US 20080293675A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0293675 A1 Lee et al. (43) Pub. Date: Nov. 27, 2008

(54) ANTIBIOTICS CONTAINING BORINIC ACID (60) Provisional application No. 60/434,375, filed on Dec. COMPLEXES AND METHODS OF USE 18, 2002. Provisional application No. 60/436,095, (75) Inventors: Ving Lee, Los Altos, CA (US); Stephen filed on Dec. 23, 2002. Provisional application No. J. Benkovic, State College, PA (US); 60/437,849, filed on Jan. 3, 2003. Stephen J. Baker, Mountain View, CA (US); Kirk R. Maples, San Jose, CA (US); Tsutomu Akama, Sunnyvale, CA (30) Foreign Application Priority Data (US); Yong-Kang Zhang, San Jose, CA (US); Rajeshwar Singh, Edmonton Jun. 14, 2005 (US)...... PCT/US05721214 (CA); Vittorio A. Sauro, Edmonton (CA); Chetan Pandit, New Delhi (IN); Zhuoyi Su, Edmonton (CA); Zhixiang Publication Classification Yang, Edmonton (CA) (51) Int. Cl. Correspondence Address: A6II 3/69 (2006.01) MORGAN, LEWIS & BOCKIUS LLP (SF) C07F 5/02 (2006.01) One Market, Spear Street Tower, Suite 2800 AOIN 55/08 (2006.01) San Francisco, CA 94105 (US) (52) U.S. Cl...... 514/64; 546/13:544/229: 544/183 (73) Assignee: ANACOR PHARMACEUTCALS INC., Palo Alto, CA (21) Appl. No.: 11/971,693 (57) ABSTRACT (22) Filed: Jan. 9, 2008 The structure and preparation of antibiotics incorporating borinic acid complexes are disclosed, especially hydrox Related U.S. Application Data ycuinoline, imidazole and picolinic acid derivatives, along (63) Continuation of application No. 10/867.465, filed on with compositions of these antibiotics and methods of using Jun. 14, 2004, which is a continuation-in-part of appli the antibiotics and compositions as bactericidal and fungi cation No. 10/740,304, filed on Dec. 18, 2003, now cidal agents as well as therapeutic agents for the treatment of abandoned. diseases caused by bacteria and fungi. Patent Application Publication Nov. 27, 2008 Sheet 1 of 2 US 2008/0293675 A1

CN CN 5 5 s t s: - O O

o

e Patent Application Publication Nov. 27, 2008 Sheet 2 of 2 US 2008/0293675 A1

S O C CN w . cN N dis tha o :2 (U (y R C O C

5. s g c US 2008/0293675 A1 Nov. 27, 2008

ANTIBOTCS CONTAINING BORNCACID (1974), 13,5345-50 and as antibacterial agents Boron-Con COMPLEXES AND METHODS OF USE taining Antibacterial Agents: Effects on Growth and Mor 0001. This application is a continuation of U.S. applica phology of Bacteria Under Various Culture Conditions. tion Ser. No. 10/867,465, filed 14 Jun. 2004, which is a Bailey, P. J.; Cousins, G.; Snow, G. A.; and White, A. J.; continuation-in-part of U.S. application Ser. No. 10/740,304, Antimicrobial Agents and Chemotherapy, (1980), 17. 549 filed 18 Dec. 2003 (non-abandoned), which claimed priority 553). The boron containing compounds with antibacterial of U.S. Provisional Applications Ser. No. 60/434,375, filed 18 activity can be sub-divided into two main classes, the diaz Dec. 2002, Ser. No. 60/436,095, filed 23 Dec. 2002, and Ser. aborinines, which have been known since the 1960's, and No. 60/437,849, filed 3 Jan. 2003, the disclosures of all of dithienylborinic acid complexes. This latter class has been which are hereby incorporated by reference in their entirety. expanded to include many different diarylborinic acid com plexes with potent antibacterial activity Preparation of dia FIELD OF THE INVENTION rylborinic acid esters as DNA methyl transferase inhibitors. 0002 The present invention relates to the field of antibi Benkovic, S.J.; Shapiro, L.; Baker, S.J.; Wahnon, D.C.; otics and particularly antibacterial and antifungal compounds Wall, M.; Shier, V. K.; Scott, C. P.; Baboval, J.; PCT Int. Appl. and uses thereof. Methods for preparing and using these (2002), WO 2002044184). Synthetic developments described antibiotics, and pharmaceutical compositions thereof, are in Benkovic et al. enabled creation of a much more diverse also provided. class of unsymmetrical di-substituted borinic acid complexes not possible before. BACKGROUND OF THE INVENTION 0003. One hallmark of the modern era of medicine has BRIEF SUMMARY OF THE INVENTION been the decline in morbidity and mortality associated with 0006. In one aspect, the present invention relates to bori bacterial and fungal infections. However, misuse of conven nate derivatives as antibiotic compounds especially borinic tional antibiotics and natural selection of the infectious bac acid complexes, and include Such compounds as derivatives terial population has resulted in the development of varying of hydroxyquinolines, picolinic acids and imidazoles. degrees of drug resistance by most bacterial infectious agents to most antibiotic agents. In severe cases, such as MRSA 0007. The antibiotic compounds are also provided as phar (Multidrug-Resistant Staph A), one or only a few antibiotics maceutical compositions that can be administered to an ani are currently effective. In addition, the existence of immuno mal, most preferably a human, for treatment of a disease deficiency syndromes results in additional incidence of having a bacterial or fungal etiology, or an opportunistic opportunistic infections requiring intensive antibiotic treat infection with a bacteria or fungus in an animal, most prefer ment. ably a human, in an immunologically compromised or debili 0004 Thus, there continues to be a need in the medical arts tated state of health. for novel, more effective, antibiotic compounds, especially for treating bacterial infections, that are resistant to currently 0008. In preferred embodiments, the compounds of the available therapies. invention are those having the structures given by Formulas 1 0005 Boron containing compounds have received or 2, with preferred substituents as disclosed herein. increasing attention as therapeutic agents over the past few 0009. The invention also provides methods for preparing years as technology in organic synthesis has expanded to the antibiotic compounds and pharmaceutical compositions include this atom. Boron Therapeutics on the horizon, Gro thereof, and methods of using said antibiotics therapeutically. ziak, M. P.; American Journal of Therapeutics (2001) 8,321 Kits and packaged embodiments of the antibiotic compounds 328 The most notable boron containing therapeutic is the and pharmaceutical compositions of the invention are also boronic acid bortezomib which was recently launched for the contemplated. treatment of multiple myeloma. This breakthrough demon strates the feasibility of usingboron containing compounds as 0010. The invention also relates to methods of treating pharmaceutical agents. Boron containing compounds have infections, preferably bacterial and/or fungal infections, been shown to have various biological activities including using the antibiotic compounds disclosed herein. herbicides Organic boron compounds as herbicides. Barns ley, G. E.: Eaton, J. K. Airs, R. S.; (1957), DE 1016978 BRIEF DESCRIPTION OF THE DRAWING 19571003), boron neutron capture therapy Molecular Design and Synthesis of B-10 Carriers for Neutron Capture 0011 FIG. 1 shows the results of HPLC (high perfor Therapy. Yamamoto, Y.; Pure Appl. Chem., (1991) 63, 423 mance liquid chromatography) for several picolinic acid 426), serine protease inhibition Borinic acid inhibitors as derivatives of the invention. probes of the factors involved in binding at the active sites of Subtilisin Carlsberg and C-chymotrypsin. Simpelkamp, J.; 0012 FIG. 2 shows the results of HPLC (high perfor Jones, J. B.: Bioorganic & Medicinal Chemistry Letters, mance liquid chromatography) for several picolinic acid (1992), 2(11), 1391-4). Design, Synthesis and Biological derivatives of the invention. Evaluation of Selective Boron-containing Thrombin Inhibi tors. Weinand, A.; Ehrhardt, C.; Metternich, R.; Tapparelli, DETAILED DESCRIPTION OF THE INVENTION C.: Bioorganic and Medicinal Chemistry, (1999), 7, 1295 1307), acetylcholinesterase inhibition New, specific and 0013 This invention provides antibiotics, and specifically reversible bifunctional alkylborinic acid inhibitor of acetyl antibacterial and anti-fungal compounds, useful in treating cholinesterase. Koehler, K. A.; Hess, G. P.; Biochemistry and/or preventing bacterial infections. US 2008/0293675 A1 Nov. 27, 2008

0014. The invention comprises a compound having the 0025. In a preferred embodiment of formulas 1 or 2, R* structure with formula and/or R* are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted cycloalkyl (C-C) or R* and R** are each a substituted or unsubstituted Formula 1 cycloalkyl (C-C). 0026. In a preferred embodiment of formulas 1 or 2, R* and/or R* are the same or are different, preferably wherein one of R* and R** is a substituted or unsubstituted alkenyl or R* and R** are each a substituted or unsubstituted alkenyl. In a further preferred embodiment thereof, the alkenyl has the Structure

Formula 2

0027 wherein R', R, and R are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, Substituted aryl, aralkyl, Substituted aralkyl, (CH)OH (where k=1, 2 or 3), CH-NH, CH-NH-alkyl, wherein B is boron, O is oxygen CHN(alkyl), COH, CO-alkyl, CONH2, S-alkyl, S-aryl, SO-alkyl, SON(alkyl), SONHalkyl, SONH, SOH, 0015 wherein R* and R* are each independently SCF, CN, halogen, CF and NO. selected from substituted or unsubstituted alkyl (C-C), sub stituted or unsubstituted cycloalkyl (C-C), substituted or 0028. In a preferred embodiment of formulas 1 or 2, R* unsubstituted alkenyl, Substituted or unsubstituted alkynyl, and/or R* are the same or are different, preferably wherein substituted or unsubstituted aralkyl, substituted or unsubsti one of R* and R** is a substituted or unsubstituted alkynyl or tuted phenyl, and substituted or unsubstituted heteroaryl, R* and R** are each a substituted or unsubstituted alkynyl. In 006) and wherein z is 0 or 1 and when z is 1, A is CH, a further preferred embodiment thereof, the alkynyl has the CR or N, Structure 0017 and wherein D is N, CH, or CR'', 0018 and wherein E is H, OH, alkoxy or 2-(morpholino -E-R )ethoxy, COH or CO-alkyl 0019) and wherein m=0-2, 0029 wherein R' is selected from the group consisting of 0020 and wherein ris 1 or 2, and wherein when ris 1, G is hydrogen, alkyl, cycloalkyl, aryl. Substituted aryl, aralkyl, =0 (double-bonded oxygen) and when r is 2, each G is inde substituted aralkyl, (CH)OH (where k=1,2 or 3), CH-NH. pendently H. methyl, ethyl or propyl. CH-NH-alkyl, CHN(alkyl), COH, CO-alkyl, CONH2, S-alkyl, S-aryl, SO-alkyl, SON(alkyl), SONHalkyl, 0021 wherein R'' is selected from (CH)OH (where k=1, 2 or 3), CH-NH, CH-NH-alkyl, CHN(alkyl), COH, SONH, SOH, SCF, CN, halogen, CF and NO. CO-alkyl, CONH2, OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, 0030) In a preferred embodiment of formulas 1 or 2, R* SON(alkyl), SONHalkyl, SONH, SO-alkyl, SOH, and/or R* are the same or are different, preferably wherein SCF, CN, halogen, CF, NO, NH, 2*-amino, 3*-amino, one of R* and R** is a substituted or unsubstituted phenyl or NHSO, and CONH, R* and R** are each a substituted or unsubstituted phenylbut excluding compounds of formula 1 whereinz is 1, A is CR', 0022 and wherein J is CR' or N D is CR, J is CR" and excluding compounds of formula 2 0023 and wherein R. RandR'' are each independently wherein the combination of substituents is such that Z is 1, A selected from the group consisting of hydrogen, alkyl, is CR'', D is CR'', m is 2, and G is H or methyl or ethyl. In cycloalkyl, (CH), OH (n=2 to 3), CH-NH, CH-NHalkyl, a separate embodiment of the foregoing, G is also not propyl. CHN(alkyl), halogen, CHO, CH=NOH, COH, CO However, in specific embodiments such excluded com alkyl, S-alkyl, SO-alkyl, S-aryl, SON(alkyl). pounds, although not being claimed as novel, may find use in SONHalkyl, SONH, NH, alkoxy, CF, SCF, NO, SOH one or more of the methods of the invention, preferably for and OH, including salts thereof. treatment against infection, most preferably in treatment against fungal infection. In a preferred embodiment, only 0024. In preferred embodiments of formula 1 or 2, R* novel compounds of the invention are contemplated for Such and/or R** are the same or are different, preferably wherein USS. one of R* and R* is a substituted or unsubstituted alkyl (C-C) or R* and R** are each a substituted or unsubstituted 0031. The novel compounds of the invention do not alkyl (C-C). include quinaldine derivatives, such as 2-methylduinoline, US 2008/0293675 A1 Nov. 27, 2008 wherein R is a methyl, A is CH, D is CH, J is CH and R'' is 0041) wherein R. R. R. R7 and R are each indepen hydrogen. However, Such compounds may be useful in the dently selected from the group consisting of hydrogen, alkyl, methods of the invention. cycloalkyl aryl, Substituted aryl, aralkyl, Substituted aralkyl, (CH)OH (where k=1, 2 or 3), CH-NH, CH-NH-alkyl, 0032 A preferred embodiment is a compound of Formula CHN(alkyl), COH, CO-alkyl, CONH CONHalkyl, 2 wherein R* and R** are each other than a phenyl or sub CONCalkyl), OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, stituted phenyl. SO-alkyl, SON(alkyl), SONHalkyl, SONH, SOH, SCF, CN, halogen, CF, NO. NH 2-amino. 3'-amino, 0033. Another preferred embodiment is a compound of NHSO, OCHCH-NH. OCHCH-NHalkyl, Formula 2 wherein one of R* or R** is benzyl or substituted OCHCHN(alkyl), oxazolidin-2-yl, or alkyl substituted benzyl. oxazolidin-2-yl. 0034. An additional preferred embodiment is a compound 0042. One highly preferred embodiment is a compound of of Formula 2 wherein r is 1, G is —O, m is 0 and E is OH. formula 1 wherein R* is 3-fluorophenyl, R** is 4-chlorophe 0035) A preferred embodiment is also a compound of For nyl, R is H. R'' is H. A. is CH, D is CH, J is CH and may be mula 2 wherein z is 1 and R is selected from alkyl (greater called (3-fluorophenyl)(4-chlorophenyl)borinic acid 8-hy than C), (CH), OH (n=1, 2 or 3), CH-NH, CHNHalkyl, droxyquinoline ester. CHN(alkyl). CHO, CH=NOH, COH, CO-alkyl, S-alkyl, 0043 Another preferred embodiment is a compound of SO-alkyl, S-aryl, alkoxy (greater than C), SCF, and NO. formula 1 wherein R* and R* are each 3-(4,4-dimethylox 0036). In one preferred embodiment the compound has the azolidin-2-yl)phenyl, R is H. R'' is H, A, is CH, D is CH, J structure of Formula 2 whereinz is 1 and R' is selected from is CH and may be called bis(3-(4,4-dimethyloxazolidin-2- alkyl (greater than C), (CH), OH (n=1, 2 or 3), CH-NH. yl)phenyl)borinic acid 8-hydroxyquinoline ester. CH-NHalkyl, CHN(alkyl). CHO, CH=NOH, COH, 0044 An additional preferred embodiment is a compound CO-alkyl, S-alkyl, SO-alkyl, S-aryl, alkoxy (greater than of formula 1 wherein R* is 3-fluorophenyl, R** is cyclopro C), SCF, and NO. pyl, R is H. R'' is H, A, is CH, D is CH, J is CH and referred 0037. In another preferred embodiment the compound has to as (3-fluorophenyl)(cyclopropyl)borinic acid 8-hydrox the structure of Formula 2 wherein z is 1 and D is CR' ycuinoline ester. wherein R' is selected from (CH)OH (where k=1, 2 or 3), 0045. A highly preferred embodiment is a compound of CH-NH, CH-NH-alkyl, CHN(alkyl), COH, CO-alkyl, formula 1 wherein R* is 4-(N,N-dimethyl)-aminomethylphe CONH2, OH, alkoxy (greater than C), aryloxy, SH, S-alkyl, nyl, R** is 4-cyanophenyl, R is H. R'' is H, A, is CH, D is S-aryl, SO-alkyl, SOH, SCF, CN, NO, NHSO, and CH, J is CH and is referred to as (4-(N,N-dimethyl)-aminom CONH. ethylphenyl)(4-cyanophenyl)borinic acid 8-hydroxyquino 0038. In an additional preferred embodiment the com line ester. pound has the structure of Formula 2 wherein Z is 1, E is 0046) Another highly preferred embodiment is a com N-(morpholinyl)ethoxy or alkoxy greater than C. Other pre pound of formula 2 wherein R* is the same as R** which is ferred embodiments are compounds having the structure of 3-chloro-4-methylphenyl, R is H. R'' is H, A, is CH, Dis CH Formula 2 wherein A or D is nitrogen, or wherein m is 2. and E is OH, m=0, ris 1, Gis =0 (double bonded oxygen) and is referred to as bis(3-chloro-4-methylphenyl)borinic acid 0039. In another preferred embodiment, the compound 3-hydroxypicolinate ester. has the structure of Formula 2 wherein one of R or R** is substituted phenyl substituted with 1 to 5 substituents each of 0047 A further highly preferred embodiment is a com which is independently selected from alkyl (greater than C), pound of formula 2 wherein R* is the same as R** which is aryl, substituted aryl, benzyl, substituted benzyl, (CH)OH 2-methyl-4-chlorophenyl, R is H. R'' is H, A, is CH, Dis CH (where k=1, 2 or 3), CH-NH, CH-NH-alkyl, CHN(alkyl). and E is OH, m=0, ris 1, Gis =0 (double bonded oxygen) and COH, CO-alkyl, CONH CONHalkyl, CONCalkyl), OH, is referred to as bis(2-methyl-4-chlorophenyl)borinic acid alkoxy (greater than C), aryloxy, SH, S-alkyl, S-aryl, 3-hydroxypicolinate ester. SO-alkyl, SOH, SCF, CN, NO. NH 2-amino. 3'-amino, NHSO, OCHCH-NH2, OCHCH-NHalkyl, 0.048. In a preferred embodiment of formula 1 or 2, R* OCHCHN(alkyl), oxazolidin-2-yl, and alkyl substituted and/or R* are the same or are different, preferably wherein oxazolidin-2-yl. one of R* and R* is a substituted or unsubstituted benzyl or R* and R** are each a substituted or unsubstituted benzyl. In 0040. In a further preferred embodiment thereof, the phe a further preferred embodiment thereof, the benzyl has the nyl has the structure Structure

- -CH R6 US 2008/0293675 A1 Nov. 27, 2008

0049 wherein R. R. R. R7 and R are each indepen pounds by one or two atoms. For example, where the boron dently selected from the group consisting of alkyl, cycloalkyl, ring of a structure of the invention comprises 5 atoms, includ aryl, substituted aryl, aralkyl, substituted aralkyl, (CH)OH ing, for example, the boron, a nitrogen, an oxygen and 2 (where k=1, 2 or 3), CH-NH, CHNH-alkyl, CHN(alkyl). carbons, insinuation of a solvent atom between the boron and COH, CO-alkyl, CONH CONHalkyl, CONCalkyl), OH, nitrogen would afforda 7 membered ring. In one example, use alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO-alkyl, SON(alkyl). of hydroxyl and amino solvents may afford structures con SONHalkyl, SONH, SOH, SCF, CN, halogen, CF, taining an oxygen or nitrogen between the ring boron and NO. NH 2'-amino. 3'-amino, NHSO, OCHCH-NH2, nitrogenatoms to increase the size of the ring. Such structures OCHCH-NHalkyl, OCHCHN(alkyl), oxazolidin-2-yl, or are expressly contemplated by the present invention, prefer alkyl substituted oxazolidin-2-yl. ably where R*** is H or alkyl 0050. One preferred embodiment is a compound of for mula 1 or 2, R* and/or R* are the same or are different, preferably wherein one of R* and R** is a substituted or Formula 1B (solvent adduct) unsubstituted heterocycle or R* and R** are each a substi R11 tuted or unsubstituted heterocycle. In a further preferred embodiment thereof, the heterocycle has the structure Y-O

Y. J O 'N N Y O Y. X R9 a Formula 2B (solvent adduct) R* : Gr R* -Y O 0051 wherein X=CH-CH, N=CH, NR' (wherein Re-d (CH2)m R"—H, alkyl, aryl or aralkyl). O, or S V E H i N 0.052 and wherein Y=CH or N 0053 and wherein R', R, and Rare each independently selected from the group consisting of hydrogen, alkyl, R9 a cycloalkyl, aryl, Substituted aryl, aralkyl, Substituted aralkyl, (CH)OH (where k=1, 2 or 3), CH-NH, CH-NH-alkyl, CHN(alkyl), COH, CO-alkyl, CONH2, S-alkyl, S-aryl, 0059. As used herein, the following terms have the stated SO-alkyl, SON(alkyl), SONHalkyl, SONH, SOH, meaning: SCF, CN, halogen, CF, NO, oxazolidin-2-yl, or alkyl sub 0060. By “alkyl, “lower alkyl, and “C-C alkyl in the stituted oxazolidin-2-yl. present invention is meant straight or branched chain alkyl 0054) A highly preferred embodiment is a compound of groups having 1-6 carbon atoms, such as, methyl, ethyl, pro formula 1 wherein R* is pyrid-3-yl, R* is 4-chlorophenyl, pyl, isopropyl. n-butyl, Sec-butyl, tert-butyl, pentyl, 2-pentyl, R is H. R' is H, A, is CH, D is CH, and J is CH (named isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methyl (pyrid-3-yl)(4-chlorophenyl)borinic acid 8-hydroxyquino pentyl. line ester). 0061. By “alkoxy”, “lower alkoxy”, and “C-C alkoxy” 0055. A highly preferred embodiment is a compound of in the present invention is meant straight or branched chain formula 1 wherein R* is 5-cyanopyrid-3-yl, R** is vinyl, R alkoxy groups having 1-6 carbonatoms, such as, for example, is H. R'' is H, A, is CH, D is CH, and J is CH (named methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, (5-cyanopyrid-3-yl)(vinyl)borinic acid 8-hydroxyquinoline tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hex ester). oxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. 0056. One preferred embodiment is a compound of for 0062 By the term “halogen' in the present invention is mula 1 wherein R is H. R'' is H, A, is CH, D is CH, and J is meant fluorine, bromine, chlorine, and iodine. CH. 0063. By “cycloalkyl, e.g., C-C, cycloalkyl, in the present invention is meant cycloalkyl groups having 3-7 0057 Another preferred embodiment is a compound of atoms such as, for example cyclopropyl, cyclobutyl, cyclo formula 2 wherein R is H. R'' is H, A, is CH, D is CH and E pentyl, cyclohexyl, and cycloheptyl. In C-C cycloalkyl is OH, m=0, r is 1, and G is =0 (double bonded oxygen). groups, preferably in Cs-C7 cycloalkyl groups, one or two of 0.058. The structures of the invention also permit solvent the carbon atoms forming the ring can be replaced with a interactions that may afford structures (such as Formulas 1B hetero atom, Such as Sulfur, oxygen or nitrogen. Examples of and 2B) that include atoms derived from the solvent encoun Such groups are piperidinyl, piperazinyl, morpholinyl, pyrro tered by the compounds of the invention during synthetic lidinyl, imidazolidinyl, oxazolidinyl, perhydroazepinyl, per procedures and therapeutic uses. Thus, Such solvent struc hydrooxazapinyl, oxepanyl, and perhydro-oxepanyl. C. and tures can especially insinuate themselves into at least Some of C, cycloalkyl groups having a member replaced by nitrogen the compounds of the invention, especially between the boron or oxygen include aziridinyl, azetidinyl, oxetanyl, and oxira and nitrogen atoms, to increase the ring size of Such com nyl. US 2008/0293675 A1 Nov. 27, 2008

0064. By “aryl is meant an aromatic carbocyclic group Many of the compounds disclosed herein are selective having a single ring (e.g., phenyl), multiple rings (e.g., biphe inhibitors of methyltransferases in microbes, while not nyl), or multiple condensed rings in which at least one is inhibitory for methyltransferases in mammals. How aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, ever, the anti-bacterial and anti-fungal activity of the anthryl, or phenanthryl), which is optionally mono-, di-, or compounds of the invention is not limited to those with trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, het said enzyme inhibitory activity, nor is the latter effect nec eroaryl, and hydroxy. Preferred aryl groups include phenyl essarily essential to said therapeutic activity. and naphthyl, each of which is optionally substituted as 0068 The invention also provides embodiments of the defined herein. compounds disclosed herein as pharmaceutical composi 0065. By “heteroaryl' is meant one or more aromatic ring tions. The pharmaceutical compositions of the present inven systems of 5-, 6-, or 7-membered rings containing at least one tion can be manufactured in a manner that is itself known, and up to four heteroatoms selected from nitrogen, oxygen, or e.g., by means of a conventional mixing, dissolving, granu Sulfur. Such heteroaryl groups include, for example, thienyl, lating, dragee-making, levigating, emulsifying, encapsulat furanyl, thiazolyl, imidazolyl, (is)oxazolyl pyridyl, pyrim ing, entrapping or lyophilizing processes. idinyl, (iso)cquinolinyl, napthyridinyl, benzimidazolyl, and 0069. Pharmaceutical compositions for use in accordance benzoxazolyl. Preferred heteroaryls are thiazolyl, pyrimidi with the present invention thus can be formulated in conven nyl, preferably pyrimidin-2-yl, and pyridyl. Other preferred tional manner using one or more physiologically acceptable heteroaryl groups include 1-imidazolyl 2-thienyl, 1-(or carriers comprising excipients and auxiliaries that facilitate 2-)quinolinyl, 1-(or 2-) isoquinolinyl, 1-(or 2-)tetrahydroiso processing of the active compounds into preparations that can quinolinyl, 2-(or 3-)furanyl and 2-tetrahydro-furanyl. be used pharmaceutically. Proper formulation is dependent 0.066 By “ligand is meant a nitrogen-containing aro upon the route of administration chosen. matic system which is capable of forming a dative bond with 0070. Non-toxic pharmaceutical salts include salts of the Lewis acidic boron center, while appended as a borinate acids such as hydrochloric, phosphoric, hydrobromic, Sulfu ester moiety. Such ligands are known to those trained in the ric, Sulfinic, formic, toluenesulfonic, methanesulfonic, arts. Examples are shown in the hydroxyethanesulfonic, nitric, benzoic, citric, tartaric, maleic, fumaric hydroiodic, alkanoic such as acetic, OH OH HOOC-(CH), CH, where n is 0-4, and the like. Non toxic pharmaceutical base addition salts include salts of bases N 3 Such as Sodium, potassium, calcium, ammonium, and func 221 7 ( tional equivalents. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addi 3S 6 N tion salts. 4 5 7 8-hydroxyquinoline 4-hydroxybenzimidazole 0071 For injection, the compounds of the invention can be OH formulated in appropriate aqueous Solutions. Such as physi ologically compatible buffers such as Hanks's Solution, Ring HOC N N CO2H 21 7 621 er's Solution, or physiological saline buffer. For transmucosal 2 2 and transcutaneous administration, penetrants appropriate to 3S 6 S 3 the barrier to be permeated are used in the formulation. Such 4 5 4 penetrants are generally known in the art. 8-hydroxyquinoline picollinic acid 0072 For oral administration, the compounds can be for 2-carboxylic acid (pyridine-2-carboxylic acid) mulated readily by combining the active compounds with CHOH pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, C CH2OH 5 slurries, Suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use benzyl H can be obtained with Solid excipient, optionally grinding a 2-hydroxymethyl- 4-hydroxymethyl resulting mixture, and processing the mixture of granules, 1N-benzylimidazole imidazole after adding suitable auxiliaries, if desired, to obtain tablets. N CROH N CHCO2H Suitable excipients are, in particular, fillers such as Sugars, 621 621 including lactose, Sucrose, mannitol, or Sorbitol; cellulose 2 2 preparations such as, for example, maize starch, wheat starch, S 3 S 3 rice starch, potato starch, gelatin, gum hydrophobic polymers 4 4 containing the therapeutic agent. Various Sustained-release 2-(hydroxymethyl)pyridine R = H 2-pyridylacetic acid materials have been established and are well known by those 2-(hydroxyleopropyl)pyridine R = Me skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature 0067. The compounds of the present invention have and the biological stability of the therapeutic reagent, addi been implicated in the inhibition of key microbial tional strategies for protein and nucleic acid stabilization can enzymes, such as bacterial DNA methyltransferase. be employed. US 2008/0293675 A1 Nov. 27, 2008

0073. The pharmaceutical compositions also can com culture, i.e., the concentration of the test compound which prise Suitable Solid or gel phase carriers or excipients. achieves a half-maximal inhibition of bacterial cell growth. Examples of Such carriers or excipients include but are not Such information can be used to more accurately determine limited to calcium carbonate, calcium phosphate, various useful doses in humans. Sugars, starches, cellulose derivatives, gelatin, and polymers 0080. It will be understood, however, that the specific dose Such as polyethylene glycols. level for any particular patient will depend upon a variety of 0074 The compounds of the invention can be provided as factors including the activity of the specific compound salts with pharmaceutically compatible counterions. Pharma employed, the age, body weight, general health, sex, diet, ceutically compatible salts can be formed with many acids, time of administration, route of administration, and rate of including but not limited to hydrochloric, Sulfuric, acetic, excretion, drug combination, the severity of the particular lactic, tartaric, malic, succinic, phosphoric, hydrobromic, disease undergoing therapy and the judgment of the prescrib Sulfinic, formic, toluenesulfonic, methanesulfonic, nitic, ben ing physician. Zoic, citric, tartaric, maleic, hydroiodic, alkanoic Such as ace 0081 For administration to non-human animals, the drug tic, HOOC-(CH2), CH where n is 0-4, and the like. Salts or a pharmaceutical composition containing the drug may tend to be more soluble in aqueous or other protonic solvents also be added to the animal feed or drinking water. It will be that are the corresponding free base forms. Non-toxic phar convenient to formulate animal feed and drinking water prod maceutical base addition salts include salts of bases such as ucts with a predetermined dose of the drug so that the animal Sodium, potassium, calcium, ammonium, and the like. Those takes in an appropriate quantity of the drug along with its diet. skilled in the art will recognize a wide variety of non-toxic It will also be convenient to add a premix containing the drug pharmaceutically acceptable addition salts. to the feed or drinking water approximately immediately 0075 For topical administration, the compounds can be prior to consumption by the animal. formulated readily by combining the active compounds with 0082 Preferred compounds of the invention will have cer pharmaceutically acceptable carriers well known in the art. tain pharmacological properties. Such properties include, but Such carriers enable the compounds of the invention to be are not limited to, oral bioavailability, low toxicity, low serum formulated as gels, slurries, Suspensions and ointments for protein binding and desirable in vitro and in vivo half-lives. topical applications. If desired, disintegrating agents can be Assays may be used to predict these desirable pharmacologi added, such as the cross-linked polyvinyl pyrrolidone, agar, cal properties. Assays used to predict bioavailability include or alginic acid or a salt thereof such as sodium alginate. transport across human intestinal cell monolayers, including 0.076 Pharmaceutical compositions of the compounds of Caco-2 cell monolayers. Serum protein binding may be pre the present invention can be formulated and administered dicted from albumin binding assays. Such assays are through a variety of means, including systemic, localized, or described in a review by Oravcova et al. (1996, J. Chromat. B topical administration. Techniques for formulation and 677: 1-27). Compound half-life is inversely proportional to administration can be found in “Remington's Pharmaceutical the frequency of dosage of a compound. In vitro half-lives of Sciences.” Mack Publishing Co., Easton, Pa. The mode of compounds may be predicted from assays of microsomal administration can be selected to maximize delivery to a half-life as described by Kuhnz and Gieschen (Drug Metabo desired target site in the body. Suitable routes of administra lism and Disposition, (1998) volume 26, pages 1120-1127). tion can, for example, include oral, rectal, transmucosal, tran 0083 Toxicity and therapeutic efficacy of such com Scutaneous, or intestinal administration. Parenteral delivery, pounds can be determined by standard pharmaceutical pro including intramuscular, Subcutaneous, and intramedullary cedures in cell cultures or experimental animals, e.g., for injections, as well as intrathecal, direct intraventricular, intra determining the LDs (the dose lethal to 50% of the popula venous, intraperitoneal, intranasal, or intraocular injections tion) and the EDs (the dose therapeutically effective in 50% are also contemplated. of the population). The dose ratio between toxic and thera 0.077 Alternatively, one can administer the compound in a peutic effects is the therapeutic index and it can be expressed local rather than systemic manner, for example, via injection as the ratio between LDso and EDso. Compounds that exhibit of the compound directly into a specific tissue, often in a high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in depot or Sustained release formulation. formulating a range of dosage for use in humans. The dosage 0078 Pharmaceutical compositions suitable for use in the of such compounds lies preferably within a range of circulat present invention include compositions wherein the active ing concentrations that include the EDs with little or no ingredients are contained in an effective amount to achieve its toxicity. The dosage can vary within this range depending intended purpose. More specifically, a therapeutically effec upon the dosage form employed and the route of administra tive amount means an amount effective to prevent develop tion utilized. The exact formulation, route of administration ment of or to alleviate the existing symptoms of the Subject and dosage can be chosen by the individual physician in view being treated. Determination of the effective amounts is well of the patient’s condition. (See, e.g. Finglet al., 1975, in “The within the capability of those skilled in the art, especially in Pharmacological Basis of Therapeutics' Ch.1, p. 1). light of the detailed disclosure provided herein. 0084 Dosage amount and interval can be adjusted indi 0079 For any compound used in the method of the inven vidually to provide plasma levels of the active moiety that are tion, the therapeutically effective dose can be estimated ini sufficient to maintain bacterial cell growth inhibitory effects. tially from cell culture assays, as disclosed herein. For Usual patient dosages for systemic administration range from example, a dose can be formulated in animal models to 100-2000 mg/day. Stated in terms of patient body surface achieve a circulating concentration range that includes the areas, usual dosages range from 50-910 mg/m/day. Usual EC, (effective dose for 50% increase) as determined in cell average plasma levels should be maintained within 0.1-1000 US 2008/0293675 A1 Nov. 27, 2008

LM. In cases of local administration or selective uptake, the buffers, media, reagents, cells, culture conditions and the like effective local concentration of the compound cannot be are not intended to be limiting, but are to be read so as to related to plasma concentration. include all related materials that one of ordinary skill in the art 0085. The compounds of the invention are useful as anti would recognize as being of interest or value in the particular biotics for the treatment of diseases of both animals and context in which that discussion is presented. For example, it humans, including but not limited to actinomycosis, anthrax, is often possible to substitute one buffer system or culture bacterial dysentery, botulism, brucellosis, cellulitis, cholera, medium for another and still achieve similar, if not identical, conjunctivitis, cystitis, diphtheria, bacterial endocarditis, epi results. Those skilled in the art will have sufficient knowledge glottitis, gastroenteritis, glanders, gonorrhea, Legionnaire's of such systems and methodologies so as to be able, without disease, leptospirosis, bacterial meningitis, plague, bacterial undue experimentation, to make such substitutions as will pneumonia, puerperal sepsis, rheumatic fever, Rocky Moun optimally serve their purposes in using the methods and pro tain spotted fever, Scarlet fever, Streptococcal pharyngitis, cedures disclosed herein. syphilis, tetanus, tuberculosis, tularemia, typhoid fever, 0091. The invention is described in more detail in the typhus, and pertussis. following non-limiting examples. It is to be understood that 0.086 The disclosures in this application of all articles and these methods and examples in no way limit the invention to references, including patents and patent applications, are the embodiments described herein and that other embodi incorporated herein by reference in their entirety. ments and uses will no doubt suggest themselves to those 0087. The compounds of the invention comprise a novel skilled in the art. class of broad-spectrum antibiotics. Medically-important 0092. The compounds of this invention are evaluated for bacterial species that provide appropriate targets for the anti their antibacterial activity as per the guidelines and proce bacterial activity of the inhibitors of the invention include dures prescribed by the National Committee for Clinical gram-positive bacteria, including cocci such as Staphylococ Laboratory Standards (NCCLS) (cf. NCCLS Document cus species and Streptococcus species; acid-fast bacterium, M7-A3, 1993-Antimicrobial Susceptibility Testing). including Mycobacterium species; bacilli, including Bacillus species, Corynebacterium species and Clostridium species; Protocol for MIC Determination filamentous bacteria, including Actinomyces species and 0093. A useful protocol for MIC determination is as fol Streptomyces species; gram-negative bacteria, including lows: cocci such as Neisseria species and Acinetobacter species; bacilli, Such as Pseudomonas species, Brucella species, 0094) 1. Approximately 2.5 mg of the compounds to be Agrobacterium species, Bordetella species, Escherichia spe tested was weighed into cryovials. cies, Shigella species, Yersinia species, Salmonella species, 0095 2.5 mg/ml stock solutions were made by adding Klebsiella species, Enterobacter species, Haemophilus spe DMSO to the samples accordingly. cies, Pasteurella species, and Streptobacillus species; spiro chetal species, Campylobacter species, Vibrio species; and 0096 3.256 g/ml working solutions were made by using intracellular bacteria including Rickettsiae species and the 5 mg/ml stock solutions and adding sterile distilled water Chlamydia species. accordingly. 0088 Specific bacterial species that are targets for the 0097. 4. A Beckman 2000 Automated Workstation was antibiotics of the invention include Staphylococcus aureus, programmed to load 96 well plates with broth and compounds Staphylococcus epidermidis, Staphylococcus saprophyticus, as follows: Streptococcus pyogenes, Streptococcus agalactiae, Strepto coccus pneumoniae, Enterococcus faecalis, Enterococcus 0.098 100 ul of the appropriate broth was added to col faecium, Bacillus anthracis, Mycobacterium avium, Myco umns 1-11 bacterium tuberculosis, Acinetobacter baumannii; Coryne 0099] 200ul of the appropriate broth was added to col bacterium diphtheria, Clostridium perfingens, Clostridium umn 12 botulinum, Clostridium tetani, Neisseria gonorrhoeae, Neis seria meningitidis, Pseudomonas aeruginosa, Legionella 0.100 100 ul of compounds at the 256 g/ml working pneumophila, Escherichia coli, Yersinia pestis, Haemophilus Solution were added to column 1 (one compound per influenzae, Helicobacter pylori, Campylobacter fetus, row) Campylobacter jejuni, Vibrio cholerae, Vibrio parahemolyti cus, Trepomena pallidum, Actinomyces israelii; Rickettsia 0101 Two-fold serial dilutions were done from column prowazeki, Rickettsia rickettsii, Chlamydia trachomatis, 1 to 10 Chlamydia psittaci, Brucella abortus, Agrobacterium tune 0102) Column 11 served as the growth control faciens; and Francisella tularensis. 0089 Medically-important fungal and yeast species that 0103) 5. The 10 organism panel was plated from stock provide appropriate targets for the antifungal activity of the vials stored at -80° C. and incubated for 24 hours at 34° C. inhibitors of the invention include Candida albicans, Can The organisms were then sub-cultured and incubated for 24 dida glabrata, Candida krusei, Candida parapsilosis, Tricho hours at 34° C. phyton mentagrophytes, Microporium canis, Aspergillus spe cies, Cryptococcus neoformans, Blastomyces dermatitidis, 0.104) The inoculums were first prepared in sterile dis Coccidiodes immitis, Histoplasma capsulatum and Paracoc tilled water with a target of 0.09-0.11 absorbance at 620 cidioides brasiliensis. nm wavelength 0090. In carrying out the procedures of the present inven 0105. A 1/100 dilution was made into the appropriate tion it is of course to be understood that reference to particular broth US 2008/0293675 A1 Nov. 27, 2008

0106 100 ul of broth with organism was added to col 0131 5. 96-well plates are used for MIC determination. umns 1-11 Each of the 8 rows can be used to test a different compound. Compounds are loaded into the first column and two-fold 0.107 Column 12 served as the blank control dilutions of are made from column 1 to 10. Column 11 is a 0108 6. The completed 96 well plates were incubated for growth control (no compound) and column 12 is a blank 24 hours at 34°C. The 96 well plates were then read using a control (no compound or organism). Manual addition of broth Beckman Automated Plate Reader at 650 nm wavelength. and compounds is performed as follows: The MIC was determined through calculations involving the 0132) 100 ul of RPMI+MOPS broth is added to col growth control (column 11) and blank control (column 12). umns 1-11 Protocol for Antifungal in vitro MIC Determination 0.133 200ul of RPMI--MOPS broth is added to column 0109) A useful protocol for antifungal activity determina 12 tion is described below. 0.134 100 ul of compounds at the 256 g/ml working Preparation Solution are added to column 1 (one compound per row) 0110 Media is prepared 1-2 weeks before the start of the 0.135 Two-fold serial dilutions are done from column 1 experiment. Media is stored in the cold room (4°C.) prior to to 10 SC. 0.136 Column 11 serves as the growth control (media+ 0111 Sabouraud Dextrose Agar Plates: organism only) 0112 1. Add 65 g of powdered of Sabouraud Dextrose Agar media into IL of dHO with gentle stirring 0.137 6. The sub-cultured organisms are used to prepare fresh inoculums for testing on the 96-well plates. Each 0113 2. Autoclave at 121°C. and 22 psi for 15 minutes 96-well plate will test a different organism. 0114) 3. Allow the media to cool to -50° C. 0.138 Colonies from the sub-cultured organisms (Step 0115) 4. Pour media into 100x15 mm sterile petridishes 1) are used to prepare inoculums with sterile saline. The target is adjusted to 70-75% transmittance at 530 nm with 20 ml aliquots wavelength using a Novospec II spectrophotometer. 0116 RPMI 1640+MOPS Broth: 0.139. A 1/1000 dilution is made into RPMI+MOPS 0117) 1 Add 1 packet of powdered RPMI media to IL of broth dHO (15° C.-30°C.) with gentle stirring 0140 100 Dl of this broth with organism is added to 0118 2. Add 2 g of NaHCO columns 1-11 (column 12 serves as the blank control) 0119) 3. Add 34.5g of MOPS 0141 7. The completed 96-well plates are incubated at 37° 0120 4. Adjust the pH to 7.0 using NaOH or HCl C. for 24 hours. The 96 well plates are then read for absor 0121 5. Sterilize with membrane filtration (0.22 bance at 650 nm wavelength using a Biomek Automated Plate micron cellulose acetate filter) Reader. 0122) Sterile Saline (0.9%) Calculations 0142. The absorbance readings from the Biomek Auto 0123 1. Dissolve 9 g of NaCl to IL of dHO mated Plate Reader are used to determine the percent inhibi 0.124 2. Autoclave at 121°C. and 22 psi for 15 minutes tion for each test well. The formula used is as follows: % Inhibition=1-(ABSes-ABSla)/(ABSea 0125 Sterile dHO growth-ABSla)k 100% 0.126 1. Autoclave dHO at 121° C. and 22 psi for 15 minutes 0143 ABS: Absorbance of the test well Procedure 0144) ABS: Absorbance of the blank well in the same row as the test well (column 12) 0127. 1. The 10 organism panel is plated from stock vials stored at -80°C. (suspended in broth with 20% glycerol) and 0145 ABSmean growth : Mean absorbance of the growth incubated at 37° C. for 24 hours. The organisms are then control wells (column 11) sub-cultured and incubated at 37° C. for 24 hours. These will 0146 The minimum inhibitory concentration (MIC) is be used to prepare fresh inoculums for Step 6. found at the lowest concentration of compound where percent 0128 2. Approximately 2.5 mg of the compounds to be inhibition is greater than or equal to 80%. tested are weighed into 2 ml cryovials. Fluconazole, Ampho 0147 These procedures were used to obtain the results in tericin B and Itraconazole are tested as reference compounds. the following tables. Representative microbiological data for 0129. 3. 5 mg/ml stock solutions are made by adding the compounds 10 to 123 are shown in Tables 1 to 4 as MIC DMSO to the samples accordingly. Compounds insoluble (Minimum Inhibitory Concentration) with the values with Vortexing only are Sonicated. expressed as micrograms per ml. 0130 4. 256 g/ml working solutions are made by using 0.148 Thus, the invention provides antibiotics that are the 5 mg/ml stock solutions and adding sterile distilled water generically called borinic acid complexes, most preferably accordingly. derived from disubstituted borinic acids. US 2008/0293675 A1 Nov. 27, 2008

Borinate Complexes tional methods such as crystallization in the presence of a 014.9 The synthesis of the compounds of the invention is resolving agent, or chromatography, using, for example a accomplished in several formats. Reaction scheme #1 dem chiral HPLC column. onstrates the synthesis of the intermediate borinic acids, and Unexpected Stability of Picolinic Acid Complexes their Subsequent conversion to the desired borinic acid com plexes. When R* and R** are identical, the reaction of two 0152. During the preparation of compounds of Formula 2 equivalents of an arylmagnesium halide (oraryllithium) with we found that complexes containing hydroxymethyl-type trialkyl borate, followed by acidic hydrolysis affords the borinic esters, e.g., 2-hydroxymethyl-pyridine (R is H, A is desired borinic acid 5. When R* and R* are not identical, the CH, D is CH, E is H., m is 0, ris 2, G is H) were not stable under reaction of one equivalent of an arylmagnesium halide (or typical HPLC conditions. For example, the 2-hydroxymeth aryllithium) with appropriate aryl (dialkoxy)borane (4), het ylpyridine complexes shown in FIGS. 1A and 1B both eluted as two peaks, one with the solvent front and one much later, eroaryl(dialkoxy)borane or alkyl (dialkoxy)borane (alkoxy indicating some manner of degradation had occurred during group comprised of methoxy, ethoxy, isopropoxy, or propoxy the HPLC process. This posed a serious problem. Instability moiety), followed by acidic hydrolysis affords the unsym issues prevent this class of compound from being developed metrical borinic acids 6 in excellent yields. Where applicable, as drug candidates. However, it was Subsequently found that the reaction of the alkylene esters (3, T=nothing, CH, CMe) picolinic acid complexes (e.g., R is H. A is CH, D is CH, E is with the appropriate organocerium, organolithium, organo H. m is 0, r is 1, G is =0 (double bonded oxygen)) were stable magnesium or equivalent reactant is convenient. under identical the same HPLC conditions. For example, the 0150. As shown in Scheme 1, the borinic acid complexes picolinic acid complexes shown in FIGS. 2A and 2B show the are obtained from the precursor borinic acids by reaction with complex to elute as a single peak indicating no breakdown of one equivalent of the desired heterocyclic ligand in Suitable the complex. The biological activities of the picolinic acid Solvents (i.e., ethanol, isopropanol, dioxane, ether, toluene, class are comparable to or better than the hydroxymethylpy dimethylformamide, N-methylpyrrolidone, or tetrahydrofu ridine complexes making the picolinic acid complexes an ran). ideal drug development candidate.

Ny. (MgX) 3 T = nothing, CH2, C(CH3)2

0151. In certain situations, compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. HPLC conditions These compounds can be, for example, racemates or optically Sample preparation: ~1 mg/mL dissolved in 100% acetonitrile Column: BetaBasic C185um 150 x 4.6 mm active forms. In these situations, the single enantiomers, i.e., Flow rate: 1 mL/min optically active forms, can be obtained by asymmetric Syn Injection vol: 10 uL thesis or by resolution of the racemates. Resolution of the Wavelength: PDA 200-450 nmi; 254 nm reported racemates can be accomplished, for example, by conven US 2008/0293675 A1 Nov. 27, 2008 10

0.153 Representative compounds of the present invention -continued include, but are not limited to, the compounds disclosed herein and their pharmaceutically acceptable acid and base HPLC conditions addition salts. In addition, if the compound of the invention is Mobile phase: Solvent A: 0.1% HPO in water obtained as an acid addition salt, the free base can be obtained Solvent B: Acetonitrile by basifying a solution of the acid salt. Conversely, if the Gradient Method: product is a free base, an addition salt, particularly a pharma ceutically acceptable addition salt, may be produced by dis Time (min) % A % B Solving the free base in a suitable organic solvent and treating O 95 the Solution with an acid, in accordance with conventional 1 95 11 O 1OO procedures for preparing acid addition salts from base com 21 O 1OO pounds. In a preferred embodiment, the compounds of the invention comprise any of compounds 10-123 (Tables 1, 2, 3 and 4), and variants thereof.

TABLE 1 Antibacterial Profile Against Select Gram-positive and Gram-negative Pathogens

S. S. S. E. M. attreus epidermidis pneumoniae faecalis E. caiarrhais ATCC ATCC ATCC ATCC faecium ATCC R* * Ligand 29213 12228 6301 29212 CT-26 2S238 10 3-CICH 8-hydroxyquinoline 1 2 2 32 4 NA 11 4-Me-3-CICH 4-hydroxybenzimidazole O.12S 4 NA 8 8 NA 12 3-CICH 5-fluoro-8-hydroxyquinoline O.12S 2 8 4 2 13 3-CICH 5-chloro-8-hydroxyquinoline O.12S 1 1 64 2 O.25 14 3-CICH 4-methyl-8-hydroxyquinoline O.12S 1 1 64 4 O.S 15 3-FCH 8-hydroxyquinoline O.12S 1 2 16 4 O.S 16 4-Me-3-CICH 2-HOC-4-hydroxy-5,7- 0.25 0.5 NA 0.5 0.25 NA dichloroquinoline 17 3-CICH 2-amino-8-hydroxyquinoline O.25 2 2 8 8 2 18 3-C-4-FCH 8-hydroxyquinoline O.25 1 2 8 4 1 19 3-CICH 5-cyano-8-hydroxyquinoline O.25 2 4 16 4 O.S 2O 3-Cl-5-FCH 8-hydroxyquinoline O.25 1 2 8 4 2 21 3-FCH 5-cyano-8-hydroxyquinoline O.S 4 2 16 8 O.25 22 3-FCH 5-nitro-8-hydroxyquinoline O.S 4 2 64 16 O.12 23 3-FCH 5-chloro-7-chloro-8- O.S 16 8 64 16 O.12 hydroxyquinoline 24 3-CICH 3-FCH 5-bromo-7-bromo-8- O.S 8 8 64 32 O.12 hydroxyquinoline 25 3-CICH 3-FCH 2-carboxy-4-hydroxy-8- O.S 8 2 16 16 2 methoxyquinoline 26 2-thieny Me 8-hydroxyquinoline O.S NA 4 4 NA 27 3-NCCH 4-Me-3-CICH 8-hydroxyquinoline O.S 1 8 2 1 28 3,4-Cl2C6H3 3-FCH 8-hydroxyquinoline O.S 2 4 2 1 29 2,4-Cl2C6H3 3-FCH 8-hydroxyquinoline O.S 2 8 2 O.S 30 3,4-Cl2C6H3 3,4-Cl2CH 8-hydroxyquinoline O.S NA 2 2 NA 31 4-Me-3-CICH 4-Me-3-CICH 2-carboxy-4-hydroxyquinoline NA 2 1 NA 32 3-CICH 3-FCH 8-hydroxyquinoline 16 2 2 33 3-Cl-5-FCH 3-MeCH 8-hydroxyquinoline 8 2 2 34 3-CICH 3-FCH 5-fluoro-8-hydroxyquinoline 2 2 8 4 1 35 3-CICH 3-MeSCH 5-fluoro-8-hydroxyquinoline 2 2 8 4 2 36 3-CICH 2-thienyl 8-hydroxyquinoline 2 8 2 4 37 3-Me-4-CICH 3-NCCH 8-hydroxyquinoline 8 2 1 38 2-FCH 3-NCCH 8-hydroxyquinoline 2 16 2 1 39 3-CICH 3-NCCH 8-hydroxyquinoline 8 2 2 40 3-NCCH Vinyl 8-hydroxyquinoline 8 2 2 41 3-NCCH Ethynyl 8-hydroxyquinoline 4 2 1 42 3-FCH Ethynyl 8-hydroxyquinoline 8 2 1 43 2-ClC6H Ethynyl 8-hydroxyquinoline 8 2 1 Ethyny Ethynyl 8-hydroxyquinoline 16 2 O.25 45 3.5-F2CH Ethynyl 8-hydroxyquinoline 8 1 1 46 3.5-Cl2CH Ethynyl 8-hydroxyquinoline 4 1 1 47 3,4-Cl2C6H3 Ethynyl 8-hydroxyquinoline 8 2 1 48 3-CI-4-FCH Ethynyl 8-hydroxyquinoline 8 2 2 49 4-ClC6H 4-CICH 5-chloro-8-hydroxyquinoline 2 16 2 O.25 50 4-ClC6H4 4-ClC6H4 8-hydroxyquinoline 2 2 2 4 4 NA 51 3-FCH 3-FCH 8-hydroxyquinoline 2 NA 8 2 NA 52 4-Me-3-CICH 4-Me-3-CICH 8-hydroxyquinoline 2 4 NA 8 16 NA 53 3-NCCH 3-NCCH 8-hydroxyquinoline 2 2 NA 64 4 2 S4 4-ClC6H4 4-CI-3-FCH 8-hydroxyquinoline 2 2 8 4 1

US 2008/0293675 A1 Nov. 27, 2008 12

0154)

TABLE 2 Antibacterial Profile Against Select Gram-positive and Gram-negative Pathogens

S. S. S. E. H. attreus epidermidis pneumonia faecais E. influenzae ATCC ATCC ATCC ATCC faecium ATCC Cmp R* R** Ligand 29213 12228 6301 292.12 CT-26 49766 01 3-CICH 3-CICHA 1-(2-marpholino-4-yl-ethyl)- O.12 4 16 64 64 4 imidazoleacetate 02 3-CICH 3-CICH 2-hydroxyisopropyl-3- O.S 1 O.25 64 2 64 hydroxypyridine 03 4-CICH 4-ClC6H4 2-hydroxyisopropyl-3- O.25 O.S O.S 4 1 64 hydroxypyridine 04 4-Me-3-CICH 4-Me-3-CICH 2-hydroxymethyl-1N- O.S 4 NA 16 32 8 benzylimidazole 05 3-CICH 3-CICHA 2-hydroxymethylpyridine O.12S 4 4 32 32 4 06 4-Me-3-CICH 4-Me-3-CICH 2-pyridylacetic acid O.S 4 NA 64 64 64 07 4-Me-3-CICH 4-Me-3-CICH 3-(2-hydroxyethoxy)picolinic O.12S 4 NA 16 8 32 acid 08 4-Me-3-CICH 4-Me-3-CICH 3-(N- O.25 4 NA 4 2 64 morpholinylethoxy)picolinic acid 09 4-Me-3-CICH 4-Me-3-CICH 3-(OCH2CH2CHCO2H)picolinic 1 4 4 32 16 16 acid 10 4-Me-3-CICH 4-Me-3-CICH 3-carboxypicolinic acid O.12S 4 NA 8 8 8 11 4-Me-3-CICH 4-Me-3-CICH 3-hydroxypicolinic acid 2 1 NA 2 2 64 12 4-Me-3-CICH 4-CHCH 3-hydroxypicolinic acid 4 2 NA 4 8 64 13 4-Me-3-CICH Phenylethyl 3-hydroxypicolinic acid O.S 1 NA 2 64 64 14 3-CICH 3-CICHA 3-hydroxypicolinic acid O.12S 8 NA 64 64 16 15 4-EtO-3-CICH 4-EtO-3-CICH 3-hydroxypicolinic acid 2 2 1 8 16 64 16 2-C-5-Br-6- 2-F-4-CICH 3-hydroxypicolinic acid 2 1 O.25 4 4 64 FCH2 17 2-Me-4-CICH 3-CICH 3-hydroxypicolinic acid 2 1 O.S 4 4 16 18 2-Me-4-CICH 2-Me-4-CICH 3-hydroxypicolinic acid 1 O.25 O.12 1 1 16 19 4-Me-3-CICH 4-Me-3-CICH 3-OAc-picolinic acid 2 1 NA 2 2 64 20 4-Me-3-CICH 4-Me-3-CICH 4-hydroxybenzimidazole O.12S 4 NA 8 8 21 3-CICH 3-CICHA 4-hydroxybenzimidazole O.12S 4 8 32 32 4 22 3-CICH 3-CICH 6-amino-3-hydroxypicolinic acid O.25 4 16 32 32 8 23 3-CICH 3-CICHA Imidazole acetic acid O.12S 2 8 32 32 8 Ceftriaxone 2 1 &O.125 64 64 O.12 Ciprofloxacin O.12 O.12 O.S O.S 64 O.12 Cloxacillin O.12 O.25 O.12 16 64 8 Erythromycin O.S O.S NA 2 NA 4 Imipenem O.12 O.12 &O.125 1 64 2 Meropenem O.O6 O.O6 NA 2 NA O.O6 Pen G. O.S 16 &O.125 1 32 O.12

O155) TABLE 3-continued TABLE 3 Anti-mycobacterium In vitro Activity Anti-mycobacterium. In vitro Activity M. tuberculosis MIC (negnL M. tuberculosis MIC (negnL Compound H37Ry* P2SP1** P1SP2** Compound H37Ry : P2SP1 :::::: P1SP2 :::::: Kanamycin <2 <2 <2 10 O.387 O.387 O.387 cycloserine 8 8 8 50 O.387 O.387 O.387 51 O.387 O.387 O.387 *Sensitive strain 53 0.775 O.775 O.387 **Multi-drug resistant strain 55 0.775 O.775 O.387 65 0.775 O.775 O.775 72 0.775 O.775 O.775 0156 The present invention also encompasses the acy 75 0.775 O.775 O.775 lated prodrugs of the compounds of the invention. Those Isoniazid (INH) &O.O62 >8 >8 skilled in the art will recognize various synthetic methodolo FMR sis > gies which may be employed to prepare non-toxic pharma Ethionamide 1 >64 32 ceutically acceptable addition salts and acylated prodrugs of p-aminosalicylate &O.25 32 16 the inventive compounds. Ofioxacin 4 32 16 - - - - Streptomycin <2 <2 <2 0157 Tables 1 to 4 also contain inhibitory activity for known antibiotics, shown at the end of the tables. US 2008/0293675 A1 Nov. 27, 2008 13

EXAMPLES THF was removed by rotary evaporator to give a white solid. 0158 Proton NMR are recorded on Varian AS 400 and Hexane was added, dissolving the solid and removed by MercuryPlus 300 MHz spectrometer and chemical shifts are rotary evaporation. The product was placed under high reported as 8 (ppm) down field from tetramethylsilane. Mass vacuum to yield a tan solid (1.17 g.97%). 'H-NMR (300.058 spectra are determined on Micromass Quattro II and Applied MHz, CDC1) 8 ppm 7.93 (1H, s), 7.3-7.4 (2H, m), 4.35 (4H, Biosystems AP3000. Compound numbers appear in paren S). theses and correspond to numbers in Tables 1 to 4. 3-Fluorophenylboronic acid ethylene glycol ester 0159 Formation of Ethylene Glycol Boronate Ester (3, (3.c) T=Nothing) 0.164 mixture of 3-fluorophenylboronic acid (7.00 g, 50.0 0160 General Procedure mmol) and ethylene glycol (2.8 mL, 50 mmol) in toluene (200

TABLE 4 Antifungal Activity for Select Borinic Acid Complexes MIC (Lig/ml

Candida Candida Aspergiiitis albicans glabrata Candida Microsporum finigatus Trichophyton ATCC ATCC parapsilosis Canis ATCC mentagrophytes Compound 90O28 15126 ATCC 22O19 ATCC 10214 204305 ATCC 10270

53 1 >32 32 16 >32 >32 124 1 >32 32 16 >32 >32 125 1 >32 32 16 >32 >32 126 1 >32 32 16 >32 >32 127 1 >32 16 16 >32 32 128 1 32 16 12 >32 16 129 1 >32 32 16 >32 32 130 1 O.S O.S O.S O.S O.S 131 2 >32 >32 32 >32 32 132 2 1 O.S O.38 >32 O.25 Amphotericin B 1 0.75 0.75 O.S 1 1 Fluconazole O.25 3 2.5 16 >64 16

0161 Boronic acid was dissolved in dry THF, dry toluene mL) was heated to reflux for 3 hours under Dean-Stark con or dry diethyl ether 110 mL/g) nitrogen. Ethylene glycol (1 ditions. The solvent was removed under reduced pressure to molar equivalent) was added to the reaction and the reaction afford 3-fluorophenylboronic acid ethylene glycol ester (7.57 was heated to reflux for 1 to 4 hours. Reaction was cooled to g, 91%). room temperature and solvent was removed under reduced pressure leaving the ethylene glycol ester as an oil or a solid. 0.165 Formation of Unsymmetrical Borinic Acid (6) from In cases where an oil was obtained or a solid that dissolved in Boronic Acid Ethylene Glycol Ester hexane, dry hexane was added and removed under reduced General Procedure A: Grignard Methodology pressure. The product was then placed under high vacuum for several hours. In cases where a solid was obtained that did not 0166 Boronic acid ethylene glycol ester was dissolved in dissolve in hexane, the solid was collected by filtration and dry THF (10-20 mL/g) under nitrogen. Solution was cooled to washed with cold hexane. -78°C. in an acetone/dry ice bath or to 0°C. in an ice/water bath. Grignard reagent (0.95 to 1.2 molar equivalent) was 3-Cyanophenylboronic acid ethylene glycol ester added dropwise to the cooled solution. The reaction was (3a) warmed to room temperature and stirred for 3-18 hours. 6N HCl (2 mL/g) was added and solvent was removed under 0162 3-Cyanophenylboronic acid (1 g, 6.8 mmol) was reduced vacuum. Product was extracted into diethyl ether (40 dissolved in dry THF (10 mL) under nitrogen. Ethylene gly mL/g) and washed with water (3x equal Volume). Organic col (379 uL, 422 mg, 6.8 mmol) was added and the reaction layer was dried (MgSO), filtered and the solvent was was heated to reflux for 4 hours then cooled to room tempera removed by rotary evaporation giving the crude product, ture. THF was removed by rotary evaporator to give a white which is either purified by column chromatography or taken solid. Cold hexane was added and the product was collected onto the next step without purification. Alternative work-up: by filtration giving a white solid (1.18 g., quant. yield). if the borinic acid product contained a basic group Such as an H-NMR (300.058 MHz, DMSO-d6) 8 ppm 7.92-8.01 (3H, amine or pyridine, then after stirring at room temperature for m), 7.50-7.64 (1H, m), 4.35 (4H, s) 3-18 hours, water (2 mL/g) was added and the pH adjusted to 5-8. Product was extracted into diethyl ether or ethyl acetate Thiophene 3-boronic acid ethylene glycol ester (3b) or THF up to three times (40 mL/g). Organic layer was dried 0163 Thiophene-3-boronic acid (1 g, 7.8 mmol) was dis (MgSO), filtered and the solvent was removed by rotary solved in dry THF (10 mL) under nitrogen. Ethylene glycol evaporation giving the crude product, which is either purified (435 uL, 484 mg, 7.8 mmol) was added and the reaction was by column chromatography or taken onto the next step with heated to reflux for 1 hour then cooled to room temperature. out purification. US 2008/0293675 A1 Nov. 27, 2008

(4-Cyanophenyl)(3-fluorophenylborinic acid (6a) removed using a rotary evaporator to yield the crude product as an orange oil. The product was purified by column chro 0167 4-Cyanophenylboronic acid ethylene glycol ester matography using silica gel and hexane:ethyl acetate 5:1 as (500 mg, 2.89 mmol) was dissolved in dry THF under nitro eluent giving the pure product as a clear oil (614 mg, 73%). gen. The solution was cooled to -78°C. in an acetone/dry ice bath and 3-fluorophenylmagnesium bromide (1M in (3-Chlorophenyl) vinylborinic acid (6c) THF)(2.74 mL, 2.74 mmol. 0.95 molar equivalent) was added dropwise to the cold solution. The reaction was allowed to 0170 This was prepared by a similar process as described warm slowly to room temperature and stirred for 18 hours. 6N for 6b by the reaction of 3-cyanophenylboronic acid ethylene HCl (1 mL) was added to the reaction causing a cloudy glycol ester with vinyllithium. appearance and the solvent was removed using a rotary evaporator. The product was extracted into diethyl ether (20 (3-Fluoro-5-chlorophenyl)ethynlborinic acid (6d) mL) and washed with water (3x20 mL). The organic layer 0171 This was prepared by a similar process as described was dried (MgSO), filtered and the solvent removed using a for 6b by the reaction of 3-fluoro-5-chlorophenyl boronic rotary evaporator to yield the crude product as an oily solid. acid ethylene glycol ester with ethynyllithium. This was taken onto the next step without purification. (4-Methyl-3-chlorophenyl)(2-thienyl)borinic acid General Procedure B: (Hetero)Aryl-Lithium Methodology (6e) 0168 The (hetero)aryl-bromide or iodide was dissolved in 0.172. This was prepared by a similar process as described dry THF (20-30 mL/g) under nitrogen and degassed. The for 6b by the reaction of 2-thienylboronic acid ethylene glycol solution was cooled to -78°C. in an acetone/dry ice bath and ester with 4-methyl-3-chlorophenyllithium. n-, sec- or tert-butyllithium in THF or other solvent (1.2-2.4 molar equivalents) was added to the cooled solution dropwise (4-Cyanophenyl)ethynylborinic acid (6f) (generally causing the Solution to turn deep yellow). The boronic acid ethylene glycol ester (1 molar equivalent) was 0173 This was prepared by a similar process as described dissolved in dry THF or diethyl ether (2-10 mL/g) under for 6b by the reaction of 4-cyanophenylboronic acid ethylene nitrogen. The boronic acid ethylene glycol ester in THF was glycol ester with ethynyllithium. added dropwise to the cooled aryl-lithium solution (generally causing the solution to turn pale yellow). The reaction was (3-Fluorophenyl)cyclopropylborinic acid (6g) warmed to room temperature and stirred for 1-18 hours. 6N 0.174. This was prepared by a similar process as described HCl (2-4 mL/g) was added and solvent was removed under for 6b by the reaction of 3-fluorophenylboronic acid ethylene reduced vacuum. Product was extracted into diethyl ether (40 glycol ester with cyclopropyllithium. mL/g) and washed with water (3x equal Volume). Organic layer was dried (MgSO), filtered and the solvent was (3-Thienyl)methylborinic acid (6h) removed by rotary evaporation giving the crude product, which is either purified by column chromatography or taken 0.175. This was prepared by a similar process as described onto the next step without purification. Alternative work-up: for 6b by the reaction of 3-thienylboronic acid ethylene glycol if the borinic acid product contained a basic group Such as an ester with methyllithium. amine or pyridine then after stirring at room temperature for 3-18 hours water (2 mL/g) was added and the pH adjusted to (4-Pyridyl)phenylborinic acid (6i) 5-8. Product was extracted into diethyl ether or ethyl acetate 0176) This was prepared by a similar process as described or THF up to three times (40 mL/g) and washed with water for 6b by the reaction of phenylboronic acid ethylene glycol (3x equal volume). Organic layer was dried (MgSO), filtered ester with 4-pyridyllithium. and the solvent was removed by rotary evaporation giving the crude product, which is either purified by column chromatog (3-Cyanophenyl)(2-fluorophenyl)borinic acid (6) raphy or taken onto the next step without purification. 0177. This was prepared by a similar process as described for 6b by the reaction of 3-cyanophenylboronic acid ethylene (3-Thienyl)(3-chlorophenyl)borinic acid (6b) glycol ester with 2-fluorophenyllithium. 0169. 3-Chloro-bromobenzene (447 uL, 728 mg, 3.8 4-(Dimethylaminomethyl)phenyl 3-fluorophenyl mmol) was dissolved in dry THF (15 mL) under nitrogen. The Solution was degassed and cooled to -78°C. in an acetone/dry borinic acid (6k) ice bath. tert-Butyllithium (1.7M in THF)(4.47 mL, 7.6 0.178 Sec-butyllithium (1.4 M in cyclohexane, 6.0 mL) mmol. 2 molar equivalent) was added to the cooled Solution was added to a solution of N,N-dimethyl-4-bromobenzy dropwise causing the solution to turn deep yellow. The solu lamine (1.50 g, 7.00 mmol) in THF (14 mL) at -78° C. under tion was stirred at -78° C. while 3-thiopheneboronic acid nitrogen atmosphere and the mixture was stirred for 15 min. ethylene glycol ester (586 mg) was dissolved in dry diethyl 3-Fluorophenylboronic acid ethylene glycol ester (1.16 g. ether (1 mL). The boronic ester solution was then added 7.00 mmol) in THF (7 mL) was added to the mixture. The dropwise to the cooled solution causing the color to change to reaction was allowed to warm to room temperature and stirred pale yellow. The reaction was warmed to room temperature for 1 h. Water was added and the mixture was washed with and stirred for 18 hours. 6NHCl (2 mL) was added and the ether. The pH was adjusted to 8 with 1M hydrochloric acid. reaction was stirred for 1 hour. The solvent was removed The mixture was extracted with ethyl acetate twice. The using a rotary evaporator. The product was extracted into organic layer was washed with brine and dried on anhydrous diethyl ether (10 mL) and washed with water (2x10 mL). The sodium sulfate. The solvent was removed under reduced pres organic layer was dried (MgSO), filtered and the solvent sure to afford the borinic acid (890 mg. 49%). US 2008/0293675 A1 Nov. 27, 2008

0179 Formation of Symmetrical Borinic Acid (5) by bromide with di(isopropoxy)methylborane. The product was Reaction of Organometallics with trialkyl borates. Bis(4- obtained by chromatography over silica gel. chlorophenyl)borinic acid (5a) (Procedure C) 0180 A cold solution (-78°C.) of trimethylborate (0.37 (4-Biphenyl)methylborinic acid (6o) ml) in dry tetrahydrofuran (THF, 25 ml) was treated dropwise 0188 In a similar manner as for 6m, the titled compound with 4-chlorophenylmagnesium bromide (6.75 ml, 1M solu was obtained from the reaction of 4-biphenyllithium with tion in ether). The reaction mixture was stirred at -78°C. for di(isopropoxy)methylborane. The product was obtained by 1 hand then stirred for 18 hat room temperature. The solvent chromatography over silica gel. was removed under reduced pressure. The resultant residue was stirred with 100 ml of ether and 15 ml of 6.Nhydrochloric (3-Chloro-4-methylphenyl)methylborinic acid (6p.) acid. Organic layer was separated and aqueous layer was extracted with ether (2x100 ml). The combined organic 0189 In a similar manner as for 6m, the titled compound extract was washed with brine and dried over anhydrous was obtained from the reaction of 3-chloro-4-methylphenyl magnesium Sulfate. Solvent was removed to give light yel lithium with di(isopropoxy)methylborane. The product was lowish Solid. The product was chromatographed over silica obtained by chromatography over silica gel. gel (Hex: Ether=1:1) to give 420mg of borinic acid. "H NMR (3-Chloro-4-methoxyphenyl)methylborinic acid (6a) (400 MHz, CDC1) 8: 5.84 (s, OH), 7.46 (d, 4H, Ar H), 7.72 (d. 4H. Ar—H). 0190. In a similar manner as for 6m, the titled compound was obtained from the reaction of 3-chloro-4-methoxyphe Bis(3-Chloro-4-methylphenyl)borinic acid (5b) nyllithium with di(isopropoxy)methylborane. The product 0181. In a similar manner as for 5a, the titled compound was obtained by chromatography over silica gel. was obtained from the reaction of 3-chloro-4-methylphenyl magnesium bromide with trimethylborate. The product was (4-Dimethylaminophenyl)methylborinic acid (6r) obtained by chromatography over silica gel. 0191 In a similar manner as for 6m, the titled compound Bis(3-Fluoro-4-methylphenyl)borinic acid (5c) was obtained from the reaction of 4-dimethylaminophenyl lithium with di(isopropoxy)methylborane. The product was 0182. In a similar manner as for 5a, the titled compound obtained by chromatography over silica gel. was obtained from the reaction of 3-fluoro-4-methylphenyl lithium with trimethyl borate. The product was obtained by (3-Pyridyl) vinyl borinic acid (6s) chromatography over silica gel. 0192) Isopropylmagnesium chloride (2.0 M in THF) (5.0 Bis(3-Chloro-4-methoxyphenyl)borinic acid (5d) mL, 10 mmol) was added to a solution of 3-bromopyridine 0183 In a similar manner as for 5a, the titled compound (1.60 g, 10.0 mmol) in THF (15 mL) under nitrogen atmo was obtained from the reaction of 3-chloro-4-methoxyphe sphere at room temperature and the mixture was stirred for 1 nyllithium with trimethyl borate. The product was obtained h. Vinylboronic acid dibutyl ester (3.4 mL) was added to the by chromatography over silica gel. reaction dropwise and the mixture was stirred at room tem perature for 18 h. Water was added and the pH was adjusted to Bis(3-Fluoro-4-methoxyphenyl)borinic acid (5e) 7 with 1 M hydrochloric acid. The mixture was extracted with 0184 In a similar manner as for 5a, the titled compound ethyl acetate. The organic layer was washed with brine and was obtained from the reaction of 3-fluoro-4-methoxyphe dried on anhydrous sodium sulfate. The solvent was removed nyllithium with trimethyl borate. The product was obtained under reduced pressure to give the title compound (1.04 g. by chromatography over silica gel. 78%). 0185. Formation of Unsymmetrical Borinic Acids (6) by (3-Chloro-4-dimethylaminophenyl) vinylborinic acid Reaction of Organometallics with alkyl(or aryl or alkenyl )dialkoxyboranes. (4-Chloro-phenyl)methyl-borinic acid (6t) (6m) (Procedure D) 0193 In a similar manner as for 6s, the titled compound was obtained from the reaction of 3-chloro-4-dimethylami 0186 To 4-chlorophenylmagnesium bromide (5.5 ml, 1M nophenyllithium with vinylboronic acid dibutyl ester. The solution in ether) at -78°C., di(isopropoxy)methylborane (1 product was obtained by chromatography over silica gel. ml, 0.78 g) was added dropwise via syringe. The reaction mixture was stirred at -78°C. for 1 h and then stirred over 0194 20 night at ambient temperature. The reaction mixture was Borinic Acid-Alkylalcohol Derivatives treated dropwise with 100 ml of ether and 15 ml of 6N hydrochloric acid, and stirred for 1 h. Organic layer was Bis(3-Chlorophenyl)borinic acid separated and aqueous layer was extracted with ether (2x100 4-(hydroxyethyl)imidazole ester (121) ml). The combined organic extract was washed with brine and dried over anhydrous sodium sulfate. Solvent was removed 0.195 To a solution of bis(3-chlorophenyl)borinic acid under reduce pressure to give 1.1 g of oil. "H NMR of the (0.4g, 1.428 mmol) in ethanol (10 ml), 4-(hydroxyethyl)imi product was consistent for (4-chlorophenyl)methyl borinic dazole hydrochloride (0.191 g, 1.428 mmol), sodium bicar acid. bonate (0.180g, 2.143 mmol) were added and the reaction mixture was stirred at room temperature for 18 h. Salt was (4-Fluorophenyl)methylborinic acid (6n) removed by filtration. Filtrate was concentrated and treated 0187. In a similar manner as for 6m, the titled compound with hexane to afford the product as a solid and was collected was obtained from the reaction of 4-fluorophenylmagnesium by filtration. (450 mg, 84.9% yield). H NMR (CDOD) & US 2008/0293675 A1 Nov. 27, 2008

(ppm) 2.92 (t, 2H), 3.82 (t, 2H), 7.0–7.2 (m,9H), 7.90 (s, 1H): ano-8-hydroxyquinoline (0.15 g). The solution was stirred at (ES)(m/z)343.11, MF CHBC1NO room temperature for 21 hours. A yellow solid precipitate formed which was collected by filtration and washed with Bis(4-Chlorophenyl)borinic acid coldethanol. The product was obtained as yellow crystals. "H 4-(hydroxymethyl)imidazole ester (126) NMR (DMSO-d6) & (ppm) 7.24-7.35 (m, 8H), 7.38 (d. 1H), 0196. In a similar manner as in Example 121, the titled 8.18 (dd. 1H), 8.40 (d. 1H), 8.86 (d. 1H), 9.50 (d. 1H). compound was obtained from the reaction of bis(4-chlo rophenyl)borinic acid with 4-(hydroxymethyl)imidazole (3-Chlorophenyl)(2-thienyl)borinic acid hydrochloride. The product was obtained as white crystals. 8-hydroxyquinoline ester (36) (ES)(m/z)328.79, MF CHBC1NO 0203 To a solution of (3-chlorophenyl)(2-thienyl)borinic acid (1.5 g) in ethanol (2 ml) was added 8-hydroxyquinoline Bis(3-Chloro-4-methylphenyl)borinic acid 1-benzyl (0.77 g) in hot ethanol (2 ml). The reaction was heated to 4-(hydroxymethyl)-imidazole ester (127) reflux and cooled to room temperature. A yellow solid pre 0197) To a solution of 1-benzyl-4-(hydroxymethyl)imida cipitated. The mixture was cooled in ice, the solid was col Zole (96 mg, 0.521 mmol) in methanol (5 ml), bis(3-chloro lected by filtration and washed with cold ethanol. The product 4-methylphenyl)borinic acid (121 mg 0.521 mmol) was was obtained as a yellow solid (1.01 g). H NMR (DMSO) & added and the reaction mixture was stirred at room tempera (ppm) 6.98-7.06 (m, 2H), 7.19-7.26 (m, 3H), 7.38-7.50 (m, ture for 2 h. Solvent was removed under reduced pressure and 4H), 7.71 (t, 1H), 7.91 (dd. 1H), 8.80 (d. 1H), 9.18 (d. 1H): the residue was treated with hexane to give a solid. The (ESI)(m/z) 350.1, MF CHBCINOS product was isolated by filtration and washed with hexane to give product (193 mg, 83%). "H NMR (CDC1) 8: 2.3 (s, 6H, (2-Thienyl)methylborinic acid 8-hydroxycduinoline 2XCH), 4.8 (brs, 2H, CH4), 5.1 (brs, 2H, CH), 6.9-7.4 ester (26) (complex, 13H, Ar H); MS (ES)(m/z) 448.78, MF 0204. In a similar manner as in Example 36, the titled CHBC1.N.O. compound was obtained from the reaction of (2-thienyl)m- ethylborinic acid with 8-hydroxyquinoline. The product was Bis(3-Chloro-4-methylphenyl)borinic acid 1-methyl obtained as yellow crystals. 2-(hydroxymethyl)-imidazole ester (128) 0198 In a similar manner as in Example 127, the titled (3-Cyanophenyl) vinylborinic acid compound was obtained from the reaction of bis(3-chloro-4- 8-hydroxycduinoline ester (40) methylphenyl)borinic acid with 1-methyl-2-(hydroxy-meth 0205. In a similar manner as in Example 36, the titled yl)imidazole hydrochloride. The product was obtained as compound was obtained from the reaction of (3-cyanophe white crystals. (ES")(m/z) 372.82, MF CHBC1NO nyl) vinylborinic acid with 8-hydroxyquinoline. The product Bis(3-Chloro-4-methylphenyl)borinic acid 1-ethyl-2- was obtained as yellow crystals. (ESI)(m/z) 285.1, MF (hydroxymethyl)-imidazole ester (129) C.HBNO 0199. In a similar manner as in Example 127, the titled (2-Chlorophenyl)ethynylborinic acid compound was obtained from the reaction of bis(3-chloro-4- 8-Hydroxyquinoline ester (43) methylphenyl)borinic acid with 1-ethyl-2-(hydroxy-meth 0206. In a similar manner as in Example 36, the titled yl)imidazole hydrochloride. The product was obtained as compound was obtained from the reaction of (2-chlorophe white crystals. (ES")(m/z) 386.83, MF CHBC1NO nyl)ethynylborinic acid with 8-hydroxyquinoline. The prod Bis(3-Chloro-4-methylphenyl)borinic acid 1-methyl uct was obtained as yellow crystals. (ESI)(m/z). 292.1, MF 4-(hydroxymethyl)-imidazole ester (130) CHBCINO 0200. In a similar manner as in Example 127, the titled Bis(ethynyl)borinic acid 8-Hydroxyquinoline (44) compound was obtained from the reaction of bis(3-chloro-4- 0207. In a similar manner as in Example 36, the titled methylphenyl)borinic acid with 1-methyl-4-(hydroxy-meth compound was obtained from the reaction of bis(ethynyl yl)imidazole hydrochloride. The product was obtained as )borinic acid with 8-hydroxyquinoline. The product was white crystals. (ES")(m/z) 372.88, MF CHBCINO obtained as light yellow crystals. (ESI) (m/z) 206. 1, MF Bis(3-Chloro-4-methylphenyl)borinic acid CHBNO 2-pyridylethanol (131) (3-Fluorophenyl)cyclopropylborinic acid 0201 In a similar manner as in Example 121, the titled 8-hydroxyquinoline ester (70) compound was obtained from the reaction of bis(3-chloro-4- 0208. In a similar manner as in Example 36, the titled methylphenyl)borinic acid with 2-pyridylethanol. The prod compound was obtained from the reaction of (3-fluorophe uct was obtained as white crystals. (ES)(m/z) 383.84, MF nyl)cyclopropylborinic acid with 8-hydroxyquinoline. The CHBC1NO product was obtained as light yellow crystals. (EST)(m/z) Hydroxyouinoline Derivatives 291.05, MF CHBFNO Bis(3-Chlorophenyl)borinic acid (3-Pyridvl)vinylborinic acid 8-hydroxyquinoline 5-cyano-8-hydroxycduinoline ester (19) ester (99) 0202) To a solution of bis(3-chlorophenyl)borinic acid 0209. A solution of (3-pyridyl) vinyl borinic acid (1.04 g. (0.25 g) in ethanol (5 ml) and water (2 ml) was added 5-cy 7.82 mmol) and 8-hydroxyquinoline (96.1 mg. 6.63 mmol) in US 2008/0293675 A1 Nov. 27, 2008

ethanol was stirred at 40° C. for 20 min. The solvent was species, Clostridium species, Actinomyces species, Entero removed under reduced pressure and the residue was crystal coccus species, and Streptomyces species. lized from diethyl ether/diisopropyl ether/hexane to afford 0215. In another preferred embodiment of such method, the title product (99) as a light yellow powder (355 mg, 21%). the bacterium is a gram negative bacterium, preferably one H NMR (DMSO-d) & (ppm) 5.23 (dd. 1H), 5.46 (dd. 1H), selected from the group consisting of Acinetobacter species, 6.43 (dd. 1H), 7.14 (d. 1H), 7.19 (dd. 1H), 7.41 (d. 1H), Neisseria species, Pseudomonas species, Brucella species, 7.6-7.8 (m, 2H), 7.88 (dd. 1H), 8.35 (dd. 1H), 8.57 (s, 1H), Agrobacterium species, Bordetella species, Escherichia spe 8.76 (d. 1H), 9.00 (d. 1H); ESI" (m/z)261 MF CHBN.O. cies, Shigella species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species, Haemophilus spe (4-(Dimethylaminomethyl)phenyl)(3-fluorophenyl cies, Pasteurella species, Streptobacillus species, spirochetal )borinic acid 8-hydroxy-quinoline ester (100) species, Campylobacter species, Vibrio species, and Helico 0210. In a similar manner as in Example 99, the titled bacter species. compound was obtained from the reaction of (4-(Dimethy 0216) In a highly preferred embodiment of the present laminomethyl)phenyl)(3-fluorophenyl)borinic acid with invention, the bacterium is a member selected from the group 8-hydroxyquinoline. The product was obtained as a light consisting of Staphylococcus aureus, Staphylococcus epider yellow powder. ESI" (m/z) 385 MF CH-BFN.O. midis, Staphylococcus saprophyticus, Streptococcus pyo genes, Streptococcus agalactiae, Streptococcus pneumo 3-Hydroxypicolinic Acid Derivatives niae, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Mycobacterium avium, Mycobacterium tubercu Bis(3-Chloro-4-methylphenyl)borinic acid losis, Acinetobacter baumanii; Corynebacterium diphtheria, 3-hydroxypicolinate ester (111) Clostridium perfingens, Clostridium botulinum, 0211 Bis(3-chloro-4-methylphenyl)borinic acid (14.6 g) Clostridium tetani, Neisseria gonorrhoeae, Neisseria men was dissolved in ethanol (120 ml) and heated to reflux. 3-Hy ingitidis, Pseudomonas aeruginosa, Legionella pneumo droxypicolinic acid (5.83 g) was added in portions to the hot phila, Escherichia coli, Yersinia pestis, Haemophilus influ solution. The reaction was stirred at reflux for 15 minutes enzae, Helicobacter pylori, Campylobacter fetus, after the addition of the last portion of 3-hydroxypicolinic Campylobacter jejuni; Vibrio cholerae, Vibrio parahemolyti acid was added and then cooled to room temperature. Reac cus, Trepomena pallidum, Actinomyces israelii; Rickettsia tion was concentrated by removal of some ethanol. Solid was prowaZeki. Rickettsia rickettsii, Chlamydia trachomatis, removed by filtration. One recrystallization from ethanol Chlamydia psittaci, Brucella abortus, Agrobacterium tune afforded the title product as white crystals (13.4 g). faciens; and Francisella tularensis. MP-1650-166.5° C. 0217. In a preferred embodiment the microbe is a fungus 0212. In a preferred embodiment, the present invention or yeast wherein said fungus is a member selected from the includes the compounds specifically recited herein, and phar group consisting of Aspergillus species, Trichophyton spe maceutically acceptable salts thereof, and compositions of cies, Microsporium species, Cryptococcus neoformans, Blas any of these compounds where these comprise a pharmaceu tomyces dermatitidis, Coccidiodes immitis, Histoplasma cap tically acceptable carrier. Sulatum, or Paracoccidioides brasiliensis and wherein said yeast is a member selected from the group consisting of 0213 The present invention also relates to a method for Candida albicans, Candida glabrata, Candida krusei, Can treating a microbial-caused disease inapatient afflicted there dida tropicalis, or Candida parapsilosis. with and/or preventing Such infection in a patient at risk of becoming so-infected, comprising administering to said 1-80. (canceled) patient a therapeutically effective amount of any of the com 81. A compound described herein. pounds of the invention, preferably one or more of those listed 82. A method for treating a microbial-caused disease in a in Tables 1 to 4. In one aspect, the compounds of the invention patient afflicted therewith comprising administering to said have anti-bacterial (i.e., bactericidal) and anti-fungal (i.e., patient a therapeutically effective amount of a compound fungicidal) activity. described herein. 83. A method for killing a microorganism or inhibiting the 0214. In a preferred embodiment, the microbe is a bacte growth of a microorganism, comprising contacting said rium, preferably a gram positive bacterium, wherein said microorganism with an amount of a compound described gram positive bacterium is a member selected from the group herein. consisting of Staphylococcus species, Streptococcus species, Bacillus species, Mycobacterium species, Corynebacterium