page 31 </formula>

wherein B is boron, O is oxygen, R * and R ** are independently selected from substituted or unsubstituted (C1-C4) alkyl, substituted or unsubstituted (C3-C7) cycloalkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl. The index ζ is 0 or 1, and when ζ is 1, A is CH, CR10 or N. D is N, CH or CR12. E is Η, OH, alkoxy or 2- (morpholino) ethoxy, CO2H or CO2 alkyl. The index m = 0-2, the index r is 1 or 2, and where, when r is 1, G is = O (double bond oxygen), and when r is 2, each G is independently H, methyl ethyl or propyl. R12 is selected from (CH2) kOH (where k = 1, 2 or .3), CH2NH2, CH2NH-alkyl, CH2N (alkyl) 2, CO2H, CO2alkyl, CONH2.0H, alkoxy, aryloxy, SH, S-alkyl , S-aryl, SO 2 N (alkyl) 2, SO 2 NH alkyl, 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, and where J is CR10 or N. R9, R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, (CH2) nOH (n = 2 to 3), CH2NH2, CH2NHalkyl, CH2N (alkyl) 2, halogen, CH0, CH = NOH, CO2H, CO2-alkyl, S-alkyl, SO2-alkyl, S-aryl, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, NH2, alkoxy, CF3, SCF3, NO2, SO3H and OH, including salts thereof. In preferred embodiments of a formula described herein, such as formulas 1, 2a, 2b, 2c or 2d, R * and / or R ** are the same or different, preferably wherein one of R * and R ** is an alkyl. Substituted or unsubstituted (C1 -C4) alkyl or R * and R ** are each substituted or unsubstituted (C1 -C4) alkyl.

In a preferred embodiment of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, R * and / or R ** are the same or different, preferably wherein one of R * and R ** is one. substituted or unsubstituted C3 -C7 cycloalkyl or R * and R ** are substituted or unsubstituted C3 -C7 cycloalkyl.

In a preferred embodiment of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, R * and / or R ** are the same or different, preferably wherein one of R * and R ** is one. substituted or unsubstituted alkenyl or R * and R ** are each substituted or unsubstituted alkenyl. In a further preferred embodiment of this specification, alkenyl has structure 2

<formula> formula see original document page 33 </formula>

wherein R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, substituted aryl, aralkyl, substituted aralkyl, (CH2) JcOH (where k = 1, 2 or 3), CH2NH2 , 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 formula described herein as formula 1, 2a, 2b, 2c or 2d, R * and / or R ** are the same or different, preferably wherein one of R * and R ** is an alkynyl. substituted or unsubstituted or R * and R ** are each substituted or unsubstituted alkynyl. In a further preferred embodiment of this specification, alkynyl has structure 3

<formula> formula see original document page 33 </formula>

wherein R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH2 JkOH (where k = 1, 2 or 3), CH2NH2, CH2NH-alkyl, CH2N (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 formula described herein as formula 1, 2a, 2b, 2c or 2d, R * and / or R ** are the same or different, preferably wherein one of R * and R * * is a phenyl. substituted or unsubstituted or R * and R * * are each substituted or unsubstituted phenyl but which exclude compounds of formula 1 where ζ is 1, A is CR10, D is CR12, J is CR10 and excluding compounds of formula 2 wherein the combination of substituents is such that ζ is 1, A is CR 10, D is CR 12, m is 2, and Ge or methyl or ethyl. In a separate mode from the foregoing, G is not propile either. However, in specific embodiments such excluded compounds, although not claimed as novel, may have use in one or more of the methods of the invention, preferably for treatment against infection, more preferably for treatment against fungal infection. In a preferred embodiment, only novel compounds of the invention are contemplated for such uses.

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

A preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * and R ** are different from a substituted phenyl or phenyl.

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

A further preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R is 1, G is = 0, mOEeEOH.

A preferred embodiment is also a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein z is 1 and R 9 is selected from alkyl (greater than C 4), (CH 2) n OH (n = 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 (greater than C 4), SCF 3, and NO 2.

In a preferred embodiment the compound has the formula described herein as formula 1, 2a, 2b, 2c or 2d, wherein z is .1 and R10 is selected from alkyl (greater than C4), (CH2) nOH (n = 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 (greater than C 4), SCF 3, and NO 2.

In another preferred embodiment the compound has the formula described herein as formula 1, 2a, 2b, 2c or 2d, wherein z is 1 and D is CR12 wherein R12 is selected from (CH2) kOH (where k = 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 (greater than C 4), aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, NO2, NH2SO2 and CONH2.

In a further preferred embodiment the compound has the formula described herein as formula 1, 2a, 2b, 2c or 2d, wherein z is 1, E is N- (morpholinyl) ethoxy or alkoxy greater than C4.

Other preferred embodiments are compounds having the structure of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein A or D is nitrogen, or wherein m is 2.

In another preferred embodiment, the compound has the structure of the formula described herein as formula 1, 2a, 2b, .2c or 2d, wherein one of R * or R ** is substituted phenyl substituted with 1 to 5 substituents. each is independently selected from alkyl (greater than C6), aryl, substituted aryl, benzyl, substituted benzyl, CH 2) kOH (where k = 1,2, or 3), CH 2 NH 2, CH 2 NH-alkyl, CH 2 N (alkyl) 2 , CO2H, CO2 alkyl, CONH2, CONHalkyl, CON (alkyl) 2.0H, alkoxy (greater than C6), aryloxy, SH, S-alkyl, S-aryl, SO2alkyl, SO3H, SCF3, CN, NO2, NH2, 2- amino, 3-amino, NH 2 SO 2, OCH 2 CH 2 NH 2, OCH 2 CH 2 N alkyl, OCH 2 CH 2 N (alkyl) 2, oxazolidin-2-yl, and substituted alkyl oxazolidin-2-yl.

In an additional preferred embodiment of this, phenyl has structure 4

<formula> formula see original document page 36 </formula>

wherein R 4, R 5, R 6, R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2) kOH (where k = 1,2, or 3), CH2NH2, CH2NH-alkyl, CH2N (alkyl) 2, CO2H, CO2 alkyl, CONH2, CONHalkyl, CON (alkyl) 2.0H, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO2alkyl, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, SO3H, SCF3, CN, halogen, CF3, NO2, NH2, 2-amino, 3-amino, NH2SO2, OCH2CH2NH2, OCH2CH2NHalkyl, OCH2CH2N (alkyl) 2, oxazolidin-2-ylazole, or substituted alkyl -2-yl.

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

Another preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * and R ** are 3- (4,4-dimethyloxazolidin-2-yl) phenyl, R 9 is H, R 11 is H, Az is CH, D is CH, J is CH and may be called 8-hydroxyquinoline bis (3- (4,4-dimethyloxazolidin-2-yl) phenyl) borinic acid ester.

A further preferred embodiment is a compound of the formula described herein, such as formula 1,2a, 2b, 2c or 2d, wherein R * is 3-fluorophenyl, R ** is cyclopropyl, R 9 is H, R 11 is H, Az is CH , D is CH, J is CH and referred to as 8-hydroxyquinoline (3-fluorophenyl) (cyclopropyl) borinic acid ester. A highly preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * is 4- (N, N-dimethyl) aminomethylphenyl, R ** is 4-cyanophenyl, R 9 is H, R 11 is H, A2 is CH, D is CH, J is CH and is referred to as (4- (N, N-dimethyl) aminomethylphenyl) (4-cyanophenyl) borinic acid ester.

A highly preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * is the same as R ** which is 3-chloro-4-methylphenyl, R 9 is H, R 11 is H, Az is CH, D is CH and E is OH, m = 0, d 1, G is = O (double bonded oxygen) and is referred to as 3-hydroxypicolinate bis (3-chloro4-methylphenyl) acid ester ) borinic.

A further highly preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * is the same as R ** which is 2-methyl-4-chlorophenyl, R 9 is H , R11 is H, Az is CH, D is CH and E is OH, m = 0, r is 1, G is = 0 (double bonded oxygen) and is referred to as bis (2-3-hydroxypicolinate) acid ester methyl4 - chlorophenyl) borinic.

In a preferred embodiment of the formula described herein as formula 1, 2a, 2b, 2c or 2d, R * and / or R ** are the same or different, preferably wherein one of R * and R * * is a benzyl. substituted or unsubstituted or R * and R * * are each substituted or unsubstituted benzyl. In an additional preferred embodiment of this, benzyl has the structure 5 <formula> formula see original document page 38 </formula>

wherein R 4, R 5, Re, R 7 and R 8 are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2) kOH (where k = 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, SO2NHalkyl, SO2NH2, SO3H, SCF3, CN, halogen, CF3, NO2, NH2, 2-amino, 3-amino, NH2SO2, OCH2CH2NH2, OCH2CH2NHalkyl, OCH2CH2N (alkyl) 2, oxazolidin-2-ylazole, or substituted alkyl -2-yl.

A preferred embodiment is a compound of the formula described herein, as formula 1, 2a, 2b, 2c or 2d, 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 substituted or unsubstituted heterocycle. In a further preferred embodiment of this, the heterocycle has the structure 6

<formula> formula see original document page 38 </formula> where X = CH = CH, N = CH, NR13 (where R13 = H, alkyl, aryl or aralkyl), O, or S and where Y = CH or N. R1, R2, and R3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH2) kOH (where k = 1.2, or .3), CH2NH2, CH2NH-alkyl, CH2N (alkyl) 2, CO2 H, CO2 alkyl, CONH2, S-alkyl, S-aryl, SO2 alkyl, SO2 N (alkyl) 2, SO2 NH4 alkyl, SO2 H, SCF3, CN, halogen, CF3, NO2, oxazolidin-2-yl, or substituted alkyl oxazolidin-2-yl. A highly preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * is pyrid-3-yl, R ** is 4-chlorophenyl, R 9 is H, R 11 is H, Az is CH, D is CH, and J is CH (termed 8-hydroxyquinoline (pyrid-3-yl) (4-chlorophenyl) borinic acid ester).

A highly preferred embodiment is a compound of the formula described herein, such as formula 1, 2a, 2b, 2c or 2d, wherein R * is 5-cyanopyrid-3-yl, R ** is vinyl, R 9 is H, R 11 is H , Az is CH, D is CH, and J is CH (termed 8-hydroxyquinoline (5-cyanopyrid-3-yl) (vinyl) borinic acid ester).

A preferred embodiment is a compound of the formula described herein, as formula 1, 2a, 2b, 2c or 2d, wherein R 9 is H, R 11 is H, Az is CH, D is CH, and J is CH.

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

The structures of the invention also allow solvent interactions that can generate structures (such as formulas Ib and .2e) <formula> formula see original document page 40 </formula>

which include atoms derived from the solvent found by the compounds of the invention during synthetic procedures and therapeutic uses. Therefore, such solvent structures can especially creep into at least some of the compounds of the invention, especially between the boron and nitrogen atoms, to increase the ring size of such by one or two atoms. For example, when the boron ring of the structure of the invention comprises 5 atoms, including, for example, boron, one nitrogen, one oxygen, and 2 carbons, the hint of a solvent atom between boron and nitrogen should generate a carbon ring. 7 members. In one example, the use of hydroxyl and amino solvents may generate structures that contain oxygen or nitrogen between the ring boron and nitrogen atoms to increase ring size. Such structures are expressly contemplated by the present invention, preferably when R * * * is H or alkyl.

Production Methods of Compounds

The synthesis of the compounds of the invention is carried out in various formats. Reaction Scheme A demonstrates the synthesis of the intermediate boronic acids, and their subsequent conversion to the desired boronic acid complexes. When R * and R * * are identical, the reaction of two equivalents of an arylmagnesium (or arylithium) halide with trialkyl borate, followed by acid hydrolysis yields the desired borinic acid 5. When R * and R * * are not identical the reaction of one equivalent of an arylmagnesium (or arylthio) halide with suitable aryl (dialkoxy) borane (4), heteroaryl (dialkoxy) borane or alkyl (dialkoxy) borane (alkoxy group comprising methoxy, ethoxy, isopropoxy, or propoxy) followed by acid hydrolysis yields the non-symmetrical boronic acids 6 in excellent yields. Where applicable, the reaction of alkylene esters (3, T = nil, CH2, C (CH3) 2) as the appropriate organochloride, organolithium, organomagnesium or equivalent reagent is convenient.

As shown in Scheme A, boronic acid complexes are obtained from the precursor boronic acids by reaction with an equivalent of the desired heterocyclic binder in suitable solvents (ie ethanol, isopropanol, dioxane, ether, toluene, dimethylformamide, N-methylpyrrolidone). , or tetrahydrofuran). Scheme A

<formula> formula see original document page 41 </formula> In certain situations, compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. Such compounds may be, for example, racemates or optically active forms. In such situations, single enantiomers, ie optically active forms, may be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of racemates can be performed, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.

I. b.) Boronic esters

In a first aspect, the invention provides a compound having the structure according to Formula I:

<formula> formula see original document page 42 </formula>

where B is boron. R 1a is a member selected from a negative charge, a counterion of salt, H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl substituted, and substituted or unsubstituted heteroaryl. M is a selected member of oxygen, sulfur and NR2a. R 2a is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl. J is a member selected from (CR3aR4a) nl and CR5a. R 3a, R 4a, and R 5a are independently selected from H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl substituted. Index nl is an integer selected from 0 to 2. W is a selected member of C = O (carbonyl), (CR6aR7a) mi and CR8a. R 6a, R 7a, and R 8a are independently selected members of H, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl substituted. The index ml is a selected integer from 0 and 1. A is a selected member of CR9a and N. D is a selected member of CR10a and Ν. E is a selected member of CRlla and N. G is a selected member of CR12a and N. R9a, R10a, Rlla and R12a are independently selected members of H, OR * 3, NR * aR ** a, SR * a, - S (O) R * a, -S (O) 2 R * a, -S (O) 2 NR * 3 R ** a, -C (O) R * 3, -C (O) OR * 3, -C (O) NR * aR * * a, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl not replaced. Each R * 3 and R ** 3 is a member independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl substituted, and substituted or unsubstituted heteroaryl. The nitrogen combination (A + D + E + G) is an integer selected from 0 to 3. A selected member of R3a, R4a, and R5a and a selected member of R6a, R7a, and R8a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring. R3a and R4a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring. R 6a and R 7a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring. R 9a and R 10a, together with the atoms to which they are attached, are optionally joined to form a 4 to 7 membered ring. R10a and R11a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring. R11a and R12a, together with the atoms to which they are attached, are optionally joined to form a 4-7 membered ring.

In one example embodiment, the compound has a structure according to Formula (Ia): <formula> formula see original document page 44 </formula>

In another exemplary embodiment, each R 3a and R 4a is a member independently selected from H, cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted benzyl. unsubstituted, substituted or unsubstituted phenyl, substituted or unsubstituted mercaptomethyl, substituted or unsubstituted mercaptoalkyl, substituted or unsubstituted aminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted indolyl and substituted or unsubstituted starch. In another exemplary embodiment, each R 3a and R 4a is a member independently selected from cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted hydroxymethyl, 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 or unsubstituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted or unsubstituted indolyl, starch replaced or not replaced.

In another exemplary embodiment, each R 3a and R 4a is a member selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, t- substituted or unsubstituted butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl. In another exemplary embodiment, R 3a 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 a member selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and benzyl. In another example embodiment, R3a is H and R4a is H.

In another example embodiment, each R 9a, R 10a, R 11a and R 12a is a member independently selected from H, OR * a, NR * aR * * a, SR * a, -S (O) R * a, -S ( O) 2R * 3, - S (O) 2NR * aR * * a, -C (O) R * 3, -C (O) 0R * a, -C (O) NR * 3 R ** 3, 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, phenyl substituted or unsubstituted, 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 mercaptomethyl or unsubstituted, substituted mercaptoalkyl substituted or unsubstituted, substituted or unsubstituted phenylthio, substituted or unsubstituted thiophenylthio, substituted or unsubstituted phenyl methylthio, substituted or unsubstituted pyridinylthio, substituted or unsubstituted pyrimidinylthio, substituted or unsubstituted benzyl, substituted or unsubstituted phenylsulfonyl, substituted benzylsulfonyl substituted or unsubstituted, substituted or unsubstituted phenylmethylsulfonyl, substituted or unsubstituted thiophenylsulfonyl, substituted or unsubstituted pyridinylsulfonyl, substituted or unsubstituted pyrimidinylsulfonyl, substituted or unsubstituted phenylsulfinyl, substituted or unsubstituted benzylsulfinyl, substituted or unsubstituted phenylsulfinyl substituted, substituted or unsubstituted thiophenylsulfinyl, substituted or unsubstituted pyridinylsulfinyl, substituted or unsubstituted pyrimidinylsulfinyl, ami unsubstituted or substituted, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted trifluoromethylamino, substituted or unsubstituted aminomethyl, substituted or unsubstituted alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl, substituted or unsubstituted arylaminomethyl, substituted benzylamino substituted or unsubstituted, substituted or unsubstituted phenylamino, substituted or unsubstituted thiophenylamino, substituted or unsubstituted pyridinylamino, substituted or unsubstituted pyrimidinylamino, substituted or unsubstituted morpholino, substituted or unsubstituted alkylamido, substituted or unsubstituted arylamido substituted, substituted or unsubstituted ureido, substituted or unsubstituted carbamoyl, and substituted or unsubstituted piperizinyl. In one exemplary embodiment, R 9a, R 10a, R 11a and R 12a are selected from the prior list of substituents with the exception of -C (O) R * 3, -C (0) 0R * a, -C (O) NR * 3 R ** 3. In another exemplary embodiment, R 9a, R 10a, R 11a and R 12a are independently selected members of fluorine, chlorine, bromine, nitro, cyano, amino, methyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl) phenylmethoxy yl, 1-ethoxycarbonylmethyloxy-, 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- (piperidin-1-yl) carbonyl) methoxy, 1- (piperidin-2-yl) carbonyl) methoxy, 1- (piperidin-3) -1yl) 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-one yl) carbonyl, 1-4- (pyrimidin-2-yl) piperazin-1-yl, 1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl), 1- (4- (pyridin-2-yl) 2-yl) piperazin-1-yl) carbonylmethyl, (1- (4- (pyridin-2-yl) piperazin-1-yl) carbonyl) methoxy), 1- (4- (pyridin-2-yl) piperazin -1-yl,? -1-indol-1-yl, morpholin-, 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) -β-indol-1-yl) ), 5-chloro-1H-indol-1-yl, 5-chloro-3- (2-cyanoethylthio) -1-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-fluorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy -cyanobenzyloxy, 3-cyanobenzyloxy, A-cyanob Enzymeoxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, A-fluorbenzyloxy, unsubstituted phenyl, unsubstituted benzyl. In one example embodiment, R 9a is H and R 12a is H.

In one exemplary embodiment, the compound according to Formula (I) or Formula (Ia) is a member selected from:

<formula> formula see original document page 49 </formula>

In one exemplary embodiment, the compound has a structure according to one of formulas I-10 with substituent selections for R 9a, R 10a, R 11a and R 12a including all possibilities contained in paragraph 90 except for H. In an exemplary embodiment, The compound has a structure according to one of formulas Ib-10 with substituent selections for R 9a, R 10a, R 11a and R 12a including all possibilities contained in paragraph 91 except for H.

In one exemplary embodiment, the compound has the formula according to Formulas (Ib) - (Ie) wherein R 1a is a member selected from H, a negative charge and a salt counterion and the remaining group r (R 9a). in Ib, R10a in Ic, R11a in Id, and R12a in Ie) is a member selected from fluorine, chlorine, bromine, nitro, cyano, amino, methyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2 - pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl) phenylmethoxy 5-yl, 1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-, 1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl, thiophen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio. fluorophenylthio, butylcarbonylphenylmethoxy, butylcarbonyl phenylmethyl, butylcarbonylmethyl, 1- (piperidin-1-yl) carbonyl) methyl, 1- (piperidin-1-yl) carbonyl) methoxy, 1- (piperidin-2-yl) carbonyl) methoxy, 1- (pip eridin-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) -1yl) 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, β-indol-1-yl, morpholin-, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3- (phenylthio) -β-indol-1-yl, 3- (2-cyanoethylthio) -1β-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) -1'-indol-1-yl yl)), dibenzylamino, benzylamino, 5-chloro-3- (phenylthio) -β-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-cy anophenylthio, 4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-chlorobenz, 4-chlorobenzyloxy, 2-fluorbenzyloxy, 3-fluorbenzyloxy and 4-fluorbenzyloxy.

In one exemplary embodiment, the compound has the formula according to Formulas (If) - (Ik) wherein R 1a is a member selected from H, a negative charge and a salt counterion and each of the two R groups. (R9a and R10a in If, R9a and R11a in Ig, R9a and R12a in Ih, R10a and R11a in Ij, R10a and R12a in Ij, R11a and R12a in Ik) is an independently selected member of fluorine, chlorine, bromine, nitro, cyano, amino, methyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizinyl, piperizinocarbonyl, piperizinylcarbon, 1-Tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl, 1-ethoxycarbonylmethyl-, 1-ethoxycarbonylmethyl-carboxymethoxy-2-thiophenyl thiophen-2-ylthio, thiophen-3-yl, thiophen-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- (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, morpholin-, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3- (phenylthio) -1H-indol-1-yl , 3- (2-Cyanoethylthio) -1H-indol-1-yl, benzylamino, 5-methoxy-3- (phenylthio) -β-indol-1-yl, 5-methoxy-3- (2-cyanoethylthio) -1H indol-1-yl)), 5-chloro-1H-indol-1-yl, 5-chloro-3- (2-cyanoethylthio) -1-indol-1-yl)), dibenzylamino, benzylamino, chloro-3- (phenylthio) -β-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-Fluorphenoxy, 4-Fluorphenoxy, 2-Cyanobenzyloxy, 3-Cyanobenzyloxy, 4-Cyanobenzyloxy, 2-Chlorobenzyloxy, 3-Chlorobenzyloxy, 4-Chlorobenzyloxy, 2-Fluorbenzyloxy, 3-Fluorbenzyloxy, and 4-Fluorbenzyl

In one exemplary embodiment, the compound has the formula according to Formulas (II) - (Io) wherein R 1a is a member selected from H, a negative charge and a salt counterion and each of the three R groups. remaining (R 9a, R 10a and R 11a in (II), R 9a, R 10a and R 12a in (Im), R 9a, R 11a and R 12a in (In), R 10a, R 11a and R 12a in (Io)) is an independently selected fluorine member, chloro, bromo, nitro, cyano, amino, methyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethyl, diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl, 1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl, 3- (butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl, 1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethoxy-ethoxy-ethoxy -2-yl, thiophen-2-ylthio, thiophen-3-yl, thiophen-3-ylthio, 4-fluorophenylthio, butylcarbonylphenylmethoxy, butylcarbonylphenylmethyl, butylcarbonylmethyl, 1- (piperidin-1-yl) c 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- il) piperazin-1-yl, 1H-indol-1-yl, morpholin-, morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido, phenylcarbamoyl, acetamido, 3- (phenylthio) -1H-indol-1-yl, 3- (2- cyanoethylthio) -β-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) -β-indol-1-yl)), dibenzylamino, benzylamino, 5-chloro-3- (phenylthio) ) -Β-indol-1-yl)), 4- (1H-tetrazol-5-yl) phenoxy, 4- (1H-tetrazol-5-yl) phenyl, 4- (1H-t etrazol-5-yl) phenylthio, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio, 4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy 3-Fluorphenoxy, 4-Fluorphenoxy, 2-Cyanobenzyloxy, 3-Cyanobenzyloxy, 4-Cyanobenzyloxy, 2-Chlorobenzyloxy, 3-Chlorobenzyloxy, 4-Chlorobenzyloxy, 2-Fluorbenzyloxy, 3-Fluorbenzyloxy, and 4-Fluorenzyloxy.

In another example embodiment, there is a condition where the compound cannot be a selected member of C1 -C40.

In another example embodiment, there is a condition where the compound cannot have the structure according to

Formula (Ix):

<formula> formula see original document page 54 </formula>

wherein R7b is a member selected from H, methyl, ethyl and phenyl. Rlob is a member selected from Η, OH, NH2, SH, halogen, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio. R11b is a member selected from Η, OH, NH2, SH, methyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkyloxy, substituted or unsubstituted phenylthio and substituted or unsubstituted phenylalkylthio. In another exemplary embodiment, there is a condition that the compound cannot have the structure according to Formula (Ix) wherein R1b is a member selected from a negative charge, H and a salt counterion. In another example embodiment, there is a condition where the compound cannot have the structure according to Formula (Ix) wherein R10b and R11b are H. In another example embodiment, there is a condition where the compound is not. may have the structure according to Formula (Ix) wherein one member selected from Rlob and Rllb is H and the other member selected from Rlob and Rllb is a member selected from halo, methyl, cyano, methoxy, hydroxymethyl and p-cyanophenyloxy . In another exemplary embodiment, there is a condition that the compound may not have the structure according to Formula (Ix) wherein R16 and R11b are independently selected members of fluorine, chlorine, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl. In another exemplary embodiment, there is a condition that the compound cannot have the structure according to Formula (Ix) wherein R1b is a member selected from a negative charge, H and a salt counterion; R7b is H; Rlob is F and Rllb is H. In another exemplary embodiment, there is a condition that the compound cannot have the structure according to Formula (Ix) wherein R11b and R12b, together with the atoms to which they are attached. , are joined to form a phenyl group. In another exemplary embodiment, there is a condition that the compound may not have the structure according to Formula (Ix) wherein R1b is a member selected from a negative charge, H and a salt counterion; R7b is H; Rlob is 4-cyanophenoxy; and R11b is H.

In another example embodiment, there is a condition where the compound cannot have the structure according to Formula (Iy).

<formula> formula see original document page 56 </formula>

wherein R10b is a member selected from substituted or unsubstituted H, halogen, CN and C1-4 alkyl.

In another example embodiment, there is a condition wherein the compound lacks the structure which is a selected member of Formulas (I) to (Io) at least one member selected from R3a, R4a, R5a, R6a, R7a, R8a, R 9a, R 10a, R 11a, and R 12a are nitro, cyano or halogen. In another example embodiment, there is a condition where when M is oxygen, W is a member selected from (CR3aR4a) ni where nl is 0, J is a member selected from (CR6aR7a) mi, where ml is 1, A is CR9a, D is CR10a, E is CR11a, G is CR12a, R9a is not halogen, methyl, ethyl, or optionally joined with R10a to form a phenyl ring; R10a is not unsubstituted phenoxy, C (CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally joined with R9a to form a phenyl ring; R11a is not halogen or optionally joined with R10a to form a phenyl ring; and R12a is not halogen. In another example embodiment, there is a condition where when M is oxygen, W is a member selected from (CR3aR4a) nl where nl is 0, J is a member selected from (CR6aR7a) mi, where ml is 1, A is CR9a, D is CR10a, E is CR11a, G is CR12a, so neither R6a nor R7a are halophenyl. In another example embodiment, there is a condition where when M is oxygen, W is a member selected from (CR3aR4a) ni where nl is 0, J is a member selected from (CR6aR7a) mi, where ml is 1, A is CR9a, D is CR10a, E is CRlla, G is CR12a, and R9a, R10a and Rlla are H, so R6a, R7a and R12a are not H. In another example embodiment, there is a condition where when M is oxygen where nl is 1, J is a selected member of (CR6aR7a) na, where ml is 0, A is CRya, D is CR10a, E is CRiia, G is CRiiiti, and R3a is H, RH, Rlla is H , R 6a is H, R 7a is H, R 12a is H, so W is not C = O (carbonyl). In another example embodiment, there is a condition where when M is oxygen, W is CR5a, J is CR8a, A is CR9a, D is C10a, G is CRlla, R6a, R7a R9a, R10a, Rlla, and R 12a are H so R 5a and R 8a, together with the atoms to which they are attached, do not form a phenyl ring.

In one exemplary embodiment, the compound of the invention has the structure that is a member selected from:

<formula> formula see original document page 57 </formula>

where q is an enti and e number 1. R9 is halogen. Ra, Rb, Rc, Rd and Re are independently selected members of a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an example embodiment, there is a condition where the compound is not a member selected from

<formula> formula see original document page 58 </formula>

In an example embodiment, the compound has a structure and is a member selected from:

<formula> formula see original document page 58 </formula>

In an example embodiment, Ra, Rd and Re are independently selected members of:

<formula> formula see original document page 58 </formula>

In one exemplary embodiment, Rb and Rc are independently selected members of H, methyl,

<formula> formula see original document page 59 </formula>

In another example embodiment, R is H and R is a member selected from H, methyl,

<formula> formula see original document page 59 </formula> In another example embodiment, Rb and Rc are, together with the nitrogen to which they are attached, optionally joined to form a selected member of.

<formula> formula see original document page 59 </formula> In an example embodiment, Ra is a selected member of

<formula> formula see original document page 60 </formula>

In an example embodiment, Rd is a member selected from

<formula> formula see original document page 60 </formula>

In one example embodiment, Re is a member selected from

<formula> formula see original document page 60 </formula>

In one example embodiment, the compound is a member selected from

<formula> formula see original document page 60 </formula> <formula> formula see original document page 61 </formula> In one example embodiment, the compound has a structure that is described in Figure 2. ® ... the embodiment For example, the compound has a structure which is described in Figure 3.

In one exemplary embodiment, the compound has a structure according to a member selected from Formulas I (b), I (c), I (d), and I (e) wherein said remaining R group (R 9a to I (b), R 10a for I (c), R 11a for I (d) and R 12a for I (e)) is carboxymethoxy.

In one exemplary embodiment, the compound has a structure that is a member selected from Formulas (If) - (Ik), wherein R 9a or R 10a for Formula (If), R 9a or R 11a for Formula (Ig), R 9a or R 12a for Formula (Ih), R10a or Rlla for Formula (li), R10a or R12a for Formula (Ij), Rlla or R12a for Formula (Ik) is halogen, and the other substituent on the pairing (eg if R9a is F in Formula ( If), then R10a is selected from the following list of substituents), is a selected member of NH2, N (CH3) H, and N (CH3) 2.

In another example embodiment, the compound has a structure that is a member selected from:

<formula> formula see original document page 62 </formula>

wherein R * and R ** are members selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl substituted. In one example embodiment, the compound is a member selected from

<formula> formula see original document page 63 </formula>

wherein R1a is a member selected from a negative charge, H and a salt counterion.

In another example embodiment, the compound has a structure that is a member selected from:

<formula> formula see original document page 63 </formula>

(Iak), where q is 1 and R9 is a selected member of fluorine, chlorine and bromine.

In another exemplary embodiment, the compounds and embodiments described above in Formulas (I) - (10) may form a hydrate with water, a solvate with an alcohol (e.g., methanol, ethanol, propanol); an adduct with an amino compound (e.g., ammonia, methylamine, ethylamine); an adduct with an acid (e.g. formic acid, acetic acid); complexes with ethanolamine, quinoline, amino acids, and others. In another example embodiment, the compound has a structure according to Formula (Ip):

<formula> formula see original document page 64 </formula>

wherein Rx2 is a member selected from substituted or unsubstituted C1-C5 to substituted alkyl and substituted or unsubstituted C1-C5 heteroalkyl. Ry2 and Rz2 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl. ** A1-M1 are undefined?

In another example embodiment, the compound has a structure according to Formula (Iq):

<formula> formula see original document page 64 </formula> where B is boron. Rx2 is a member selected from substituted or unsubstituted substituted or unsubstituted C1-C5 alkyl and substituted or unsubstituted C1-C5 heteroalkyl. Ry2 and Rz2 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl. In another exemplary embodiment, at least one selected member of Rja, Rqa, Rba, R6a, R7a, R8a, R9a, R10a, R R12a is a selected member of nitro, cyano and halogen.

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

<formula> formula see original document page 65 </formula>

in another exemplary embodiment, the compound has the formula according to Formulas (Ib) - (Ie) wherein at least one member is selected from R 3a, R 4a, R 5a, R 6a, R 7a, R 8a, R 9a, R 10a, R 11a and R12a is a selected member of nitro, cyano, fluorine, chlorine, bromine and cyanophenoxy. In another example embodiment, the compound is a member selected from

<formula> formula see original document page 65 </formula> <formula> formula see original document page 66 </formula>

In another example embodiment, the compound is a member selected from

<formula> formula see original document page 66 </formula>

In another example embodiment, there is a condition where the compound cannot have the structure according to Formula (Iaa):

<formula> formula see original document page 66 </formula>

wherein R6b, R9b, Rlob, R11b and R12b have the same substituent lists as described for Formulas (Ix) and (Iy) above.

In another exemplary embodiment, the invention provides poly or multivalent species of the compounds of the invention. In one exemplary embodiment, the invention provides a dimer of the compounds described herein. In one exemplary embodiment, the invention provides a dimer of the compounds described herein. In one exemplary embodiment, the invention provides a dimer of a compound which is a member selected from C1-C96. In one example embodiment the dimer is a member selected from

<formula> formula see original document page 67 </formula>

In one exemplary embodiment, the invention provides an anhydride of the compounds described herein. In one exemplary embodiment, the invention provides an anhydride of the compounds described herein. In one exemplary embodiment, the invention provides an anhydride of a compound which is a member selected from C1-C96. In one example embodiment anhydride is a member selected from

<formula> formula see original document page 67 </formula>

In one exemplary embodiment, the invention provides a trimer of the compounds described herein. In one exemplary embodiment, the invention provides a trimer of the compounds described herein. In one exemplary embodiment, the invention provides a trimer of a compound that is a selected member of C1-C96. In one example embodiment the trimer is a member selected from

<formula> formula see original document page 68 </formula>

In another example embodiment, R10a is a member selected from

<formula> formula see original document page 68 </formula> where R15 is a selected member of CN, C00H and

<formula> formula see original document page 68 </formula> R16 and R17 are independently selected members of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or unsubstituted and substituted or unsubstituted heteroaryl. The index ρ is an integer selected from 1 to 5. 0 index z is an integer selected from 1 to 8. X is a selected member of S and 0.

In another exemplary embodiment, the compound has a structure according to Formula (VIII):

<formula> formula see original document page 69 </formula>

wherein R4a is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl. R10a 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 example embodiment, the compound has a structure wherein the compound is a member selected from:

<formula> formula see original document page 69 </formula>

In another example embodiment, the compound is

<formula> formula see original document page 69 </formula>

In another aspect, the invention provides compounds useful in methods having the structure according to Formula IX:

<formula> formula see original document page 70 </formula>

wherein the variables A, D, E and G are described elsewhere in this. R20, R21 and R22 are independently selected members from a negative charge, a counterion of salt, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or unsubstituted, and substituted or unsubstituted heteroaryl.

In another example embodiment, the compound has a structure according to Formula (X): <formula> formula see original document page 70 </formula>

In another example embodiment, it is a member selected from:

<formula> formula see original document page 70 </formula>

The compounds of the invention may form a hydrate with water, alcohol solvates such as methanol, ethanol, propanol, and the like; adducts with amino compounds such as ammonia, 30 methylamine, ethylamine, and the like; acid adducts such as formic acid, acetic acid and others; complexes with ethanolamine, quinoline, amino acids, and others.

In one exemplary embodiment, the compound has a structure which is a member selected from 5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol (Cl), 1,3-Dihydro-1-hydroxy 2,1-Benzoxaborol (C2), 5-Fluoro-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborol (C3), 6-Fluoro-1-hydroxy-1,2,2,3 (C4), 4-Tetrahydro-2,1-benzoxaborine, 5,6-Difluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol (C5), 5-Cyano-1,3-dihydro-1 (C6) -hydroxy-2,1-benzoxaborol, 1,3-Dihydro-1-hydroxy-5-methoxy-2,1-benzoxaborol (C7), 1,3-Dihydro-1-hydroxy-5-methyl-2 (C8) -1-Benzoxaborol, 1,3-Dihydro-1-hydroxy-5-hydroxymethyl-2,1-benzoxaborol (C9), 1,3-Dihydro-5-fluoro-1-hydroxy-2,1- benzoxaborol (C10), 1,3-Dihydro-2-oxa-1-cyclopenta [a] naphthalene (Cll), 7-Hydroxy-2,1-oxaborolane [5,4-c] pyridine (C 12), 1,3 -Dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborol (C13), 3-Benzyl-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborol (C14), 3-Benzyl -1,3-dihydro-1-hydroxy-2,1-benzoxaborol (C15), 1,3-Dihydro-4-fluoro-1-hydroxy-2,1-benzoxaborol (C16), 5- (4-Cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol (C17), 6- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1 benzoxaborol (C18), 6- (3-Cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol (Cl 9), 6- (4-Chlorophenoxy) -1,3-dihydro-1-hydroxy -2,1-benzoxaborol (C20), 6-Phenoxy-1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C21), 5- (4-Cyanobenzyloxy) -1,3-dihydro-1-hydroxy (C22) -2,1-Benzoxaborol, 5- (2-Cyanophenoxy) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C23), 5-Phenoxy-1,3-Dihydro-1-hydroxy -2,1-benzoxaborol (C 24), 5- [4- (N, N-Diethylcarbamoyl) phenoxy] -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C 25), 1,3-Dihydro 1-hydroxy-5- [4- (morpholinocarbonyl) phenoxy] -2,1-benzoxaborol (C26), 5- (3,4-Dicyanophenoxy) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol ( C27), 6-Phenylthio-1,3-dihydro-1-hydroxy-2,1-benzoxaborol (C 28), 6- (4-trifluoromethoxyphenoxy) -1,3-Dihydro-1-hydroxy-2,1- (C29) benzoxaborol, 5- (N-Methyl-N-phenylsulfonylamino) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C30), 6- (4-Methoxyphenoxy) -1,3-dihi Dro-1-hydroxy-2,1-benzoxaborol (C 31), 6- (4-Methoxyphenylthio) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C32), 6- (4-Methoxyphenylsulfonyl) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C33), 6- (4-Methoxyphenylsulfinyl) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C34), 5- Trifluoromethyl-1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C35), 4- (4-cyanophenoxy) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C36), .5 - (3-Cyanophenoxy) -1,3-Dihydro-1-hydroxy-2,1-benzoxaborol (C37), 5- (4-Carboxyphenoxy) -1-hydroxy-2,1-benzoxaborol (C38), 1-Hydroxy -5- [4- (tetrazol-1-yl) phenoxy] -2,1-benzoxaborol (C39), 5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 1,3-Dihydro -1-hydroxy-2,1-benzoxaborol, 5-fluoro-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborol, 6-fluoro-1-hydroxy-1,2,3,4-tetrahydro -2,1-benzoxaborino, 5,6-Difluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 5-Cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 1,3-Dihydro-1-hydroxy-5-methoxy-2,1-benzoxaborol, 1,3-Dihydro-1-hydroxy-5-methyl-2,1-benzoxaborol, 1,3-Dihydro-hydroxy -5-hydroxymethyl-2,1-benzoxaborol, 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, 1,3-Dihydro-2-oxa-1-cyclopenta [a] naphthalene, 7 -Hydroxy-2,1-oxaborolane [5,4-c] pyridine, 1,3-Dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborol, 3-Benzyl-1,3-dihydro-1-one hydroxy-3-methyl-2,1-benzoxaborol, 3-Benzyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 1,3-Dihydro-4-fluoro-1-hydroxy-2,1- benzoxaborol, 5- (4-Cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-Cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (3-Cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-Chlorophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- Phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 5- (4-

Cyanobenzyloxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 5- (2-Cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 5-Phenoxy-1,3 -dihydro-1-hydroxy-2,1-benzoxaborol, 5- [4- (N, N-Diethylcarbamoyl) phenoxy] -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 1,3-Dihydro 1-hydroxy-5- [4- (morpholinocarbonyl) phenoxy] -2,1-benzoxaborol, 5- (3,4-dicyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6-phenylthio -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-trifluoromethoxyphenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 5- (N-Methyl N-phenylsulfonylamino) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-Methoxyphenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-Methoxyphenylthio) -1 , 3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-Methoxyphenyl sulfonyl) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 6- (4-Methoxyphenylsulfinyl) -1, 3-Dihydro-1-hydroxy-2,1-benzoxaborol, 5-Trifluoromethyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborol, 4- (4-Cyanophenoxy) -1,3-Dihydro-1- hydroxy-2,1-benzoxaborol, 5- (3-cyanophenoxy) -1,3-dihydro-1-hydroxy -2,1-benzoxaborol, 5- (4-Carboxyphenoxy) -1-hydroxy-2,1-benzoxaborol, 1-Hydroxy-5- [4- (tetrazol-1-yl) phenoxy] -2,1-benzoxaborol, 4- (4-Cyanophenoxy) phenylboronic acid, .3- (4-Cyanophenoxy) phenylboronic acid, and 4- (4-Cyanophenoxy) -2-Methylphenylboronic acid. In one example embodiment, the compound has a structure that is a selected member of the following compounds:

<formula> formula see original document page 74 </formula>

Production Methods of Compounds

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

Preparation of boron-containing editing domain inhibitors

Compounds for use in the present invention may be prepared using commercially available starting materials, known intermediates, or by using the synthetic methods published in the references described herein and incorporated by reference.

Boronic esters

The following example schemes illustrate methods of preparing boron-containing molecules of the present invention. These methods are not limited to the production of the compounds shown, but may 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 not explicitly illustrated in the schemes but are within the skill of the art. The compounds may be prepared using readily available materials from known intermediates.

In the following schemes, X represents bromine or iodine. Y is selected from H, lower alkyl and arylalkyl. Z is selected from H, alkyl, and aryl. The PG symbol represents protection group. The symbols A, D, E, G, Rxf Ry, Rz, R1a, R2a, R3a, R4a, R5a, R6a, RS% R * a> R10a, Rlla, and R12a may be used to refer to the corresponding symbols in the compounds described herein. Boronic Acid Preparation Strategy # 1

In Scheme 1, Step 1 and 2, compounds 1 or 2 are 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 also be used as reducing agents. The reducing agents may be used in amounts ranging from 0.5 to 5 equivalents with respect to compound 1 or .2. Suitable solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,

combinations of these and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; reaction completion times range from 1 to 24 h.

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. Aluminum lithium hydride, or sodium borohydride may also be used as reducing agents. The reducing agents may be used in amounts ranging from 0.5 to 5 equivalents to compound 2. Suitable solvents include lower alcohol such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, combinations of these and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; reaction completion times range from 1 to 24 h.

In step 3, the hydroxyl group of compound 3 is protected

with a protecting group that is stable under neutral or basic conditions. The protecting group is typically 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 methyl chloromethyl 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-ene, and inorganic bases such as sodium hydroxide, sodium, potassium hydroxide, potassium carbonate, combinations of these and others. The bases may be used in amounts ranging from 1 to 3 equivalents relative to compound 3. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; preferably between 0 and 40 ° C; Reaction completion times range from 1 h 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 p-toluenesulfonic acid pyridinium, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, hydrogen chloride, sulfuric acid, combinations of these and others. Suitable solvents include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene, and acetonitrile combinations thereof and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; preferably between 0 and 60 ° C, and is complete in 1h to 5 days.

In the case of trialkylsilyl, compound 3 is treated with 1 to 3 equivalents of chlorotrialkylsilylane 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. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; preferably between 0 and 40 ° C; reaction completion times range from 1 to 4 8 h.

In step 4, compound 4 is converted to boronic acid (5) by halogen metal exchange reaction. Compound 4 is treated with 1 to 3 equivalents of alkylmetal reagent relative to compound 4, such as n-butyllithium, sec-butyllithium, tert-butyllithium chloride,

isopropylmagnesium or Mg turnings with or without an initiator such as diisobutylaluminum hydride (DiBAl), followed by the addition of 1 to 3 equivalents of trialkyl borate relative to compound 4, such as trimethyl borate, triisopropyl borate, or tributyl borate. Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. Alkylmetal reagent may also be added in the presence of trialkyl borate. Addition of butyllithium is performed at -100 to 0 ° C, preferably at -80 to -40 ° C. Addition of isopropyl magnesium chloride is carried out at -80 to 40 ° C, preferably at -20 to 30 ° C. The addition of Mg turnings, with or without DiBA1, is performed at -80 to 40 ° C, preferably at -35 to 300 ° C. The addition of trialkyl borate is performed at -100 to 20 ° C. After the addition of trialkyl borate, the reaction is allowed to warm to room temperature, which is typically between -30 and 30 ° C. When the alkylmetal reagent is added in the presence of trialkyl borate, the reaction mixture is allowed to warm to room temperature after addition. Reaction completion times range from 1 to 12 h. Compound 5 may not be isolated and may be used for the next step without purification or in a pot.

In step 5, the protecting group of compound 5 is removed under acidic conditions to generate the compound of the invention. Suitable acids include acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid and others. Acids may be used in amounts ranging from 0.1 to .20 equivalents relative to compound 5. When the protecting group is trialkylsilyl, basic reagents such as tetrabutylonium fluoride may also be used. Suitable solvents include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, acetonitrile, acetone, combination thereof and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; preferably between 10 ° C and solvent reflux temperature; reaction completion times range from 0.5 to 48 h. The product may be purified by methods known to those skilled in the art.

In another aspect, the invention provides a method of producing a tetrahydropyran-containing boronic ester, said ester having the structure according to the following formula:

<formula> formula see original document page 80 </formula>

wherein R1 and R2 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl. R 1 and R 2, together with the atoms to which they are attached, may optionally be joined to form a 4 to 7 membered ring. R 9a, R 10a, R 11a and R 12a are independently selected members of H, OR *, NR * R **, SR *, -S (O) R *, -S (O) 2R *, -S (O) 2NR * R **, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl. R * and R ** are a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl. The method comprises: a) subjecting a first compound to Grignard or organolithium conditions, said first compound having the structure according to the following formula:

<formula> formula see original document page 81 </formula> (b) contacting the product of step a) with a borate ester, thereby forming said tetrahydropyran-containing boronic ester. In one exemplary embodiment, halogen is a member selected from iodine and bromine. In another exemplary embodiment, the borate ester is a member selected from B (OR1) 2 (OR2) i wherein R1 and R2 are independently selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl substituted or unsubstituted, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted t-butyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl. R1 and R2, together with the atoms to which they are attached, may optionally form a member selected from substituted or unsubstituted dioxaborolane, substituted or unsubstituted dioxaborinane and substituted or unsubstituted dioxaborepane. In another exemplary embodiment, the borate ester is a member selected from B (OR1) 2 (OR2) i wherein R1 and R2, together with the atoms to which they are attached, form a member selected from dioxaborolane, substituted tetramethyldioxaborolane or unsubstituted, substituted or unsubstituted phenyldioxaborolane, dioxaborinan,

dimethyldioxaborinane and dioxaborepane. In another exemplary embodiment, Grignard or organolithium conditions also comprise diisobutyl aluminum hydride. In another example embodiment, the Grignard reaction temperature does not exceed about 35 ° C. In another example embodiment, the Grignard reaction temperature does not exceed about 40 ° C. In another exemplary embodiment, the Grignard reaction temperature does not exceed about 45 ° C. In an exemplary embodiment, step (b) is performed at a temperature of from about -30 ° C to about -20 ° C. In another exemplary embodiment, step (b) is performed at a temperature of from about -35 ° C to about -2.5 ° C. In another example embodiment, step (b) is performed at a temperature of about -35 ° C. about -50 ° C to about -0.0 ° C. In another exemplary embodiment, step (b) is performed at a temperature of from about -40 ° C to about -20 ° C. In another exemplary embodiment, the tetrahydropyran-containing boronic ester is

<formula> formula see original document page 82 </formula>

In another aspect, the invention provides a method of producing a compound having the structure according to the following formula.

<formula> formula see original document page 82 </formula> said method comprising: a) subjecting a first compound to Grignard or organolithium conditions, said first compound has the structure according to the following formula:

<formula> formula see original document page 83 </formula>

b) quenching the reaction with water and an organic acid, thereby forming said compound. In an exemplary embodiment, wherein said organic acid is a member selected from acetic acid. In another example embodiment, the extinction step has essentially no contact with a strong acid. In another exemplary embodiment, the compound is? 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol. In another exemplary embodiment, the compound is purified by recrystallization from a recrystallization solvent, wherein said recrystallization solvent essentially contains no acetonitrile. In one 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 one exemplary embodiment, the recrystallization solvent contains less than 0.1% acetonitrile. In one exemplary embodiment, the recrystallization solvent contains toluene and a hydrocarbon solvent. In one 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 one exemplary embodiment, the recrystallization solvent contains about 3: 1 toluene: hydrocarbon solvent. In one exemplary embodiment, the recrystallization solvent contains about 4: 1 toluene: hydrocarbon solvent. In one exemplary embodiment, the hydrocarbon solvent is a member selected from heptane, octane, hexane, pentane and nonane. In one exemplary embodiment, the recrystallization solvent is 3: 1 toluene: heptane.

Boronic Acid Preparation Strategy # 2

In Scheme 2, Step 6, compound 2 is converted to boronic acid (6) by means of a transition metal catalyzed cross-linking reaction. Compound 2 is treated with 1 to 3 equivalents of bis (pinacolate) diboro or? 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of transition metal catalyst, using binder and appropriate base as needed. Suitable transition metal catalysts include palladium (II) acetate, palladium (II) acetoacetonate, tetrakis (triphenylphosphino) palladium, dichlorobis (triphenylphosphino) palladium, [1,1 '- bis (diphenylphosphino) ferrocene] dichloropalladium (II), combinations of these and others. The catalyst may be used in amounts ranging from 1 to 5 mol% relative to compound 2. Suitable binders include triphenylphosphine, tri (o-tolyl) phosphino, tricyclohexylphosphine, combinations thereof and the like. The binder may be used in amounts ranging from 1 to 5 equivalents to compound 2. Suitable bases include sodium carbonate, potassium carbonate, potassium phenoxide, triethylamine, combinations thereof and the like. The base may be used in amounts ranging from 1 to 5 equivalents relative to compound 2. Suitable solvents include N, N-dimethylformamide, dimethylsufoxide, tetrahydrofuran, 1,4-dioxane, toluene, combinations thereof and the like. Reaction temperatures range from 200 ° C to the boiling point of the solvent used; preferably between 50 and 150 ° C; reaction completion times range from 1 to 72 h.

Pinacol ester is then oxidatively cleaved to yield compound 6. Pinacol ester is treated with sodium periodate followed by acid. Sodium periodate may be used in amounts ranging from 2 to 5 equivalents 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 of these and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; preferably between 0 and 50 ° C; reaction completion times range from 1 to 72 h.

In step 7, the carbonyl group of compound 6 is treated with a reducing agent in a suitable solvent to generate a compound of the invention. Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, boranedimethylsulfide, combinations thereof and the like. Lithium aluminum hydride, or sodium borohydride may also be used as reducing agents. Reducing agents may be used in amounts ranging from 0.5 to 5 equivalents relative to compound 6. Suitable solvents include lower alcohol such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, combinations of these and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; reaction completion times range from 1 to 24 h.

Scheme 2 E

<formula> formula see original document page 86 </formula>

Boronic Acid Preparation Strategy # 3

In Scheme 3, Step 8, the compounds of the invention may be prepared in one step from compound 3. Compound 3 is mixed with trialkyl borate then treated with alkylmetal reagent. Suitable alkylmetal reagents include n-butyllithium, secbutylithium, tert-butyllithium combinations thereof and the like. Suitable trialkyl borates include trimethyl borate, triisopropyl borate, tributyl borate, combinations thereof and the like. Addition of butyllithium is performed at -100 to -0 ° C, preferably at -80 to -40 ° C. The reaction mixture is allowed to warm to room temperature after addition. Reaction completion times range from 1 to 12 h. Trialkyl borate may be used in amounts ranging from 1 to 5 equivalents with respect to compound 3. The alkylmetal reagent may be used in amounts ranging from 1 to 2 equivalents with respect to compound 3. Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. Reaction completion times range from .1 to 12 h. Alternatively, the mixture of compound 3 and trialkyl borate may be refluxed for 1 to 3 h and the ester-exchange alcohol molecule may be distilled prior to the addition of alkylmetal reagent.

Scheme 3

<formula> formula see original document page 87 </formula>

Boronic Acid Preparation Strategy # 4

In Scheme 4, Step 10, the methyl group of compound 7 is brominated using N-bromosuccinimide. N-bromosuccinimide may 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. Reaction temperatures range from 20 ° C to the boiling point of the solvent used; preferably between 50 and 150 ° C; reaction completion times range from 1 to .12 h.

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. Such acetates may 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, dimethyl sulfoxide, combinations of these and others. Reaction temperatures range from 20 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; reaction completion times range from 1 to 12 h. The resulting acetate is hydrolyzed to compound 3 under basic conditions. Suitable bases include sodium hydroxide, IIthio hydroxide, potassium hydroxide, combinations thereof and the like. The base may be used in amounts ranging from 1 to 5 equivalents to compound 8. Suitable solvents include methanol, ethanol, tetrahydrofuran, water, combinations thereof and the like. Reaction temperatures range from 200 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; reaction completion times range from 1 to 12 h. Alternatively, compound 8 may be directly converted to compound 3 under conditions similar to those above.

Steps 3 to 5 convert compound 3 to a compound of the invention.

Scheme 4

<formula> formula see original document page 88 </formula>

Boronic Acid Preparation Strategy # 5

In Scheme 5, Step 12, compound 2 is treated with (methoxymethyl) triphenylphosphonium chloride or (methoxymethyl) triphenylphosphonium bromide in the presence of base followed by acid hydrolysis to generate compound 9. Suitable bases include sodium hydride, tert-butoxide potassium, lithium diisopropylamide, butyllithium, lithium hexamethyldisilazane, combinations of these and others. (Methoxymethyl) triphenylphosphonium salt may be used in amounts ranging from 1 to 5 equivalents to compound 2. The base may be used in amounts ranging from 1 to 5 equivalents to compound 2. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, ether, toluene, hexane, NiN-dimethylformamide, combinations thereof and others. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; preferably between 0 and 30 ° C; reaction completion times range from 1 to 12 h. The enolether formed is hydrolyzed under acidic conditions. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid and others. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methanol, ethanol, combination thereof and others. Reaction temperatures range from 200 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; reaction completion times range from 1 to 12 h.

Steps 2 to 5 convert compound 9 to a compound of the invention.

Scheme 5

<formula> formula see original document page 89 </formula> Boronic Acid Preparation Strategy # 6

In Scheme 6, compound (I) wherein R 1 is H is converted to compound (I) wherein 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. Alcohol (R1OH) may be used as the solvent as well. Reaction temperatures range from 200 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; reaction completion times range from 1 to 12 h.

Scheme 6,

<formula> formula see original document page 90 </formula>

Boronic Acid Preparation Strategy # 7

In Scheme 7, compound (Ia) is converted to its amino alcohol complex (Ib). Compound (Ia) is treated with HOR1NRlaR1b. The amino alcohol may be used in amounts ranging from 1 to 10 equivalents with respect to compound (Ia). Suitable solvents include methanol, ethanol, propanol, tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, water, a combination thereof and others. Reaction temperatures range from 200 ° C to the boiling point of the solvent used; preferably between 50 and 100 ° C; reaction completion times range from 1 to 24 h.

Scheme 7

<formula> formula see original document page 90 </formula> The compounds of the invention may be converted to hydrates and solvates by methods similar to those described above.

I. c.) Borinic esters

In one aspect, the invention provides compounds useful in methods having the structure according to Formula XI:

<formula> formula see original document page 91 </formula>

wherein the variables Rc, A, D, E, G, J, WeM are described elsewhere in this.

In an exemplary embodiment of Formula (XI), R1c is substituted or unsubstituted (C1 -C4) alkyl. In an exemplary embodiment of Formula (XI), R1c is substituted or unsubstituted alkyloxy. In an exemplary embodiment of Formula (XI), R 1c is substituted or unsubstituted (C 3 -C 7) cycloalkyl. In an exemplary embodiment of Formula (XI), R 1c is substituted or unsubstituted alkenyl. In such a further exemplary embodiment, the substituted alkenyl has the structure r25C

<formula> formula see original document page 91 </formula>

wherein R23c, R24c, and R25c are independently selected members of H, haloalkyl, aralkyl, substituted aralkyl, (CH2) rOH (where r = 1 to 3), CH2NR26cR27c (wherein R26c and R27c are independently selected from hydrogen and alkyl ), CO2H, CO2 alkyl, CONH2, S-alkyl, S-aryl, SO2 alkyl, SO3H, SCF3, CN, halogen, CF3, NO2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted heterocycloalkyl or unsubstituted, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In another exemplary embodiment of Formula (XI), R1c is a substituted or unsubstituted alkynyl. In such an additional exemplary embodiment, the substituted alkynyl has the structure

<image> image see original document page 92 </image>

wherein R23c is as defined above.

In an exemplary embodiment of Formula (XI), R1c is substituted or unsubstituted aryl. In such an additional example embodiment, the substituted aryl has the structure

<formula> formula see original document page 92 </formula>

wherein R28c, R29c, R30c, R31c and R32c are independently selected members of H, aralkyl, substituted aralkyl, (CH2) sOH (where s = 1 to 3), CO2H, CO2alkyl, CONH2, CONHalkyl, 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 (wherein R 26 and R 27 are independently selected from hydrogen, alkyl, and alkanoyl) (t = 0 to 2), SO2NH2, OCH2CH2NH2, OCH2CH2NHalkyl, OCH2CH2N (alkyl) 2, oxazolidin-2-yl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted cycloalkyl or unsubstituted, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment of Formula (XI), R1c is a substituted or unsubstituted aralkyl. In an additional exemplary embodiment of this the substituted aralkyl has the structure

<formula> formula see original document page 93 </formula>

wherein R28c, R29c, R30c, R31c and R32c are as defined above, and n1 is an integer selected from 1 to 15.

In an exemplary embodiment of Formula (XI), R1c is a substituted or unsubstituted heteroaryl. In such an additional exemplary embodiment, heteroaryl has the structure

<formula> formula see original document page 93 </formula>

wherein X is a member selected from CH = CH, N = CH, NR35c (where R35c = H, alkyl, aryl or benzyl), O, or S. Y = CH or N. R33c and R34c are independently selected members of H, haloalkyl, aralkyl, substituted aralkyl, (CH2) uOH (where u = 1, 2 or 3), (CH2) vNR26cR27c (wherein R26c and R27c are independently selected from hydrogen, alkyl and alkanoyl) (ν = 0 a 3), CO2H, CO2 alkyl, CONH2, S-alkyl, S-aryl, SO2 alkyl, SO3H, SCF3, CN, halogen, CF3, NO2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, heterocycloalkyl substituted or unsubstituted, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

The structures of the invention also allow solvent interactions that can generate structures (Formula XVII) that include atoms derived from the solvent found by the compounds of the invention during synthetic manipulations and therapeutic uses. Structure XVII arises from the formation of a dative bond between the solvent (s) and the Lewis acid boron center. Thus, these solvent complexes could be stable entities with comparative bioactivities. Such structures are expressly contemplated by the present invention, wherein R 40c is H or alkyl.

<formula> formula see original document page 94 </formula>

Formula (XVII)

In one exemplary embodiment, the invention provides the structure which is a selected member of Formula (Ic), (IIc) and (Mc):

<formula> formula see original document page 94 </formula> where B is boron. ql and q2 are independently selected integers from 1 to 3. q3 is an integer selected from 0 to 4. M is a selected member of H, halogen, -OCH3, and -CH2-O-CH2-O-CH3. M1 is a member selected from halogen, -CH2OH, and -OCH3. X is a selected member of 0, S, and NRxc. Rxc is a member selected from H and substituted or unsubstituted alkyl. R 1c, R 3c, R 4c, R 2c and R 5c are independently selected members of Η, OH, NH 2, SH, CN, NO 2, SO 2, OSO 2 OH, OSO 2 NH 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 heteroaryl. R41c is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted and substituted or unsubstituted heteroaryl vinyl.

The compounds of the invention may form a hydrate with water, a solvate with an alcohol such as methanol, ethanol, propanol and the like; adducts with an amino compound such as ammonia, methylamine, ethylamine and the like; acid adducts such as formic acid, acetic acid and others; complexes with ethanolamine, quinoline, amino acids, and others.

In one exemplary embodiment, the compound has a structure that is a member selected from 2- (3-Chlorophenyl) - [1,3,2] -dioxaborolane, (3-Chlorophenyl) (4'-fluoro- (2 ') - (methoxymethoxy) methyl) phenyl) borinic 1- (3-chlorophenyl) -5-fluoro-1,3-dihydrobenzo [c] [1,2] oxaborol, 1- (3-chlorophenyl) -6- fluoro-1,3-dihydrobenzo [c] [1,2] oxaborol, 1- (3-chlorophenyl) -1,3-dihydrobenzo [c] [1,2] oxaborol, 5-chloro-1- (3- Fluorphenyl) -1,3-Dihydrobenzo [c] [1,2] oxaborol, 2- (3-fluorphenyl) 41,3,2] dioxaborolane, 3- (Benzo [c] [1,2] oxaborol-1 (3H) -

yl) benzonitrile, 2- (3-cyanophenyl) 41,3,2] -dioxaborolane,

(3-Chlorophenyl) (5'-fluoro (2 '- (methoxymethoxy) methyl) -

phenyl) -borinic, 1- (3-Chlorophenyl) -1,3-dihydro-3, 3dmethylbenzo [c] [1,2] oxaborol, (3-chlorophenyl) (2- (2- (methoxymethoxy) propan-2yl acid) ) phenylborinic, 1- (3-Chlorophenyl) -1,3-dihydro-3,3-dimethylbenzo [c] [1,2] oxaborol, 1- (4-

Chlorophenyl) -1,3-Dihydrobenzo [c] [1,2] oxaborol, 2- (4-

chlorophenyl) - [1,3,2] -dioxaborolane, 4- (Benzo [c] [1,2]

oxaborol-1 (3H) -yl) benzonitrile, 2- (4-cyanophenyl) 41,3,2] -

dioxaborolane, 4- (5-Fluorbenzo [c] [1,2] oxaborol-1 (3H) -

yl) benzonitrile, 2- (4-cyanophenyl) - [1,3,2] dioxoxololane, 3- (5-Fluorbenzo [c] [1,2] oxaborol-1 (3H) -yl) benzonitrile, 2- ( 3-cyanophenyl) - [1,3,2] -dioxaborolane, 3- (6-Fluorbenzo [c] [1,2] oxaborol-1 (3H) -yl) benzonitrile, 2- (3-cyanophenyl) -

[1,3,2] -dioxaborolane, 1- (3-Cyanophenyl) -5,6-dimethoxy-1,3-dihydrobenzo [c] [1,2] oxaborol, 2- (3-chlorophenyl) - [1 , 3.2] -

dioxaborolane, (4- (5- (Fluorbenzo [c] [1,2] oxaborol-1 (3H) -

yl) phenylmethanamine, 5-Fluoro-2- (methoxymethoxymethyl) phenyl] -

[1,2,2] -ioxaborolane, 4- (5- (Fluorbenzo [c] [1,2] oxaborol-1 (3H) -yl) phenylmethanamine, (3- (5- (Fluorbenzo [c] [1, 2]

oxaborol-1 (3H) -yl) phenylmethanamine, (4- (5- (Fluorbenzo [c]

[1,2] oxaborol-1 (3H) -yl) phenyl) methanol, (3- (5- (Fluorbenzo [c] [1,2] oxaborol-1 (3H) -yl) phenyl) methanol, 3- ( 6-Fluorbenzo [c] [1,2] oxaborol-1 (3H) -yl) phenol, 3- (5-Fluorbenzo [c] [1,2]

oxaboroll (3H) -yl) pyridine, (2- (Benzo [c] [1,2] oxaborol-1 (3H) -yl) phenyl) methanol, 2 - [(Methoxymethoxy) methyl] phenyl acid

boronic, 2 - [(methoxymethoxymethyl) phenyl] - [1,3,2] dioxaborolane, Bis [2- (methoxymethoxymethyl) phenyl] boronic acid, (2- (Benzo [c] [1,2] oxaborol-1 ( 3H) -yl) phenyl) methanol, (2- (Benzo [c] [1,2] oxaborol-1 (3H) -yl) phenyl) -NiN-dimethylmethanamine, (2- (Benzo [c] [1,2] ] oxaborol-1 (3H) -yl) -5-chlorophenyl) -N, N-dimethylmethanamine, (2- (Benzo [c] [1,2] oxaborol-1 (3H) -yl) -5-chlorophenyl) methanol , (2- (Benzo [c] [1,2] oxaborol-1 (3H) -yl) -5-chlorophenyl) methanol, (5-Chloro-2- (5-chlorobenzo [c] [1,2] oxaborol -1 (3H) -yl) phenyl) methanol, Bis [4-chloro-2- (methoxymethoxymethyl) phenyl] boronic acid, (5-chloro-2- (5-chlorobenzo [c] [1,2] oxaborol 1 (3H) -yl) phenyl) methanol, (5-Chloro-2- (5-chlorobenzo [c] [1,2] oxaborol-1 (3H) -yl) phenyl-N, N-dimethylmethanamine, 1- ( 4-chloro-2-methoxyphenyl) -1,3-dihydrobenzo [c] [1,2] benzoxaborol, ethylene glycol 4-Chloro-2-methoxyphenylboronic acid ester, 1- (4-chloro-2-methoxyphenyl) -1 , 3-Dihydrobenzo [c] [1,2] benzoxaborol, 2- (Benzo [c] [1,2] oxaboral-1 (3H) -yl) -5-chlorophenol, 2- (3- (Benzo [c] [1.2] oxaborol-1 (3H) -yl) phenoxy) -5-chlorophenol, 2- (3- (Benzo [c] [1,2] oxaborol-1 (3H) -yl) phenoxy) -5-chlorophenol, 4- ((3- (5-Fluorbenzo [c ] [1,2] oxaborol-1 (3H) -yl) phenyl) methyl) morpholine, 3- (5-Fluorbenzo [c] [1,2] oxaborol-1 (3H) -yl] phenyl) methyl-8 -hydroxy-quinoline-2-carboxylate, 1- (3-Chlorophenyl) -2,3-dihydro-2- (methoxymethyl) -1H-benzo [c] [1,2] azaborol, 3-Chlorophenyl 2- [N, N-bis (methoxymethyl) aminomethyl] phenylborinic, 1- (3-Chlorophenyl) -2,3-dihydro-2- (methoxymethyl) -β-benzo [c] [1,2] azaborol, 1- (3 (Chlorophenyl) -1,3,4,5-tetrahydrobenzo [c] [1,2] oxaborepine, 1- (3-chlorophenyl) -3,4-dihydro-1H-benzo [c] [1,2 ] -oxaborinine, 2- (3-chlorophenyl) [1,3,2] dioxaborolane, (3-chlorophenyl) (2 '- (2- (methoxymethoxy) ethyl) phenyl) -borinic acid and 1- (3-chlorophenyl) - 3,4-dihydro-1H-benzo [c] [1,2] oxaborinine. I. d.) Preparation of boron containing compounds

Compounds for use in the present invention may be prepared using commercially available starting materials, known intermediates, or by using the synthetic methods published in the references described herein and incorporated by reference.

I. e.) Boronic esters

Methods of producing boronic esters are known in the art, and are well known to one skilled in the art to use these methods to make the boronic esters described herein. Examples include Pat. U.S. 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 Pat. U.S. Prov. We. 60 / 754,750, 60 / 774,532 and 60 / 746,361, which are incorporated herein by reference. Another example of a synthetic route for the preparation of compounds for use in the invention is shown below: <formula> formula see riginal document page 98 </formula> I. f) Boronic esters

Methods of producing boronic esters are known in the art, and it is well known to those skilled in the art to use such methods to produce the boronic esters described herein. Examples include U.S. Patent No. 10,868,268 and and 11,743,665 which are incorporated herein by reference.

II. Tests for periodontal disease inhibition

Recognized genetics and molecular / cell biology techniques are in use to identify compounds that are suitable for inhibiting periodontal disease. Examples of assays used for this determination are provided herein.

III. Oral Hygiene Compositions

In another aspect, the present invention provides an oral hygiene composition comprising a compound of the invention. In one exemplary embodiment, the compound is a boron-containing compound described herein. In another exemplary embodiment, the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro4-methylphenyl) borinic acid. 3-hydroxypicolinate ester ), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane (bis (3-Chloro4-Methylphenyl) borinic acid 3-hydroxypicolinate ester). Such oral hygiene compositions are for use in the methods of the invention.

An oral hygiene composition of the present invention may have any physical form suitable for application to an oral surface. In various illustrative embodiments the composition may be a liquid solution suitable for irrigation, rinsing or spraying; a dentifrice such as a powder, toothpaste or dental gel; a liquid suitable for painting a dental surface (for example, a liquid whitener); a chewing gum; a dissolvable, partially dissolvable or non-dissolvable strip or film (for example, a bleaching strip); a wafer; a handkerchief or handkerchief; an implant; a thong; toothpaste, prophylactic toothpaste, dental polishers, gels, professional gels and other related products applied by dentists, as well as oral mouthwashes, mouthwashes, dental flosses, chewing gum, lozenges, tablets, edible food products, Pockets insertion periochips periodontal (made of material such as chlorhexidine gluconate) and others. The composition may contain active and / or transported ingredients in addition to those mentioned above.

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

In certain embodiments the composition is adapted for application to an oral surface of a small domestic animal, for example a cat or dog. Such a composition is typically edible or chewable by the animal, and may be in the form, for example, of a cat or dog food, cookie or toy.

Illustratively, the composition of any of the above described embodiments is an oral rinse, an oral spray, a dentifrice, an oral strip, a whitening liquid or a chewing gum. The mouthwashes include liquids adapted for irrigation by means of devices such as high pressure water jets. Toothpastes include, without limitation, toothpastes, gels and powders. A "liquid whitener" herein encompasses semi-liquid compositions such as gels as well as fluid liquids, provided that the composition is capable of application to a dental surface by painting with a brush or other suitable device.

"Painting" in the present context means applying a thin layer of a composition to the dental surface. In one embodiment the composition is a toothpaste or toothpaste gel.

The composition of the invention may comprise, in addition to the boron-containing compounds described herein, a vitamin or vitamin derivative or antioxidant component or one or more active ("active") agents.

Useful assets include those that lead, without limitation, to changes in appearance and structural teeth, plaque treatment and prevention, calculus, dental caries, tooth decay, abscesses, inflamed and / or bleeding gums, gingivitis, infectious oral conditions and / or inflammatory in general, dental sensitivity, halitosis and others.

Therefore, the composition of the invention may contain one or more actives such as bleaching agents, fluoride ion sources, additional antimicrobial agents to the boron-containing compound described herein, desensitizing agents, anti-calculus (tartar control), stannous ion sources. , zinc ion sources, sialagogues, breath freshening agents, anti-plaque agents, anti-inflammatory agents additional to any boron-containing compound having anti-inflammatory properties, periodontal agents, analgesics and nutrients. Active agents should be selected for compatibility with each other and with other ingredients of the composition.

Useful active agents therein are usually present in a composition in amounts selected to be safe and effective, that is, sufficient amount to provide a desired benefit, for example a therapeutic, prophylactic, nutritional or cosmetic effect, when the composition is repeatedly used as described herein, with no unwanted side effects such as toxicity, irritation or allergic reaction, corresponding to a reasonable risk / benefit ratio. Such a safe and effective amount will commonly, but not necessarily, be within ranges approved by regulatory agencies. A safe and effective amount in a particular case depends on a number of factors, including the particular desired benefit or condition being treated or to be prevented, the particular individual who uses it, or who receives it, the composition, frequency and duration of use. etc. Active agents are typically present in a total amount from 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. One or more active agents, including the boron-containing compound described herein, may optionally be present in encapsulated form in the composition. For example, blood cells containing one or more active agents may be adapted to rupture during brushing or chewing to release the active agents to the oral surface.

Additionally, the composition of the invention may include any of the components conventionally present or desirable in an oral care product. For example, the composition may include a bleaching agent such as peroxy compounds, chlorine dioxide, chlorites and hypochlorites, a polymer-peroxide complex, polyvinylpyrrolidone-hydrogen peroxide complex (PVP-H2O2); a source of fluoride ions (monofluorophosphate and fluororsilicate salts, antibacterial agents. Agents active as antibacterial agents may include, for example, those listed in US Patent No. 5,776,435 to Gaffar et al, the contents of which are incorporated herein. The composition may also include a dental antisensitivity agent, a sialagoguo (saliva stimulating agent), a breath-freshening agent, an anti-plaque agent, or plaque disrupting agent.

Among carriers useful for optional inclusion in the composition of the invention are diluents, abrasives, bicarbonate salts, pH modifying agents, surfactants, foam modulators, thickening agents, viscosity modifiers, wetting, sweetening, flavoring and coloring agents. A carrier material, or more than one carrier material of the same or different classes, may optionally be present. Water is a preferred diluent and in some compositions such as mouthwashes and bleach liquids may be accompanied by an additional solvent such as an alcohol, for example ethanol.

The composition may contain abrasives, pH modifying agents, surfactants, foam modulators, thickening agents, viscosity modifiers, humectants, sweeteners, flavorings, colorants.

The invention also provides an oral hygiene method comprising a step of applying a composition as described herein to an oral surface of an individual. In one embodiment the composition is a toothpaste or toothpaste gel, and the application step comprises brushing the surface, for example the tooth surface and the periodontal surface adjacent thereto, with the toothpaste.

According to one embodiment of the invention, there is further provided a method of inhibiting inflammation in an oral tissue of an individual. The method of such embodiment comprises applying to a tissue proximal oral surface of a compound of the invention. In one exemplary embodiment, the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro4-methylphenyl) borinic acid 3-hydroxypicolinate ester), 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, and 5- (4-

cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) borane. In another embodiment, an oral health promotion method is provided in an individual. The method of such embodiment comprises applying to a subject's oral surface a compound of the invention.

Practicing a method of the invention may promote any aspect or aspects of oral health. As an example, such a method may promote periodontal and / or gum health, for example by reducing bacterial infection and / or inflammation. As another example, such a method may provide a refreshing breath benefit, for example through antibacterial and / or antioxidant activity. In yet another example, such a method may promote dental retention, for example by reducing or preventing dental caries and preventing the destruction of the bone matrix that holds the tooth in place. In yet another example, such a method may provide an anti-plaque benefit. In yet another example, such a method may reduce damage to free radical oral tissues, including those occurring as a result of contact with tobacco or polluted air.

It is well known that improved oral health, in particular better periodontal and / or gum health associated with infection and / or reduced bacterial inflammation, may lead to systemic benefits or the overall health of the body. Vitamin release from an oral surface as provided herein may also improve overall health by supplementing the vitamins ingested with food.

Systemic conditions that may be ameliorated as a result of improved oral health following the practice of a method of the invention include cardiovascular disease including atherosclerosis, coronary heart disease (CHD), and stroke; diabetes; respiratory infections including bacterial pneumonia; low birth weight at preterm birth; gastric ulcers; bacteremia, - infectious endocarditis; prosthetic device infection; chronic obstructive pulmonary disease (COPD); and brain abscesses.

The practice of the methods may consist of a single application as described herein, or may comprise repetitions of such applications. In one embodiment a method as described herein is repeated at regular intervals, for example, twice or once a day, twice or once a week, twice or once a month, in a home-based program or regimen. / or in a professional or clinical setting.

The subject in any of the above methods may be a human or non-human mammal, for example, a dog, cat, horse or exotic mammal. In certain embodiments the individual is a small domestic animal, for example a cat or dog, and the composition in the form of a food, cookie or toy is given to the animal to chew.

The oral hygiene compositions of this invention may also include various other components, including hydrophilic liquid carriers, including, but not limited to, glycerine, propylene glycol, polyethylene glycol, and hydrophobic liquid carriers such as triglyceride, diglyceride, and organic oils including mineral oil. , essential oils, and fatty vegetable oils. Such hydrophilic and hydrophobic liquid carriers may be used alone or in combination and preferably may be added in a ratio of from about 2 to about 50% by weight (in the case of compositions comprising liquid carriers), especially from about 10 to about 50%. about 35% by weight based on total composition. Using one or more such liquid carriers, the oral cavity composition of the present invention may preferably be formulated in a form of use as a gel, liquid, or paste.

The oral hygiene compositions of the present invention may also contain flavor components, typically in the form of natural flavors or aroma oils and / or herbal extracts and oils. These flavor components not only serve to generate a palatable flavor to an oral hygiene composition, but can act as natural antibacterial agents and preservatives at the same time. Oils suitable for use in the present invention include, without limitation, citrus oil, Sicilian lemon oil, lemon oil, lemongrass oil, orange oil, lime orange oil, grapefruit oil, pomegranate oil, apricot oil, tangerine extract, mandarin oil, mint oil, peppermint oil, sage oil, rosemary oil, cinnamon oil, wintergreen oil, clove oil, eucalyptus oil, ginger oil, sassafras, menthol, field mint oil, synthetic mint flavors and oils, carvone, eugenol, methylhekenol, methyl salicylate, methyl eugenol, thymol, anethole, millefolium extract, chamomile, lavender oil, myrrh, eugenol,, oil tea tree, sage oil, mauve, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, linalol, ethylinalol, thyme, almond oil, nutmeg, and vanillin. Any of these flavors or a mixture of two or more of these flavors may be used in the toothpaste composition. The content of these ranges from about 3% to about 20% by weight, as from about 4% to about 15% by weight, based on the total composition. Silica abrasives may also be incorporated into the oral hygiene composition of the present invention without departing from the scope of the invention. Specific silica abrasives suitable for use with the present invention include, without limitation, silica gels, precipitated silicas, silicates, and hydrated silica. Silica gels suitable for use with the present invention are hydrogels, hydrogels, xerogels, and aerogels, such as those known in the art and described in U.S. Pat. No. 6,440,397. Precipitated silicas are those known in the art, such as suitable oral hygiene type precipitated silicas described in U.S. Pat. No. 5,589,160. Suitable silicates are any of those naturally occurring or synthetic silicates suitable for use with oral hygiene compositions. These silica abrasives may be used alone or in combination. An example of silica abrasive for use with the present invention includes silica gels. Silica abrasives may be used in conjunction with the calcium salt or in place of the calcium salt component.

Water may optionally be incorporated into the oral hygiene compositions of the present invention, such as toothpastes and oral rinses. Water used in the preparation of commercially suitable oral hygiene compositions should preferably be deionized and free of organic impurities. Water may generally comprise from about 0% to about 40% by weight of toothpaste compositions therein.

In addition to the above described components, the oral hygiene composition of the present invention may also contain various optional ingredients and carriers generally used for oral cavity preparations, such as toothpastes and oral rinses. Such optional components include, without limitation, such components as abrasives, surfactants, thickening agents, buffers, humectants, preservatives, and antibiotic and anti-caries agents. All of these additives, described in more detail below, are generally customary and should be known to one skilled in the art.

Dental abrasives useful in the dentifrice compositions of the present invention include several different materials known in the art. Preferably, the abrasive material should be one that is compatible with the composition of interest and does not exert excessive abrasion to dentin. Suitable abrasives include, for example, silicas including gels and precipitates; insoluble polymetaphosphate, hydrated alumina, resinous abrasives such as polymerized resins (eg urea, melamine, cross-linked epoxides, phenolic and others), and mixtures thereof.

Another optional component of the oral hygiene compositions of the present invention is a humectant. The humectant serves to maintain the compositions as hardening toothpaste compositions upon exposure to air, and to give the mouthwash and toothpaste compositions a feeling of moisture in the mouth. Certain humectants may also impart desirable sweet taste to the oral rinse and toothpaste compositions. Suitable humectants for use in compositions of the present invention include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, polyethylene glycol, and propylene glycol. The oral hygiene compositions of the present invention may also optionally contain sweeteners such as sodium saccharin, acesulfame potassium, glycyrrhizin, perilartine, thaumatin, aspartylphenylalanyl methyl ester and xylitol.

Buffering agents are another optional component of the oral hygiene compositions of the present invention. Buffering agents serve to retain the pH of the compositions in the preferred range. Buffering agents suitable for use in dentifrice compositions of the present invention include soluble phosphate salts.

Other optional components of the oral hygiene compositions of the present invention are preservatives, such as those that prevent microbial growth in oral hygiene compositions. Suitable preservatives include, without limitation, methylparaben, propylparaben, bezoates, and alcohols such as ethanol.

Binders and thickeners may also optionally be used in the oral hygiene compositions of the present invention, particularly in toothpaste compositions. Preferred binders and thickeners include, without limitation, carrageenan (e.g. Viscarin, Irish moss, and others); cellulose derivatives such as hydroxyethyl cellulose, v-carboxymethyl cellulose, and sodium carboxymethyl hydroxypropyl cellulose, carboxyvinyl polymers; natural gums such as karaya gum, arabic gum, and tragacanth; polysaccharide gums such as xanthan gum; vaporized silica; and aluminum magnesium colloidal silicate.

Compositions of the present oral hygiene compositions may also optionally contain a surfactant. Suitable surfactants are those which are reasonably stable and preferably form bubbles in the pH range of dentifrice compositions. Surfactants may also be added to act as solubilizing agents to help retain moderately soluble components in solutions or mixtures. Surfactants useful in dentifrice compositions as sudsing agents may be soaps, polysorbates, poloxamers, and synthetic detergents that are anionic, nonionic, cationic, zwiterionic, or amphoteric and mixtures thereof.

The oral hygiene compositions of the present invention may also optionally comprise anti-caries agents. Preferred anti-caries agents are water soluble fluoride ion sources. The number of such fluoride ion sources is large and well known to those skilled in the art, and include those disclosed in U.S. Pat. No. 3,53 5,421. Examples of fluoride ion source materials include sodium fluoride, potassium fluoride, sodium monofluorophosphate and mixtures thereof.

Antimicrobial and anti-plaque agents may also optionally be present in the oral hygiene compositions of the present condition. Such agents may include: triclosan (5-chloro-2- (2,4-dichlorophenoxy) phenol); chlorhexidine; chlorhexidine digluconate (CHX); alexidine, hexetidine (HEX); sanguinarine (SNG); benzalkonium chloride; salicylanilide; domifen bromide; cetylpyridinium chloride (CPC); tetradecylpyridinium chloride (TPC); N-tetra-decyl-4-ethylpyridinium chloride (TDEPC); octenidine; delmopinol; octapinol, and other piperidino derivatives; nicine preparations; zinc / stannous ion agents; antibiotics such as augmentin, amoxacillin, tetracycline, deoxycycline, minocycline, and metronidazole; peroxide, such as peroxide cylium, hydrogen peroxide, and magnesium monopertalate and their analogues; and analogs and salts of the antimicrobial and antiplatelet agents listed above.

Oral hygiene compositions of the present invention may also optionally include one or more anti-calculus (anti-tartar) agents. Anti-calculus agents that may be useful in the dentifrice compositions of the present invention include antimicrobials such as chlorhexidine, nidamycin, and triclosan, metals and metal salts such as zinc citrate, Vitamin C, bisphosphonates, triclosanpyrophosphates, pyrophosphates, polyphosphates, polyacrylates and other polyacrylates , polyepoxysuccinates, ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid and related compounds, polyphosphonates, and polypyrophosphates such as sodium hexametaphosphate, as well as other known anti-calculus agents, such as those described in KJ Fairbrother et al., "Anticalculus agents, "Journal of Clinical Periodontology Vol. 27, p. 285 301 (2000).

Nutrients and vitamins may also be optionally added to the oral hygiene compositions of the present invention. Such agents may include folates, retinoids (Vitamin A), Vitamin B (B-thiamine, B2-riboflavin, B3-niacin, B5-pantothenic acid, B6-pyridoxine, B7-biotin, B8 / B9 / Bc-folic acid, B12 -cyanocobalamin), Vitamin C (ascorbic acid, sodium ascorbate), Vitamin E, Vitamin E analogues (dl-α-tocopherol acetate, tocopherol succinate, tocopherol nicotinate) and zinc. A number of different additives may also optionally be formulated in the oral hygiene compositions of the present invention as dental desensitizing agents (e.g. potassium and strontium salts), condensed anti-tartar agents such as sodium and potassium tetrapyrophosphate, whitening agents such as sodium oxide. aluminum and calcium peroxide, debridement agents such as sodium bicarbonate, pigments and dyes such as Blue 15- C174160, Green 7-C174260, reds 4-CI12085 and 40 CI16035, Yellow 115 CI47005: 1 and 5 CI19140, and Carmin 5 CI16035 ), as well as additives such as mica and sparkling.

As with the other optional oral hygiene additives, use may be made of one of these ingredients or a mixture of two or more of these ingredients in amounts suitable for the oral hygiene composition.

IV. V. Methods of Inhibiting Microorganism Growth or Killing Microorganisms In another aspect, the invention provides a method of inhibiting the growth of a microorganism, or killing a microorganism, preferably a bacterium, fungus, virus, yeast or parasite. comprising contacting the microorganism with a compound comprising contacting the organism with a compound described herein. In one exemplary embodiment, the compound is a boron-containing compound described herein. In one example embodiment, the microorganism is in the oral cavity of an animal, which is a selected member of a human, cattle, deer, reindeer, goat, bee, pig, sheep, horse, cow, bull, dog, piglet. guinea fowl, gerbil, rabbit, cat, camel, yak (Tibetan ox), elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan and turkey. In another exemplary embodiment, the animal is a human being. Alternatively, the method is used in vitro, for example, to eliminate microbial contaminants in a cell culture. In another exemplary embodiment, the compound is a member selected from 3-hydroxypyridine-2-carbonyloxybis (3-chloro-4-methylphenyl) borane (bis (3-Chloro4-methylphenyl) borinic acid 3-hydroxypicolinate ester) 1,3-dihydro-5-fluorol-hydroxy-2,1-benzoxaborol, and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol. 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 one example embodiment, the microorganism is a selected member of a fungus and a yeast. In another example embodiment, the fungus or yeast is a selected member of Candida species, Trichophyton species, Microsporium species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodiodes species, Histoplasma species, Paraeoeeidiodes, Phyeomyeetes species, Malassezia species, Fusarium species, Epidermophyton species, Seytalidium species, Scopulariopsis species, Alternaria species, Penieillium species, Phialophora species, Rhizopus species, Scedosporium species and Zygomyeetes class. In another exemplary embodiment, the fungus or yeast is a selected member of Aspergillus fumigatus (A. fumigatus), Blastomyees dermatitidis, Candida albieans (C. albieans, both sensitive and fluconazole resistant strains), Candida glabrata (C. glabrata), Candida krusei (C. krusei), Cryptococcus neoformans (C. neoformans), Candida parapsilosis (C. parapsilosis), Candida tropicalis (C. tropicalis), Cocciodiodes immitis, Epidermophyton floccosum (E. floccosum), Fusarium solani (F. solani), Histoplasma capsulatum, Malassezia furfur {M. furfur), Malassezia pachydermatis (M. pachydermatis), Malassezia sympodialis (M. sympodialis), Microsporum audouinii {M. audouinii), Microsporum canis {M. canis), Microsporum gypseum {M. gypseum), Paracoccidiodes brasiliensis and Phycomycetes spp., Triehophyton mentagrophytes (T. mentagrophytes), Triehophyton rubrum (T. rubrum), Triehophyton tonsurans (T. tonsurans). In another exemplary embodiment, the fungus or yeast is a selected member of Triehophyton eoneentrieum, T. violaeeum, T. sehoenleinii, T. verrueosum, T. soudanense, Microsporum gypseum, M. equinum, Candida guilliermondii, Malassezia globosa, M. obtuse, M. restrieta, M. slooffiae and Aspergillus flavus. In another exemplary embodiment, the fungus or yeast is a selected member of dermatophytes, Triehophytonl Mierosporum, Epidermophyton Aspergillus, Blastomyees, Candida,

Coecidioides, Cryptoeoecus, Hendersonula, Histoplasma, Paecilomyees, Paraeoceidioides, Pneumoeystis, Trichosporium and yeast-like fungi. IV. b) Methods involving bacteria

In one example embodiment, the microorganism is a bacterium. In one exemplary embodiment, the bacterium is a gram-positive bacterium. In another exemplary embodiment, gram-positive bacteria are a selected member of Staphylococcus species, Streptococcus species, Baeillus species, Mycobaeteriuml species Corynebaeterium species (Propionibaeterium species), Clostridium species, Aetinomyees species, Enteroeoeeus species and Streptomyees species. In another exemplary embodiment, the bacterium is a negative bacterium. In another exemplary embodiment, gram-negative bacteria is a selected member of Aeinetobaeter species, Neisseria species, Pseudomonas species, Brueella species, Agrobaeterium species, Bordetella species, Eseheriehia species, Yersinia species, Shigellal species, Salmonella species, Klebsiellal species Enterobaeter species, Haemophilus species, Pasteurella species, Streptobacillus species, Spirochete species, Campilobaeterl species Vibrio species and Helieobaeter species. In another exemplary embodiment, the bacterium is a selected member of Propionibaeterium aenes; Staphyloeoeeus aureus; Staphyloeoeeus epidermidis, Staphyloeoeeus saprophytieus; Streptoeoeeus pyogenes; Streptoeoecus agalaetiae; Streptoeoeeus pneumoniae; Enteroeoeeus faeealis; Enteroeoeeus faeeium; Baeillus anthraeia; Myeobaeterium avium - intracellular; Myeobaeterium tubereulosis, Aeinetobaeter baumanii; Corynebaeterium diphtheria; Clostridium perfringens; Clostridium botulinum; Clostridium tetani; Clostridium diffieile; Neisseria gonorrhoeae; Neisseria meningitidis; Pseudomonas aeruginosa, - Legionella pneumophila; Eseheriehia eoli; Yersinia pestis; Haemophilus influenzae; Helieobaeter pilori; Campilobaeter fetus; Campilobaeter jejuni; Vibrio cholerae; Vibrio parahemolyticus; Trepomena pallidum; Actinomyces israelii; Riekettsia prowazekii; Riekettsia riekettsi; Chlamydia traehomatis; Chlamydia psittaei; Brueella abortus; Agrobacterium tumefaeiens; and Franeisella tularensis.

In one exemplary embodiment, the bacterium is a member selected from alcohol-acid resistant bacteria, including Myeobaeterium species; bacilli, including Bacillus species, Corynebaeterium (also Propionibaeterium) species and Clostridium species; filamentous bacteria, including Aetinomyees species and Streptomyees species; bacilli, such as Pseudomonas species, Brueella species, Agrobacterium species, Bordetella species, Eseheriehial species Shigella species, Yersinia species, Salmonella species, Klebsiellal species Enterobacter species, Haemophilus species, Pasteurella species, and Streptobacillus species; spirochete species, Campilobaeter species, Vibrio species; and intracellular bacteria, including Riekettsiae species and Chlamydia species.

The compounds for use in the invention are active against various bacterial organisms. They are active against Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphyloeoeci, for example S. aureus; Enterococci, e.g. E. faeealis- Streptoeoeci, e.g. S. pneumoniae; Haemophili, for example H. influenza; Moraxella, for example M eatarrhalis; and Eseheriehia, for example, E. eoli. The compounds of use in the present invention are also active against mycobacteria, e.g. M. tuberculosis. The compounds of use in the present invention are also active against intercellular microbes, for example Chlamydia and Rickettsiae. The compounds of use in the present invention are also active against mycoplasma, e.g. M. pneumoniae.

In addition, compounds of use in this invention are active against Staphylococci organisms such as S. aureus and coagulase negative Staphyloccus strains such as S. epidermidis that are resistant (including multiple resistance) to other antibacterial agents, for example β-lactam antibiotics such as for example methicillin, acrolides, aminoglycosides, and lincosamides. Compounds for use in the present invention are therefore useful in the treatment of MRSA, MRCNS and MRSE. Compounds for use in the present invention are also active against vancomycin resistant strains of E. faeealis strains and therefore for use in the treatment of infections associated with VRE organisms. In addition, the compounds of use in the present invention are useful in the treatment of staphylococcal organisms that are mupirocin resistant.

In another example embodiment, the bacterium is a selected member of AetinobaeilIus species, Porphyromonas species, Tannerella species, Prevotellal species Eubaeteriuml species Treponema species, Bulleidia species, Mogibaeterium species, Slaekia species, Campylobaeter species, Eikenella species, Peptostreptoeousus species, , Capnocytophagal species Fusobaeterium species, Porphyromonas species and Baeteroides species. In yet another exemplary embodiment, the bacterium is a selected member of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythensis, Prevotella intermedia, Eubacterium nodatum, Treponema denticola, Bulleidia extructa, Mogibacterium timidum Sylaeceptaeusus, Phylenaeusus reella Peptostreptoeoceus anaerobius, Capnoeytophaga oehraeea, Fusobaeterium nueleatum, Porphyromonas asaeeharolytiea and Baeteroides forsythus. In another exemplary embodiment, the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane (bis (3-Chloro4-methylphenyl) borinic acid 3-hydroxypicolinate ester) 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol, and 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxybis (3-chloro-4-methylphenyl )borane. IV. c) Methods involving viruses

The compounds of the invention are useful for treating animal and human diseases involving viruses. In one example embodiment, the microorganism is a virus. In one exemplary embodiment, the virus is a selected member of hepatitis ABC, human rhinovirus, yellow fever virus, human respiratory coronavirus, severe acute respiratory syndrome (SARS), syncytial respiratory virus, influenza virus, parainfluenza virus 1-4 , human immunodeficiency virus 1 (HIV-I), human immunodeficiency virus 2 (HIV-2), herpes simplex virus .1 (HSV-I), herpes simplex virus 2 (HSV-2), human cytomegalovirus (HCMV) ), varicella zoster virus, Epstein-Barr virus (EBV), poliovirus, coxsackie virus, ecovirus, rubella virus, neurodermatrophic virus, smallpox virus, papovirus, rabies virus, dengue virus and West Nile virus. In another exemplary embodiment, the virus is a selected member of picornaviridae, fIaviviridae, coronaviridae, paramyxoviridae,

orthomyxoviridae, retroviridae, herpesviridae and

hepadnaviridae. In another exemplary embodiment, the virus is a selected member of a virus included in the following table.

Table A. Virus <table> table see original document page 121 </column> </row> <table> <table> table see original document page 122 </column> </row> <table>

IV. d) Methods of treating diseases involving parasites

The compounds of the invention are useful for the treatment of animal and human diseases involving parasites including protozoa and helminths. Examples of such parasite species include, but are not limited to, Entamoeba, Leishmaniar Toxoplasma, Trichinella and Schistosoma. In one exemplary embodiment, the parasite is a selected member of Plasmodium falciparum, P. vivax, P. ovale, P. malariae, P. berghei, Leishmania donovani, L. infantum, L. chagasi, L. mexicana, L. amazonensis , L. venezuelensis, L. tropics, L. major, L. minor, L. aetiopica, L. Biana braziliensis, L. (V) guyanensis, L. (V.) panamensis, L. (V) peruviana, Trypanosoma brucei rhodesiense, T. brucei gambiense, T. cruzi, Giardia intestinalis, G. lamblia, Toxoplasma gondii, Entamoeba histolytica, Trichomonas vaginalis, Pneumocystis carinii and Cryptosporidium parvum. In one exemplary embodiment, the disease caused by the parasite is a selected member of malaria, Chagas disease, Leishmaniasis, African sleeping sickness (African human trypanosomiasis), giardiase, toxoplasmosis, amoebiasis and cryptosporidiosis. V. Methods of Treatment or Prevention of Periodontal Disease

In another aspect, the invention provides a method of treating or preventing periodontal disease, or both. The method includes administering to the animal a therapeutically effective amount of a compound of the invention. In one exemplary embodiment, the compound is a member selected from a boron-containing compound described herein sufficient to treat or prevent said disease. In another exemplary embodiment, the compound is a member selected from 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-

methylphenyl) borane (bis (3-chloro4-methylphenyl) borinic acid .3-hydroxypicolinate ester), 1,3-dihydro-5-fluoro-hydroxy-2,1,1-benzoxaborol, and 5- (4-cyanophenoxy) - 1,3-dihydro-1-hydroxy-2,1-benzoxaborol. In another exemplary embodiment, the compound is 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl )borane. In another example embodiment, the animal is a selected member of a human, cattle, deer, reindeer, goat, bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit , cat, camel, yak (Tibetan ox), elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan and turkey. In another exemplary embodiment, the animal is a human being. In another exemplary embodiment, the animal is a selected member of a human being, cattle, goat, pig, ram, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. In another exemplary embodiment, the infection is a selected member of a gingivitis, periodontitis or juvenile / acute periodontitis.

The invention is also illustrated by the following Examples. The Examples are not intended to define or limit the scope of the invention.

EXAMPLES

General: Melting points were obtained using a Mel-Temp-II melting point apparatus and are uncorrected. 1H NMR spectra were recorded on an Oxford 300 (300 MHz) spectrometer (Varian). Mass spectra were determined in API 3000 (Applied Biosystems). HPLC purity (relative area) was determined using ProStar Model 330 (PDA detector, Varian), Model 210 (pump, Varian), and a BetaBasic-18 4.6 χ 150 mm column (Thermo Electron Corporation) with a linear gradient from 0 to 100% MeCN in 0.01% H 3 PO 4 for 10 minutes followed by 100% MeCN for a further 10 minutes at 220 nm.

EXAMPLE 1

Preparation of 3 from 1

.1.1 Reduction of carboxylic acid

To a solution of 1 (23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a solution of BH3 / THF (1.0 M, 55 mL, 55 mmol) at 0 ° C, and the mixture The reaction mixture was stirred overnight at room temperature. Thereafter, the mixture was cooled again with an ice bath, and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no more bubbles were 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 rotary evaporation residue was purified by flash column chromatography over silica gel to give 20.7 mmol of 3. 1.2 Results

Exemplary compounds of structure 3 prepared by the above method are shown below. ..2.a 2-Bromo-5-chlorobenzyl alcohol

1 H NMR (300 MHz, DMSO-d 5): δ 7.57 (d, J = 8.7 Hz, 1H), δ 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.

..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)., 43 (t, J = 5.7 Hz, 1H), 4.44 (d, J = 5.1 H 2 H 2), 3.76 (s, .H) .

EXAMPLE 2

Preparation of 3 from 2

..1. Aldehyde Reduction

To a solution of 2 (Ζ = H, 10.7 mmol) in methanol (30 mL) was added sodium borohydride (5.40 mol), and the mixture was stirred at room temperature for 1 hour. 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 of 3. 2 Results

Exemplary compounds of structure 3 prepared by the above method are shown below.

..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, 2Η), 6.88 (dd, J = 8.5, 2.9 Hz, 1Η ), 7.02 (d, J = 8.8 Hz, 1Η), 7.26 (d, J = 2.6 Hz, 1Η), 7.56 (d, J = 8.5 Hz, 1Η), 7.62 (d, J = Q1Hz Hz, 2Η).

.2.2.b 2-Bromo-4- (4-cyanophenoxy) benzyl alcohol

1H NMR (300 MHz, DMSO-dff): δ 7.83 (d, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 7.18 (dd, 1H), 7 , IF (d, 2H), 5.48 (t, 1H) and 4.50 (d, 2H) ppra. .2 . 2.c 5- (4-Cyanophenoxy) -I-Indanol

Federal Police. 50-53 ° C. MS (ESI +): m / z = 252 (M + 1). HPLC: 99.7% pure at 254 nm and 99.0% at 220 nm 1H NMR (300 MHz, DMSO-dff): 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-butyldimethylsilyl) benzyl alcohol

1H NMR (300 MHz, CDCl3) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s, 1 H), 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).

Additional examples of compounds that may be produced by this method include 2-bromo-4- (3-cyanophenoxy) benzyl alcohol; 2-bromo-4- alcohol (4-

chlorophenoxy) benzyl; 2-bromo-4-phenoxybenzyl alcohol; 2-bromo-5- (3,4-dicyanophenoxy) benzyl alcohol; 2- (2-bromo-5-fluorophenyl) ethyl alcohol; 2-bromo-5- alcohol

fluorbenzyl; and 1-bromo-2-naphthalenemethanol. EXAMPLE 3

Preparation of 4 from 3 .3.1 Protective Alkylation

Compound 3 (20.7 mmol) was dissolved in CH 2 Cl 2 (150 mL) and cooled to 0 ° C with an ice bath. To this solution under nitrogen, N, N-diisopropyl ethyl amine (5.4 ml, 31.02 mmol, 1.5 eq) and methyl chloromethyl ether (2 ml, 25.85 mmol, 1, 25 eq). The reaction mixture was stirred overnight at room temperature, and washed with saturated NaHCO3-water and then saturated NaCl-water. After rotary evaporation, the residue was purified by flash column chromatography over silica gel to give 17.6 mmol of 4.

.3.2 Results

Exemplary compounds of structure 4 prepared by the above method are shown below. .3.2.a 2-Bromo-5-chloro-1- (methoxymethoxymethyl) benzene

1H NMR (300 MHz, DMSO-d6): δ 7.63 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 2.4 & 0.6 Hz, 1H), 7.32 (dd, J = 8.4 & 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- (methoxymethoxy) ethyl] benzene

1H NMR (300.058 MHz, CDCl3) 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), 7.4 (dd, J = 8.8, 5.3 Hz, 1H). .3.2.c 2-Bromo-5-fluoro-1- [2- (methoxymethoxy) ethyl] benzene

1H NMR (300.058 MHz, CDCl3) δ ppm 3.04 (t, J = 6.7 Hz, .2H), 3.31 (S, 3H), 3.77 (t, J = 6.7 Hz 2.62 (s, 2H), 6.82 (td, J = 8.2, 3.2 Hz, 1H), 7.04 (dd, J = 9.4, 2.9 Hz 1 H), 7.48 (dd, J = 8.8, 5.3 Hz, 1H).

.3. 2.d 2-Bromo-4,5-fluoro-1- (methoxymethoxymethyl) benzene

1H NMR (300.058 MHz, CDCl3) 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 . and 2-Bromo-5-cyano-1- (methoxymethoxymethyl) benzene

1H NMR (300.058 MHz, CDCl3) δ ppm 3.43 (s, 3H), 4.65 (s, 2Η), 4.80 (s, 2Η), 7.43 (dd, J = 8.2, 4 , 1 Hz, 1Η), 7.66 (d, J = 8.2 Hz, 1Η), 7.82 2 (d, J = 4.1 Hz, 1Η). 3.2.2 2-Bromo-5-methoxy-1- (methoxymethoxymethyl) benzene 1H NMR (300 MHz, DMSO-d6): δ 7.48 (dd, J1 = 1.2 Hz, J2 = 1.2 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.83 (dd, J1 = 3 Hz, J2 = .3 Hz, 1H), 4.69 (d, J = 1, 2 Hz, 2H), 4.5 (s, 2H), 3.74 (d, J = 1.5 Hz, 3H), 3.32 (d, J = 2.1 Hz, 3H) ppm. .3.2.g 1-Benzyl-1- (2-bromophenyl) -1- (methoxymethoxy) ethane

1H NMR (300 MHz, DMSO-d6): 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-1- (methoxymethoxymethyl) benzene

1H NMR (300 MHz, CDCl3) 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), 7.4 (d, J = 8.2 Hz, 1H ).

.3.2.i 2-bromo-4- (4-cyanophenoxy) -1- (methoxymethoxymethyl) benzene

1H NMR (300 MHz, DMSO-d6): 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) -

.1- (methoxymethoxymethyl) benzene

1H NMR (300 MHz, CDCl3) 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) -1- (methoxymethoxymethyl) benzene

1H NMR (300 MHz, CDCl3) 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 Hzi 1Η), 7.28 (d, J = 2.9 Hz, 1Η), 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).

3.2.1 2-Bromo-5-phenoxy-1- (methoxymethoxymethyl) benzene

1H NMR (300 MHz, CDCl3) 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 (1, J = 7.6 Hz, 2H), 7.48 (d, J = 8.5 Hz, 1H).

Additional examples of compounds that may 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; l-bromo-2-

(methoxymethoxymethyl) naphthalene; 2-bromo-4 - fluorine-1-

(methoxymethoxymethyl) benzene; 2-phenyl-1- (2-bromophenyl) -1-

(methoxymethoxy) ethane; 2-bromo-5- (4-cyanophenoxy) -1-

(methoxymethoxy methyl) 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. EXAMPLE 4

Preparation of I from 4 by 5 4.1 Metallation and boronylation

To a solution of 4 (17.3 mmol) in anhydrous THF (80 mL) at -10 ° C under nitrogen was added dropwise tert-BuLi or n-BuLi (11.7 mL), and the solution turned a brown color. . Next, B (OMe) 3 (1.93 mL, 17.3 mmol) was injected in one portion, and the cooling bath was removed. The mixture was gradually heated with stirring for 30 minutes and then stirred with a water bath for 2 hours. After addition of 6 N HCl (6 mL), the mixture was stirred overnight at room temperature and about 50% hydrolysis occurred as demonstrated 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 hydrolysis was completed as indicated by TLC analysis. Rotational evaporation gave a residue which was dissolved in EtOAc, washed with water, dried and then evaporated. The crude product was purified by flash column chromatography over silica gel to give a solid of 80% purity. The solid was further purified by washing with hexane to give 7.2 mmol of I.

4.2 Results

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

.4.2.a 5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.5-Chlorobenzo [c] [1,2] oxaborol -1 (3H) -ol (Cl)

Federal Police. 2-150 ° C. MS (ESI): m / z = 169 (M + 1, positive) and .167 (M-1, negative). HPLC (220 nm). 99% purity. 1H NMR (300 MHz, DMSO-d6): 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-Dihydro-1-hydroxy-2,1-benzoxaborol

Benzo [c] [1,2] oxaborol-1 (3H) -ol (C 2)

Federal Police. 83 - 86 ° C. MS (ESI): m / z = 135 (M + 1, positive) and 133 (M-1, negative). HPLC (220 nm). 95.4% purity. 1H NMR (300 MHz, DMS0-d5): δ 9.14 (s, 1H), 7.71 (d, J = 7.2 Hz, δ), 7.45 (t, J = 7.5 Hz, 1Η), 7.38 (d, J = 7.5 Hz, 1Η),

7.32 (t, J = 7.1 Hz, 1Η) and 4.97 (s, 2H) ppm.

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

1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (d, J = 6.4 Hz,? 3H), 5.17 (q, J = 6.4 Hz, 1?), 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-1-hydroxy-1,2,3,4-tetrahydro-2,1-one

benzoxaborine

.6-Fluoro-3,4-dihydrobenzo [c] [1,2] oxaborinin-1-ol (C4) 1H NMR (300 MHz, DMSO-d6) 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-Difluor-1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.5,6-Difluorbenzo [c] [1,2] oxaborol-1 (3H) -ol (C5)

1H NMR (300 MHz, DMSO-d6) 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, 1H).

.4. 2.f 5-Cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5

carbonitrile (C6)

1H NMR (300 MHz, DMS0-d5) 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-Dihydro-1-hydroxy-5-methoxy-2,1-benzoxaborol

.5-Methoxybenzo [c] [1,2] oxaborol-1 (3H) -ol (C7) M.p. 102-104 ° C. MS ESI: m / z = 165.3 (M + 1) and 162.9 (δ-). 1H NMR (300 MHz, DMSO-dff): δ 8.95 (s, 1H), 7.60 (d, J = .8 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.91 (s, 2H), 3.77 (s, 3 H) ppm. .4.2.h 1,3-Dihydro-1-hydroxy-5-methyl-2,1-benzoxaborol

.5-Methylbenzo [c] [1,2] oxaborol-1 (3H) -ol (C8) M.p. 124-128 ° C. ESI MS: m / z = 148.9 (M + 1) and 146.9 (δ-). 1H NMR (300 MHz, DMSO-d6): 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.

.4.2.1 1,3-Dihydro-1-hydroxy-5-hydroxymethyl-2,1-benzoxaborol

5- (Hydroxymethyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C9) MS: m / z = 163 (M-1, ESI-). 1H NMR (300 MHz, DMSO-d *): 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. 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol .5 - Fluorbenzo [c] [1,2] oxaborol-1 (3H) -ol (C10) m.p. 110-114 ° C. MS ESI: m / z = 150.9 (M-1). 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.73 (dd, J1 = 6 Hz, J2 = 6 Hz, 1H), 7.21 (m, 1H), 7 , 14 (m, 1H), 4.95 (s, 2H) ppm. .4.2.k 1,3-Dihydro-2-oxa-1-cyclopenta [a] naphthalene Naphtho [1,2-c] [1,2] oxaborol-1, (3H) -ol (Cll) M.p. 139-143 ° C. ESI MS: m / z = 184.9 (M + 1). 1H NMR (300 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.28 (dd, Ji = 6.9 Hz, J2 = .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-Dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborol

.6-Fluorbenzo [c] [1,2] oxaborol-1- (3H) -ol (C13)

Federal Police. 110-117.5 ° C. MS (ESI): m / z = 151 (M-1, negative). HPLC (220 nm): 100% purity. 1H NMR (300 MHz, DMSO-d5): 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-dihydro-1-hydroxy-3-methyl-2,1-one

benzoxaborol-3-Benzyl-3-methylbenzo [c] [1,2] oxaborol-1 (3H) -ol (C14) MS (ESI): m / z = 239 (M + 1, positive). HPLC: 99.5% of

purity at 220 nm and 95.9% at 254 nm. 1H NMR (300 MHz, DMSO-d6): 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 3-Benzyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.3-Benzylbenzo [c] [1,2] oxaborol-1 (3H) -ol (C15)

MS (ESI +): m / z = 225 (M + 1). HPLC: 93.4% pure at .220 nm. 1H NMR (300 MHz, DMSO-d6): 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.ρ 1,3-Dihydro-4-fluoro-1-hydroxy-2,1-benzoxaborol

.4- Fluorbenzo [c] [1,2] oxaborol-1- (3H) -ol (C16)

1H NMR (300 MHz, DMSO-dff) 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-dihydro-1-hydroxy-2,1-one

benzoxaborol

.4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) benzonitrile (C17)

1H NMR (300 MHz, DMSO-d5) 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-dihydro-1-hydroxy-2,1-one

benzoxaborol

.4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yloxy) benzonitrile (C18)

Federal Police. 148-151 ° C. MS: m / z = 252 (M + 1) (ESI +) and m / z = 250 (M-I) (ESI-). HPLC: 100% pure at 254 nm and 98.7% at 220 nm. 1H NMR (300 MHz, DMSO-d6): 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-dihydro-1-hydroxy-2,1-benzoxaborol

.3- (I-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yloxy) benzonitrile (C19)

Federal Police. 146-149 ° C. MS: m / z = 252 (M + 1) (ESI +) and m / z = 250 (M-I) (ESI-). HPLC: 100% pure at 254 nm and 97.9% at 220 nm. 1H NMR (300 MHz, DMSO-d6): 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-dihydro-1-hydroxy-2,1-benzoxaborol

.6- (4-Chlorophenoxy) benzo [c] [1,2] oxaborol-1 (3H) -ol (C 20) M.p. 119-130 ° C. MS: m / z = 261 (M + 1) (ESI +) and m / z = 259 (M-I) (ESI-). HPLC: 100% pure at 254 nm and 98.9% at 220 nm. 1H NMR (300 MHz, DMSO-d6): 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-dihydro-1-hydroxy-2,1-benzoxaborol .6-Phenoxybenzo [c] [1,2] oxaborol -1 (3H) -ol (C21) M.p. 95-990C. MS: m / z = 227 (M + 1) (ESI +) and m / z = 225 (M-I) (ESI-). HPLC: 100% pure at 254 nm and 98.4% at 220 nm. 1H NMR (300 MHz, DMSO-d6): 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.ν 5- (4-Cyanobenzyloxy) -1,3-dihydro-1-hydroxy-2,1-one

benzoxaborol .4 - ((1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) methyl) benzonitrile (C22)

1H NMR (300 MHz, DMSO-d6) 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-dihydro-1-hydroxy-2,1-one

benzoxaborol

.2 - (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) benzonitrile (C23)

1H NMR (300 MHz, DMSO-d6) 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-dihydro-1-hydroxy-2,1-benzoxaborol

.5-Phenoxybenzo [c] [1,2] oxaborol-1 (3H) -ol (C24)

1H NMR (300 MHz, DMSO-d6) 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-Diethylcarbamoyl) phenoxy] -1,3-dihydro-1-hydroxy-2,1-benzoxaborol

N, N-diethyl-4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) benzamide (C25) 1H NMR (300 MHz, DMS0-d5) 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). .4.2.1,3-Dihydro-1-hydroxy-5- [4- (morpholinocarbonyl) phenoxy] -2,1-benzoxaborol (4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) phenyl) (morpholino) methanone (C26)

1H NMR (300 MHz, DMSO-dff) 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-dihydro-1-hydroxy-2,1-one

benzoxaborol

.4- (I-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) phthalonitrile (C27)

1H NMR (300 MHz, DMS0-d6) 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, 1H).

.4.2.ab 6-Phenylthio-1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.6- (Phenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C28) M.p. 121-124 ° C. MS: m / z = 243 (M + 1) (ESI +) and m / z = 241 (M-I) (ESI-). HPLC: 99.6% pure at 254 nm and 99.6% at 220 nm. 1H NMR (300 MHz, DMS0-ds): 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-dihydro-1-hydroxy-2,1-benzoxaborol

.6- (4- (Trifluoromethoxy) phenoxy) benzo [c] [1,2] oxaborol-1 (3H) -ol (C29)

Federal Police. 97-101 ° C. MS: m / z = 311 (M + 1) (ESI +) and m / z = 309 (M-I) (ESI-). HPLC: 100% pure at 254 nm and 100% at 220 nm. 1H (300 MHz, DMS0-d6): 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-dihydro-1-hydroxy-2,1-benzoxaborol

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

Federal Police. 85-95 ° C. MS: m / z = 304 (M + 1) (ESI +) and m / z = 302 (M-I) (ESI-). HPLC: 96.6% pure at 254 nm and 89.8% at 220 nm. 1H NMR (300 MHz, DMSO-d6): 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-dihydro-1-hydroxy-2,1-one

benzoxaborol

6- (4-Methoxy phenoxy) benzo [c] [1,2] oxaborol-1 (3H) -ol (C31) m.p. 126-129 ° C. MS: m / z = 257 (M + 1) (ESI +) and m / z = 255 (M-I) (ESI-). HPLC: 98.4% pure at 254 nm and 98.4% at 220 nm. 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.36 (d, 15 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-Methoxyphenyl) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.6- (4-Methoxyphenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C 32)

Federal Police. 95-100 ° C. MS: m / z = 272 (Μ +), 273 (M + 1) (ESI +) and m / z = 271 (M-I) (ESI-). HPLC: 100% purity at 254 nm and 99.2% at 220 nm. 1H NMR (300 MHz, DMSO-CZ5): 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, 3H) ppm.

.4.2.ag 6- (4-Methoxyphenylsulfonyl) -1,3-dihydro-1-hydroxy-2,1-benzoxaborol

.6- (4-Methoxyphenylsulfonyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C33)

Federal Police. 180-192 ° C. MS: m / z = 305 (M + 1) (ESI +) and m / z = 303 (M-I) (ESI-). HPLC: 96.8% pure at 254 nm and 95.5% at 220 nm. 1H NMR (300 MHz, DMSO-d6): 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-dihydro-1-hydroxy-2,1-benzoxaborol

.6- (4-Methoxyphenylsulfinyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C34)

1H NMR (300 MHz, DMSO-d6): δ 9.37 (s, 1H), 8.02 (d, 10 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-dihydro-1-hydroxy-2,1-benzoxaborol

.5- (Trifluormethyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C35)

Federal Police. 113-118 ° C. MS: m / z = 203 (M + 1) (ESI +) and m / z = 201

(M-I) (ESI-). HPLC: 100% pure at 254 nm and 100% at 220 nm. 1H NMR (300 MHz, DMSO - d6): 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-dihydro-1-hydroxy-2,1-benzoxaborol

.4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-4-yloxy) benzonitrile (C36)

For the coupling reaction between 4-fluorbenzonitrile and substituted phenol to generate starting material 2, see Igarashi, S .; et al Chemical & Pharmaceutical Bulletin (2000), 48 (11), 1,689-1,697.

1H NMR (300 MHz, DMS0-dff) (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-dihydro-1-hydroxy-2,1-one

benzoxaborol

.3- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) benzonitrile (C37)

For coupling between 3-fluorbenzonitrile and phenol

substituted to generate starting material 2: Li, F. et al., Organic Letters (2003), 5 (12), 2,169-2,171.

1H NMR (300 MHz, DMSOd6r) (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 10 Hz, 1H).

.4.2.al 5- (4-Carboxyphenoxy) -1,3-dihydro-1-hydroxy-2,1-one

benzoxaborol

4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) benzoic acid (C38) To a solution of 5- (4-cyanophenoxy) -1-hydroxy-2,1 -

C17 benzoxaborol (430 mg, 1.71 mmol) 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 / 1.3 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), followed by trituration with diisopropyl ether to give the target compound (37 mg, 8%).

1H NMR (300 MHz, DMSO-d6) 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 72H), 9.19 (s, 1H), 12.8 (br s, 1H).

.4.2.am 1-Hydroxy-1,3-dihydro-5- [4- (tetrazol-1-yl) phenoxy] -2,1-benzoxaborol .5- (4- (1H-tetrazol-5-yl) phenoxy ) benzo [c] [1,2] oxaborol-1 (3H) -ol (C39)

A mixture of 5- (4-cyanophenoxy) -1-hydroxy-2,1-benzoxaborol (200 mg, 0.797 mmol), sodium azide (103 mg, 1.59 mmol) and ammonium chloride (85 mg, 1 , 6 mmol) in N, N-dimethylformamide (5 mL) was stirred at 80 ° C for two 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), followed by trituration with ethyl acetate to give the target compound (55 mg, 23%).

1H NMR (300 MHz, DMSO-d6) 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 H 1 H), 8.05 (d, J = 8.5 Hz 1 2 H), 9.18 (br s, 1H).

EXAMPLE 5

Preparation of I from 2 through 6

.5.1 Catalytic Boronylation, Reduction and Cyclization

A mixture of 2 (10.0 mmol), bis (pinacolato) diboro

(2.79 g, 11.0 mmol), PdCl 2 (dppf) (250 mg, 3 mol%) and potassium acetate (2.94 g, 30.0 mmol) in 1,4-dioxane (40 mL) 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 at room temperature for 30 minutes, 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 give 6.3 mmol of the corresponding boronic acid. To the solution of the obtained boronic acid (0.595 mmol) in methanol (5 mL) was added sodium borohydride (11 mg, 0.30 mmol), and the mixture was stirred at room temperature for 1 hour. 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 Results

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

.5. 2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol (CIO)

Analytical data for this compound are listed in 4.2. j.

EXAMPLE 6

Preparation of I from 3

6.1 Boronilation and Cyclization in a Pot

To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35 mL, 5.86 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.6 mol / 1 in hexanes; 7 ml, 10.7 mmol) dropwise over 15 minutes at -78 ° C under a nitrogen atmosphere, and the mixture was stirred for 2 hours, allowing to warm to room temperature. The reaction was quenched 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 Results

Analytical data for exemplary compounds of structure I are provided below. 6.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol (CIO)

Analytical data for this compound are listed in 4. 2 . j.

EXAMPLE 7

Preparation of I from 3 7.1 Boronylation and cyclization in a distilled pot

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 hour. The solvent, generated isopropyl alcohol and excess triisopropyl borate were removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and cooled to -10 ° C. n-Butyllithium (3.2 mL, 5.1 mmol) was added dropwise over 10 minutes, and the mixture was stirred for 1 hour, allowing to warm to room temperature. The reaction was quenched 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 Results

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

.7.2.al. 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol (CIO)

The analytical data for this compound are listed in 4.2.j.

EXAMPLE 8

Preparation of 8 from 7

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 N1 N-azoisobutyl nitrile (414 mg, 5 mol%), and 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 give crude methylbrominated intermediate 8.

EXAMPLE 9

Preparation of 3 from 8

9.1 Hydroxylation

To crude Compound 8 (49.5 mmol) was added dimethylformamide (150 mL) and sodium acetate (20.5 g, 250 mmol), and the mixture was stirred at 800 ° 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 room temperature for 1 hour. The reaction mixture was concentrated to about one third of 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 followed by trituration with dichloromethane to give 21.8 mmol of 3.

9.2 Results

Exemplary compounds of structure 3 prepared by the above method are shown below.

9.2.a 2-bromo-5-cyanobenzyl alcohol

1H NMR (300 MHz, DMSO-d5) 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) .

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

EXAMPLE 10

Preparation of 9 from 2

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 room temperature overnight. The reaction was quenched with 6 N HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (x 2) and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added tetrahydrofuran (60 mL) and 6% HCl, and the mixture was heated at 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 16.6 mmol of 9.

EXAMPLE 11

Step 13 Preparation Method

11.1 Reaction

A solution of I in an appropriate alcohol solvent (R1-OH) was refluxed under a nitrogen atmosphere and then distilled to remove alcohol to give the corresponding ester.

EXAMPLE 12

Preparation of Ib from Ia

12.1 Reaction

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

12.2 Results

Ia (500 mg, 33 mmol) was dissolved in toluene (37 mL) at 80 ° C, and ethanolamine (0.20 mL, 3.3 mmol) was added. The mixture was cooled to room temperature, then ice bath, and filtered to give C40 as a white powder (600.5 mg, 94%). .12.2a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol ethanolamine adduct (C40)

1H NMR (300 MHz, DMS0-d5) 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 Preparation of Pyridinyloxaborols .14a. Metallation and boronylation

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) at -780 ° C under nitrogen was added dropwise. n-BuLi (13.6 mL, 21.8 mmol) is added. Then the cooling bath was removed. The mixture was gradually heated with stirring for 30 minutes and then stirred with a water bath for 2 hours. Then brine was added and the pH adjusted to 7 using 6 N HCl. The mixture was washed with THF (x2), and the aqueous layer (containing product) was evaporated) to dryness. The residue was washed with THF and the product was extracted into ethanol (x2). 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-oxaborolane [5,4-c] pyridine [[1,2] oxaborolo [3,4-c] pyridin-1 (3H) -ol] (C12)

1H NMR (300 MHz, DMSO - d6): 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) ", C6H6BNO2 = 135.

EXAMPLE 14

Cyclic borinic esters

Additional compounds may be produced by the methods described herein. By choosing the appropriate starting material such as, for example, 1 or 3, Examples 1-7 may be used to formulate the following compounds. When available, melting point characterization (m.p.) is provided for these compounds.

14. Results

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

.14a Ethyl 2- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-S-yloxy) acetate (C41)

<formula> formula see original document page 147 </formula>

Federal Police. 134-1370C. Exemplary starting material: ethyl 2- (4-bromo-3- (hydroxymethyl) phenoxy) acetate.

.14b 2- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) acetic acid (C42)

<formula> formula see original document page 147 </formula>

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

.14c 6- (thiophen-2-ylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C43)

<formula> formula see original document page 147 </formula>

Federal Police. 99-104 ° C. Exemplary starting material: (2-bromo-4- (thiophen-2-ylthio) phenyl) methanol.

.14d 6- (4-fluorophenylthio) benzo [c] [1,2] oxaborol-1 [3H) -ol (C44)

<formula> formula see original document page 147 </formula> 13 5 -13 8 0C. Exemplary starting material: (2-bromo-4- (4-fluorophenylthio) phenyl) methanol.

1-14- (3 - ((1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) methyl) phenyl) pentan-1-one (C45)

<formula> formula see original document page 148 </formula>

Federal Police. 96 - 98 ° C. Exemplary starting material: 1- (3 - ((4-bromo-3- (hydroxymethyl) phenoxy) methyl) phenyl) pentan-1-one.

.14f 2- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) -1- (piperidin-1-yl) ethanone (C46)

<formula> formula see original document page 148 </formula>

Federal Police. 158-163 ° C. Exemplary starting material: 2- (4-bromo-3- (hydroxymethyl) phenoxy) -1- (piperidin-1-yl) ethanone. .14g 2- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) -1- (4- (pyrimidin-2-yl) piperazin-1-yl) ethanone (C47 )

<formula> formula see original document page 148 </formula>

Federal Police. 190-195 ° C. Exemplary starting material: 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] oxaborol-1 (3H) -ol (C48) <formula> formula see original document page 149 < / formula>

Federal Police. 13 5-138 ° C. Exemplary starting material: (2-bromo-4- (4- (pyridin-2-yl) piperazin-1-yl) phenyl) methanol.

.14i 6-nitrobenzothc] [1,2] oxaborol-1 (3H) -ol (C49)

<formula> formula see original document page 149 </formula>

Federal Police. 163-171 ° C. Exemplary starting material: benzo [c] [1,2] oxaborol-1 (3H) -ol. See JACS 82, 2,172, 1960 for preparation.

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

<formula> formula see original document page 149 </formula>

Federal Police. 145-148 ° C. Exemplary starting material: 6-nitrobenzo [c] [1,2] oxaborol-1 (3H) -ol.

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

<formula> formula see original document page 149 </formula>

Federal Police. 12 0-123 ° C. Exemplary starting material:? 6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol.

.141 N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl) benzamide (C52;

<formula> formula see original document page 149 </formula> 18-196 ° C. Exemplary starting material: 6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol.

14m 6- (4-phenylpiperazin-1-yl) benzo [c] [1,2] oxaborol-1 (3H) -ol. (C53)

<formula> formula see original document page 150 </formula>

Federal Police. 159 -1610C. Exemplary starting material: (2-bromo-4- (4-phenylpiperazin-1-yl) phenyl) methanol.

14- 6- (1H-indol-1-yl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C55)

<formula> formula see original document page 150 </formula>

Federal Police. 135-144 ° C. Exemplary starting material: (2-bromo-4- (1H-indol-1-yl) phenyl) methanol. .14p 6-morpholinobenzo [c] [1,2] oxaborol-1 (3H) -ol (C56)

<formula> formula see original document page 150 </formula>

Federal Police. 128-132 ° C. Exemplary starting material: (2-bromo-4-morpholinophenyl) methanol.

.14q 6- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) nicotinonitrile

<formula> formula see original document page 150 </formula>

Federal Police. 193-198 ° C. Exemplary starting material: 6- (4-bromo-3- (hydroxymethyl) phenoxy) nicotinonitrile. .14r 5-fluoro-6-nitrobenzo [c] [1,2] oxaborol-1 (3H) -ol (C58) <formula> formula see original document page 151 </formula>

Federal Police. 162-167 ° C. Exemplary starting material: 5-fluorbenzo [c] [1,2] oxaborol-1 (3H) -ol.

.14s 5-bromo-6- (hydroxymethyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C59)

<formula> formula see original document page 151 </formula>

Federal Police. > 257 ° C. Exemplary starting material: (2,5-dibromo-4- (methoxymethyl) phenyl) methanol. .14t 3,7-dihydro-1,5-dihydroxy-1H, 3H-benzo [1,2-c: 4,5-c '] bis [1,2] oxaborol (C60)

<formula> formula see original document page 151 </formula>

Federal Police. > 25 ° C. Exemplary starting material: (2,5-dibromo-1,4-phenylene) dimethanol.

.14u 1- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6 yl) -3 phenylurea (C61)

<formula> formula see original document page 151 </formula>

Federal Police. 213-215 ° C. Exemplary starting material: 6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol.

.14v N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl) benzenesulfonamide (C62)

<formula> formula see original document page 151 </formula> 175-184 ° C. Exemplary starting material:? 6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol.

.14w N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl-acetamide (C63)

<formula> formula see original document page 152 </formula>

Federal Police. 176-185 ° C. Exemplary starting material: 6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol.

.14x 7- (hydroxymethyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C64;

<formula> formula see original document page 152 </formula>

Federal Police. 241-250 ° C. Exemplary starting material: (2-bromo-1,3-phenylene) dimethanol. .14y 7-methylbenzo [c] [1,2] oxaborol-1 (3H) -ol (C65)

<formula> formula see original document page 152 </formula>

Federal Police. 107-111 ° C. Exemplary starting material: (2 · bromo-3-methylphenyl) methanol.

.14z 6- (3- (phenylthio) -β-indol-1-yl) benzo [c] [1,2] oxaborol .1 (3H) -ol (C66)

<formula> formula see original document page 152 </formula>

Federal Police. 159-163 ° C. Exemplary starting material: (2-bromo-4- (3- (phenylthio) -β-indol-1-yl) phenyl) methanol. 14aa 3- (1- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl) -1H-indol-3-ylthio) propanenitrile (C67)

<formula> formula see original document page 153 </formula>

Federal Police. 135-141 ° C. Exemplary starting material: 3- (1- (3-bromo-4- (hydroxymethyl) phenyl) -1H-indol-3-ylthio) propanenitrile.

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

<formula> formula see original document page 153 </formula>

Federal Police. 120-124 ° C. Exemplary starting material: (2-bromo-4- (5-methoxy-1H-indol-1-yl) phenyl) methanol.

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

<formula> formula see original document page 153 </formula>

Federal Police. 185-189 ° C. Exemplary starting material: (6-bromobenzo [d] [1,3] dioxol-5-yl) methanol.

.14dd 6-amino-5 fluorbenzo [c] [1,2] oxaborol-1 (3H) -ol (CIO)

<formula> formula see original document page 153 </formula>

Federal Police. 14 2-145 ° C. Exemplary starting material: 6-nitro-5-fluorbenzo [c] [1,2] oxaborol-1 (3H) -ol.

14e 6- (benzylamino) -5-fluorbenzo [c] [1,2] oxaborol-1 (3H) -ol (C71) <formula> formula see original document page 154 </formula>

Federal Police. 159-164 ° C. Exemplary starting material: 6-amino-5-fluorbenzo [c] [1,2] oxaborol-1 (3H) -ol.

.14ff 6- (5-Methoxy-3- (phenylthio) -1H-indol-1-yl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C72)

<formula> formula see original document page 154 </formula>

Federal Police. 13 5 -1410C. Exemplary starting material: (2-bromo-4- (5-methoxy-3- (phenylthio) -β-indol-1-yl) phenyl) methanol.

.14gg 3- (1- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl) -5-methoxy-1H-indol-3-ylthio) propanenitrile (C73)

<formula> formula see original document page 154 </formula>

Federal Police. 149-154 ° C. Exemplary starting material: 3- (1- (3-bromo-4- (hydroxymethyl) phenyl) -5-methoxy-1H-indol-3-ylthio) propanenitrile.

.4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-7-yloxy) benzonitrile (C74)

<formula> formula see original document page 154 </formula>

Federal Police. 148-153 ° C. Exemplary starting material: 4- (2-bromo-3- (hydroxymethyl) phenoxy) benzonitrile.

.14ii 6- (5-chloro-1H-indol-1-yl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C75;

<formula> formula see original document page 155 </formula>

Federal Police. 149-154 ° C. Exemplary starting material: (2-bromo-4- (5-chloro-1H-indol-1-yl) phenyl) methanol.

.14 j 3- (5-chloro-1- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl) -1H-indol-3-ylthio) propanenitrile (C76)

<formula> formula see original document page 155 </formula>

Federal Police. > 225 ° C. Exemplary starting material: 3- (1- (3-bromo-4- (hydroxymethyl) phenyl) -5-chloro-1H-indol-3-ylthio) propanenitrile.

.14kk 6- (benzylamino) benzo [c] [1,2] oxaborol-1 (3H) -ol (Cll)

<formula> formula see original document page 155 </formula>

Federal Police. 126-133 ° C. Exemplary .6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol starting material.

.1411 6- (dibenzylamino) benzo [c] [1,2] oxaborol-1 (3H) -ol (C78)

<formula> formula see original document page 155 </formula>

Federal Police. 115-123 ° C. Exemplary starting material: 6-aminobenzo [c] [1,2] oxaborol-1 (3H) -ol.

.14mm 7- (4- (1H-tetrazol-5-yl) phenoxy) benzo [c] [1,2] oxaborol-1 (3H) -ol (C79)

<formula> formula see original document page 156 </formula>

Federal Police. decomposition at 215 ° C. Exemplary starting material: 4- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-7-yloxy) benzonitrile.

.14nn 6- (5-chloro-3- (phenylthio) -1H-indol-1-yl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C80;

<formula> formula see original document page 156 </formula>

Federal Police. 145-151 ° C. Exemplary starting material: (2-bromo-4- (5-chloro-3- (phenylthio) -β-indol-1-yl) phenyl) methanol. .14pp 6- (4- (pyrimidin-2-yl) piperazin-1-yl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C82)

<formula> formula see original document page 156 </formula>

Federal Police. NA ° C. Exemplary starting material: (2-bromo-4- (4- (pyrimidin-2-yl) piperazin-1-yl) phenyl) methanol.

.14qq 7- (benzyloxy) benzo [c] [1,2] oxaborol-1 [3H) -ol (C83) <formula> formula see original document page 157 </formula>

Federal Police. NA0C. Exemplary starting material: (3- (benzyloxy) -2-bromophenyl) methanol.

.14rr 4- (1-Hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-6-ylthio) pyridinium chloride (C84)

<formula> formula see original document page 157 </formula>

Federal Police. NA ° C. Exemplary starting material: (2-bromo-4- (pyridin-4-ylthio) phenyl) methanol.

.14ss 6- (pyridin-2-ylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C85)

<formula> formula see original document page 157 </formula>

Federal Police. NA ° C. Exemplary starting material: (2-bromo-4- (pyridin-2-ylthio) phenyl) methanol.

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

<formula> formula see original document page 157 </formula>

Federal Police. 120-124 ° C. Exemplary starting material: (2-bromo-3-fluorophenyl) methanol.

14uu 6- (4- (trifluoromethyl) phenoxy) benzo [c] [1,2] oxaborol .1 (3H) -ol (C87)

<formula> formula see original document page 157 </formula> 98-105 ° C. Exemplary starting material: (2-bromo-4- (4- (trifluoromethyl) phenoxy) phenyl) methanol.

.14vv 6- (4-chlorophenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C88)

<formula> formula see original document page 158 </formula>

Federal Police. 157-161 ° C. Exemplary starting material: (2-bromo-4- (4-chlorophenylthio) phenyl) methanol.

.14ww 6- (4-chlorophenylsulfinyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C89)

<formula> formula see original document page 158 </formula>

Federal Police. 154-161 ° C. Exemplary starting material: 6- (4-chlorophenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol.

.14xx 6- (4-chlorophenylsulfonyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C 90)

<formula> formula see original document page 158 </formula>

Federal Police. 157-163 ° C. Exemplary starting material: 6- (4-chlorophenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol. .14yy N- (1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yl) -N- (phenylsulfonyl) benzenesulfonamide (C91)

<formula> formula see original document page 158 </formula> 2-152 ° C. Exemplary starting material: N- (4-bromo-3- (hydroxymethyl) phenyl) -N- (phenylsulfonyl) benzenesulfonamide.

.14zz 6- (4- (trifluoromethyl) phenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C92)

<formula> formula see original document page 159 </formula>

Federal Police. 111-113 ° C. Exemplary starting material: (2-bromo-4- (4- (trifluoromethyl) phenylthio) phenyl) methanol.

.14aaa 6- (4- (trifluoromethyl) phenylsulfinyl) benzo [c] [1,2] oxaborol-1 (3H) -ol (C93)

<formula> formula see original document page 159 </formula>

Federal Police. 79-88 ° C. Exemplary starting material: 6- (4- (trifluoromethyl) phenylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol. .14bbb 6- (4- (methylthio) phenylthio) benzo [c] [1,2] oxaborol-1 (3H) ol (C94)

<formula> formula see original document page 159 </formula>

Federal Police. 117-120 ° C. Exemplary starting material: (2 bromo-4- (4- (methylthio) phenylthio) phenyl) methanol.

.14ccc 6- (p-tolylthio) benzo [c] [1,2] oxaborol-1 (3H) -ol (C95)

<formula> formula see original document page 159 </formula> 139-144 ° C. Exemplary starting material: (2-bromo-4- (p-tolylthio) phenyl) methanol.

.14ddd 3- ((1-hydroxy-1,3-dihydrobenzo [c] [1,2] oxaborol-5-yloxy) methyl) benzonitrile (C96)

<formula> formula see original document page 160 </formula>

Federal Police. 14.7-150 ° C. Exemplary starting material: 3 - ((4-bromo-3- (hydroxymethyl) phenoxy) methyl) benzonitrile.

EXAMPLE 15

Precursors for CBOs and CBEs

.15.1 2-Bromo-5-fluoro [1- (methoxymethoxy) 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 room temperature for 1 h. Water was added, and the solvent was removed under reduced pressure at about half 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 methyl chloromethyl ether (27 mL, 0.35 mmol) at 0 ° C and The mixture was stirred at room temperature 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 to give 5b (73.2 g, quant). 1H NMR (300MHz, CDCl3) δ (ppm) 3.43 (s, 3H), 4.62 (s, 2Η), 4.78 (s, 2Η), 6.88 (td, J = 8.5, 3.2 Hz, 1Η), 7.25 (dd, J = 9.6, 3.1 Hz, 1Η), 7.48 (dd, J = 8.8, 5.3 Hz, 1Η).

.15.2 2-Bromo [1- (methoxymethoxy) methyl] benzene (5a)

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

.15.3 2- [4-Fluoro-2 - [(methoxymethoxy) methyl] phenyl-1,3,2] dioxaborolane (6)

To a solution of 5b (16.2 g, 65.1 mmol) in THF (130 mL) was added secBuLi (1.4 M, 56 mL) and (MeO) 3B (14.5 mL, 130 mmol) at - 78 ° C under a nitrogen atmosphere, and the mixture was allowed to warm to room temperature 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 1N HCl, and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4. Then the solvent was removed under reduced pressure to generate boronic acid, which was used for the next step without purification. To a solution of boronic acid in toluene (300 mL) was added ethylene glycol (3.29 g, 53 mmol), and the mixture was refluxed for 3 h with a Dean-Stark trap. The solvent was removed under reduced pressure to yield 6 (12.1 g, 77%). 1H-NMR (300MHz, CDCl3) 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] dioxaborolane (7b; Riii = 3-Cl-Ph)

3-Chlorophenylboronic acid (3.041g, 19.4mmol) was dissolved in 75 mL of dry THF under nitrogen atmosphere. Ethylene glycol (1.32 g, 21.3 mmol) was added and the solution was refluxed for 18 h. The solution was cooled and THF was removed under reduced pressure to yield 7b (3.55 g, 100%) as a brown oil which solidified with freezer cooling. 1H NMR (300MHz, CDCl3) 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, 1H), 7.78 (br s, 1H).

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

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

1H NMR (300MHz, DMS0-d6) 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] dioxaborolane (7c; Riii = 4-C1-Ph)

1H NMR (300MHz, CDCl3) 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-Fluorphenyl) [1,2,2] dioxaborolane (7d; Riii = 3-F-Ph)

1H NMR (300MHz, CDCl3) 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-Fluorphenyl) [1,3,2-dioxaborolane (7e; Riii = 4-F-Ph)

1H NMR (300MHz, DMS0-d6) 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) [1,2,2] dioxaborolane (7f; Riii = 3-Me-Ph). 1H NMR (300MHz, DMSO-ds) 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 (7h; Riii = stiryl)

1H NMR (300MHz, DMSO-d6) δ (ppm) 4.20 (s, 4H), 6.15 (d, J = 18.5Hz, 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] dioxaborolane (7j; Riii-thiophen-3-yl)

1H NMR (300MHz, DMSO-d6) 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-Methylthiophen-3-yl) [1,2,2] dioxaborolane <7k; R111 = .4-methylthiophen3-yl)

1H NMR (300MHz, DMSO-d6) 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-dihydro-5-fluoro-2,1-benzoxaborol (91)

Compound 5b (1.06g, 4.20 mmol) was dissolved in 50 mL of dry THF under nitrogen atmosphere and cooled to -78 ° C. tert-BuLi (1.7M in pentane, 5.3 mL) was slowly added to the solution. After stirring for 10 minutes at -78 ° C, compound 7b (764 mg, 4.20 mmol) in 10 mL of dry THF was added and the solution was stirred for a further 0.5 h. The solution was then allowed to warm to room temperature and stirred for 18 h. The solvent was removed under reduced pressure, and the residue was partitioned between 40 mL H 2 O and 80 mL diethyl ether. The solution was vigorously stirred for several minutes then neutralized (pH 7) with 6 N HCl. The organic layer was separated and the aqueous solution extracted again with ether (2 x 8OmL). The ether extracts were combined, dried over MgSO4, filtered and evaporated to give crude 8f (1.22g) 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 of THF and 4 mL of concentrated HCl. The solution was stirred at room temperature for 12 h. Water (10 mL) was then added and THF was removed under reduced pressure. This generated a suspension. The precipitates were filtered under vacuum and washed with water (10 mL) then hexanes (5 mL) and dried to give compound 9f (334 mg, 59%) as a white solid: mp 112-114 ° C; 1H NMR (300MHz, DMS0-d6) 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, 2H), 7.65-7.72 (m, 3H); ESI-MS m / z 247.08, 249.03 (M-H) -; HPLC purity: 97.1%; Anal. (C13 H9 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-Dihydro-1-phenyl-2,1-benzoxaborol (9a)

Colorless oil; 1H NMR (300MHz, DMS0-d6) 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-Dihydro-5-fluoro-1-phenyl-2,1-benzoxaborol (9b)

mp 90 - 90 ° C; 1H NMR (300MHz, DMS0-d6) 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-dihydro-2,1-benzoxaborol (9c)

colorless oil; 1H NMR (300MHz, DMS0-d6) δ (ppra) 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%; Anal (C13H10BC10) C, H.

.16.4 1,3-Dihydro-1- (3-fluorophenyl) -2,1-benzoxaborol (9d)

colorless oil; 1H NMR (300MHz, DMSO-d6) δ (ppm) 5.28 (δ, 2H), 7.23 (m, 1H), 7.34 (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%; Anal (C13 H10 BFO) C, H.

.16.5 1,3-Dihydro-1- (4-fluorophenyl) -2,1-benzoxaborol (9e)

mp 53 - 55 ° C; 1H NMR (300MHz, DMSO-d6) 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, 3H); ESI-MS m / z not observed; HPLC purity: 99.3%; Anal. (C13 H10 BFO) C, H.

.16.6 1,3-Dihydro-5-fluoro-1- (3-fluorophenyl) -2,1-benzoxaborol (9g)

mp 80 - 80 ° C; 1H NMR (300MHz, DMS0-d6) 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%; Anal. (C 13 H 9 BF 2 O) C, H.

.16.7 1,3-Dihydro-5-fluoro-1- (4-fluorophenyl) -2,1-benzoxaborol (9h)

mp 75-77 ° C; 1H NMR (300 MHz, DMSO-d6) 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%; Anal. (C 13 H 9 BF 2 O) C, H. 16.8 1,3-Dihydro-5-fluoro-1- (3-methylphenyl) -2,1-benzoxaborol (9i)

mp 48-49 ° C; 1H NMR (300MHz, DMSO-d6) 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%; Anal. (C14H12BFO) C, H.

.16.9 1,3-Dihydro-5-fluoro-1- (4-methylphenyl) -2,1-benzoxaborol (9 j)

mp 48-49 ° C; 1H NMR (300MHz, DMSO-d6) 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%; Anal. (C14H12BFO) C, H.

.16.10 1,3-Dihydro-1-stiryl-2,1-benzoxaborol (10a)

mp 57-59 ° C; 1H NMR (300MHz, DMSO-d6) 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, 2H), 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 + +) 1; HPLC purity: 98.5%; Anal. (C13H10BFO - 0.1 H2O) C, .20 H.

.16.11 1,3-Dihydro-5-fluoro-1-stiryl-2,1-benzoxaborol (10b) m.p. 1H NMR (300MHz, DMSO-d6) 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, 1H); ESI-MS mlz 239 (M + H) +; HPLC purity: 99.1%; Anal. (C13H10BFO) C, H.

.16.12 1,3-Dihydro-5-fluoro-1- (furan-3-yl) -2,1-benzoxaborol (12)

colorless oil; 1H NMR (300MHz, DMS0-ds) δ (ppm) 5.34 (s, 2Η), 6.84 (m, 1Η), 7.24 (m, 1Η), 7.37-7.40 (d, J = 9.4 Hz, 1Η), 7.83 (m, 1Η), 8.14-8.18 (dd, J = 8.2, 5.9 Hz, 1Η), .8.49 (m, IH); ESI-MS m / z 203 (δ + H) 1; HPLC purity: .96.9%; Anal. (ChH8BFO2) C, Η.

.16.13 1,3-Dihydro-5-fluoro-1- (thiophen-3-yl) -2,1-benzoxaborol (13)

mp 33-35 ° C; 1H NMR (300MHz, DMSO-d6) 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) 1; HPLC purity: 97.8%; Anal. (C11H8BFO2) C, H.

.16.14 1,3-Dihydro-5-fluoro-1- (4-methylthiophen-3-yl) -2,1-benzoxaborol (14)

mp 51-53 ° C; 1H NMR (300MHz, DMSO-d6) 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%; Anal. (C12 H10BFO2) C, H.

.16.15 1,3-Dihydro-5-fluoro-1-vinyl-2,1-benzoxaborol (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) as 1.7 M solution in pentane was Added slowly, after stirring at -78 ° C for 30 minutes, dibutyl boronic acid dibutyl ester was added dropwise. The mixture was stirred at -78 ° C for 1h, then warmed to room temperature and stirred overnight. Concentrated HCl (4 mL) was added and stirred at room temperature for 4h. 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 hexane / ethyl acetate) to afford 11 (383 mg, 30%) as a yellowish oil; 1H NMR (300MHz, DMSOd6) δ (ppm) 5.27 (s, 2H), 6.25 (t, J = 8.5 Hz, 1H), 6.50 (d, J = .9.4 Hz, 2H), 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. (C9H8BFO - 0.1 H2O) C, H.

.16.16 3- (1,3-Dihydro-5-fluoro-2,1-benzoxaborol-1-yl) pyridine (15)

To a solution of 3-bromopyridine (731 mg, 4.63 mmol) in THF (5 µl) was added isopropylmagnesium chloride (1 M in THF; 2.3 mL) at room temperature under a nitrogen atmosphere, and the mixture was added. 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 room temperature overnight. Water was added and the 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). To the mixture was added 1 N HCl (10 mL), 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-Pr20 to give compound 15 (76 mg, 7.7%): mp 210-212 ° C; 1H NMR (300 MHz, DMSO-d6) 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, 1H): ESI-MS m / z 214 (M + H) +; Anal (C12 H9 BFNO - 0.6 H2O) C, Η, N.

Example 17

Precursors for CBOs

.17.1 2-Bromo-5-fluoro [1- (methoxymethoxy) 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 stirred for 2 hours while warming to room temperature. The reaction was quenched 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 the reaction mixture was stirred at room temperature 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 hexane / ethyl acetate) to give 18c (4.97 g, 2 steps 94%): 1 H NMR (300MHz, CDCl 3) (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-1- (methoxymethoxymethyl) benzene (18d)

To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a solution of BH3 THF (1.0 M, 55 mL). at .0 ° C and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled in an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble 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 rotary evaporation residue was purified by silica gel column chromatography (5: 1 hexane / EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88%): 1 H NMR (300 mL). 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 in an ice bath. To this solution under nitrogen were added in sequence i-Pr2NEt (5.4 mL, 31 mmol) and chloromethyl methyl ether (2.0 mL, 26 mmol). The reaction mixture was stirred overnight at room temperature and washed with saturated NaHCO3-water and then brine. The residue after rotary evaporation was purified by silica gel column chromatography (5: 1 hexane / EtOAc) to afford 18d (4.67 g, 85%) as a colorless oil: 1H NMR (300 MHz, DMSO-d6). : 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- (methoxymethoxymethyl) toluene (18e)

This compound was made from 2-bromo-5-methylbenzoic acid in the same manner as compound 18d: 1H NMR (300MHz, DMSO-d6) δ (ppm) 2.27 (s, 3H), 3.30 (s , 3H), 4.51 (S, 2Η), 4.68 (S, 2Η), 7.05 (dd, J = 7.9, 2.3 Hz, 1Η), 7.30 (d, J = 1.5 Hz, 1Η), 7.46 (d, J = 8.2 Hz, 1Η).

.17.4 2-Bromo-5-methoxy-1- (methoxymethoxymethyl) benzene (18g) This compound was made from 2-bromo-5-methoxybenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, DMSO- d6): 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 made from 4-bromo-1,3-phthalic acid in the same manner as compound 18d: 1 H NMR (300MHz, 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-1- (methoxymethoxymethyl) benzene (18k)

This compound was made from 2-bromo-4,5-difluorbenzoic acid in the same manner as compound 18d: 1 H NMR (300MHz, CDCl 3) 6 (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-1- (methoxymethoxymethyl) benzene (181)

This compound was made from 2-bromo-6-fluorbenzoic 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 = 8.2.2, 9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H).

.17.8 2-Bromo-4-fluoro-1- (methoxymethoxymethyl) benzene (18m)

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

17.9 4-Bromo-3- (methoxymethoxymethyl) benzonitrile (180

To a solution of 17 (10.0 g, 4 9.5 mmol) in carbon tetrachloride (200 mL) was added N-bromosuccinimide (8.81 g, 49.5 mmol) and 2,2'-azobis (isobutyronitrile). ) (414 mg, 5 mol%), and the mixture was refluxed for 3 h. 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 room temperature for 1 h. The reaction mixture was concentrated to about one third of 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 (3: 1 hexane / ethyl acetate) followed by trituration with dichloromethane to give 2-bromo-5-cyanobenzyl alcohol (4.63 g , 44% overall): 1H NMR (300MHz, DMS0-d6) 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) was added diisopropylethylamine (5.6 mL, 32 mmol) and chloromethyl methyl ether (2.3 mL, 30 mmol) at 0 ° C, and the reaction mixture was stirred at room temperature 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 hexane / ethyl acetate) to give 18f (4.08 g, 71%): 1H NMR (300MHz, CDCl3) δ (ppm) 3.43 (s 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-1- (methoxymethoxymethyl) benzene (18i)

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

.17.11 1-Bromo-2- (methoxymethoxymethyl) naphthalene (18j)

This compound was made from 1-bromonaphthaldehyde in the same manner as compound 5b: 1 H NMR (300MHz, 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-Dihydro-1-hydroxy-2,1-benzoxaborol (19a)

This compound was purchased from Lancaster Synthesis.

.17.13 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborol (19b)

To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) for 45 min at -78 ° C under nitrogen atmosphere. Anion rushed. After 5 minutes, (i-PrO) 3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about half 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 a 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 at about half 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-Pr20 / hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120 ° C; 1H NMR (300MHz, DMSO-d6) 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%; Anal (C7H6BFO2) C, H.

17.14 1,3-Dihydro-5-fluoro-1-hydroxy-3-methyl-2,1-benzoxaborolane (19c)

This compound was made from 18c in the same manner as compound 19b: mp 72-76 ° C. 1H NMR (300MHz, DMSO-d6) 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 (δ-) -; HPLC purity 95.2%; Anal (C8H9BO2) C, H.

17.15 5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborol (19d) This compound was made from 18d in the same manner as compound 19b: mp 142-144 ° C. 1H NMR (300MHz, DMSO-d6) 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, 1H); ESI-MS m / z 167 (M-H) -; HPLC purity 99.0%; Anal (C7H6BClO2 - 0.1 H2O) C, H.

.17.16 1,3-Dihydro-1-hydroxy-5-methyl-2,1-benzoxaborol (19e)

This compound was made from 18e in the same manner as compound 19b: mp 124-128 ° C; 1H NMR (300 MHz, DMS0-d6) 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, 1H); 9.05 (s, 1H); ESI-MS m / z 147 (M-H) -; HPLC purity 99.0%; Anal (C8H9BO2) C, H.

.17.17 1,3-Dihydro-1-hydroxy-5-methoxy-2,1-benzoxaborol (19g)

This compound was made from 18g in the same manner as compound 19b: mp 102-104 ° C; 1H NMR (300 MHz, DMS0-d6) δ (ppm) 3.77 (s, 3 Η), 4.91 (s, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6 , 94 (s, 1H); 7.60 (d, J = 8.1 Hz, 1H); 8.95 (s, 1H); ESI-MS m / z 163 (M-H) -; HPLC purity 100%; Anal (C8H9BO3) C, H.

.17.18 1,3-Dihydro-1-hydroxy-5-hydroxymethyl-2,1-benzoxaborol (19h)

This compound was made from 18h in the same manner as compound 19b: mp 124-128 ° C; 1H NMR (300 MHz, DMSO-d6) 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, 1H); 9.08 (s, 1H); ESI-MS m / z 163 (M-H) "; 100% HPLC purity.

.17 .19 1,3 - Dihydro-1-hydroxy-5-trifluoromethoxy-benzoxaboro 1 (191)

This compound was made from 18i in the same manner as compound 19b: mp 113-118 ° C; 1H NMR (300 MHz, DMSO-d6) 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, 1H), 9.47 (S, 1H); ESI-MS m / z 201 (M-H) -; HPLC purity 100%.

17.20 1,3-Dihydro-1-hydroxy-2,1-naphtho [2,1-d] oxaborol (19j)

This compound was made from 18j in the same manner as compound 19b: mp 139-143 ° C; 1H NMR (300 MHz, DMSO-d6) 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 (CnH9BO2) C, H.

17.21 1,3-Dihydro-4-fluoro-1-hydroxy-2,1-benzoxaborol (191)

This compound was made from 18L 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%; Anal (C7H6BFO2) C, H.

17.22 1,3-Dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborol (19m)

This compound was made 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, 2H), 9.29 (s, 1H); ESI-MS m / z 151 (M-H) "; 100% HPLC purity; Anal (C7H6BFO2) C, H.

17,23 5,6-Difluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborolane (19k)

To a solution of 18k (2.97 g, 11.1 mmol) and (i-PrO) 3B (2.8 mL, 12 mmol) in THF (30 mL) was added n-BuLi (1.6 mol / L in hexane; 7.5 mL) for 30 minutes at -78 ° C under a nitrogen atmosphere, and the mixture was stirred for 2 hours to warm to room temperature. The reaction was quenched 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 room temperature 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. 1H NMR (300MHz, DMS0-ds) 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, 1H), ESI-MS m / z 169 (MH) "; HPLC purity 96.6%; Anal (C7H5BF2O2) C, H.

.17.24 5-Cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborolane (19f)

This compound was made from 18f in the same manner as compound 19k: mp 98-101 ° C. 1H-NMR (300MHz, DMSO-d6) 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); ESI-MS m / z 158 (M-H) "; HPLC purity 97.7%.

.17.25 1,3-Dihydro-7-fluoro-1-hydroxy-2,1-benzoxaborolane (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 1.4 M solution at -78 ° C. The mixture was stirred at -78 ° C for 1h before (i-PrO) 3B (8.10 mL, 35.0 mmol) was added, the reaction warmed to room temperature very slowly, then stirred overnight. To the other. Water was added, and the pH was adjusted to 12, then it was washed with ethyl ether. The aqueous layer was acidified to pH 2 using 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 hexane / acetate). ethyl) to give 19n (270 mg) as a white solid: mp 120-124 ° C. 1H NMR (300MHz, DMSO-d6) 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%; Anal (C8H6BNO2) C, H.

EXAMPLE 18

Benzoxaborine

.18.1 2-Bromo-5-fluorophenylacetaldehyde (21a)

A mixture of 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 mol) in N, N-dimethylformamide (50 mL) was stirred at room temperature overnight. The reaction was quenched 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. To the residue was added tetrahydrofuran (60 mL) and 6 N hydrochloric acid, and the mixture was heated at 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 21a (3.60 g, 83%): 1 H NMR (300MHz, 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 1-Bromo-4-fluoro-2- [2- (methoxymethoxy) 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 room temperature for 2 hours. 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 room temperature overnight. the other. 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 hexane / ethyl acetate) to give 22a (2.99 g, 2 steps 68%) as a colorless oil: 1H NMR (300MHz, CDCl3) 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 I-Bromo-2-12- (methoxymethoxy) ethyl] benzene (22b)

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

18.4 6-Fluoro-1-phenyl-1,2,3,4-tetrahydro-2,1-benzoxaborine (23a)

This compound was synthesized from 22a and 7a in a similar manner to compound 9f: colorless oil; 1H NMR (300MHz, CDCl3) δ (ppm) 3.02 (t, J = 6.1 Hzi 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 - 0.1 H 2 O) C, H.

18.5 1-Phenyl-1,2,3,4-tetrahydro-2,1-benzoxaborine (23b)

This compound was synthesized from 22b and 7a in a similar manner to compound 9f: colorless oil; 1H NMR (300MHz, DMSO-d6) 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%; Anal (C14H13BO) C. H.

18 6 6-Fluoro-1-hydroxy-1,2,3,4-tetrahydro-2,1-benzoxaborine (24)

This compound was synthesized from 22a in a similar manner to compound 19b. Silica gel column chromatography (2: 1 hexane / ethyl acetate) followed by trituration with pentane 24 as a white powder: mp 77-82 ° C; 1H NMR (300MHz, DMS0-d6) 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); ESI-MS m / z 165 (M-H) -; HPLC purity 99.0%; Anal (C8H8BFO2) C, H. EXAMPLE 19

Formation of Ethylene Glycol Boronate Ester (3, T = nothing) General Procedure

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

Ethylene Glycol 3-Cyanophenylboronic Acid Ester (3a)

3-Cyanophenyl boronic acid (1 g, 6.8 mmol) was dissolved in dry THF (10 mL) under nitrogen. Ethylene glycol (379 μΐ ;, 422 mg, 6.8 mmol) was added and the reaction was heated at reflux for 4 hours then cooled to room temperature. THF was removed by rotary evaporator to give a white solid. Cold hexane was added and the product was collected by filtration yielding a white solid (1.18 g, quant. Yield). 1H-NMR (300.058 MHz, DMS0-d6) δ ppm 7.92-8.01 (3H, m), 7.50-7.64 (1H, m), 4.35 (4H, s)

Ethylene glycol 3-boronic acid thiophene ester (3b)

Thiophene-3-boronic acid (1 g, 7.8 mmol) was dissolved in dry THF (10 mL) under nitrogen. Ethylene glycol (435 μΙ1ι, 484 mg, 7.8 mmol) was added and the reaction was heated at reflux for 1 hour then cooled to room temperature. THF was removed by rotary evaporator to give a white solid. Hexane was added, dissolving the solid and removed by rotary evaporation. The product was placed under high vacuum to yield a brown solid (1.17 g, 97%). 1H-NMR (300.058 MHz, CDCl3) δ ppm 7.93 (1H, s), 7.3-7.4 (2H, m), 4.35 (4H, s).

Ethylene Glycol 3-Fluorphenylboronic Acid 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 at reflux for 3 hours under Deanette conditions. Stark The solvent was removed under reduced pressure to give 3-fluorophenylboronic acid ethylene glycol ester (7.57 g, 91%). Formation of Non-Symmetric Boronic Acid (6) from Ethylene Glycol Boronic Acid Ester General Procedure A: Grignard Methodology

Ethylene glycol boronic acid 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 at 0 ° C in an ice / water bath. Grignard reagent (0.95 to 1.2 molar equivalents) was added dropwise to the cooled solution. The reaction was warmed to room temperature and stirred for 3-18 hours. 6N HCl (2 mL / g) was added and the solvent was removed under reduced vacuum. The product was extracted into diethyl ether (40 mL / g) and washed with water (3 times by equal volume). The organic layer was dried (MgSO4), filtered and the solvent was removed by rotary evaporation yielding crude product, which is purified by column chromatography or taken to the next step without purification. Alternative Development: If the borinic acid product contained a basic group such as an amine or pyridine, then after stirring at room temperature for 3-18 hours, water (2 mL / g) was added and the pH adjusted to 5-8. The product was extracted into diethyl ether or ethyl acetate or THF up to three times (40 mL / g). The organic layer was dried (MgSO 4), filtered and the solvent was removed by rotary evaporation yielding crude product, which is purified by column chromatography or taken to the next step without purification.

(4-cyanophenyl) (3-fluorophenyl) borinic acid (6a)

Ethylene glycol 4-Cyanophenyl boronic acid 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-fluorphenylmagnesium bromide (IM in THF) (2.74 mL, 2.74 mmol, 0.95 molar equivalents) was added dropwise to the Cold solution. The reaction was allowed to slowly warm to room temperature and stirred for 18 hours. 6N HCl (1 mL) was added to the reaction causing a cloudy appearance and the solvent was removed using a rotary evaporator. The product was extracted into diethyl ether (20 mL) and washed with water (3X20 mL). The organic layer was dried (MgSO 4), filtered and the solvent removed using a rotary evaporator to yield the crude product as an oily solid. This was taken to the next step without purification.

General Procedure B: (Straight) Aryl Lithium Methodology

(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 a dry ice acetone bath and η-, sec- or tert-butyl lithium in THF or other solvent (1.2-2.4 molar equivalents) was added to the cooled solution. in drops causing the solution to turn dark yellow. Ethylene glycol boronic acid ester (1 molar equivalent) was dissolved in dry THF or diethyl ether (2-10 mL / g) under nitrogen. The ethylene glycol boronic acid ester in THF was added dropwise to the cooled aryl lithium solution causing the solution to turn pale yellow. The reaction was warmed to room temperature and stirred for 1-18 hours. 6N HCl (2-4 mL / g) was added and the solvent was removed under reduced vacuum. The product was extracted into diethyl ether (40 mL / g) and washed with water (3 χ equal volume). The organic layer was dried (MgSO 4), filtered and the solvent removed by rotary evaporation yielding the crude product, which is purified by column chromatography or taken to the next step without purification. Alternative Development: If the borinic acid product contained a basic group such as an amine or pyridine, then after stirring at room temperature for 3-18 hours, water (2 mL / g) was added and the pH adjusted to 5-8. The product was extracted into diethyl ether or ethyl acetate or THF up to three times (40 mL / g) and washed with water (3 x equal volume). The organic layer was dried (MgSO4), filtered and the solvent was removed by rotary evaporation yielding crude product, which is purified by column chromatography or taken to the next step without purification.

(3-Thienyl) (3-chlorophenyl) borinic 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. Terc-Butyl lithium (1.7 M in THF, 4.47 mL, 7.6 mmol, 2 molar equivalents) was added to the drop-cooled solution causing the solution to turn dark yellow. The solution was stirred at -78 ° C while ethylene glycol 3-thiophenoboronic acid ester (586 mg) was dissolved in dry diethyl ether (1 mL). The boronic ester solution was then added dropwise to the cooled solution making the color change to pale yellow. The reaction was warmed to room temperature and stirred for 18 hours. 6N HCl (2 mL) was added and the reaction was stirred for 1 hour. The solvent was removed using a rotary evaporator. The product was extracted into diethyl ether (10 mL) and washed with water (2 x 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 silica gel and 5: 1 hexane: ethyl acetate as eluent yielding the pure product as a clear oil (614 mg, 73%).

(3-Chlorophenyl) vinylborinic acid (6c)

This was prepared by a similar process as described for 6b by a reaction of 3-cyanophenyl boronic acid ethylene glycol ester with vinylmagnesium bromide. (3-Fluoro-5-chlorophenyl) ethynylborinic acid (6d)

This was prepared by a similar process as described for 6b by a reaction of ethylene glycol 3-fluoro-5-chlorophenyl boronic acid ester with ethinyl lithium. (4-Methyl-3-chlorophenyl) (2-thienyl) borinic acid (6e)

This was prepared by a similar process as described for 6b by a reaction of 2-thienyl boronic acid ethylene glycol ester with 4-methyl-3-chlorophenyl lithium. (4-Cyanophenyl) ethinylborinic acid (6f)

This was prepared by a similar process as described for 6b by a reaction of 4-cyanophenyl boronic acid ethylene glycol ester with ethinyl lithium bromide. (3-Fluorphenyl) Cyclopropylborinic Acid (6g)

This was prepared by a similar process as described for 6b by a reaction of 3-fluorophenylboronic acid ethylene glycol ester with cyclopropyl lithium. (3-Thienyl) methylborinic acid (6h)

This was prepared by a similar process as described for 6b by a reaction of 3-thienylboronic acid ethylene glycol ester with methyl lithium. (4-Pyridyl) phenylborinic acid (6i)

This was prepared by a similar process as described for 6b by a reaction of ethylene glycol phenylboronic acid ester with 4-pyridyl lithium. (3-Cyanophenyl) (2-fluorophenyl) boronic acid (6j) This was prepared by a similar procedure as described for 6b by a reaction of 3-cyanophenylboronic acid ethylene glycol ester with 2-fluorophenyl-lithium. .4- (Dimethylaminomethyl) phenyl 3-fluorophenyl borinic 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 nitrogen atmosphere and the mixture was stirred for 15 min. Ethylene glycol 3-fluorophenylboronic acid 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 h. Water was added and the mixture was washed with ether. The pH was adjusted to 8 with IM hydrochloric acid. The mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford borinic acid (890 mg, 49%). Symmetrical borinic acid formation (5) by reaction of organometallic compounds with trialkyl borates: Bis (4-Chlorophenyl) Borinic acid (5a) (Procedure C)

A cold (-78 ° C) solution of trimethyl borate (0.37 mL) in dry tetrahydrofuran (THF, 25 mL) was treated dropwise with 4-chlorophenylmagnesium bromide (6.75 mL, IM ether solution) . The reaction mixture was stirred at -78 ° C for 1 hour and then stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The resulting residue was stirred with 100 mL ether and 15 mL 6N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ether (2 x 100 mL). The combined organic extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed to give a light yellowish solid. The product was chromatographed on silica gel (Hex: Ether = 1: 1) to give .420 mg of borinic acid. 1H NMR (400 MHz, CDCl3) 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 as for 5a, the title compound was obtained from a reaction of? 3-chloro-4-methylphenylmagnesium bromide with trimethyl borate. The product was obtained by silica gel chromatography. Bis (3-Fluoro-4-methylphenyl) borinic acid (5c) In a similar manner as for 5a, the title compound was obtained from a reaction of 3-fluoro-4-methylphenyl-Ixtio with trimethyl borate. The product was obtained by silica gel chromatography.

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

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

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

In a similar manner as for 5a, the title compound was obtained from the reaction of 3-fluoro-4-methoxyphenyl lithium with trimethyl borate. The product was obtained by silica gel chromatography. Formation of asymmetric boronic acids (6) by reaction of organometallic compounds with alkyl (or aryl or alkenyl) dialkoxyboranes.

(4-Chlorophenyl) methylborinic acid (6m) (Procedure D)

To 4-chlorophenylmagnesium bromide (5.5 mL, IM solution in ether) at -78 ° C, di (isopropoxy) methylborane (1 mL, 0.78 g) was added dropwise via syringe. The reaction mixture was stirred at -78 ° C and then stirred overnight at room temperature. The reaction mixture was treated dropwise with 100 mL ether and 15 mL 6N hydrochloric acid and stirred for 1 h. The organic layer was separated and the aqueous layer was extracted with ether (2 x 100 mL). The combined organic extract was 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 product was consistent for (4-chlorophenyl) methyl boronic acid.

(4-Fluorphenyl) methyl borinic acid (6n)

In a similar manner as for 6m, the title compound was obtained from a reaction of 4-fluorphenylmagnesium bromide with di (isopropoxy) methylborane. The product was obtained by silica gel chromatography. (4-Biphenyl) methylborinic acid (6th)

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

(3-Chloro-4-methylphenyl) methyl borinic acid (6p)

In a similar manner as for 6m, the title compound was obtained from a reaction of 3-chloro-4-methylphenyl lithium with di (isopropoxy) methylborane. The product was obtained by silica gel chromatography. (3-Chloro-4-methoxyphenyl) methylborinic acid (6q)

In a similar manner as for 6m, the title compound was obtained from a reaction of 3-chloro-4-methoxyphenyl lithium with di (isopropoxy) methylborane. The product was obtained by silica gel chromatography. (4-Dimethylaminophenyl) methylborinic acid (6r)

In a similar manner as for 6m, the title compound was obtained from a reaction of 4-dimethylaminophenyl lithium with di (isopropoxy) methylborane. The product was obtained by silica gel chromatography. (3-Pyridyl) vinylborinic acid (6s)

To a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) under an atmosphere of nitrogen at room temperature and the mixture was stirred for 1 h. To the reaction, vinyl boronic acid dibutyl ester (3.4 mL) was added dropwise and the mixture was stirred at room temperature for 18 h. Water was added and the 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) vinylborinic acid (6t)

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

Borinic-Alkyl Alcohol Derivatives .4 - (hydroxyethyl) imidazole Bis (3-Chlorophenyl) borinic acid ester (121)

To a solution of bis (3-chlorophenyl) boronic 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 room temperature for 18 h. Salt was removed by filtration. The filtrate was concentrated and treated with hexane to give the product as a solid and was 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 C17H15BCl2N2O .4 - (hydroxymethyl) imidazole bis (4-Chlorophenyl) borinic acid ester (126) In a similar manner as in Example 121, the title compound was obtained. from a reaction of bis (4-chlorophenyl) borinic acid with 4- (hydroxymethyl) imidazole hydrochloride The product was obtained as white crystals. (ESI-): (m / z) 328.79, MF C16H13BCl2N2O

.1-benzyl-4- (hydroxymethyl) imidazole bis (3-chloro-4-methylphenyl) borinic acid ester (127)

To a solution of 1-benzyl-4- (hydroxymethyl) imidazole (96 mg, 0.521 mmol) in methanol (5 mL), bis (3-chloro-4-methylphenyl) borinic acid (121 mg, 0.521 mmol) was added and The reaction mixture was stirred at room temperature for 2h. 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%). 1H NMR (400 MHz, CDCl3) δ: 2.3 (s, .6H, 2XCH3), 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.

.1-methyl-2- (hydroxymethyl) imidazole bis (3-chloro-4-methylphenyl) borinic acid ester (128)

In a similar manner to example 127, the title compound was obtained from the reaction of bis (3-chloro-4-methylphenyl) borinic acid with 1-methyl-2- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals. (ESI +): m / z = 372.82, MF C19H21BCl2N2O. .1-ethyl-2- (hydroxymethyl) imidazole bis (3-chloro-4-methylphenyl) borinic acid ester (129)

In a similar manner to Example 127, the title compound was obtained from the reaction of bis (3-chloro-4-methylphenyl) borinic acid with 1-ethyl-2- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals. (ESI +): (m / z) 386.83, MF C 20 H 23 BCl 2 N 2 O. .1-methyl-4- (hydroxymethyl) imidazole bis (3-chloro-4-methylphenyl) borinic acid ester (130) In a similar manner to Example 127, the title compound was obtained from the bis ( 3-Chloro-4-methylphenyl) borinic acid with 1-methyl-4- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals. (ESI +): (m / z) 372.88, MF C 19 H 2 IBCl 2 N 2 O. .2-pyridylethanol bis (3-chloro-4-methylphenyl) borinic acid ester (131)

In a similar manner to Example 121, the title compound was obtained from a reaction of bis (3-chloro-4-methylphenyl) borinic acid with 2-pyridylethanol. The product was obtained as white crystals. (ESI +): (m / z) 383.84, MF C21H20BC12NO.

Hydroxyquinoline Derivatives

.5-cyano-8-hydroxyquinoline bis (3-chlorophenyl) borinic acid 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 room temperature for 21 hours. A yellow solid precipitate formed which was collected by filtration and washed with cold ethanol. The product was obtained as yellow crystals. 1H 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).

(8-Hydroxyquinoline) (3-Chlorophenyl) (2-thienyl) borinic acid ester (36) To a solution of (3-chlorophenyl) (2-thienyl) borinic acid (1.5 g) in ethanol (2 ml) 8-hydroxyquinoline (0.77 g) in hot ethanol (2 ml) was added. The reaction was heated to reflux and cooled to room temperature. A yellowish solid was precipitated. The mixture was chilled on ice, the solid collected by filtration and washed with cold ethanol. The product was obtained as a yellow solid (1.01 g), 1H NMR (400 MHz, CDCl3) 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 C19 H13 BCINO

.8-hydroxyquinoline (2-Thienyl) methyl borinic acid ester (26)

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

(8) -hydroxyquinoline (3-Cyanophenyl) vinylborinic acid ester (40)

In a similar manner to Example 36, the title compound was obtained from a reaction of (3-cyanophenyl) vinylborinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals. (ESI +): (m / z) 285.1, MF C18H13BN2O.

.8-Hydroxyquinoline (2-Chlorophenyl) ethynyl borinic acid ester (43)

In a similar manner to Example 36, the title compound was obtained from a 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.

.8-Hydroxyquinoline bis (ethynyl) borinic acid (44)

In a similar manner to Example 36, the title compound was obtained from a reaction of bis (ethynyl) borinic acid with 8-hydroxyquinoline. The complex product was obtained as light yellow crystals. (ESI +) (m / z) 206.1, MF C13H8BNO.

(8-hydroxyquinoline) (3-

Fluorphenyl) cyclopropylborin (70)

In a similar manner to Example 36, the title compound was obtained from a reaction of (3-fluorophenyl) cyclopropylborinic acid with 8-hydroxyquinoline. The product was obtained as light yellow crystals. (ES-) (m / z) 291.05, MF C18H15BFNO. (8-Hydroxyquinoline) (3-Pyridyl) vinylborinic acid ester (99)

A solution of (3-pyridyl) vinyl boronic 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 / hexane to give the title product (99) as a light yellow powder (355 mg, .21%). 1H NMR (DMSOe) 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 C16H13BN2O.

.8-hydroxy-quinoline (4- (Dimethylaminomethyl) phenyl) (3-fluorophenyl) borinic acid ester (100)

In a similar manner to 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 a light yellow powder. ESI + (m / z) 385 MF C 24 H 22 BFN 2 O.

3-Hydroxypicolinic acid derivatives .3-hydroxypicolinate Bis (3-Chloro-4-methylphenyl) borinic acid ester (111)

Bis (3-chloro-4-methylphenyl) borinic acid (14.6 g) was dissolved in ethanol (120 mL) and heated to reflux. ? 3-Hydroxypolycinic acid (5.83 g) was added portionwise to the hot solution. The reaction was stirred at reflux for 15 minutes after the addition of the last portion of 3-hydroxypolycinic acid was added and then cooled to room temperature. The reaction was concentrated by removing some ethanol. Solid was removed by filtration. Recrystallization from ethanol yielded the title product as white crystals (13.4 g). Melting point = 165.0-166.5 ° C. EXAMPLE 20

Anti-inflammatory data for 3-hydroxypyridine-2-carbonyloxy-bis (3-chloro-4-methylphenyl) -borane Proinflammatory cytokines: THP-1 cells, LPS @ 1 mg / mL, .24 hr

TNF-α: 2.7 [tM; IL-ΐβ: 1.0 μΜ; IL-6: 5.3 μΜ; IL-8: 9.6 μΜ Cytokines TH1: PBMC, PHA @ 20 mg / mL, 24h IFN-g:> 25 μΜ; IL-2:> 25 μΜ TH2 cytokines: PBMC, PHA @ 20 mg / mL, 24h

IL-4:> 25 μΜ; IL-5: 9.3 μΜ; IL-10: 14.5 μΜ; IL-13:> 10 μΜ Regulatory cytokines: PBMC, PHA @ 10 mg / mL, 24h

IL-3:> 10 μΜ. EXAMPLE 21

Formulation of Toothpaste Containing Calcium Sulphate and About 0.5% by weight of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4-yl) methylphenyl) boronic acid 3-hydroxypicolinate ester)

A toothpaste formulation according to the present invention is prepared as follows.

To a suitable measuring container is added 6 mL of grapefruit oil, 2 mL of citrus oil, 2 mL of lime orange oil, 2 mL of mint oil, and 2 mL of eucalyptus oil, and the flavor oils are mixed. at room temperature. Thick liquid [food grade] paraffin (also known as mineral oil) is then added in an amount sufficient to bring the total volume of the mixture up to 100 mL. The oil component is mixed to form a homogeneous solution. This is the oily flavoring component for use in the toothpaste examples described herein.

At 30 g of fine gypsum powder (calcium sulfate dihydrate; pure for the food industry), 0.2 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. The two solids are mixed to form a homogeneous solid, and then 12 g of the above flavoring oil component is added. The composition of the powders and oils is mixed to form a smooth paste. The paste is then packed in a tube.

EXAMPLE 22

Formulation of Toothpaste Containing Calcium Sulphate and About 5.0% by weight of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4- methylphenyl) boronic acid 3-hydroxypicolinate ester)

The pulp composition in Example 21 is reformed, this time using 2.2 g of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4-

Methylphenyl) boronic acid 3-hydroxypicolinate ester) in the same manner as described. The paste is formed into a smooth paste as before and packaged in a tube. EXAMPLE 23

Formulation of Toothpaste Containing Sulphate Calcium Dihydrate, about 5.0% by weight of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-4 methylphenyl) boronic acid 3-hydroxypicolinate ester), and Glycerin

At 60 g of fine powdered plaster (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 powder, and the two solids are mixed to form a homogeneous powder. This solid powder is then mixed with 32 g of the oil component (as prepared in Example 21) for 30 minutes. The result is a smooth, semi-liquid paste. To this paste is added 4 g glycerine (available from numerous commercial sources), and mixing is continued for an additional 30 minutes. The paste product is packed in aluminum tubes and is ready for use. EXAMPLE 24 Oral rinse containing about 0.5% by weight of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4-methylphenyl) boronic acid .3hydroxypicolinate ester)

An oral mouthwash is conventionally prepared for the following composition:% w / w

Sorbitol 70% Solution (not 5 crystalline)

Ethanol 96% BP (% by volume) 7 Sodium saccharin BP Crist (76% 0.02 Sac)

Polyethylene glycol-40 0.15 hydrogenated castor oil

(available under the tradename Croduret 4 0 ET 0080 DF)

Polyoxyethylene sorbitan 0.15

monolaurate

(available under the tradename Tween 20)

Sodium Fluoride BP 0.05

sodium benzoate BP 0.1

Blue 12401 Anst 0.0006

Yellow 2G Anst 0.00055

Bentonite BP 1 flavor of 0.1 mouthwash (% by volume) Boron (3- 0.5-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) -borane (bis (3-chloro-3-chloro) 4-methylphenyl) boronic acid 3 hydroxypicolinate ester)) Purified Water Total Balance 100.0%

The mouthwash is made by mixing at room temperature ethanol and water, after which the additional components are mixed with the aqueous alcoholic medium, the surfactants, taste, humectants, copolymer, and boron-containing compound which are in the formula. The finished mouthwash is then filtered if necessary.

EXAMPLE 2 5

Toothpaste Containing about 0.3% by weight of 3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4-methylphenyl) boronic acid 3-hydroxypicolinate ester )

A toothpaste is conventionally prepared for the following composition:

wt%

Precipitated Silica 25.0 Freezing Silica 2.0

Sorbitol 20.0

Propylene Glycol 2.5

Sodium Carboxymethyl Cellulose 1.0

Diethyl Lauryl Amide 1.0

Sodium Lauryl Sulfate 1.5

Sodium lauroyl sarcosinate 0.3 Saccharin Sodium 0.1

Ethyl p-oxybenzoate 0.1

Boron-containing compound (3- 0,3-hydroxypyridine-2-carbonyl-bis (3-chloro-4-methylphenyl) borane (bis (3-chloro-4-methylphenyl) boronic acid .3hydroxypicolinate ester)

Stannous gluconate 0.3

Gelatin 0, 2

flavor 0, 8

Purified Water Total balance 100.0%

The components are mixed at room temperature to form a smooth homogeneous paste. The paste is then packed in a tube. EXAMPLE 2 6 MIC Test

All MIC tests followed the National Committee for Clinical Laboratory Standards (NCCLS) guidelines for antimicrobial testing of 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, N0 .16), except Malassezia species, which were incubated in a urea broth (Nakamura et al. Antimicrobial Agents And Chemotherapy, 2000, 44 (8) pp. 2,185-2,186) The results of the MIC tests are shown in FIG.

The compounds of this invention are evaluated for their antibacterial activity according to the guidelines and procedures prescribed by the National Committee for Clinical Laboratory Standards (NCCLS) (cf. NCCLS Document M7-A3, 1993 -Antimicrobial Susceptibility Testing).

Protocol for MIC determination

A useful protocol for MIC determination is as follows:

1. Approximately 2.5 mg of the compounds to be tested were weighed in cryospheres.

2.5 mg / mL stock solutions were made by adding DMSO to the samples.

3. 256 ng / mL development solutions were made by using 5 mg / mL stock solutions and adding sterile distilled water.

4. A "Beckman 2000 Automated Workstation" has been programmed to load broth and composite 96-well plates as follows:

.100 pL of suitable broth was added to columns 1-11 .200 pL of suitable broth was added to column 12 .100 pL of compounds in 256 µg / ml of development solution were added to column 1 (one compound per row)

Serial dilutions twice were made from column 1 to 10

column 11 served as the growth control .5. The panel of 10 organisms was plated from stock vials stored at -80 ° C and incubated for 24 hours at 34 ° C. The organisms were then subcultured and incubated for 24 hours at 34 ° C.

Inocula were first prepared in sterile distilled water with a target of 0.09-0.11 absorbance at .620 nm wavelength.

A {fraction (1/100)} dilution was made in the appropriate broth

.100 μΐι of organism broth was added to columns 1-11

Column 12 served as the empty control .6. The complete 96-well plates were incubated for .24 hours at 340 ° C. 96-well plates were then read using a Beckman Automatic plate bed at .600 nm wavelength. MIC was determined by calculations involving growth control (lane 11) and empty control (lane 12).

Protocol for Determination of Antifungal In Vitro MIC

A useful protocol for determining antifungal activity is described below.

Preparation

The medium is prepared 1-2 weeks before the start of the experiment. The medium is stored in the cold room (4 ° C) before use.

Sabouraud Agar Dextrose Plates:

1. Add 65 g of Dextrose Sabouraud Agar Powder Medium to 1 L of dH20 with gentle agitation.

2. Autoclaving at 121 ° C and 22 psi (151.68 KPa) for 15 minutes

3. Allow medium to cool to about 50 ° C.

4. Pour the medium into sterile 100 X .15 mm Petri dishes with 20 mL aliquots

RPMI 1640 broth + MOPS:

1. Add 1 pack of RPMI powder media to 1 L dH20 (15 ° C-300C) with light agitation

2. Add 2 g of NaHCO3

3. Add 34.5 g of MOPS

4. Adjust pH to 7.0 using NaOH or HCl

5. Sterilize with membrane filtration (0.22 micron cellulose acetate filter) Sterile saline (0.9%)

1. Dissolve 9 g of NaCl in 1 L of dH20

2. Autoclaving at 121 ° C and 22 psi (151.68 KPa) for 15 minutes of sterile dH20

1. Autoclaving dH20 at 121 ° C and 22 psi (151.68 KPa) for 15

minutes

Procedure

1. The 10 organism panel was plated from stock vials stored at -80 ° C (suspended in 20% glycerol broth) and incubated at 37 ° C for 24 hours. The organisms are then subcultured and incubated at 37 ° C for 24 hours. These will be used to prepare fresh inoculum for Step 6.

2. Approximately 2.5 mg of the compounds to be tested were weighed in 2 mL cryovials. Fluconazole, Amphotericin B and Itraconazole are tested as reference compounds.

3.5 mg / mL stock solutions were made by adding DMS0 to the samples. Insoluble swirling compounds are only sounded.

4. 256 μg / mL development solutions were made by using 5 mg / mL stock solutions and adding sterile distilled water.

5. 96-well plates are used for MIC determination. Each of the 8 rows can be used to test a different compound. Compounds are loaded into the first column and two-fold dilutions are made from column 1 to .10. Column 11 is a growth control (no compound) and column 12 is an empty control (no compound or organism). Manual addition of broth and compounds is performed as follows:

.100 pL RPMI + MOPS broth is added to columns 1-11 .200 pL RPMI + MOPS broth is added to column 12 .100 pL of compounds in 256 μg / ml of development solution was added to column 1 (one compound per row)

Serial dilutions twice were made from column 1 to 10

column 11 served as growth control (medium + organism only)

6. Subcultured organisms are used to prepare fresh inoculum for testing in 96-well plates. Each 96-well plate will test a different organism.

Colonies of subcultured organisms (Step 1) are used to prepare inocula with sterile saline. The target is adjusted to 70-75% emission at 530 nm wavelength using a Novospec II spectrophotometer.

A {fraction (1/100)} dilution was made in RPMI + MOPS broth

.100 μΐ. of this organism broth is added to columns 1-11 (column 12 serves as the empty control)

7. Complete 96-well plates were incubated at .37 ° C for 24 hours. The 96-well plates were then read using a Beckman Automatic plate bed at .650 nm wavelength. Calculations

Absorbance readings from the Biomek automatic plate reader are used to determine percent inhibition for each test well. The formula used is as follows:

% Inhibition = [1- (ABExample-ABS Empty) / (ABSAgrowth- ABS Empty)] X .100%

ABStest = Absorbance of empty cavity ABS: Empty cavity absorbance in the same row as the test cavity (column 12) ABScresc. Average: Average absorbance of growth control wells (column 11) Minimum inhibitory concentration (MIC) is found at the lowest compound concentration where percent inhibition is greater than or equal to 80%.

Therefore, the invention provides antibiotics which are generically called borinic acid complexes, more preferably derivatives of disubstituted borinic acids.

All patents, patent applications, and other publications cited in that application are incorporated herein by reference in their entirety.

Claims (24)

An oral hygiene composition comprising: a compound having a structure according to one of the following formulas: wherein B is boron, O is oxygen R * and R ** are independently selected from substituted or unsubstituted (C1-C4) alkyl, substituted or unsubstituted (C3-C7) cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted phenyl substituted, and substituted or unsubstituted heteroaryl; z is 0 or 1 and when z is 1, A is CH, CR10 or N; D is N, CH, or CR12; E is Η, OH, alkoxy or 2- (morpholino) ethoxy, CO2H or CO2 alkyl; m = 0-2; r is 1 or 2, and where when r is 1, G is = 0 (double bonded oxygen) and when r is 2, each G is independently H, methyl, ethyl or propyl; R 12 is selected from (CH 2) kOH (where k = 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 1 SO 2 NH alkylf 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, and where J is CR 10 or N ; R9, R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, (CH2) nOH (n = 2 to 3), CH2NH2, CH2NHalkyl, CH2N (alkyl) 2, halogen, CHO, CH = NOH, CO2H CO2-alkyl, S-alkyl, SO2-alkyl, S-aryl, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, NH2, alkoxy, CF3, SCF3, NO2, SO3H and OH, including salts thereof. Oral hygiene composition according to claim 1, characterized in that said oral hygiene composition is a member selected from a partially dissolvable oral rinse, dentifrice, liquid whitener, chewing gum, strip or film. or non-dissolvable, handkerchief, implant and dental floss. Oral hygiene composition according to claim 2, characterized in that said dentifrice is a selected member of a powder, toothpaste and dental gel. Oral hygiene composition according to claim 1, characterized in that said compound is present in a therapeutically effective amount. Oral hygiene composition according to claim 1, characterized in that said compound is present in an amount from about 0.1% w / w to about 5% w / w. Oral hygiene composition according to claim 1, characterized in that said compound is present in an amount from about 0.3% w / w to about 0.6% w / w. Oral hygiene composition according to claim 2, characterized in that said compound has a structure according to <m> formula wherein m is 0. Oral hygiene composition according to claim 2, characterized in that said compound has a structure according to <formula> formula see original document page 208 </formula> Oral hygiene composition according to claim 7, characterized in that E is OH, R 9 is H and R * and R ** are independently selected from substituted or unsubstituted phenyl. Oral hygiene composition according to claim 9, characterized in that R * and R ** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. Oral hygiene composition according to claim 10, characterized in that R * and R ** are 4-methyl, 3-chloro phenyl. Oral hygiene composition according to claim 11, characterized in that said compound is present in an amount from about 0.3% w / w to about 0.6% w / w. A method for killing a microorganism or inhibiting the growth of a microorganism comprising contacting said microorganism with a therapeutically effective amount of a compound having a structure according to one of the following formulas: see original document page 209 </formula> where B is boron, 0 is oxygen, R * and R ** are independently selected from substituted or unsubstituted (C1-C4) alkyl, substituted or unsubstituted (C3-C7) cycloalkyl substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; z is O or 1 and when z is 1, A is CH, CR10 or N; D is N, CH, or CR12; E is H, OH, alkoxy or 2- (morpholino) ethoxy, CO 2 H or CO 2 alkyl; m = O - 2; r is 1 or 2, and where when r is 1, G is = O (double bond oxygen) and when r is 2, each G is independently H, methyl, ethyl or propyl; R 12 is selected from (CH 2) kOH (where k = 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, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, SO2alkyl, SO3H, SCF3, CN, halogen, CF3, NO2, NH2, 2-amino, 3rd-amino, NH2SO2 and CONH2, and where J is CR10 or N; R9, R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, (CH2) nOH (n = 2 to 3), CH2NH2, CH2Nalkyl, CH2N (alkyl) 2, halogen, CHO, CH = NOH, CO2H , CO2-alkyl, S-alkyl, SO2-alkyl, S-aryl, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, NH2, alkoxy, CF3, SCF3, NO2, SO3H and OH, including salts thereof wherein said microorganism is a selected member of Actinobacillus species, Porphyromonas species, Tannerella species, Prevotella species, Eubacterium species, Treponema species, Mogibacterium species, Slackia species, Campylobacter species, Peptostreptococcus species, Peptostreptococcus species, Pornocytophaga species, species and Bacteroides species. Method according to claim 13, characterized in that said microorganism is a selected member of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythensis, Prevotella intermedia, Eubacterium nodatum, Treponema dentieola, Bulleidia extrueta, Mogibaeterek exidum, Campylobaeter reetus, Eikenella corrodens, Peptostreptococcus micros, Peptostreptoeoceus anaerobius, Capnoeytophaga oehraeea, Fusobaeterium 7 nueleatum, Porphyromonas asaeeharolytiea and Baeteroides forsythus. Method according to claim 13, characterized in that said compound has a structure according to <formula> where m is 0. Method according to claim 15, characterized in that E is OH, R 9 is H and R * and R ** are independently selected from substituted or unsubstituted phenyl. Method according to claim 16, characterized in that R * and R ** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. Method according to claim 17, characterized in that R * and R ** are 4-methyl, 3-chloro phenyl. A method for treating or preventing periodontal disease in a human or animal, said method comprising administering to the human or animal a therapeutically effective amount of a compound having a structure according to a where B is boron, 0 is oxygen, R * and R ** are independently selected from substituted or unsubstituted (C1-C4) alkyl, cycloalkyl ( Substituted or unsubstituted C3 -C7, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; is 0 or 1 and when z is 1, A is CH, CR10 or N; D is N, CH, or CR12; E is Η, OH, alkoxy or 2- (morpholino) ethoxy, CO2H or CO2 alkyl; m = O - 2; r is 1 or 2, and where when r is 1, G is = O (double bond oxygen) and when r is 2, each G is independently H, methyl, ethyl or propyl; R 12 is selected from (CH 2) kOH (where k = 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 NH alkyl, 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, and where J is CR 10 or N; R9, R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, (CH2) nOH (n = 2 to 3), CH2NH2, CH2Nalkyl, CH2N (alkyl) 2, halogen, CHO, CH = NOH, CO2H , CO2-alkyl, S-alkyl, SO2-alkyl, S-aryl, SO2N (alkyl) 2, SO2NHalkyl, SO2NH2, NH2, alkoxy, CF3, SCF3, NO2, SO3H and OH, including salts thereof Method according to claim 19, characterized in that said compound has a structure according to formula wherein m is 0. Method according to claim 20, characterized in that E is OH, R 9 is H and R * and R ** are independently selected from substituted or unsubstituted phenyl. Method according to claim 21, characterized in that R * and R ** are independently selected from 4-alkyl, 3-halogen phenyl and 4-halogen, 3-alkyl phenyl. Method according to claim 22, characterized in that R * and R ** are 4-methyl, 3-chloro phenyl. A method according to claim 19, characterized in that said periodontal disease is a selected member of gingivitis, periodontitis, and juvenile / acute periodontitis.