WO2016003929A1 - Boronic acid derivatives and therapeutic uses thereof - Google Patents

Boronic acid derivatives and therapeutic uses thereof Download PDF

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Publication number
WO2016003929A1
WO2016003929A1 PCT/US2015/038364 US2015038364W WO2016003929A1 WO 2016003929 A1 WO2016003929 A1 WO 2016003929A1 US 2015038364 W US2015038364 W US 2015038364W WO 2016003929 A1 WO2016003929 A1 WO 2016003929A1
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WIPO (PCT)
Prior art keywords
compound
optionally substituted
alkyl
group
halogen
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PCT/US2015/038364
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French (fr)
Inventor
Raja K. Reddy
Tomasz Glinka
Maxim Totrov
Scott Hecker
Olga Rodny
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Rempex Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rempex Pharmaceuticals, Inc. filed Critical Rempex Pharmaceuticals, Inc.
Priority to EP15815718.0A priority Critical patent/EP3164406A4/en
Priority to CA2952968A priority patent/CA2952968A1/en
Priority to CN201580039809.8A priority patent/CN106536529B/en
Priority to AU2015284307A priority patent/AU2015284307A1/en
Priority to US15/323,081 priority patent/US10206937B2/en
Priority to JP2016575893A priority patent/JP6700203B2/en
Priority to MX2016016666A priority patent/MX2016016666A/en
Priority to EA201692301A priority patent/EA201692301A1/en
Priority to KR1020177002769A priority patent/KR20170024087A/en
Publication of WO2016003929A1 publication Critical patent/WO2016003929A1/en
Priority to ZA2016/08682A priority patent/ZA201608682B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to boronic acid antimicrobial compounds, compositions, their preparation, and their use as therapeutic agents.
  • Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy.
  • the increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs.
  • ⁇ -lactamases can be grouped into 4 classes based on their amino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes in classes A, C, and D include active-site serine ⁇ -lactamases, and class B enzymes, which are encountered less frequently, are Zn-dependent. These enzymes catalyze the chemical degradation of ⁇ -lactam antibiotics, rendering them inactive. Some ⁇ - lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi-resistant strains severely limits ⁇ -lactam treatment options available.
  • class D ⁇ -lactamase-expressing bacterium strains such as Acinetobacter baumannii
  • A. baumannii strains express A, C, and D class ⁇ -lactamases.
  • the class D ⁇ -lactamases such as the OXA families are particularly effective at destroying carbapenem type ⁇ -lactam antibiotics, e.g., imipenem, the active carbapenems component of Merck's Primaxin® (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J.
  • New ⁇ -lactamases have recently evolved that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other ⁇ -lactam antibiotics.
  • carbapenemases belong to molecular classes A, B, and D.
  • Class A carbapenemases of the KPC-type predominantly in Klebsiella pneumoniae but now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii.
  • the KPC carbapenemase was first described in 1996 in North Carolina, but since then has disseminated widely in the US.
  • the zinc-dependent class B metallo ⁇ -lactamases are represented mainly by the VIM, IMP, and NDM types.
  • IMP and VIM-producing K. pneumonia were first observed in 1990s in Japan and 2001 in Southern Europe, respectively.
  • IMP -positive strains remain frequent in Japan and have also caused hospital outbreaks in China and Australia.
  • dissemination of IMP -producing Enterobacteriaceae in the rest of the word appears to be somewhat limited.
  • VIM-producing enterobacteria can be frequently isolated in Mediterranean countries, reaching epidemic proportions in Greece. Isolation of VIM- producing strains remains low in Northern Europe and in the United States.
  • a characteristic of NDM-producing K. pneumonia isolates has been their rapid dissemination from their epicenter, the Indian subcontinent, to Western Europe, North America, Australia and Far East.
  • NDM genes have spread rapidly to various species other than K. pneumonia.
  • the plasmid-expressed class D carbapenemases belong to OXA-48 type.
  • OXA-48 producing K. pneumonia was first detected in Turkey, in 2001.
  • the Middle East and North Africa remain the main centers of infection.
  • recent isolation of OXA-48-type producing organisms in India, Senegal and Argentina suggest the possibility of a global expansion. Isolation of OXA-48 in bacteria other than K. pneumonia underlines the spreading potential of OXA-48.
  • Another mechanism of ⁇ -lactamase mediated resistance to carbapenems involves combination of permeability or efflux mechanisms combined with hyper production of beta-lactamases.
  • One example is the loss of a porin combined in hyperproduction of ampC beta-lactamase results in resistance to imipenem in Pseudomonas aeruginosa.
  • Efflux pump over expression combined with hyperproduction of the ampC ⁇ -lactamase can also result in resistance to a carbapenem such as meropenem.
  • Some embodiments disclosed herein include a compound having structure of Formula (I):
  • A is selected from the group consisting of C 3-10 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5- 10 membered heterocyclyl;
  • X A is -C(R e R f )-, -0-, -S-, -S(O)-, -S(0) 2 -, or -NR 1 -;
  • R a is selected from the group consisting of -H, halogen, optionally substituted -Ci-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C 1-6 alkyl, -NR'R 2 , -N(0R 3 )R 2 , optionally substituted -S-C 1 -6 alkyl, -C(0)NR 1 R 2 , -S(0) 2 NR 1 R 2 , CN, optionally substituted -S(0)-C 1-6 alkyl, optionally substituted -S(0)2-C 1-6 alkyl, and a carboxylic acid isoster;
  • R b is selected from the group consisting of -H, halogen, optionally substituted -C, -6 alkyl, -OH, -C(0)OR, optionally substituted -0-C 1 -6 alkyl, -NR J R 2 , -N(0R 3 )R 2 , optionally substituted -S-Ci -6 alkyl, -C(0)NR'R 2 , -S(0) 2 NR'R 2 , -CN, optionally substituted -S(0)-Ci- alkyl, optionally substituted -S(0) 2 -Ci- alkyl, and a carboxylic acid isoster, and
  • R c is selected from the group consisting of-OH, optionally substituted -0-Ci- alkyl -NR'R 2 , and -N(OR 3 )R 2 , or
  • R b and R c together with intervening atoms form a 5-8 membered boron ester ring, optionally comprising additional 1-3 heteroatoms selected from Oxygen (O), Sulfur(S) or Nitrogen(N);
  • R d is selected from the group consisting of -OH, optionally substituted -0-C 1 -6 alkyl -NR ⁇ 2 , and -N(OR 3 )R 2 , or
  • R b and R c do not together form a 5-8 membered boron ester ring, then optionally R c and R d together with intervening atoms form a 5- 15 membered boron ester or amide ring, optionally comprising additional 1-3 heteroatoms selected from O, S, and N;
  • Y is selected from the group consisting of -S-, -S(O)-, -S(0) 2 -, -0-, -CH 2 - and
  • 6alkylene-C 3-7 carbocyclyl optionally substituted by one or more R 10 , Ci -6 alkylene-3- 10 membered heterocyclyl optionally substituted by one or more R 10 , C, -6 alkylene-C 6- 10 aryl optionally substituted by one or more R 10 , and Ci- 6 alkylene-5-10 membered heteroaryl optionally substituted by one or more R 10 ;
  • R e and R f are each independently selected from the group consisting of H, C 1-6 alkyl, -OH, -OCi- alkyl, -SCi- alkyl, C 3- iocycloalkyl, C 2- ioalkenyl, C 2- i 0 alkynyl, -NR'C(0)R 5 , -NR' S(0) 2 R 3 , -C(0)R 5 , -C(0)OR 3 , alkylaryl, optionally substituted C 6-10 aryl, optionally substituted -0-C -ioaryl, -CN, optionally substituted 5-10 membered heteroaryl, optionally substituted -O-heteroaryl, optionally substituted 3-10 membered heterocyclyl, -S(0)R 3 ' -S(0) 2 R 3 , -R 1 -0-C(0)OR 3 , or R e and R f together with the carbon to which they are attached form a C 3-8 cycloalkyl or
  • R 7 is present 1 to 5 times and each R 7 is independently selected from the group consisitng of -H, -OH, halogen, -CH 3 , -CF 3 , C]-C 6 alkenyl, Ci-C 6 alkynyl, Ci- C 6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 3-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(C 1 -C 6 )alkyl, aryloxy, sulfhydryl (mercapto), and -CH 2 ) m -Y'-(CH 2 ) p M', or
  • n and p are independently 0 to 3 ;
  • Y' is selected from the group consisting of -S-, -S(O)-, -S(0) 2 -, -0-, -CR 5 R 6 -, and -NR 1 -;
  • -NR R halogen, -C(0)NR'R 2 , and -NR'C(0)R 5 ; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4 alkyl, -OR 3 , -NR'R 2 , halogen, -C(0)NR'R 2 , and -NR'C(0)R 5 ;
  • X is hydrogen or optionally substituted Ci ⁇ alkyl
  • Z is selected from optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
  • R is selected from the group consisting of -H, -C, -9 alkyl, -CR 5 R 6 OC(0)C, -9 alkyl, -CR 5 R 6 OC(0)OC, -9 alkyl,
  • each R 1 , R 2 , R la and R 2a are independently selected from the group consisting of -H, optionally substituted -C 1-10 alkyl, optionally substituted C 2-1 oalkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3- 7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6- ioaryl, and optionally substituted 5-10 membered heteroaryl;
  • R is hydrogen, optionally substituted C 1-10 alkyl, -optionally substituted Ci.ioalkyl-COOH, optionally substituted C 2- ioalkenyl, optionally substituted C 2- ioalkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C -ioaryl, and optionally substituted 5-10 membered heteroaryl;
  • each R 5 , R 6 , R 8 and R 9 are independently selected from the group consisting of -H, -OH, -NH 2 , -optionally substituted alkoxyl, optionally substituted -Ci-ioalkyl, optionally substituted C 2 -ioalkenyl, optionally substituted C 2 -ioalkynyl, optionally substituted C 3- 7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl; each n is independently 0-3;
  • each R 10 is independently -(CH 2 ) 0-6 R U ;
  • each R 1 1 is independently selected from Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C]-C 6 heteroalkyl; C3-C7 carbocyclyl optionally substituted with halo, amine, cyano, Ci-C 6 alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy; Q3-C7- carbocyclyl-Ci-C -alkyl optionally substituted with halo, amine, cyano, Ci-C alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, C]-C 6 alkyl, C]-C 6 alkoxy, C]-C 6 haloalkyl, and Ci-C 6 haloalk
  • Some embodiments disclosed herein include a compound having the structure of formula 1-1 or formula 1-2:
  • Some embodiments disclosed herein include a compound having structure of formula 1-3 or formula 1-4:
  • Y is selected from the group consisting of -S-, -0-, -CH 2 -, and -NH-; n is 0-3;
  • J, L, and M are each independently selected from the group consisting of CR 7 and N;
  • R is selected from a group consisting of -H, -C, -9 alkyl, -CR 5 R 6 OC(0)C 1-9 alkyl, -CR 5 R 6 0C(0)0C 1-9 alkyl, and
  • R 1 , R 2 , R 3 , R 5 and R 6 are each independently selected from -H and -C ⁇ alkyl;
  • R 7 is selected from the group consisting of-H, -Ci- 4 alkyl, -OH, -OC 1-4 alkyl, and halogen.
  • Some embodiments relate to a chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative and a compound having the structure of formula (I) described herein.
  • compositions comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.
  • Other embodiments disclosed herein include a method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof a compound disclosed herein.
  • compounds that contain a boronic acid moiety that act as antimicrobial agents and/or as potentiators of antimicrobial agents
  • Various embodiments of these compounds include compounds having the structures of Formula I as described above or pharmaceutically acceptable salts thereof.
  • R 7 is present 1 to 5 times and each R 7 is independently selected from the group consisitng of -H, -OH, halogen, -CF 3 , Ci-C 6 alkenyl, C -C alkynyl, C -C heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(Ci-C 6 )alkyl, aryloxy, sulfhydryl (mercapto), and - (CH 2 ) m -Y'-(CH 2 ) p M';
  • R is selected from the group consisting of -H, -Ci ⁇ alkyl, -CR 5 R 6 OC(0)C].
  • each R 1 , R 2 , R la and R 2a are independently selected from the group consisting of -H, optionally substituted -C 1-10 alkyl, optionally substituted C2 -10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3- 7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6- ioaryl, and optionally substituted 5-10 membered heteroaryl; and
  • each R 5 , R 6 , R 8 and R 9 are independently selected from the group consisting of -H, -OH, -optionally substituted alkoxyl, optionally substituted -Ci.i 0 alkyl, optionally substituted C2 -10 alkenyl, optionally substituted C2 -10 alkynyl, optionally substituted C 3- 7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl.
  • A can be selected from the group consisting of phenyl, biphenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, indanyl, pyridyl, pyrrolyl, oxazolyl, indolyl and thienyl.
  • A can be phenyl.
  • R b is attached to ring A at a position that is vicinal to the point of attachment of X a to ring A.
  • Y can be -CH 2 -, -S(O)-, -S(0) 2 -, -O- or -S-. In some embodiments, Y can be -CH 2 -, -S(O)-, -S(0) 2 -, -O- , -NH-, or -S-.
  • Y can be -CH 2 -, -0-, -S- or -NH-.
  • Y can be -CH 2 -, -O- or -S-.
  • Y can be -O- or -S-.
  • R d is -OH.
  • X a is -CH 2 -.
  • R A is selected from the group consisting of -H, halogen, optionally substituted -C 1-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C 1-6 alkyl, -NR ! R 2 , -N(OR 3 )R 2 , optionally substituted -S-C, -6 alkyl, -C(0)NR 1 R 2 , -S(0) 2 NR 1 R 2 , CN, optionally substituted -S(0)-C 1-6 alkyl, and optionally substituted -S(0)2-C 1-6 alkyl.
  • R A is a carboxylic acid isoster.
  • R B is selected from the group consisting of -H, halogen, optionally substituted -Ci -6 alkyl, -OH, -C(0)OR, optionally substituted -0-C 1 -6 alkyl, -NR'R 2 , -N(OR 3 )R 2 , optionally substituted -S-Ci -6 alkyl, -C(0)NR'R 2 , -S(0) 2 NR 1 R 2 , -CN, optionally substituted -S(0)-Ci- alkyl, and optionally substituted -S(0) 2 -Ci- alkyl.
  • R B is -OH.
  • R B is a carboxylic acid isoster.
  • R C is -OH.
  • Some embodiments of the compounds of Formula (I) or their pharmaceutically acceptabl lts can have the structure of Formula (F):
  • R 8 is H and R 9 is
  • Some embodiments of the compounds of Formula (I) or their pharmaceutically acceptable salts can have the structure of Formula (1-3) or Formula (1-4):
  • J, L, and M are each independently selected from the group consisting of CR and N.
  • two adjacent R 7 together with any intervening atoms can form a 5-8 membered heteroaryl ring.
  • two adjacent R together with any intervening atoms form an imidazole ring.
  • n is 0 or 1.
  • Y is selected from the group consisting of -S-, -0-, -CH 2 -, and -NH-;
  • R 1 , R 2 , R la , R 2a , R 3 , R 5 and R 6 are independently selected from -H and -Ci -4 alkyl; and R 7 is selected from the group consisting of -H, -C, -4 alkyl, -OH, -OC l-4 alkyl, -SC 1-4 alkyl and halogen.
  • Y is O or S;
  • G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, azetidine, pyrazine, pyrimidine, pyridazine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of Ci -4 alkyl, -OR 3 , -NR'R 2 , halogen, -C(0)NR'R 2 , and -NR' C(0)R 5 ; R 1 , R 2 and R 5 in G are ⁇
  • Y is -O- or -S-;
  • G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of C alkyl, -OR 3 , -Ci -6 alkylene-COOR 3 , -SR 3 , -NR'R 2 , halogen, -C(0)NR'R 2 , and - NR 1 C(0)R 5 , wherein R 1 , R 2 and R 5 in G are independently selected from -H and -Ci -4 alkyl; and J, L and M are CR 7
  • G when Y is -NR 1 , G cannot be -C(0)NR 1 R 2 or -C(0)OR 3 .
  • n can be 0 or 1. In some such embodiments, n is 0. In some embodiments, n can be 1. In some embodiments, n can be 2. In some embodiments, n can be 3.
  • Some embodiments of Formula I) can have the structure of Formula (Ie)
  • Some embodiments of Formula I) can have the structure of Formula (If):
  • n 0;
  • R 7 is selected from H, F, CI, -CH 3 , -CF 3 , and -Y'-(CH 2 ) P M'; and p is 0 or 1.
  • G can be a 5-10 membered heteroaryl optionally substituted with one or more R 10 .
  • G can be a thiadiazole optionally substituted with one or more R 10 .
  • G can be a thiazole optionally substituted with one or more R 10 .
  • G can be an imidazole optionally substituted with one or more R 10 .
  • G can be a triazole optionally substituted with one or more R 10
  • G can be a 3-10 membered heterocyclyl optionally substituted with one or more R 10 .
  • G can be an azetidine o tionally substituted with one or more R 10 .
  • G can be .
  • G can be a piperazine optionally substituted with one
  • G can be . In some embodiments, G can be - CONH 2 . In some embodiments, G can be -CN. In some embodiments, G can be -Ci -4 alkyl. In some embodiments, G can be -CH .
  • R 10 is R 11 .
  • R 10 is -CH 2 R U , - (CH 2 ) 2 R n , -(CH 2 ) 3 R n , or -(CH 2 ) 4 R n .
  • R 10 is -CH 2 R n .
  • R 10 is -(CH 2 ) 2 R U .
  • R 10 is -(CH 2 ) 3 R U .
  • R 10 is -(CH 2 ) 4 R n .
  • G is thiadiazole.
  • G is thiadiazole optionally substituted with -NR'R 2 or -NR' C(0)R 5 , wherein R 1 and R 5 are independently H or -Ci- 4 alkyl.
  • G is triazole optionally substituted with 1 2 erein 1 5
  • NR R , wh R , R and R J are independently H or -C 1 - 4 alkyl.
  • G is tetrazole optionally substituted with methyl.
  • G is pyridine, thiazole, or phenyl.
  • G is optionally substituted azetidine.
  • G is optionally substituted pyridine.
  • G is optionally substituted thiazole.
  • G is optionally substituted phenyl.
  • G is triazole optionally substituted with -Ci- alkylene-COOH.
  • G is triazole optionally substituted with -(CH 2 ) 3 -COOH.
  • R is H and R is H. In some embodiments, R is Ci -4 alkyl and 2
  • R is Ci -4 alkyl.
  • Y is -CH 2 -; n is 0 to 2; G is -C(0)NR'R 2 ; and J, L and M are CR 7 .
  • Some embodiments of Formula (I) can have the structure of Formula (Ig) or (Ih):
  • n 0;
  • each Z I , Z 2 , Z 3 and Z 4 are independently selected from N, NR 12 , O, S, and CR 12 provided that Z 1 to Z 4 are selected such that a five membered aromatic ring is formed;
  • each R is independently H or (CH 2 )o-sR ;
  • each R I I is independently selected from Ci-C alkyl; haloCi- alkyl; -OR 3 ; -C]. 6alkylene-COOR 3 ; -SR 3 ; halogen; -CO-Ci -4 alkyl; C(0)NR'R 2 ; -NR'R 2 ; -NR ⁇ CH ⁇ O .
  • Z 2 and Z 3 can be i ⁇ ndependently N, NR 12 , or CR 12. In some embodiments, Z can be N or CR 12 . In some embodiments, Z 1 to Z 4 can be selected to form a five-membered aromatic rin selected from the group consisting of
  • R can be H. In some embodiments, R can be
  • R 11 can be -CH 2 -R 11. In some embodiments, R 12 can be -(CH 2 ) 2 -
  • R can be -(CH 2 ) 3 -R . In some embodiments, R can be -
  • R n can be -CF 3i CHF 2 , or CH 2 F.
  • R 11 can be CF 3 .
  • R 11 can be Ci-C alkyl.
  • R n can be CH 3 .
  • R 1 1 can be a Ci -4 alkyl optionally substituted with a 3-10 membered heterocyclyl.
  • R 11 can be -CH 2 - piperazine.
  • R 1 1 can be an optionally substituted Ci- 6 alkylene-3-10 membered heterocyclyl.
  • R 11 can be azetidine optionally substituted , , -!-N /— NH 2
  • R can be ⁇ .
  • R can be -(CH 2 )o- 4 NR 1 R 2 .
  • R can be NH 2 , -
  • R can be NR R , R is H, and R" is an optionally susbstituted -Ci -4 alkyl or an optionally substituted 3-8 membered heterocyclyl.
  • embo R can be -(CH 2 ) 2 -
  • R can be pyrrolidine. In some embodiments, R can be - (CH 2 ) 2 -NH 2 or -(CH 2 ) 3 -NH 2 .
  • R can be -C(0)NR'R". In some embodiments, R can be -CONH 2 . In some embodiments, R can be -NR ⁇ CC R 5 . In some embodiments, R 1 1 can be -NHCOH or -NHCOCH3. In some embodiments, R 1 1 can be -N((CH 2 ) 0-4 - NR ! R 2 ) 2 . In some embodiments, R can be -N((CH 2 ) 2 -NH 2 ) 2 . In some embodiments, R can be -NR' -CH- ⁇ CH ⁇ -NR ⁇ R ⁇ . In some embodiments, R N can be -NHCH(CH 2 - NH 2 ) 2 .
  • R can be - ⁇ ( ⁇ 2 ) ⁇ -4 - ⁇ 2 .
  • R can be -NH(CH 2 ) 2 -NH- azetidine.
  • R 11 can be -S(CH 2 )o -4 -3- 10 membered heterocyclyl.
  • R can be -S(CH 2 ) 2 -piperazine. In some embodiments, R can be -S(0) 2 NR'R 2 . In some embodiments, R can be -S(0) 2 NH 2 . In some embodiments, R can be -SCCH ⁇ -NR ⁇ 2 . In some embodiments, R 1 1 can be -S(CH 2 ) 2 NH 2 or -S(CH 2 ) 3 NH 2 . In some embodiments, R can be -SR 3 . In some embodiments, R can be azetidine or piperidine. In some embodiments, R N can be -S(CH 2 ) 1- -3- 10 membered heterocyclyl.
  • R can be— S(CH 2 ) 2 -morpholine. In some embodiments, R can be -S(CH 2 ), -4 -R 3 . In some embodiments, R N can be -S(CH 2 ) 0-4 -5- 10 membered heteroaryl-NH 2 . In some embodiments, some embodiments, R can be -OR 3 . In some embodiments,
  • R 11 can be - ⁇ ( ⁇ 2 ) 0-4 - ⁇ 2 . In some embodiments, R 11 can be -0(CH 2 ) 2 NH 2 .
  • R 7 is selected from the group consisting of -H, -OH, -Ci -4 alkyl, -0-Ci -4 alkyl, -S-C] -4 alkyl, halogen, -CF 3 , and cyano. In other embodiments, R 7 is selected from the group consisting of F, CI, Me, -CF 3 , -SMe, and -OMe. In some embodiments, R 7 is H. In other embodiments, R 7 is F. In some embodiments, R 7 is -OMe. In some embodiments, R 7 is -SMe. In some embodiments, R 7 is -S(0)Me. In some ⁇
  • R is independently selected from -OH, -Ci -4 alkyl, -0-C 1-4 alkyl, -S-Ci -4 alkyl, - S(0)-C 1-4 alkyl, and halogen.
  • R 7 is present 1 to 3 times and each R 7 is triazole.
  • R 7 is present 1 to 3 times and each R 7 is independently -(CH 2 ) m -Y'-(CH 2 ) p M'; m and p are independently 0 to 3; Y' is selected from the group consisting of -S-, -O- and -NR 1 -; M' is selected from the group consisting of NR !
  • R 7 is present once. In some embodiments, R 7
  • R 7 is present three times.
  • Y' is O. In some embodiments, Y' is NH. In some embodiments, p is 0, 1, or 2.
  • M' is cyclopropyl, -S0 3 CH 3 , SCH 3 , -NH 2 , or -CN.
  • M' is C 1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR 3 , -NR R 2 , halogen, -C(0)NR 1 R 2 , and -NR 1 C(0)R 5 .
  • M' is CHF 2 , CF 3 , (CH 2 ) 2 F, or (CH 2 ) 2 OCH 3 ,
  • M' is CH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 CH 2 CH(CH 3 ) 2 .
  • M' is C(0)NR 1 R 2 .
  • R 1 is H and R 1 is azetidine. In some embodiments, R 7 is
  • R' is -0(CH 2 )CONH 2 .
  • M' is a 5 to 10 membered heteroaryl. In some embodiments, M' is thiadiazole.
  • R is present 1 to 3 times and each R is independently selected from the group consisitng of -OH, halogen, -CF 3 , C ⁇ -C(, alkenyl, Ci- C alkynyl, Ci-C 6 heteroalkyl, C 3 -C 7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C 6 alkoxy(C 1 -C 6 )alkyl, aryloxy, sulfhydryl (mercapto), and - (CH 2 ) M -Y'-(CH 2 ) p M' ; m and p are independently 0 to 3 ; Y' is selected from the group consisting of -S-, -S(O)-, -S(0) 2 -, -0-, -CR 5 R 6 -, and -NR 1 -; M' is selected from the group consisting of -C(0)NR
  • R is independently selected from -OH, -Ci -4 alkyl, - 0-C 1-4 alkyl, -S-C 1-4 alkyl, -S(0)-C 1-4 alkyl, and halogen; and with the proviso that the compound does not have the structure selected from the group consisting of
  • R a can be C(0)OH. In some embodiments, R a can be C(0)OR, and R can be -CR 5 R 6 OC(0)C, -9 alkyl or -CR 5 R 6 OC(0)OC 1-9 alkyl. In some embodiments, R can be -CH 2 OC(0)OCH(CH 3 )2. In some embodiments, R can be -CH 2 OC(0)OC(CH 3 ) 3 . In some embodiments, R can be -CH 2 OC(0)OC(CH 2 ) 2 CH 3 . In some embodiments, R can be -CH 2 0C(0)OCH(CH 2 CH 3 ) 2 . In some embodiments, R can be
  • R can be
  • NR' C( NR 2 )NR L A R 2A ; aryl optionally substituted with 0-2 substituents selected from the group consisting of -OR 3 , -NR ! R 2 , halogen, -C(0)NR 1 R 2 , and -NR 1 C(0)R 5 ; heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of -OR 3 , -NR J R 2 , halogen, -C(0)NR 1 R 2 , and -NR 1 C(0)R 5 ; and heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of -OR , -NR R , halogen, -C(0)NR 1 R 2 , and -NR 1 C(0)R 5 ..
  • the compound described herein does not have the structure selected from the group consisting of:
  • prodrugs e.g., prodrug esters
  • metabolites e.g., metabolites, stereoisomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts of those compounds.
  • the monosaccharide or monosaccharide derivative is meglumine.
  • the compounds disclosed herein may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.
  • Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the compounds described herein may convert to or exist in equilibrium with alternate forms. Accordingly, in some embodiments, the compounds described herein may exist in combination with one or more of these forms. For example, as shown below, the compounds disclosed herein may exist in cyclic form as cyclic boronate monoesters as formula I or in acyclic form as boronic acids as formula I.l (Biochemistry, 2000, 39, 5312- 21), or may exist as a mixture of the two forms depending on the medium.
  • the compounds descrived herein may exist in cyclic dimeric form as Formula (C) or trimeric form as Formula (D), tetrameric form as
  • X' is -Y-(CR R )n-G in Formula C, D and E.
  • X' can be -Y-CH 2 -G in Formula C, D and E.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug derivative Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference in its entirety.
  • pro-drug ester refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group.
  • Other examples of prodrug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S.
  • Methodabolites of the compounds disclosed herein include active species that are produced upon introduction of the compounds into the biological milieu.
  • Solvate refers to the compound formed by the interaction of a solvent and a compound described herein, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).
  • C a to Ct or “C a-b " in which "a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to "b", inclusive, carbon atoms.
  • a “Ci to C 4 alkyl” or “Ci -4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH3CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • halogen or "halo,” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20" refers to each integer in the given range; e.g. , "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group of the compounds may be designated as "Ci -4 alkyl” or similar designations.
  • C 1-4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
  • alkoxy refers to the formula -OR wherein R is an alkyl as is defined above, such as “C 1 -9 alkoxy", including but not limited to methoxy, ethoxy, n- propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
  • alkylthio refers to the formula -SR wherein R is an alkyl as is defined above, such as “C 1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
  • the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
  • the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
  • the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
  • the alkenyl group of the compounds may be designated as "C 2-4 alkenyl" or similar designations.
  • C 2-4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3- yl, buten-4-yl, 1 -methyl -propen-l-yl, 2-methyl-propen-l-yl, 1-ethyl-ethen-l-yl, 2-methyl- propen-3-yl, buta-l,3-dienyl, buta-l,2,-dienyl, and buta-l,2-dien-4-yl.
  • Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
  • the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
  • the alkynyl group of the compounds may be designated as "C 2-4 alkynyl" or similar designations.
  • C 2-4 alkynyl indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2- butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
  • heteroalkyl refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone.
  • the heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term "heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
  • the heteroalkyl group of the compounds may be designated as "C 1-4 heteroalkyl" or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • C 1-4 heteroalkyl indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
  • carbocyclic aromatic e.g., phenyl
  • heterocyclic aromatic groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
  • aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as "C 6-10 aryl,” “C 6 or Cio aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as is defined above, such as “C 6-10 aryloxy” or “C 6- i 0 arylthio” and the like, includingbut not limited to phenyloxy.
  • an "aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such "C 7-14 aralkyl” and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
  • heteroaryl is a ring system, every ring in the system is aromatic.
  • the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated.
  • the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
  • the heteroaryl group may be designated as "5-7 membered heteroaryl,” "5-10 membered heteroaryl,” or similar designations.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
  • a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmefhyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as "C 3-6 carbocyclyl" or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • a "(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C 4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • the alkylene group is a lower alkylene group.
  • cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
  • An example is cyclohexenyl.
  • heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
  • the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl” where no numerical range is designated.
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations.
  • the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4- dioxinyl, 1 ,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, trioxanyl
  • a "(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • R is hydrogen, C 1-6 alkyl, C 2- 6 alkenyl, C 2 - 6 alkynyl, C 3- 7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • R is selected from hydrogen, Ci -6 alkyl, C 2- 6 alkenyl, C 2- alkynyl, C3 -7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a "cyano" group refers to a "-CN” group.
  • a "cyanato” group refers to an "-OCN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-SCN” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “sulfonyl” group refers to an “-S0 2 R” group in which R is selected from hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C3 -7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • S-sulfonamido refers to a "-S0 2 NRAR B " group in which RA and RB are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3- 7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-sulfonamido refers to a "-N(R A )S0 2 R B " group in which R A and R b are each independently selected from hydrogen, C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3- 7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • amino group refers to a "-NRARB” group in which RA and RB are each independently selected from hydrogen, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 3- 7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • aminoalkyl refers to an amino group connected via an alkylene group.
  • alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C 2-8 alkoxyalkyl” and the like.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • substituted it is meant that the group is substituted with one or more subsitutents independently selected from Ci-C 6 alkyl, C]-C 6 alkenyl, Ci-C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C 7 carbocyclyl (optionally substituted with halo, C -C alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and C -C haloalkoxy), C 3 - C 7 -carbocyclyl-Ci-C -alkyl (optionally substituted with halo, C]-C 6 alkyl, Ci-C 6 alkoxy, Ci- C 6 haloalkyl, and Ci-C 6
  • substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from Ci-C 4 alkyl, amino, hydroxy, and halogen.
  • radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH3)CH 2 - and the like.
  • Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene” or "alkenylene.”
  • alkylene means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl).
  • the alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated.
  • the alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms.
  • the alkylene group could also be a lower alkylene having 1 to 4 carbon atoms.
  • the alkylene group may be designated as "C 1-4 alkylene" or similar designations.
  • C alkylene indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-l,l-diyl, propylene, propan-l,l-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-l,l-diyl, butan-2,2-diyl, 2-methyl- propan-l,l-diyl, 1-methyl-propylene, 2-methyl -propylene, 1 , 1-dimethyl-ethylene, 1,2- dimethyl-ethylene, and 1-ethyl-ethylene.
  • alkenylene means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon- carbon double bond that is attached to the rest of the molecule via two points of attachment.
  • the alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated.
  • the alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms.
  • the alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms.
  • the alkenylene group may be designated as "C 2- 4 alkenylene" or similar designations.
  • C2 -4 alkenylene indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-l,l-diyl, propenylene, propen-l,l-diyl, prop-2-en-l,l-diyl, 1-methyl- ethenylene, but-l-enylene, but-2-enylene, but-l,3-dienylene, buten-l,l-diyl, but-l,3-dien-l,l- diyl, but-2-en-l,l-diyl, but-3-en-l,l-diyl, l-methyl-prop-2-en-l,l-diyl, 2-methyl-prop-2-en- 1,1-diyl, 1 -ethyl-ethenylene, 1 ,2-dimethyl
  • agent includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms “agent”, “substance”, and “compound” are used interchangeably herein.
  • analog is used herein to refer to a molecule that structurally resembles a reference molecule but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent. Compared to the reference molecule, an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify variants of known compounds having improved characteristics (such as higher binding affinity for a target molecule) is an approach that is well known in pharmaceutical chemistry.
  • mammal is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.
  • microbial infection refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism.
  • a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal.
  • a mammal is "suffering" from a microbial infection when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal.
  • this description applies to a bacterial infection.
  • the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Oilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • an "effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
  • “Monosaccharide” as used herein refers to a chemical compound of general formula C X (H 2 0) X , where x is 3 to 10.
  • Examples of monosaccharide include but are not limited to glucose (dextrose), arabinose, mannitol, fructose (levulose) and galactose.
  • “Monosaccharide derivative” as used herein refers to a monosaccharide wherein one or more -OH groups can be replaced by the substituents described above in the definition of "substituted.” In some monosaccharide derivatives, one ore more -OH groups on the monosaccharide can be replaced by one or more -NH 2 or -NH-CH 3 groups.
  • One example of a monosaccharide derivative includes meglumine.
  • Other examples of a monosaccharide derivative can include an amino alcohol.
  • isosteres are different compounds that have different molecular formulas but exhibit the same or similar properties.
  • tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid.
  • carboxylic acid isosteres contemplated include - COOH, -S0 3 H, -S0 2 HNR 9 , -P0 2 (R 9 ) 2 , -P0 3 (R 9 ) 2 , -CONHNHS0 2 R 9 , -COHNS0 2 R 9 , and - CONR 9 CN.
  • carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH 2 , O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions.
  • the following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be optionally substituted at one or more positions with R 9 .
  • R 9 substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be permitted at one or more atom(s) which maintain(s) or is/are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.
  • Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated.
  • the compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W.
  • protecting groups for oxygen atoms are selected for their compatibility with the requisite synthetic steps as well as compatibility of the introduction and deprotection steps with the overall synthetic schemes (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)). Handling of protecting and/or sterodirecting groups specific to boronic acid derivatives is described in a recent review of chemistry of boronic acids: D.G. Hall (Ed.), Boronic Acids. Preparation and Application in Organic Synthesis and Medicine, Wiley VCH (2005) and in earlier reviews: Matteson, D. S. (1988). Asymmetric synthesis with boronic esters.
  • Compounds of formula III where X is bromo may be made analogously to the chloro compounds of Scheme 1, utilizing dibromomethane (J Am. Chem. Soc.
  • Matteson reaction precursors of formula IV may be made by palladium mediated coupling of pinanediol diboronate from corresponding appropriately protected benzyl alcohols (J Am. Chem. Soc. 2011, 133, 409-41 1) or benzyl bromides of V (Tetrahedron Letters 2003, 44, 233-235; J Am. Chem. Soc., 2010, 132, 11825-11827).
  • the compounds of formula V may be achieved by means of several earlier known methods (WO0458679) with conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum, 1973); and Protecting Groups in Organic Synthesis P.G.M.
  • the starting compound of Ia-1 can be a salicyclic acid derivative, wherein Y' can be -OH, halogen, -CH 3 , halogen substituted - CH 3 , or a protected hydroxyl group; and J, T, M can be CR 7 or N.
  • the compound of Formula Ia-1 can be treated first with protection groups and then undergo halogenation to form a benzyl halide compound of Formula Ia-3.
  • the halogen of Formula Ia-3 e.g., bromide
  • the compound of Formula Ia-4 undergoes homologation to yield a compound of Formula Ia- 5 (wherein X' is a halogen).
  • Various types of thiol, amine, alcohol and other precursors can then react with the compound of Formula Ia-5 to substitute the halogen X' and form a compound of Formula Ia-6.
  • the compound of Formula Ia-6 can then undergo the deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula la where R is H.
  • a compound of Formula (1-1) wherein Y is -CH 2 - can be prepared by using the general synthetic Scheme lb illustrated below.
  • the starting compound of Formula I- la can be a salicyclic acid derivative.
  • the compound of Formula I- lb can be treated with a protection group and then undergo a cross coupling reaction to form a vinyl compound of Formula I-lc.
  • the double bond of Formula I-lc can be converted into an aldehyde of Formula I- Id.
  • the aldehyde compound of Formula I- Id then undergoes a Wittig reaction to yield a compound of Formula I-le, which then reacts with boronation agent to form a pinacol boronic ester of Formula I- If.
  • the G' group in Formula I-le, added by a Wittig reagent, can be any group that is suitable to couple to the negatively charged carbon of the Wittig reagent.
  • Examples of the G's groups can include, but are not limited to, -COOR 1 , -C(0)R', amide, and Ci ⁇ alkyl.
  • G' can be -C(0)OC(CH3)3.
  • the boronic ester compound of Formula I- If can react with pinanediol to yield a Pinanediol Methylboronic Ester compound of Formula I-lg.
  • the compound of Forumla I-lg can undergo deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula 1-1, and G' can be the final G group in the compound of Formula 1-1 (i.e., G' and G are the same).
  • the compound of Formula I-lg can react with different types of thiol, amine, and alcohol precursors to replace the G' group with a G group (as defined herein) to form a compound of Formula I-lh.
  • the compound of Formula I-lh can then undergo the deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula 1-1.
  • Compounds of formula I where the R is a prodrug moiety may be synthesized by a variety of known methods of different carboxylic acid prodrugs ⁇ Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed., Springer, New York, 2007).
  • These prodrugs include but are not limited to substituted or non-substituted alkyl esters, (acyloxy)alkyl (Synthesis 2012, 44, 207), [(alkoxycarbonyl)oxy]methyl esters (WOl 0097675), or (oxodioxolyl)methyl esters (J Med. Chem. 1996, 39, 323-338).
  • acid or in neutral conditions e.g., carbodiimide coupling
  • ROH alcohols
  • RX base promoted esterification with RX where X is a leaving group in the presence of an appropriate base.
  • prodrug moiety R can be -Ci-galkyl, -CR R O -
  • boronate esters of formula VI or corresponding tetrafluoroborates may be also utilized for introduction of prodrugs and convert them to final prodrugs (Scheme 2b).
  • Such carboxylic acids (VI) can be made from compounds of formula II by selective deprotection of OR'.
  • the prodrug group may also be introduced earlier in the sequence in compounds of formula V where R' is R. Such sequence where prodrug is introduced in earlier intermediates is only feasible when the ester is stable under the final deprotection conditions to remove the phenol protective group and boronate ester group.
  • Such benzaldehyde derivatives of VIII can be converted to bromomethyl intermediates via one ⁇ Tetrahedron Lett., 1984 , 25, 1 103-1104) or two step transformations via reduction and halide formation.
  • Compounds where X' is substituted with bromo or iodo groups can be attained from appropriately protected commercial 2,5-hydroxy-benzoic acid derivatives (J Med. Chem.. 2003 . 46, 3437-3440).
  • Intermediates of VIII can also be prepared via carboxylation. of derivatives of formula IX where Z' is a fluoro, OR'", or SR'" by earlier described methods (WO12106995).
  • the starting compound of Formula VII- 1 can be prepared from a protected phenol derivative, wherein X 3a can be C 1-4 alkyl, -OR 1 , or halogen; and R 3a can be a suitable hydroxyl protection group and R 3b can be a suitable carboxyl protecting group.
  • the compound of Formula VII-2 can be prepared via carboxylation of the phenol derivative of Formula VII- 1. The carboxylic group on the Formula VII-2 is protected.
  • the compound of Formula VII-2 can then react with a boronation agent at X 3a to form a Pinanediol Methylboronic Ester compound of Formula VII-3.
  • the boron ester of Formula VII-3 can then undergo a homologation reaction to yield a compound of Formula VII-4.
  • Various types of thiol, amine, alcohol, and other precursors can then react with the compound of Formula VII-4 to substitute the halogen and form a compound of Formula VII-5.
  • the compound of Formula VII- 5 then undergoes the deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula VII.
  • the compound of formula VII-2 where X 3a is a -CH 2 OH group can be prepared from a salicylic acid derivative of Formula VII-6.
  • the compound of Formula VII-6 upon diallylation under basic conditions followed by thermal Claisen rearrangement (Org. React. 1975, 22, 1-252) and ester hydrolysis gives compound of Formula VII-7.
  • Such compounds undergo isomerization of double bond to give a styryl derivative, The styryl double bond can be oxidized to form an aldehyde of Formula VII-8.
  • the halogen group X 3b in the compound of Formula VII-8 can be replaced by various R groups to form a compound of Formula VII-9, which then undergoes reduction to convert the aldehyde group into the hydroxyl group of Formula VII-2.
  • the compound of Formula VII-2 can further undergo the steps listed above in Scheme 3a to form an ortho-carboxylate- substituted compound of formula VII.
  • FIG. 3c One exemplary but non-limiting general synthetic scheme for preparing the compound of Formula VII is shown in scheme 3c.
  • the compound of Formula VII-2, X 3a can be -C 1-4 alkyl, -C 1-4 alkyl-OH, -OR 1 , or halogen; R 3a can be a suitable hydroxyl protection group; and R 3b can be a suitable carboxyl protecting group.
  • the compound of Formula VII-2 can be prepared from the compound of Formula VII- la through either a carboxylation step followed by a halogenation step or a halogenation step followed by a carboxylation step.
  • the compound of Formula VII-2 can then undergo boronation to form the compound of Formula VII-3 as shown in scheme 3a above.
  • a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • compositions containing a pharmaceutically-acceptable carrier include compositions containing a pharmaceutically-acceptable carrier.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Oilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyr
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • compositions described herein are preferably provided in unit dosage form.
  • a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
  • the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • routes for administration for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • a liquid composition, which is formulated for topical ophthalmic use is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
  • the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
  • Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as a saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • Some boronic acid derivatives described herein can form an oligomer such as a dimer, trimer or tetramer.
  • some embodiments include pharmaceutical compositions in which an excipient is included that prevents or limits the formation of oligomers.
  • the excipient can be a monosaccharide or monosaccharide derivative.
  • the excipient is meglumine.
  • Other excipients include but are not limited to ethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane (Tris), L-lysine, and Pyridine-2-methanol.
  • Some embodiments described herein relate to a chemical complex formed between the monosaccharide or monosaccharide derivative and the compound of Formula (I) described herein.
  • the interaction between the two components helps increase the stability and/or solubility of the compound of Formula (I).
  • the monosaccharide or monosaccharide derivative can form a chemical complex with any compound containing a boronate moiety.
  • the compound containing a boronate moiety can be a boronic acid derivative described herein such as a compound of Formula (I) described herein.
  • the compound containing a boronate moiety can be any other boronate containing compounds, for example, known boronate-containing pharmaceutical agents.
  • the monosaccharide or monosaccharide derivative used in forming the stable complex can be meglumine.
  • the pH of the composition can be in the range of about 5 to about 9, about 6 to 8, about 6 to about 7.5, about 7.1 to about 7.3, or about 7.1 to about 7.2. In some embodiments, the pH of the composition can be in the range of about 7.0-7.3. In some embodiments, the pH of the composition can be about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, and 7.8. In some embodiments, the pH of the composition can be about 7.1. In some embodiments, the pH of the composition can be about 7.2.
  • the amount of the boronic acid derivatives that are present in a monomer form can vary depending on the pH of the solution, the oligomer-preventing excipient included, and the amount of the excipient in the composition.
  • the percentage of the monomer form can be more than 85%, more than 88%, more than 90%, more than 92%, more than 95%, more than 97% by weight, based on the total amount of the boronic acid derivative in the composition.
  • the percentage of the monomer form can be more than 96% by weight based on the total amount of the boronic acid derivative in the composition.
  • the percentage of the monomer form can be more than 97% by weight based on the total amount of the boronic acid derivative in the composition.
  • Some embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions comprising the compounds described herein. Some methods include administering a compound, composition, pharmaceutical composition described herein to a subject in need thereof.
  • a subject can be an animal, e.g., a mammal (including a human).
  • the bacterial infection comprises a bacteria described herein.
  • methods of treating a bacterial infection include methods for preventing bacterial infection in a subject at risk thereof.
  • the subject is a human.
  • Further embodiments include administering a combination of compounds to a subject in need thereof.
  • a combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
  • Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • co-administration it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered i.v.
  • Examples of additional medicaments include an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent and an anti-allergic agent.
  • Preferred embodiments include combinations of a compound, composition or pharmaceutical composition described herein with an antibacterial agent such as a ⁇ - lactam.
  • ⁇ -lactams include Amoxicillin, Ampicillin (e.g., Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g., Dicloxacillin, Flucloxacillin), Ox
  • Preferred embodiments include ⁇ -lactams such as Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Apapenem, and Panipenem.
  • the ⁇ -lactam can be Tebipenem or Apapenem.
  • the ⁇ -lactam can be Tebipenem.
  • Additional preferred embodiments include ⁇ -lactams such as Aztreonam, Tigemonam, and Carumonam.
  • Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a monobactam.
  • additional agent comprises a monobactam.
  • monobactams include aztreonam, tigemonam, nocardicin A, carumonam, and tabtoxin.
  • the compound, composition and/or pharmaceutical composition comprises a class A, C, or D beta-lactamase inhibitor.
  • Some embodiments include co-administering the compound, composition or pharmaceutical composition described herein with one or more additional agents.
  • Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a class B beta lactamase inhibitor.
  • a class B beta lactamase inhibitor includes ME 1071 (Yoshikazu Ishii et al, "In Vitro Potentiation of Carbapenems with ME 1071, a Novel Metallo-B-Lactamase Inhibitor, against Metallo-B-lactamase Producing Pseudomonas aeruginosa Clinical Isolates.” Antimicrob. Agents Chemother. dok lO.l 128/AAC.01397-09 (July 2010)).
  • Some embodiments include co-administering the compound, composition or pharmaceutical composition described herein with one or more additional agents.
  • Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises one or more agents that include a class A, B, C, or D beta lactamase inhibitor. Some embodiments include co-administering the compound, composition or pharmaceutical composition described herein with the one or more additional agents.
  • Bacterial infections that can be treated with the compounds, compositions and methods described herein can comprise a wide spectrum of bacteria.
  • Example organisms include gram-positive bacteria, gram-negative bacteria, aerobic and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.
  • More examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Prote
  • Step 6 Synthesis of (R)-3-(l,3,4-thiadiazol-2-ylthio)-2-hydroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (1)
  • Compound 7 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with N-(5-mercapto- l,3,4-thiadiazol-2-yl)acetamide.
  • Compound 12 was prepared following similar procedure described in example 1 (steps 1 -6) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with 1H-1 ,2,3- triazole-4-thiol.
  • step 6 Final deprotection (step 6) was done by isobutyl boronic acid following procedure described in step 7 of example 19.
  • 1H NMR 400 MHz, CD 3 OD
  • Compound 15 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 4-methyl-4H- l,2,4-triazole-3 -thiol.
  • Example 20 (R)-3-(4-amino-4H-l,2,4-triazol-3-ylthio)-7-fluoro-2-hydroxy-3,4-dihydro-2H- benzo[el[L21oxaborinine-8-carboxylic acid (20) [0239]
  • Compound (20) was prepared from 19G (example 19) following methods described in steps 5 and 6 of ex H- 1 ,2,4-triazole-3-thiol.
  • Compound 23 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 2-amino-5-mercapto-L3,4- thiadiazole.
  • Compound 24 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 4-methyl-3-mercapto- 1,2,4- triazole.
  • reaction mixture was slowly warmed up to room temperature over a period of 6 hours and stirred overnight.
  • the solvent was evaporated and the residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 26E (16.5 g, 88 %) as light yellow solid.
  • Compound 27 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 5-amino-l,3,4- thiadiazole-2-thiol.
  • Compound 30 was prepared following the procedure described in Example 25 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol with 5-amino-l,3,4-thiadiazole-2- thiol.
  • Compound 33 was prepared from 2,4-Difluoro-6-hydroxybenzoic acid (WO 2009129938) following the procedure described in Example 26 except replacing 4- amino-4H-l,2,4-triazole-3 -thiol in step 5 with 5-amino-l,3,4-thiadiazole-2-thiol.
  • 1H NMR 400 MHz, CD 3 OD
  • ⁇ 6.55 655 (t, 1H), 3.60 (t, 1H), 3.21 (dd, 1H), 2.95 (dd, 1H).
  • Compound 37 was made starting from 3,4-difluorophenol following procedures described in Example 38.
  • Compound 39 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with lH-l,2,3-triazole-4- thiol.
  • Examples 40 and 41 (R -3-(l-(3-carboxypropyl -lH-L2,4-triazol-3-ylthio)-2-hydroxy-7- methoxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (40) and (R)-3-(4-(3- carboxypropyl)-4H-l,2,4-triazol-3-ylthio)-2-hvdroxy-7-methoxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (41)
  • reaction mixture was slowly warmed up to room temperature over a period of 6 hours and stirred overnight.
  • the solvent was evaporated and the residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/50) to afford compound 44E (9.1 g, 88 %) as yellow oil.
  • Compound (46) was prepared from 19G (example 19) following methods described in steps 5 and 6 of example 1 utilizing N-Boc-3-mercapto-azetidine in step 5.
  • Compound 48 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 5 -mercapto- 1 ,2,3 -thiadiazole (US4758557).
  • Compound 49 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 2-mercaptoacetamide (US4758557).
  • Compound 50 was prepared following methods described in Example 43 except replacing 26E in step 4 with 19G of Example 19.
  • Compound 51 was prepared following methods described Example 19 replacing MeOI l-potassium carbonate in step 6 with mercaptoacetonitrile sodium salt ( WO K) 135504).
  • Compound 49 was prepared from 19G (Example 19) following methods described in step 5 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 2- aminothiazole-5-thiol.
  • Compound 53 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 and replacing 2-mercapto-l,3,4-thiadiazole with 2- sulfanylthiazole-5-carboxamide.
  • Compound 54 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 2-sulfanylthiazole-4-carboxamide as described in Sanghvi et. al., J Heterocyclic Chem. , 1988 , 25, (623-633), which is incorporated herein by reference in its entirety.
  • Compound 55 was prepared from 19G (Example 19) following methods described in step 5 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 5- (trifluoromethyl)-l,3,4-thiadiazole-2-thiol as described in PCT publication WO 2010/03081 1. Wagman et al., which is incorporated herein by reference in its entirety..

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Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

Description

BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF
BACKGROUND
Field of the Invention
[0001] The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to boronic acid antimicrobial compounds, compositions, their preparation, and their use as therapeutic agents.
Description of the Related Art
[0002] Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs.
[0003] Various bacteria have evolved β-lactam deactivating enzymes, namely, β- lactamases, that counter the efficacy of the various β-lactam antibiotics, β-lactamases can be grouped into 4 classes based on their amino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes in classes A, C, and D include active-site serine β-lactamases, and class B enzymes, which are encountered less frequently, are Zn-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β- lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi-resistant strains severely limits β-lactam treatment options available.
[0004] The increase of class D β-lactamase-expressing bacterium strains such as Acinetobacter baumannii has become an emerging multidrug-resistant threat. A. baumannii strains express A, C, and D class β-lactamases. The class D β-lactamases such as the OXA families are particularly effective at destroying carbapenem type β-lactam antibiotics, e.g., imipenem, the active carbapenems component of Merck's Primaxin® (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat to the effective use of drugs in that category to treat and prevent bacterial infections. Indeed the number of catalogued serine-based β-lactamases has exploded from less than ten in the 1970s to over 300 variants. These issues fostered the development of five "generations" of cephalosporins. When initially released into clinical practice, extended- spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains by the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of the extended-spectrum β-lactamase (ESBL) phenotype.
[0005] New β-lactamases have recently evolved that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other β-lactam antibiotics. These carbapenemases belong to molecular classes A, B, and D. Class A carbapenemases of the KPC-type predominantly in Klebsiella pneumoniae but now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The KPC carbapenemase was first described in 1996 in North Carolina, but since then has disseminated widely in the US. It has been particularly problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported. These enzymes have also been recently reported in France, Greece, Sweden, United Kingdom, and an outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems can be associated with poor outcomes.
[0006] The zinc-dependent class B metallo^-lactamases are represented mainly by the VIM, IMP, and NDM types. IMP and VIM-producing K. pneumonia were first observed in 1990s in Japan and 2001 in Southern Europe, respectively. IMP -positive strains remain frequent in Japan and have also caused hospital outbreaks in China and Australia. However dissemination of IMP -producing Enterobacteriaceae in the rest of the word appears to be somewhat limited. VIM-producing enterobacteria can be frequently isolated in Mediterranean countries, reaching epidemic proportions in Greece. Isolation of VIM- producing strains remains low in Northern Europe and in the United States. In stark contrast, a characteristic of NDM-producing K. pneumonia isolates has been their rapid dissemination from their epicenter, the Indian subcontinent, to Western Europe, North America, Australia and Far East. Moreover, NDM genes have spread rapidly to various species other than K. pneumonia.
[0007] The plasmid-expressed class D carbapenemases belong to OXA-48 type. OXA-48 producing K. pneumonia was first detected in Turkey, in 2001. The Middle East and North Africa remain the main centers of infection. However, recent isolation of OXA-48-type producing organisms in India, Senegal and Argentina suggest the possibility of a global expansion. Isolation of OXA-48 in bacteria other than K. pneumonia underlines the spreading potential of OXA-48.
[0008] Treatment of strains producing any of these carbapenemases with carbapenems can be associated with poor outcomes.
[0009] Another mechanism of β-lactamase mediated resistance to carbapenems involves combination of permeability or efflux mechanisms combined with hyper production of beta-lactamases. One example is the loss of a porin combined in hyperproduction of ampC beta-lactamase results in resistance to imipenem in Pseudomonas aeruginosa. Efflux pump over expression combined with hyperproduction of the ampC β-lactamase can also result in resistance to a carbapenem such as meropenem.
[0010] Thus, there is a need for improved β-lactamase inhibitors.
Summary
[0011] Some embodiments disclosed herein include a compound having structure of Formula (I):
Figure imgf000004_0001
(I) or pharmaceutically acceptable salts thereof, wherein:
A is selected from the group consisting of C3-10 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5- 10 membered heterocyclyl;
XA is -C(ReRf)-, -0-, -S-, -S(O)-, -S(0)2-, or -NR1-;
Ra is selected from the group consisting of -H, halogen, optionally substituted -Ci-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C1-6 alkyl, -NR'R2, -N(0R3)R2, optionally substituted -S-C1 -6 alkyl, -C(0)NR1R2, -S(0)2NR1R2, CN, optionally substituted -S(0)-C1-6 alkyl, optionally substituted -S(0)2-C1-6 alkyl, and a carboxylic acid isoster;
Rb is selected from the group consisting of -H, halogen, optionally substituted -C, -6 alkyl, -OH, -C(0)OR, optionally substituted -0-C1 -6 alkyl, -NRJR2, -N(0R3)R2, optionally substituted -S-Ci-6 alkyl, -C(0)NR'R2, -S(0)2NR'R2, -CN, optionally substituted -S(0)-Ci- alkyl, optionally substituted -S(0)2-Ci- alkyl, and a carboxylic acid isoster, and
Rc is selected from the group consisting of-OH, optionally substituted -0-Ci- alkyl -NR'R2, and -N(OR3)R2, or
Rb and Rc together with intervening atoms form a 5-8 membered boron ester ring, optionally comprising additional 1-3 heteroatoms selected from Oxygen (O), Sulfur(S) or Nitrogen(N);
Rd is selected from the group consisting of -OH, optionally substituted -0-C1 -6 alkyl -NR^2, and -N(OR3)R2, or
when Rb and Rc do not together form a 5-8 membered boron ester ring, then optionally Rc and Rd together with intervening atoms form a 5- 15 membered boron ester or amide ring, optionally comprising additional 1-3 heteroatoms selected from O, S, and N;
Y is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, -CH2- and
-NR2-;
G is selected from the group consisting of -NR'R2, -N3, -C(0)NR'R2, - SCO^NR^2, -SR3, -OR3, -CH2NR1C(0)R5, -C(=NOR3)-X, C(=NOR3)-Z, -C(0)OR3, -C(0)NR' (OR3), -NR' (OR3), -NR' C(0)R5, -NR' C(0)NR2Rl a, -NR' C(0)OR3, - NR1S(0)2R3, -NR1S(0)2NR2Rla, -NR^R^13, -C(0)NR1NR2Rla, -S(0)2NR1NR2Rla, -C(=NR')R5, -C(=NR')NR2Rl a, -NR'CR5(=NR2), -NR1 C(=NR2)NR' aR2a, -CN, C 0 alkyl optionally substituted by one or more R10, C2-ioalkenyl optionally substituted by one or more R10, C2-ioalkynyl optionally substituted by one or more R10, C3-7 carbocyclyl optionally substituted by one or more R10, 3-10 membered heterocyclyl optionally substituted by one or more R10, C6-ioaryl optionally substituted by one or more R10, 5-10 membered heteroaryl optionally substituted by one or more
6alkylene-C3-7carbocyclyl optionally substituted by one or more R10, Ci-6alkylene-3- 10 membered heterocyclyl optionally substituted by one or more R10, C,-6alkylene-C6- 10aryl optionally substituted by one or more R10, and Ci-6alkylene-5-10 membered heteroaryl optionally substituted by one or more R10;
Re and Rf are each independently selected from the group consisting of H, C1-6 alkyl, -OH, -OCi- alkyl, -SCi- alkyl, C3-iocycloalkyl, C2-ioalkenyl, C2-i0alkynyl, -NR'C(0)R5, -NR' S(0)2R3, -C(0)R5, -C(0)OR3, alkylaryl, optionally substituted C6-10 aryl, optionally substituted -0-C -ioaryl, -CN, optionally substituted 5-10 membered heteroaryl, optionally substituted -O-heteroaryl, optionally substituted 3-10 membered heterocyclyl, -S(0)R3' -S(0)2R3, -R1-0-C(0)OR3, or Re and Rf together with the carbon to which they are attached form a C3-8 cycloalkyl or a 4-8 membered heterocyclyl;
R7 is present 1 to 5 times and each R7 is independently selected from the group consisitng of -H, -OH, halogen, -CH3, -CF3, C]-C6 alkenyl, Ci-C6 alkynyl, Ci- C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 3-10 membered heteroaryl, cyano, Ci-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl (mercapto), and -CH2)m-Y'-(CH2)pM', or
two adjacent R together with any intervening atoms form a 5-10 membered heteroaryl;
m and p are independently 0 to 3 ;
Y' is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, -CR5R6-, and -NR1-; M' is selected from the group consisting of - C(0)NR'R2; -C(0)NROR3; -NR'C(0)R5; -NR'C(0)NR2Rl a; -NR'C(0)OR3; - NR1S(0)2R3; -NR1S(0)2NR2Rla; -C(=NR1)R5; -C(=NR1)NR2Rla; -NR1CR5(=NR2); - NR'C(=NR2)NRlaR2a; NR'R2; -S03R3; -CN; C alkyl optionally substituted with 0-
2 substituents selected from the group consisting, -OR 3 , -NR 1 R2 , halogen, - C(0)NR'R2, and -NR'C(0)R5; C3-IO cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, -OR 3 , 1
-NR R2 , halogen, -C(0)NR'R2, and -NR'C(0)R5; C6-i0 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR 3 , 1 2
-NR R , halogen, - C(0)NR'R2, and -NR'C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR 3 , 1 2
-NR R , halogen, -C(0)NR'R2, and -NR'C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5;
X is hydrogen or optionally substituted Ci^alkyl;
Z is selected from optionally substituted C3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
R is selected from the group consisting of -H, -C,-9alkyl, -CR5R6OC(0)C,-9alkyl, -CR5R6OC(0)OC,-9alkyl,
Figure imgf000007_0001
each R1, R2, Rlaand R2a are independently selected from the group consisting of -H, optionally substituted -C1-10alkyl, optionally substituted C2-1oalkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-ioaryl, and optionally substituted 5-10 membered heteroaryl;
R is hydrogen, optionally substituted C1-10alkyl, -optionally substituted Ci.ioalkyl-COOH, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C -ioaryl, and optionally substituted 5-10 membered heteroaryl;
each R5, R6, R8 and R9 are independently selected from the group consisting of -H, -OH, -NH2, -optionally substituted alkoxyl, optionally substituted -Ci-ioalkyl, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl; each n is independently 0-3;
each R10 is independently -(CH2)0-6RU; and
each R1 1 is independently selected from Ci-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C]-C6 heteroalkyl; C3-C7 carbocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy; Q3-C7- carbocyclyl-Ci-C -alkyl optionally substituted with halo, amine, cyano, Ci-C alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, C]-C6 alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and Ci-C6 haloalkoxy; 3-10 membered heterocyclyl-Ci-Ce-alkyl optionally substituted with halo, amine, cyano, Ci-C alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and Ci-C6 haloalkoxy; aryl optionally substituted with halo, amine, cyano, C C6 alkyl, Ci-C alkoxy, Ci-C haloalkyl, and Ci-C haloalkoxy; aryl(Ci-C )alkyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C C6 alkoxy, C C6 haloalkyl, and Ci-C haloalkoxy; 5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C C6 alkyl, C C6 alkoxy, C C6 haloalkyl, and Ci-C6 haloalkoxy; 5-10 membered heteroaryl(Ci-C )alkyl optionally substituted with halo, amine, cyano, Ci- C6 alkyl, C C6 alkoxy, Ci-C6 haloalkyl, and C C6 haloalkoxy; Ci-6alkylene-C3- 7carbocyclyl optionally substituted with halo, amine, cyano, Ci-C alkyl, C]-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy; Ci^alkylene-S-lO membered heterocyclyl optionally substituted with halo, amine, cyano, C]-C6 alkyl, C]-C6 alkoxy, C C6 haloalkyl, and Ci-C6 haloalkoxy; Ci^alkylene-Ce-io ryl optionally substituted with halo, amine, cyano, Ci-C alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and Ci-C6 haloalkoxy; C^alkylene-S-lO membered heteroaryl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and C]-C6 haloalkoxy; halo; cyano; hydroxy; C -C alkoxy(Ci-C6)alkyl (ether); aryloxy; halo(C]-C6)alkyl; halo(C]-C6)alkoxy; amino; amino(Ci-C6)alkyl; nitro; O-carbamyl; N-carbamyl; O-thiocarbamyl; N-thiocarbamyl; C-amido; N-amido; S-sulfonamido; N- sulfonamido; C-carboxy; O-carboxy; acyl; cyanate; isocyanate; thiocyanato; isothiocyanato; sulfonyl; oxo; -OR3; -C1-6alkylene-COOR3; -SR3; C(0)NR'R2; - NR!R2; -NR1(CH2)o-4COR5; -NR1(CH2)0-4C(=NR2)R5; -NR1-CH-[(CH2)0-4-NRlaR2a]2; -NR^CH^-R3; -NR1(CH2)1-4-NR, aR2a; -NKCH^^-NR^2],; -S(CH2)0- 4C(=NR1)R5; -S(CH2)1 -4-R3; -8(ΟΗ2)0-4-Ν^2; -S-CH-KCH^-NR^2],; -S[(CH2)i- 4-NR'R2]2; -S(CH2)O-4-3-10 membered heterocyclyl; -S(CH2)0-4-3-10 membered heterocyclyl-N^R2; -S(CH2)0-4-5-10 membered heteroaryl-NR^2; -S^NR1^; and -0-Ci-6alkylene-NR'R2.
[0012] Some embodiments disclosed herein include a compound having the structure of formula 1-1 or formula 1-2:
Figure imgf000009_0001
(1-1) (1-2)
or pharmaceutically acceptable salt thereof,
[0013] Some embodiments disclosed herein include a compound having structure of formula 1-3 or formula 1-4:
Figure imgf000009_0002
(1-3) (1-4)
or pharmaceutically acceptable salt thereof, wherein:
Y is selected from the group consisting of -S-, -0-, -CH2-, and -NH-; n is 0-3;
G is selected from the group consisting of -C(0)NR1R2; -C(0)NR1OR3; -NR1C(0)R5; -NR1C(0)NR2R2a; -NR1C(0)OR3; - NR'S(0)2R3; -NR1S(0)2NR2Rla; -C(=NR')R5; -C(=NR')NR2Rla; -NR'CR5(=NR5); - NR1C(=NR2)NRlaR2a; C6-10aryl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR1C(0)R5; 5-10 membered heteroaryl optionally substituted with 0-2
3 1 2 substituents selected from the group consisting of C1-4 alkyl, -OR , -NR R , halogen, - C(0)NR1R2, and -NR1C(0)R5; and 5-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, - OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5;
J, L, and M are each independently selected from the group consisting of CR7 and N;
R is selected from a group consisting of -H, -C,-9alkyl, -CR5R6OC(0)C1-9alkyl, -CR5R60C(0)0C1-9alkyl, and
Figure imgf000010_0001
R1, R2, R3, R5 and R6 are each independently selected from -H and -C^alkyl; and
R7 is selected from the group consisting of-H, -Ci-4alkyl, -OH, -OC1-4alkyl, and halogen.
[0014] Some embodiments relate to a chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative and a compound having the structure of formula (I) described herein.
[0015] Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient. [0016] Other embodiments disclosed herein include a method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof a compound disclosed herein.
DETAILED DESCRIPTION
[0017] In some embodiments, compounds that contain a boronic acid moiety are provided that act as antimicrobial agents and/or as potentiators of antimicrobial agents Various embodiments of these compounds include compounds having the structures of Formula I as described above or pharmaceutically acceptable salts thereof.
[0018] In some embodiments of Formula (I), G is selected from the group consisting of -NR R2, -N3, -C(0)NR1R2, -S(0)2NR1R2, -SR3, -OR3, -CH2NR1C(0)R5, - C(=NOR3)-X, C(=NOR3)-Z, -C(0)OR3, -C(0)NR1 (OR3), -NR' (OR3), -NR' C(0)R5, - NR1C(0)NR2Rla, -NR1C(0)OR3, -NR^O^R3, -NR1S(0)2NR2Rla, -NR^R 3, - C(0)NR'NR2Rla, -S(0)2NR'NR2Rl a, -C(=NR')R5, -C(=NR')NR2Rla, -NR'CR5(=NR2), - NR1C(=NR2)NRlaR2a, optionally substituted CM 0 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-1oalkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted Ci-6alkylene-C3-7carbocyclyl, optionally substituted C]-6alkylene-5-10 membered heterocyclyl, optionally substituted C\. 6alkylene-C6-ioaryl, and optionally substituted Ci^alkylene-S-lO membered heteroaryl;
R 7 is present 1 to 5 times and each R 7 is independently selected from the group consisitng of -H, -OH, halogen, -CF3, Ci-C6 alkenyl, C -C alkynyl, C -C heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C6 alkoxy(Ci-C6)alkyl, aryloxy, sulfhydryl (mercapto), and - (CH2)m-Y'-(CH2)pM';
M' is selected from the group consisting of -C(0)NR'R2; -C(0)NROR3; - NR1C(0)R5; -NR1C(0)NR2Rla; -NR1C(0)OR3; -NR^O^R3; -NR^CO^NR 3; - C(=NR')R5; -C(=NR')NR2Rl a; -NR' CR5(=NR2); -NR1 C(=NR2)NR' aR2a; C alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR , -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C6-IO aryl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5;
R is selected from the group consisting of -H, -Ci^alkyl, -CR5R6OC(0)C].
Figure imgf000012_0001
each R1, R2, Rla and R2a are independently selected from the group consisting of -H, optionally substituted -C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-ioaryl, and optionally substituted 5-10 membered heteroaryl; and
each R5, R6, R8 and R9 are independently selected from the group consisting of -H, -OH, -optionally substituted alkoxyl, optionally substituted -Ci.i0alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3- 7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl.
[0019] In some embodiments of Formula (I), G can be selected from the group consisting of -NR'R2, -N3, -C(0)NR'R2, -S(0)2NR'R2, -SR3, -OR3, -CH2NR'C(0)R5, - C(=NOR3)-X, C(=NOR3)-Z, -C(0)OR3, -C(0)NR1(OR3), -NR^OR3), -NR1C(0)R5, - NR'C(0)NR2Rla, -NR'C(0)OR3, -NR' S(0)2R3, -NR' S(0)2NR2Rl a, -NR'NR 3, - C(0)NR1NR2Rla, -S(0)2NR1NR2Rla, -C(=NR1)R5, -C(=NR1)NR2Rla, -NR1CR5(=NR2), - NR'C(=NR2)NRlaR2a, optionally substituted CM0 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl.
[0020] In some embodiments of Formula (I), each R11 can be independently selected from Ci-C6 alkyl; haloCi-6alkyl; -OR3; -C1-6alkylene-COOR3; -SR3; halogen; -CO- C,-4alkyl; C(0)NR1R2; -NRJR2; -NR1(CH2)0-4COR5; -NR1(CH2)0-4C(=NR2)R5; -NR^CH- [(CH2)o-4-NRl aR2a]2; -NR^CFy^-R3; -NR'CCH^^-NR^R23; -N[(CH2)I-4- R,R2]2; - S(CH2)o-4C(=NR1)R5; -S(CH2)1 -4-R3; -SCCH^-NR^2; -S-CH-KCH^-NR^2],; - S[(CH2)1-4-NR'R2]2; -S(CH2)o-4-3-10 membered heterocyclyl; -S(CH2)0-4-3-10 membered heterocyclyl-N^R2; -S(CH2)0-4-5-10 membered heteroaryl-N^R2; -S^NR1^; and -O-C,.
1 2
6alkylene-NR R ; C3-7 carbocylcyo optionally substituted with halo, amine, cyano, C\-Ce alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and C]-C6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and C]-C6 haloalkoxy; 6 to 10 membered aryl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy; and 5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci-C6 alkoxy, C]-C6 haloalkyl, and Ci-C6 haloalkoxy.
[0021] In some embodiments of Formula (I), A can be selected from the group consisting of phenyl, biphenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, indanyl, pyridyl, pyrrolyl, oxazolyl, indolyl and thienyl. In some embodiments of Formula (I), A can be phenyl.
[0022] In some embodiments of Formula (I), Rb is attached to ring A at a position that is vicinal to the point of attachment of Xato ring A.
[0023] In some embodiments, Y can be -CH2-, -S(O)-, -S(0)2-, -O- or -S-. In some embodiments, Y can be -CH2-, -S(O)-, -S(0)2-, -O- , -NH-, or -S-.
[0024] In some embodiments, Y can be -CH2-, -0-, -S- or -NH-.
[0025] In some embodiments, Y can be -CH2-, -O- or -S-.
[0026] In some embodiments, Y can be -O- or -S-.
[0027] In some embodiments, Rd is -OH.
[0028] In some embodiments, Xa is -CH2-. [0029] In some embodiments, RA is selected from the group consisting of -H, halogen, optionally substituted -C1-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C1-6 alkyl, -NR!R2, -N(OR3)R2, optionally substituted -S-C, -6 alkyl, -C(0)NR1R2, -S(0)2NR1R2, CN, optionally substituted -S(0)-C1-6 alkyl, and optionally substituted -S(0)2-C1-6 alkyl.
[0030] In some embodiments, RA is a carboxylic acid isoster.
[0031] In some embodiments, RB is selected from the group consisting of -H, halogen, optionally substituted -Ci-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C1 -6 alkyl, -NR'R2, -N(OR3)R2, optionally substituted -S-Ci-6 alkyl, -C(0)NR'R2, -S(0)2NR1R2, -CN, optionally substituted -S(0)-Ci- alkyl, and optionally substituted -S(0)2-Ci- alkyl.
[0032] In some embodiments, RB is -OH.
[0033] In some embodiments, RB is a carboxylic acid isoster.
[0034] In some embodiments, RC is -OH.
[0035] Some embodiments of the compounds of Formula (I) or their pharmaceutically acceptabl lts can have the structure of Formula (F):
Figure imgf000014_0001
(!')·
[0036] In some embodiments of Formula (I), (Γ), (1-1) or (1-2), R8 is H and R9 is
H.
[0037] Some embodiments of the compounds of Formula (I) or their pharmaceutically acceptable salts can have the structure of Formula (1-3) or Formula (1-4):
Figure imgf000015_0001
(1-3) (1-4)
η wherein J, L, and M are each independently selected from the group consisting of CR and N.
[0038] In some embodiments of Formula (1-1), (1-2), (1-3), or (1-4), two adjacent R7 together with any intervening atoms can form a 5-8 membered heteroaryl ring. In some η
embodiments, two adjacent R together with any intervening atoms form an imidazole ring.
[0039] Some embodiments of compounds of Formula (I) or Formula (1-1) or their pharmaceutically acceptable salts have the following stereochemistry as shown in the structure of formula (la):
Figure imgf000015_0002
(la)
[0040] Some embodiments of compounds of Formula (I) or Formula (1-1) or their pharmaceutically acceptable salts have the following stereochemistry as shown in the structure of formula (lb):
Figure imgf000015_0003
(lb)
[0041] Some embodiments of compounds of Formula (I) or Formula (1-2) or their pharmaceutically acceptable salts have the following stereochemistry as shown in the structure of formula (Ic):
Figure imgf000016_0001
(Ic)
[0042] Some embodiments of compounds of Formula (I) or Formula (1-2) or their pharmaceutically acceptable salts have the following stereochemistry as shown in the structure of formula (Id):
Figure imgf000016_0002
(Id)
[0043] In some embodiments, n is 0 or 1.
[0044] In some embodiments, Y is selected from the group consisting of -S-, -0-, -CH2-, and -NH-; G is selected from the group consisting of -C(0)NR'R2; -C(0)NROR3; - NR1C(0)R5; -NR1C(0)NR2R2A; -NR1C(0)OR3; -NR1S(0)2R3; -NR^O^NR 3; - C(=NR')R5; -C(=NR')NR2RL A; -NR' CR5(=NR5); -NR1 C(=NR2)NR' AR2A; C6-i0aryl optionally substituted with 0-2 substituents selected from the group consisting of Q-4 alkyl, -OR , -C\. 6alkylene-COOR3, -SR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; 5- 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -Ci-6alkylene-COOR3, -SR3, -NR'R2, halogen, -C(0)NR'R2, and - NR1C(0)R5; and 5- 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of d-4 alkyl, -OR3, -C1-6alkylene-COOR3, -SR3, -NR'R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; R is selected from a group consisting of -H, -Q_
Figure imgf000017_0001
9alkyl, -CR5R6OC(0)C1-9alkyl, and ' each R1, R2, Rla, R2a, R3, R5 and R6 are independently selected from -H and -Ci-4alkyl; and R7 is selected from the group consisting of -H, -C,-4alkyl, -OH, -OCl-4alkyl, -SC1-4alkyl and halogen.
[0045] In some embodiments, Y is O or S; G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, azetidine, pyrazine, pyrimidine, pyridazine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of Ci-4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; R1 , R2 and R5 in G are η
independently selected from -H and -Ci-4alkyl; and J, L and M are CR .
[0046] In some embodiments, Y is -O- or -S-; G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of C alkyl, -OR3, -Ci-6alkylene-COOR3, -SR3, -NR'R2, halogen, -C(0)NR'R2, and - NR1C(0)R5, wherein R1, R2 and R5 in G are independently selected from -H and -Ci-4alkyl; and J, L and M are CR7.
[0047] In some embodiments, when Y is -NR1, G cannot be -C(0)NR1R2 or -C(0)OR3.
[0048] In some embodiments, n can be 0 or 1. In some such embodiments, n is 0. In some embodiments, n can be 1. In some embodiments, n can be 2. In some embodiments, n can be 3.
[0049] Some embodiments of Formula I) can have the structure of Formula (Ie)
Figure imgf000017_0002
(Ie) or pharmaceutically acceptable salts thereof, wherein n is 0; R is selected from H, F, CI, -CH3, -CF3, and -Y'-(CH2)PM'; and p is 0 or 1.
[0050] Some embodiments of Formula I) can have the structure of Formula (If):
Figure imgf000018_0001
(if)
or pharmaceutically acceptable salts thereof,
wherein n is 0;
R7 is selected from H, F, CI, -CH3, -CF3, and -Y'-(CH2)PM'; and p is 0 or 1.
[0051] In some embodiments, G can be a 5-10 membered heteroaryl optionally substituted with one or more R10. In some embodiments, G can be a thiadiazole optionally substituted with one or more R10. In some embodiments, G can be a thiazole optionally substituted with one or more R10. In some embodiments, G can be an imidazole optionally substituted with one or more R10. In some embodiments, G can be a triazole optionally substituted with one or more R10 In some embodiments, G can be a 3-10 membered heterocyclyl optionally substituted with one or more R10. In some embodiments, G can be an azetidine o tionally substituted with one or more R10. In some embodiments, G can be
Figure imgf000018_0002
. In some embodiments, G can be a piperazine optionally substituted with one
Figure imgf000018_0003
or more R . In some embodiments, G can be . In some embodiments, G can be - CONH2. In some embodiments, G can be -CN. In some embodiments, G can be -Ci-4 alkyl. In some embodiments, G can be -CH .
[0052] In some embodiments, R10 is R11. In some embodiments, R10 is -CH2RU, - (CH2)2Rn, -(CH2)3Rn, or -(CH2)4Rn . In some embodiments, R10 is -CH2Rn . In some embodiments, R10 is -(CH2)2RU. In some embodiments, R10 is -(CH2)3RU. In some embodiments, R10 is -(CH2)4Rn. [0053] In some such embodiments, G is thiadiazole. In other embodiments, G is thiadiazole optionally substituted with -NR'R2 or -NR' C(0)R5, wherein R1 and R5 are independently H or -Ci-4alkyl. In other embodiments, G is triazole optionally substituted with 1 2 erein 1 5
NR R , wh R , R and RJ are independently H or -C1-4alkyl. In other embodiments, G is tetrazole optionally substituted with methyl. In still other embodiments, G is pyridine, thiazole, or phenyl. In other embodiments, G is optionally substituted azetidine. In some embodiments, G is optionally substituted pyridine. In other embodiments, G is optionally substituted thiazole. In still other embodiments, G is optionally substituted phenyl. In some embodiments, G is triazole optionally substituted with -Ci- alkylene-COOH. In some embodiments, G is triazole optionally substituted with -(CH2)3-COOH.
[0054] In some embodiments, Y is S; n is 1 or 2; G is -C(O) NR!R2 or C(=NR')R5; and J, L, and M are CR7. In some such embodiments, R7 is H. In other embodiments, 1 1
R is H and R is H. In some embodiments, R is Ci-4 alkyl and 2
R is Ci-4 alkyl.
[0055] In some embodiments, Y is -CH2-; n is 0 to 2; G is -C(0)NR'R2; and J, L and M are CR7.
[0056] Some embodiments of Formula (I) can have the structure of Formula (Ig) or (Ih):
Figure imgf000019_0001
or pharmaceutically acceptable salts thereof, wherein n is 0;
each Z I , Z 2 , Z 3 and Z 4 are independently selected from N, NR 12 , O, S, and CR12 provided that Z1 to Z4 are selected such that a five membered aromatic ring is formed;
12 11
each R is independently H or (CH2)o-sR ; and
each R I I is independently selected from Ci-C alkyl; haloCi- alkyl; -OR 3 ; -C]. 6alkylene-COOR3; -SR3; halogen; -CO-Ci-4alkyl; C(0)NR'R2; -NR'R2; -NR^CH^O. 4COR5; -NR1(CH2)o-4C(=NR2)R5; -NR1-CH-[(CH2)o-4-NRLAR2A]2; -NR1 -(CH2) 1 _5-R3 ; - NR'(CH2)1-4-NR, AR2A; -NtCCFy^-NR^2],; -S(CH2)O-4C(=NR')R5; -S(CH2)1-4-R3; - SCCH^o^-N^R2; -S-CH-KCH^-NR^2],; -8[( Η2)1 -4-Ν^2]2; -S(CH2)0-4-3-10
1 2
membered heterocyclyl; -S(CH2)0-4-3-10 membered heterocyclyl-NR R ; -S(CH2)0-4- 5-10 membered heteroaryl-NR'R2; -SCO^NR^2; and -O-Cealkylene-NR^2; C3-7 carbocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C C6 alkoxy, Ci-C haloalkyl, and C]-C6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C C6 alkoxy, C C6 haloalkyl, and Ci-C haloalkoxy; 6 to 10 membered aryl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C C6 alkoxy, C C6 haloalkyl, and Ci-C6 haloalkoxy; and 5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci- C6 alkoxy, Ci-C6 haloalkyl, and C C6 haloalkoxy. In some embodiments, Z1 can be
S. In some embodiments, Z 2 and Z 3 can be i ·ndependently N, NR 12 , or CR 12. In some embodiments, Z can be N or CR12. In some embodiments, Z1 to Z4 can be selected to form a five-membered aromatic rin selected from the group consisting of
Figure imgf000020_0001
1 12
[0057] In some embodiments, R can be H. In some embodiments, R can be
R 11. In some embodiments, R 12 can be -CH2-R 11. In some embodiments, R 12 can be -(CH2)2-
1 1 12 1 1 12
R" . In some embodiments, R can be -(CH2)3-R . In some embodiments, R can be -
(CH2)4-R
[0058] In some embodiments, Rn can be -CF3i CHF2, or CH2F. In some embodiments, R11 can be CF3. In some embodiments, R11 can be Ci-C alkyl. In some embodiments, Rn can be CH3. In some embodiments, R1 1 can be a Ci-4 alkyl optionally substituted with a 3-10 membered heterocyclyl. In some embodiments, R11 can be -CH2- piperazine. In some embodiments, R1 1 can be an optionally substituted Ci-6alkylene-3-10 membered heterocyclyl. In some embodiments, R11 can be azetidine optionally substituted , , -!-N /— NH2
with one or more NH2. In some embodiments, R can be ^ . In some embodiments, R can be -(CH2)o-4NR1R2. In some embodiments, R can be NH2, -
CH2NH2, or -(CH2)4NH2.
[0059] In some embodiments, 11 1 2 1 * 2 *
R can be NR R , R is H, and R" is an optionally susbstituted -Ci-4alkyl or an optionally substituted 3-8 membered heterocyclyl. In some
embodiments,
In some embo
Figure imgf000021_0001
R can be -(CH2)2-
2 2 piperazine. In some embodiments, R can be pyrrolidine. In some embodiments, R can be - (CH2)2-NH2 or -(CH2)3-NH2.
• 1 1 1 2
[0060] In some embodiments, R can be -C(0)NR'R". In some embodiments, R can be -CONH2. In some embodiments, R can be -NR^CC R5. In some embodiments, R1 1 can be -NHCOH or -NHCOCH3. In some embodiments, R1 1 can be -N((CH2)0-4- NR!R2)2. In some embodiments, R can be -N((CH2)2-NH2)2. In some embodiments, R can be -NR' -CH-^CH^-NR^R^. In some embodiments, RN can be -NHCH(CH2- NH2)2. In some embodiments, R can be -ΝΗ( Η2)ι-4-Ν^2. In some embodiments, R can be -NH(CH2)2-NH- azetidine. In some embodiments, R can be -NR' (CH2)0- 4C(=NR1)R5. In some embodiments, R11 can be -NHC(=NH)NH2. In some embodiments, R11 can be -S(CH2)0-4C(=NR')R5. In some embodiments, R1 1 can be -SCH2C(=NH)NH2. In some embodiments, R11 can be -S(CH2)o-4-3- 10 membered heterocyclyl. In some embodiments, R can be -S(CH2)2-piperazine. In some embodiments, R can be -S(0)2NR'R2. In some embodiments, R can be -S(0)2NH2. In some embodiments, R can be -SCCH^-NR^2. In some embodiments, R1 1 can be -S(CH2)2NH2 or -S(CH2)3NH2. In some embodiments, R can be -SR3. In some embodiments, R can be azetidine or piperidine. In some embodiments, RN can be -S(CH2)1- -3- 10 membered heterocyclyl. In some embodiments, R can be— S(CH2)2-morpholine. In some embodiments, R can be -S(CH2), -4-R3. In some embodiments, RN can be -S(CH2)0-4-5- 10 membered heteroaryl-NH2. In some embodiments,
Figure imgf000022_0001
some embodiments, R can be -OR3. In some embodiments,
R11 can be -Ο(ΌΗ2)0-4-^^2. In some embodiments, R11 can be -0(CH2)2NH2.
[0061] In some embodiments, R7 is selected from the group consisting of -H, -OH, -Ci-4alkyl, -0-Ci-4alkyl, -S-C]-4alkyl, halogen, -CF3, and cyano. In other embodiments, R7 is selected from the group consisting of F, CI, Me, -CF3, -SMe, and -OMe. In some embodiments, R 7 is H. In other embodiments, R 7 is F. In some embodiments, R 7 is -OMe. In some embodiments, R7 is -SMe. In some embodiments, R7 is -S(0)Me. In some η
embodiments, R is independently selected from -OH, -Ci-4alkyl, -0-C1-4alkyl, -S-Ci-4alkyl, - S(0)-C1-4alkyl, and halogen. In some embodiments, R7 is present 1 to 3 times and each R7 is triazole.
[0062] In some embodiments, R7 is present 1 to 3 times and each R7 is independently -(CH2)m-Y'-(CH2)pM'; m and p are independently 0 to 3; Y' is selected from the group consisting of -S-, -O- and -NR1-; M' is selected from the group consisting of NR!R2, -S03R3, -CN, -C(0)NR1R2; -C1-4 alkyl optionally substituted with 1-2 substituents selected from the group consisting, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C3-io cycloalkyl optionally substituted with 1-2 substituents selected from the group consisting of C alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C6-IO aryl optionally substituted with 1-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 1-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 1-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5.
some embodiments, R 7 is present once. In some embodiments, R 7
[0063] In is present twice. In some embodiments, R7 is present three times.
[0064] In some embodiments, Y' is O. In some embodiments, Y' is NH. In some embodiments, p is 0, 1, or 2.
[0065] In some embodiments, M' is cyclopropyl, -S03CH3, SCH3, -NH2, or -CN. In some embodiments, M' is C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR3, -NR R2, halogen, -C(0)NR1R2, and -NR1C(0)R5. In some embodiments, M' is CHF2, CF3, (CH2)2F, or (CH2)2OCH3, In some embodiments, M' is CH3, CH2CH3, or CH(CH3)2CH2CH(CH3)2. In some embodiments, M' is C(0)NR1R2. In
some embodiments, R1 is H and R1 is azetidine. In some embodiments, R7 is
Figure imgf000023_0001
η
In some embodiments, R' is -0(CH2)CONH2. In some embodiments, M' is a 5 to 10 membered heteroaryl. In some embodiments, M' is thiadiazole.
7 7
[0066] In some embodiments, R is present 1 to 3 times and each R is independently selected from the group consisitng of -OH, halogen, -CF3, C\-C(, alkenyl, Ci- C alkynyl, Ci-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl (mercapto), and - (CH2)M-Y'-(CH2)pM' ; m and p are independently 0 to 3 ; Y' is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, -CR5R6-, and -NR1 -; M' is selected from the group consisting of -C(0)NR1R2; -C(0)NR1OR3; -NR1C(0)R5; -NR1C(0)NR2RL A; -NR1C(0)OR3; -NR' S(0)2R3; -NR' S(0)2NR2RL A; -C(=NR')R5; -C(=NR')NR2RL A; -NR' CR5(=NR2); - NR1C(=NR2)NRLAR2A; C alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; C6-io aryl optionally substituted with 0-2 substituents selected from the group consisting of C alkyl, -OR , - NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR , - NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; and with the proviso that the compound does not have the structure selected from the group consisting of
Figure imgf000024_0001
Figure imgf000024_0002
0r pharmaceutically acceptable salts thereof.
η
[0067] In some embodiments, R is independently selected from -OH, -Ci-4alkyl, - 0-C1-4alkyl, -S-C1-4alkyl, -S(0)-C1-4alkyl, and halogen; and with the proviso that the compound does not have the structure selected from the group consisting of
Figure imgf000024_0003
[0068] In some embodiments, Ra can be C(0)OH. In some embodiments, Ra can be C(0)OR, and R can be -CR5R6OC(0)C,-9alkyl or -CR5R6OC(0)OC1-9alkyl. In some embodiments, R can be -CH2OC(0)OCH(CH3)2. In some embodiments, R can be -CH2OC(0)OC(CH3)3. In some embodiments, R can be -CH2OC(0)OC(CH2)2CH3. In some embodiments, R can be -CH20C(0)OCH(CH2CH3)2. In some embodiments, R can be
-CH2C(0)OCH2CH3. In some embodiments, R can be
Figure imgf000025_0001
[0069] For some embodiments of Formula (I), M' is selected from the group consisting of -C(0)NR'R2; -C(0)NROR3; -NR' C(0)R5; -NR' C(0)NR2RL A; -NR' C(0)OR3; -NR1S(0)2R3; -NR^CO^NR 3; -C(=NR1)NR2RLA; -NR1CR5(=NR2);
NR' C(=NR2)NRL AR2A; aryl optionally substituted with 0-2 substituents selected from the group consisting of -OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of -OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; and heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of -OR , -NR R , halogen, -C(0)NR1R2, and -NR1C(0)R5..
[0070] Some specific embodiments of the compounds described herein have the following structures:
Figure imgf000025_0002
Figure imgf000026_0001
[0071] Some specific embodiments of the compounds described herein have the following structures:
Figure imgf000026_0002
thereof.
[0072] Some specific embodiments of the compounds described herein have the following structures:
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000028_0002
-27-
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
-30-
Figure imgf000032_0001
-31-
Figure imgf000033_0001
Figure imgf000034_0001
-33-
Figure imgf000035_0001
, or pharmaceutically acceptable salts thereof.
[0074] In some embodiments, the compound described herein does not have the structure selected from the group consisting of:
Figure imgf000036_0001
Figure imgf000037_0001
or pharmaceutically acceptable salts thereof.
[0075] Some embodiments of any of the compounds described above include prodrugs (e.g., prodrug esters), metabolites, stereoisomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts of those compounds.
[0076] In some embodiments, the monosaccharide or monosaccharide derivative is meglumine.
[0077] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.
[0078] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.
[0079] Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0080] In some embodiments, due to the facile exchange of boron esters, the compounds described herein may convert to or exist in equilibrium with alternate forms. Accordingly, in some embodiments, the compounds described herein may exist in combination with one or more of these forms. For example, as shown below, the compounds disclosed herein may exist in cyclic form as cyclic boronate monoesters as formula I or in acyclic form as boronic acids as formula I.l (Biochemistry, 2000, 39, 5312- 21), or may exist as a mixture of the two forms depending on the medium.
Figure imgf000038_0001
I 1.1
[0081] In some embodiments, the compounds descrived herein may exist in cyclic dimeric form as Formula (C) or trimeric form as Formula (D), tetrameric form as
Formula (E) as shown below, or acylic dimeric, trimeric or tetrameric forms and the like. In some embodiments, X' is -Y-(CR R )n-G in Formula C, D and E. In some embodiments, X' can be -Y-CH2-G in Formula C, D and E.
Figure imgf000038_0002
D
Figure imgf000039_0001
E
Definitions
[0082] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference in its entirety.
[0083] The term "pro-drug ester" refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group. Other examples of prodrug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examples of esters useful as prodrugs for compounds containing carboxyl groups). Each of the above-mentioned references is herein incorporated by reference in their entirety.
[0084] "Metabolites" of the compounds disclosed herein include active species that are produced upon introduction of the compounds into the biological milieu.
[0085] "Solvate" refers to the compound formed by the interaction of a solvent and a compound described herein, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
[0086] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).
[0087] As used herein, "Ca to Ct," or "Ca-b" in which "a" and "b" are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "Ci to C4 alkyl" or "Ci-4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.
[0088] The term "halogen" or "halo," as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
[0089] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g. , "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as "Ci-4 alkyl" or similar designations. By way of example only, "C1-4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
[0090] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl as is defined above, such as "C1-9 alkoxy", including but not limited to methoxy, ethoxy, n- propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
[0091] As used herein, "alkylthio" refers to the formula -SR wherein R is an alkyl as is defined above, such as "C1-9 alkylthio" and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto
(isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert- butylmercapto, and the like.
[0092] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group of the compounds may be designated as "C2-4 alkenyl" or similar designations. By way of example only, "C2-4 alkenyl" indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3- yl, buten-4-yl, 1 -methyl -propen-l-yl, 2-methyl-propen-l-yl, 1-ethyl-ethen-l-yl, 2-methyl- propen-3-yl, buta-l,3-dienyl, buta-l,2,-dienyl, and buta-l,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
[0093] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group of the compounds may be designated as "C2-4 alkynyl" or similar designations. By way of example only, "C2-4 alkynyl" indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2- butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
[0094] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term "heteroalkyl" where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of the compounds may be designated as "C1-4 heteroalkyl" or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "C1-4 heteroalkyl" indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
[0095] The term "aromatic" refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
[0096] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl" where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as "C6-10 aryl," "C6 or Cio aryl," or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
[0097] As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an aryl as is defined above, such as "C6-10 aryloxy" or "C6-i0 arylthio" and the like, includingbut not limited to phenyloxy.
[0098] An "aralkyl" or "arylalkyl" is an aryl group connected, as a substituent, via an alkylene group, such "C7-14 aralkyl" and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).
[0099] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
[0100] A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmefhyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).
[0101] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl" where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as "C3-6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl. [0102] A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C4-10 (carbocyclyl)alkyl" and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
[0103] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0104] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.
[0105] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl" where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4- dioxinyl, 1 ,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathiinyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, trioxanyl, hexahydro-l,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3- dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-l,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.
[0106] A "(heterocyclyl)alkyl" is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
[0107] As used herein, "acyl" refers to -C(=0)R, wherein R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
[0108] An "O-carboxy" group refers to a "-OC(=0)R" group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0109] A "C-carboxy" group refers to a "-C(=0)OR" group in which R is selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2- alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=0)OH).
[0110] A "cyano" group refers to a "-CN" group.
[0111] A "cyanato" group refers to an "-OCN" group.
[0112] An "isocyanato" group refers to a "-NCO" group.
[0113] A "thiocyanato" group refers to a "-SCN" group.
[0114] An "isothiocyanato" group refers to an " -NCS" group.
[0115] A "sulfinyl" group refers to an "-S(=0)R" group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0116] A "sulfonyl" group refers to an "-S02R" group in which R is selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2- alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. [0117] An "S-sulfonamido" group refers to a "-S02NRARB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0118] An "N-sulfonamido" group refers to a "-N(RA)S02RB" group in which RA and Rb are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0119] An "O-carbamyl" group refers to a "-OC(=0)NRARB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0120] An "N-carbamyl" group refers to an "-N(RA)OC(=0)RB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0121] An "O-thiocarbamyl" group refers to a "-OC(=S)NRARB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aC6-io ryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0122] An "N-thiocarbamyl" group refers to an "-N(RA)OC(=S)RB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-7 carbocyclyl, C6-i0 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0123] A "C-amido" group refers to a "-C(=0)NRARB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0124] An "N-amido" group refers to a "-N(RA)C(=0)RB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0125] An "amino" group refers to a "-NRARB" group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0126] An "aminoalkyl" group refers to an amino group connected via an alkylene group.
[0127] An "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as a "C2-8 alkoxyalkyl" and the like.
[0128] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted," it is meant that the group is substituted with one or more subsitutents independently selected from Ci-C6 alkyl, C]-C6 alkenyl, Ci-C6 alkynyl, Ci-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C -C alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and C -C haloalkoxy), C3- C7-carbocyclyl-Ci-C -alkyl (optionally substituted with halo, C]-C6 alkyl, Ci-C6 alkoxy, Ci- C6 haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C]-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heterocyclyl-Ci-C6-alkyl (optionally substituted with halo, C -C alkyl, C -C alkoxy, C]-C6 haloalkyl, and Ci-C6 haloalkoxy), aryl (optionally substituted with halo, C]-C6 alkyl, C -C alkoxy, C -C haloalkyl, and C -C haloalkoxy), aryl(Ci-C6)alkyl (optionally substituted with halo, C]-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), 5- 10 membered heteroaryl (optionally substituted with halo, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heteroaryl(C]-C6)alkyl (optionally substituted with halo, Ci-C6 alkyl, C -C alkoxy, Ci-C6 haloalkyl, and C -C haloalkoxy), halo, cyano, hydroxy, Ci-C6 alkoxy, Ci-C6 alkoxy(Ci-C )alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-C6)alkyl (e.g., -CF3), halo(Ci-C6)alkoxy (e.g., -OCF3), C -C alkylthio, arylthio, amino, amino(Ci-C )alkyl, nitro, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C- carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as "optionally substituted" that group can be substituted with the above substituents.
[0129] In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from Ci-C4 alkyl, amino, hydroxy, and halogen.
[0130] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2- and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene" or "alkenylene."
[0131] As used herein, "alkylene" means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as "C1-4 alkylene" or similar designations. By way of example only, "C alkylene" indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-l,l-diyl, propylene, propan-l,l-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-l,l-diyl, butan-2,2-diyl, 2-methyl- propan-l,l-diyl, 1-methyl-propylene, 2-methyl -propylene, 1 , 1-dimethyl-ethylene, 1,2- dimethyl-ethylene, and 1-ethyl-ethylene.
[0132] As used herein, "alkenylene" means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon- carbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as "C2-4 alkenylene" or similar designations. By way of example only, "C2-4 alkenylene" indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-l,l-diyl, propenylene, propen-l,l-diyl, prop-2-en-l,l-diyl, 1-methyl- ethenylene, but-l-enylene, but-2-enylene, but-l,3-dienylene, buten-l,l-diyl, but-l,3-dien-l,l- diyl, but-2-en-l,l-diyl, but-3-en-l,l-diyl, l-methyl-prop-2-en-l,l-diyl, 2-methyl-prop-2-en- 1,1-diyl, 1 -ethyl-ethenylene, 1 ,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl- propenylene, 3-methyl-propenylene, 2-methyl-propen-l,l-diyl, and 2,2-dimethyl-ethen-l,l- diyl.
[0133] The term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms "agent", "substance", and "compound" are used interchangeably herein.
[0134] The term "analog" is used herein to refer to a molecule that structurally resembles a reference molecule but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent. Compared to the reference molecule, an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify variants of known compounds having improved characteristics (such as higher binding affinity for a target molecule) is an approach that is well known in pharmaceutical chemistry.
[0135] The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species. [0136] The term "microbial infection" refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal. Thus, a mammal is "suffering" from a microbial infection when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal. Specifically, this description applies to a bacterial infection. Note that the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.
[0137] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Oilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
[0138] "Subject" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
[0139] An "effective amount" or a "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing" means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
[0140] "Treat," "treatment," or "treating," as used herein refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease or condition.
[0141] "Monosaccharide" as used herein refers to a chemical compound of general formula CX(H20)X, where x is 3 to 10. Examples of monosaccharide include but are not limited to glucose (dextrose), arabinose, mannitol, fructose (levulose) and galactose. "Monosaccharide derivative" as used herein refers to a monosaccharide wherein one or more -OH groups can be replaced by the substituents described above in the definition of "substituted." In some monosaccharide derivatives, one ore more -OH groups on the monosaccharide can be replaced by one or more -NH2 or -NH-CH3 groups. One example of a monosaccharide derivative includes meglumine. Other examples of a monosaccharide derivative can include an amino alcohol.
[0142] As used herein, "isosteres" are different compounds that have different molecular formulas but exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated include - COOH, -S03H, -S02HNR9, -P02(R9)2, -P03(R9)2, -CONHNHS02R9, -COHNS02R9, and - CONR9CN. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be optionally substituted at one or more positions with R9.
Figure imgf000053_0001
[0143] It is also contemplated that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R9, then the substitution cannot eliminate the carboxylic acid isosteric properties of the compound. It is also contemplated that the placement of one or more R9 substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be permitted at one or more atom(s) which maintain(s) or is/are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound. Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated.
Methods of Preparation
[0144] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
[0145] In the following schemes, protecting groups for oxygen atoms are selected for their compatibility with the requisite synthetic steps as well as compatibility of the introduction and deprotection steps with the overall synthetic schemes (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)). Handling of protecting and/or sterodirecting groups specific to boronic acid derivatives is described in a recent review of chemistry of boronic acids: D.G. Hall (Ed.), Boronic Acids. Preparation and Application in Organic Synthesis and Medicine, Wiley VCH (2005) and in earlier reviews: Matteson, D. S. (1988). Asymmetric synthesis with boronic esters. Accounts of Chemical Research, 21(8), 294-300, and Matteson, D. S. (1989). Tetrahedron, 45(7), 1859- 1885), all of which are incorporated herein by reference in their entirety. The latter review articles also describe methodology for stereoselective insertion of halomethine functionality next to the boronate which is employed in the synthetic schemes below.
[0146] In addition to standard acid catalyzed deprotection, special methods for removal of boronic acid protecting and/or sterodirecting groups methods using fluorides (Yuen, A. K. L., & Hutton, C. A. (2005). Tetrahedron Letters, 46(46), 7899-7903 - incorporated herein by reference in its entirety) or periodate oxidation (Coutts, S. J., et al. (1994). Tetrahedron Letters, 35(29), 5109-5112 - incorporated herein by reference in its entirety) can also be employed in preparations of the compounds disclosed herein. [0147] In strategies employing pinanediol or other diol-based chiral auxiliaries for stereospecific introduction of new chiral centers, the early stages of chemistry on boronic intermediates can be performed on chiral boronate esters or alternatively nonchiral borate/boronate intermediates can be used in early stages followed by transesterification with chiral diols prior to the step where stereo selection is required.
Synthesis of Compounds of Formula I
[0148] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds encompassed herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
[0149] Compounds of formula la where R is H can be prepared as depicted in scheme 1 from key intermediates of formula III, which may be assembled by known reactions (Boronic Acids: Preparations and Applications in Organic Synthesis, Medicine and Materials, D. G. Hall, ed., Wiley- VCH, Weinheim, 2011).
Scheme 1
Figure imgf000055_0001
[0150] Such key intermediates of formula III where X = CI and R' and R" are alkyl groups may be prepared by earlier described methods (WO09064414, WO10130708). In an alternate sequence, compounds of formula III where X = CI and R' is Boc and R" is t- Butyl or R' and R" are protected together as isopropylidine or any other groups protected separately or together in cyclic form may be made from compounds of formula IV via homologation to give chloromethylene addition product with good stereocontrol by Matteson reaction conditions (WO0946098). Compounds of formula III where X is bromo may be made analogously to the chloro compounds of Scheme 1, utilizing dibromomethane (J Am. Chem. Soc. 1990, 112, 3964-969). The halo derivatives of formula III where X is CI or Br undergo stereospecific substitution to form thioethers (WO 04064755), ethers (WO 12067664), amines (J Organomet. Chem. 1979, 170, 259-64) or acetates (Tetrahedron 2005, 61, 4427-4536), to give compounds of formula II. In an alternate approach, compounds of formula II where Y is S can be made via a thiol intermediate by alkylation or arylation to introduce various G groups. Such compounds may also be made via alkyl or thiomethylene boronate esters by reaction with substituted benzyl halides (US 6586615).
[0151] Matteson reaction precursors of formula IV may be made by palladium mediated coupling of pinanediol diboronate from corresponding appropriately protected benzyl alcohols (J Am. Chem. Soc. 2011, 133, 409-41 1) or benzyl bromides of V (Tetrahedron Letters 2003, 44, 233-235; J Am. Chem. Soc., 2010, 132, 11825-11827). The compounds of formula V may be achieved by means of several earlier known methods (WO0458679) with conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum, 1973); and Protecting Groups in Organic Synthesis P.G.M. Wutts, T.W. Green, Wiley, New York, 1999) from commercially available salicylic acid derivatives. Compounds of formula V where X is methyl can be readily transformed to corresponding benzyl bromides (Bioorg. Med.Chem. Lett. 1999, 9, 34-346) for boronation reaction to give IV.
[0152] Simultaneous deprotection of pinane ester and salicylic acid protective groups of compounds of formula II can be achieved by heating with dilute HC1, affording the desired compounds of structure I. This transformation may also be achieved by treatment with BC13 or BBr3 (WO09064414). Alternatively, the deprotection may be attained via trans- esterification with isobutyl boronic acid in presence of dilute acid (WO09064413) or via other known methods (J Org. Chem. (2010), 75, 468-471). [0153] Compounds of formula lb may be made following the sequence described above via (-)-pinanediol substituted intermediate of IV.
[0154] One exemplary but non-limiting general synthetic scheme for preparing a compound of Formula la is shown below in Scheme la. The starting compound of Ia-1 can be a salicyclic acid derivative, wherein Y' can be -OH, halogen, -CH3, halogen substituted - CH3, or a protected hydroxyl group; and J, T, M can be CR7 or N. The compound of Formula Ia-1 can be treated first with protection groups and then undergo halogenation to form a benzyl halide compound of Formula Ia-3. The halogen of Formula Ia-3 (e.g., bromide) can then react with Bis(pinacolato)diboron to yield a boronic ester compound of Formula Ia-4. The compound of Formula Ia-4 undergoes homologation to yield a compound of Formula Ia- 5 (wherein X' is a halogen). Various types of thiol, amine, alcohol and other precursors can then react with the compound of Formula Ia-5 to substitute the halogen X' and form a compound of Formula Ia-6. The compound of Formula Ia-6 can then undergo the deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula la where R is H.
Scheme la
Figure imgf000057_0001
[0155] A compound of Formula (1-1) wherein Y is -CH2- can be prepared by using the general synthetic Scheme lb illustrated below. The starting compound of Formula I- la can be a salicyclic acid derivative. The compound of Formula I- lb can be treated with a protection group and then undergo a cross coupling reaction to form a vinyl compound of Formula I-lc. The double bond of Formula I-lc can be converted into an aldehyde of Formula I- Id. The aldehyde compound of Formula I- Id then undergoes a Wittig reaction to yield a compound of Formula I-le, which then reacts with boronation agent to form a pinacol boronic ester of Formula I- If. The G' group in Formula I-le, added by a Wittig reagent, can be any group that is suitable to couple to the negatively charged carbon of the Wittig reagent. Examples of the G's groups can include, but are not limited to, -COOR1, -C(0)R', amide, and Ci^alkyl. In some embodiments, G' can be -C(0)OC(CH3)3. The boronic ester compound of Formula I- If can react with pinanediol to yield a Pinanediol Methylboronic Ester compound of Formula I-lg. In some embodiments, the compound of Forumla I-lg can undergo deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula 1-1, and G' can be the final G group in the compound of Formula 1-1 (i.e., G' and G are the same).
[0156] In some alternative embodiments, after removing the protection group on the G' group, the compound of Formula I-lg can react with different types of thiol, amine, and alcohol precursors to replace the G' group with a G group (as defined herein) to form a compound of Formula I-lh. The compound of Formula I-lh can then undergo the deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula 1-1.
Scheme lb
Figure imgf000059_0001
Synthesis of Prodrugs
[0157] Compounds of formula I where the R is a prodrug moiety may be synthesized by a variety of known methods of different carboxylic acid prodrugs {Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed., Springer, New York, 2007). These prodrugs include but are not limited to substituted or non-substituted alkyl esters, (acyloxy)alkyl (Synthesis 2012, 44, 207), [(alkoxycarbonyl)oxy]methyl esters (WOl 0097675), or (oxodioxolyl)methyl esters (J Med. Chem. 1996, 39, 323-338). Such prodrugs can be made from compounds of formula I where R = H by treatment with acid or in neutral conditions (e.g., carbodiimide coupling) in the presence of alcohols (ROH) or via base promoted esterification with RX where X is a leaving group in the presence of an appropriate base.
[0158] One exemplary but non-limiting general synthetic scheme for preparing the prodrug is shown in Scheme 2a below. The boronic acid of Formula la where R is hydrogen can react with a chloro/bromo-substituted prodrug moiety to form a prodrug of
If 1 2
Formula If. Examples of the prodrug moiety R can be -Ci-galkyl, -CR R O -
CR1R2OC(0)OC,-9alkyl, -CR1R2OC(0)C1-9aryl, -CR1R2OC(0)OC1-9aryl, and
Figure imgf000060_0001
Scheme
Figure imgf000060_0002
[0159] Alternatively, boronate esters of formula VI or corresponding tetrafluoroborates (Chem. Rev. 2008, 108, 288-325) may be also utilized for introduction of prodrugs and convert them to final prodrugs (Scheme 2b). Such carboxylic acids (VI) can be made from compounds of formula II by selective deprotection of OR'. The prodrug group may also be introduced earlier in the sequence in compounds of formula V where R' is R. Such sequence where prodrug is introduced in earlier intermediates is only feasible when the ester is stable under the final deprotection conditions to remove the phenol protective group and boronate ester group.
Scheme 2b
Figure imgf000060_0003
Synthesis of ortho-Carboxylate Substituted Compounds
[0160] Compounds of formula VII to attain compounds of formula la where M is CR7 may be prepared as shown in scheme 3. Such intermediates of formula VII can be synthesized from VIII where X' is substituted as bromomethylene or triflate or bromo or iodo fuctionalities. Compounds of formula VIII where X' is substituted as -CH2Br may be transformed to VII under palladium catalysed reaction conditions utilizing diboronate ester of desired enantiomerically pure pinanediol ester {Tetrahedron Lett., 2003, 44, 233-235). Intermediates of formula VIII where X = Br, I, OTf can be transformed to VII by utilizing Reformatsky reagent of bromomethylene boronate ester (J Org. Chem., 2013, 78, 8250- 8266; Chem Lett., 1993, 845-848.), or by reaction of methylenediboronate ester {Org. Lett. 2011, 13, 3368-3371). Derivatives of VIII where X' = -CHO and Z' = F may be utilized to introduce diverse groups of R7 containing OR or SR' by displacement of corresponding F group {Journal of Medicinal Chemistry, 2008 , 51, 1925-1944). Such benzaldehyde derivatives of VIII can be converted to bromomethyl intermediates via one {Tetrahedron Lett., 1984 , 25, 1 103-1104) or two step transformations via reduction and halide formation. Compounds where X' is substituted with bromo or iodo groups can be attained from appropriately protected commercial 2,5-hydroxy-benzoic acid derivatives (J Med. Chem.. 2003 . 46, 3437-3440). Intermediates of VIII can also be prepared via carboxylation. of derivatives of formula IX where Z' is a fluoro, OR'", or SR'" by earlier described methods (WO12106995).
Scheme 3
Figure imgf000061_0001
X' ■■ Me, OR, Br, I Vlll VII
Z CI, F, OR'", SR"
[0161] One exemplary but non-limiting general synthetic scheme for preparing ortho-Carboxylate Substituted compound of formula VII is shown below in scheme 3 a. The starting compound of Formula VII- 1 can be prepared from a protected phenol derivative, wherein X3a can be C1-4 alkyl, -OR1, or halogen; and R3a can be a suitable hydroxyl protection group and R3b can be a suitable carboxyl protecting group. The compound of Formula VII-2 can be prepared via carboxylation of the phenol derivative of Formula VII- 1. The carboxylic group on the Formula VII-2 is protected. The compound of Formula VII-2 can then react with a boronation agent at X3a to form a Pinanediol Methylboronic Ester compound of Formula VII-3. The boron ester of Formula VII-3 can then undergo a homologation reaction to yield a compound of Formula VII-4. Various types of thiol, amine, alcohol, and other precursors can then react with the compound of Formula VII-4 to substitute the halogen and form a compound of Formula VII-5. The compound of Formula VII- 5 then undergoes the deprotection of the pinane ester and salicylic acid protective groups to afford the compound of Formula VII.
Scheme 3 a
Figure imgf000062_0001
[0162] In another exemplary synthetic scheme 3b, the compound of formula VII-2 where X3a is a -CH2OH group can be prepared from a salicylic acid derivative of Formula VII-6. The compound of Formula VII-6 upon diallylation under basic conditions followed by thermal Claisen rearrangement (Org. React. 1975, 22, 1-252) and ester hydrolysis gives compound of Formula VII-7. Such compounds undergo isomerization of double bond to give a styryl derivative, The styryl double bond can be oxidized to form an aldehyde of Formula VII-8. The halogen group X3b in the compound of Formula VII-8 can be replaced by various R groups to form a compound of Formula VII-9, which then undergoes reduction to convert the aldehyde group into the hydroxyl group of Formula VII-2. The compound of Formula VII-2 can further undergo the steps listed above in Scheme 3a to form an ortho-carboxylate- substituted compound of formula VII.
Scheme 3b.
Figure imgf000063_0001
[0163] One exemplary but non-limiting general synthetic scheme for preparing the compound of Formula VII is shown in scheme 3c. The compound of Formula VII-2, X3a can be -C1-4 alkyl, -C1-4alkyl-OH, -OR1, or halogen; R3a can be a suitable hydroxyl protection group; and R3b can be a suitable carboxyl protecting group. The compound of Formula VII-2 can be prepared from the compound of Formula VII- la through either a carboxylation step followed by a halogenation step or a halogenation step followed by a carboxylation step. The compound of Formula VII-2 can then undergo boronation to form the compound of Formula VII-3 as shown in scheme 3a above.
Scheme 3 c
Figure imgf000063_0002
Administration and Pharmaceutical Compositions
[0164] The compounds are administered at a therapeutically effective dosage. While human dosage levels have yet to be optimized for the compounds described herein, generally, a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
[0165] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
[0166] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0167] In addition to the selected compound useful as described above, come embodiments include compositions containing a pharmaceutically-acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Oilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
[0168] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
[0169] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
[0170] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
[0171] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et ah, Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
[0172] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
[0173] The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
[0174] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
[0175] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
[0176] Compositions described herein may optionally include other drug actives.
[0177] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included. [0178] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
[0179] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
[0180] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
[0181] Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
[0182] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. [0183] In a similar vein, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
[0184] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
[0185] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
[0186] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
[0187] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
[0188] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
[0189] Some boronic acid derivatives described herein can form an oligomer such as a dimer, trimer or tetramer. To prevent the boronic acid derivatives from forming such oligomers, some embodiments include pharmaceutical compositions in which an excipient is included that prevents or limits the formation of oligomers. In some embodiments, the excipient can be a monosaccharide or monosaccharide derivative. In one embodiment, the excipient is meglumine. Other excipients include but are not limited to ethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane (Tris), L-lysine, and Pyridine-2-methanol.
[0190] Some embodiments described herein relate to a chemical complex formed between the monosaccharide or monosaccharide derivative and the compound of Formula (I) described herein. In some embodiments, the interaction between the two components helps increase the stability and/or solubility of the compound of Formula (I).
[0191] More generally, in some embodiments the monosaccharide or monosaccharide derivative can form a chemical complex with any compound containing a boronate moiety. In some embodiments, the compound containing a boronate moiety can be a boronic acid derivative described herein such as a compound of Formula (I) described herein. In other embodiments, the compound containing a boronate moiety can be any other boronate containing compounds, for example, known boronate-containing pharmaceutical agents. In some other embodiments, the monosaccharide or monosaccharide derivative used in forming the stable complex can be meglumine.
[0192] In some embodiments, of the inclusion of meglumine in a pharmaceutical composition prevents or reduces the formation of oligomers at a pH range desirable for pharmaceutical administration. In some embodiments, the pH of the composition can be in the range of about 5 to about 9, about 6 to 8, about 6 to about 7.5, about 7.1 to about 7.3, or about 7.1 to about 7.2. In some embodiments, the pH of the composition can be in the range of about 7.0-7.3. In some embodiments, the pH of the composition can be about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, and 7.8. In some embodiments, the pH of the composition can be about 7.1. In some embodiments, the pH of the composition can be about 7.2.
[0193] The amount of the boronic acid derivatives that are present in a monomer form can vary depending on the pH of the solution, the oligomer-preventing excipient included, and the amount of the excipient in the composition. In some embodiments, the percentage of the monomer form can be more than 85%, more than 88%, more than 90%, more than 92%, more than 95%, more than 97% by weight, based on the total amount of the boronic acid derivative in the composition. In some embodiments, the percentage of the monomer form can be more than 96% by weight based on the total amount of the boronic acid derivative in the composition. In some embodiments, the percentage of the monomer form can be more than 97% by weight based on the total amount of the boronic acid derivative in the composition.
Methods of Treatment
[0194] Some embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions comprising the compounds described herein. Some methods include administering a compound, composition, pharmaceutical composition described herein to a subject in need thereof. In some embodiments, a subject can be an animal, e.g., a mammal (including a human). In some embodiments, the bacterial infection comprises a bacteria described herein. As will be appreciated from the foregoing, methods of treating a bacterial infection include methods for preventing bacterial infection in a subject at risk thereof.
[0195] In some embodiments, the subject is a human. [0196] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
[0197] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By "co-administration," it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.
[0198] Examples of additional medicaments include an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent and an anti-allergic agent.
[0199] Preferred embodiments include combinations of a compound, composition or pharmaceutical composition described herein with an antibacterial agent such as a β- lactam. Examples of such β-lactams include Amoxicillin, Ampicillin (e.g., Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g., Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Ceftazidime, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam and Carumonam.
[0200] Preferred embodiments include β-lactams such as Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Apapenem, and Panipenem. In some embodiments, the β-lactam can be Tebipenem or Apapenem. In some embodiments, the β-lactam can be Tebipenem.
[0201] Additional preferred embodiments include β-lactams such as Aztreonam, Tigemonam, and Carumonam.
[0202] Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a monobactam. Examples of monobactams include aztreonam, tigemonam, nocardicin A, carumonam, and tabtoxin. In some such embodiments, the compound, composition and/or pharmaceutical composition comprises a class A, C, or D beta-lactamase inhibitor. Some embodiments include co-administering the compound, composition or pharmaceutical composition described herein with one or more additional agents.
[0203] Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a class B beta lactamase inhibitor. An example of a class B beta lactamase inhibitor includes ME 1071 (Yoshikazu Ishii et al, "In Vitro Potentiation of Carbapenems with ME 1071, a Novel Metallo-B-Lactamase Inhibitor, against Metallo-B-lactamase Producing Pseudomonas aeruginosa Clinical Isolates." Antimicrob. Agents Chemother. dok lO.l 128/AAC.01397-09 (July 2010)). Some embodiments include co-administering the compound, composition or pharmaceutical composition described herein with one or more additional agents.
[0204] Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises one or more agents that include a class A, B, C, or D beta lactamase inhibitor. Some embodiments include co-administering the compound, composition or pharmaceutical composition described herein with the one or more additional agents.
Indications
[0205] The compounds and compositions comprising the compounds described herein can be used to treat bacterial infections. Bacterial infections that can be treated with the compounds, compositions and methods described herein can comprise a wide spectrum of bacteria. Example organisms include gram-positive bacteria, gram-negative bacteria, aerobic and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.
[0206] More examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.
[0207] The following examples will further describe the present invention, and are used for the purposes of illustration only, and should not be considered as limiting.
EXAMPLES
Example 1 : (R)-3-(l,3,4-thiadiazol-2-ylthio)-2-hydroxy-3,4-dihydro-2H- benzo[el[E21oxaborinine-8-carboxylic acid (1)
Figure imgf000075_0001
Step 1 : Synthesis of compound IB
[0208] To the solution of compound 1 A (100 g, 0.657 mol) in THF (400 mL) was added Boc20 (573 g, 2.63 mol), DMAP (24 g, 0.197 mol) and lBuOH (800 mL). The resulting solution was stirred at 60 °C for 6 hours before it was concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound IB (85.9 g, 42.5% yield) as colorless oil. Step 2: Synthesis of compound 1C
[0209] To the solution of compound IB (44.3 g, 144 mmol) and NBS (28.1 g, 158 mmol) in CC14 (400 mL) was added BPO (3.5 g, 14.4 mmol). The resulting mixture was refluxed at 80 °C for 15 hours. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized with hexanes to afford the titled compound 1C (32.0 g, 57.6% yield) as white solid.
Step 3: Synthesis of compound ID
[0210] The mixture of compound 1C (47.5 g, 123 mmol), bis(pinanediolato)diboron (39.9 g, 112 mmol), KOAc (32.9 g, 336 mmol) and PdCl2(dppf) (4.5 g, 5.6 mmol) in dioxane (500 mL) was degassed for three times and flushed with nitrogen. The mixture was stirred at 95 °C for 8 hours. After concentrated to dryness, the residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound ID (40 g, 59% yield) as slightly yellow oil.
Step 4: Synthesis of Compound IE
[0211] To a solution of CH2C12 (4.2 mL, 65.8 mmol) in THF (160 mL) at -100 °C was added 2.5 M n-butyl lithium in hexane (18.4 mL, 46.0 mmol) slowly under nitrogen and down the inside wall of the flask, maintaining the temperature below -90 °C. The reaction mixture was stirred at -100 °C for another 30 minutes before the addition of Compound ID from step 3 (16.0 g, 32.9 mmol) in THF (30 mL) at -90 °C and then the reaction was allowed to warm to room temperature where it was stirred for 16 h. The reaction was concentrated in vacuo directly to dryness and then chromatographed (100% hexane~20% EtOAc-hexane) to obtain the titled compound IE (15.0 g, 85% yield) as slightly yellow oil.
Step 5: Synthesis of IF
[0212] To the solution of compound IE (113 mg, 0.21 mmol) and 2-mercapto- 1,3,4-thiadiazole (32 mg, 0.27 mmol) in DCM (1.5 mL) was added triethylamine (42 mg, 0.42 mmol) at room temperature. After stirring for 2 hours, the reaction diluted with DCM and washed with dilute aqueous HC1 and water. After concentration, the titled compound IF (132 mg) was obtained as slightly yellow oil, which was used for next step without further purification.
Step 6: Synthesis of (R)-3-(l,3,4-thiadiazol-2-ylthio)-2-hydroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (1)
[0213] To the mixture of TFA (6 mL) and triethylsilane (1 mL) was added compound IF (127 mg, crude). The resulting solution was stirred at room temperature for 1 hour before it was concentrated to dryness. The residue purified by reverse-phase prep-HPLC to afford 1 (43.2 mg) as white solid.
1H NMR (400 MHz, CD3OD) δ 9.28 (s, 1H), 7.76 (d, 1 H, J = 8.0 Hz), 7.35 (d, 1 H, J = 7.6 Hz), 6.94 (dd, 1 H, J= 8.0, 8.0 Hz), 3.80 - 3.90 (m, 1H), 3.25 - 3.30 (m, 1H), 3.08 (dd, 1H, J = 2.8, 16 Hz).
MS calcd for (CnHgBNiC Si): 308
MS (ESI, positive) found: (M+l): 309
MS (ESI, negative) found: (M+H20-1): 325
Example 2: (R)-3-(4H-1.2,4-triazol-3-ylthio)-2-hvdroxy-3.4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (2)
Figure imgf000077_0001
2
[0214] (R)-3-(4H-l,2,4-triazol-3-ylthio)-2-hydroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (2) was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 4H- 1 ,2,4-triazole-3 -thiol
1H NMR (400 MHz, CD3OD) δ 8.61 (bs, 1H), 7.73 (d, 1 H, J = 7.6 Hz), 7.31 (d, 1 H, J = 7.6 Hz), 6.91 (dd, 1 H, J = 7.6, 7.6 Hz), 3.82 (s, 1H), 3.22 (dd, 1 H, J = 5.2, 15.6 Hz), 2.98 (dd, 1H, J= 2.8, 15.6 Hz). MS calcd for (C1 1H10BN3O4S): 291
MS (ESI, positive) found: (M+l): 292
MS (ESI, negative) found: (M-l): 290
Example 3 : (R)-3-(2-amino-2-oxoethylthio)-2-hydroxy-3,4-dihydro-2H- benzo[el[E21oxaborinine-8-carboxylic acid (3)
Figure imgf000078_0001
3
[0215] (R)-3-(2-amino-2-oxoethylthio)-2-hydroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (3) was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 2- mercaptoacetamide.
1H NMR (400 MHz, CD3OD) δ 7.82 (dd, 1 H, J= 1.6, 8.0 Hz), 7.30 (m, 1 H), 6.90 (dd, 1 H, J = 7.6, 8.0 Hz), 3.35 (d, 1H, J = 13.6 Hz), 3.35 (d, 1H, J = 14.0 Hz), 3.07 (dd, 1H, J = 5.2, 15.6 Hz), 2.75 (dd, 1H, J= 7.6, 15.6 Hz), 2.53 (dd, 1H, J= 5.2, 7.6 Hz).
MS calcd for (CnH12BN05S): 281
MS (ESI, positive) found: (M+l): 282
MS (ESI, negative) found: (M -1): 280
Example 4: (R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-2-hydroxy-3,4-dihydro-2H- benzo[el[E21oxaborinine-8-carboxylic acid (4)
Figure imgf000078_0002
[0216] (R)-3-(5-amino-l,3,4-thiadiazol-2-ylthio)-2-hydroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (4) was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with 5- amino-l ,3,4-thiadiazole-2-thiol.
1H NMR (400 MHz, CD3OD) δ 7.80 (d, 1 H, J= 8.0 Hz), 7.34 (d, 1 H, J= 7.6 Hz), 6.96 (dd, 1 H, J= 7.6, 7.6 Hz), 3.69 (S, 1H), 3.23 (dd, 1H, J= 5.6, 16 Hz), 3.02 (d, 1H, J= 16 Hz). MS calcd for (C11H10BN3O4S2): 323
MS (ESI, positive) found: (M+l): 324
MS (ESI, negative) found: (M -1): 322
Example 5 : (R)-2-hydroxy-3 -( 1 -methyl- 1 H-tetrazol-5-ylthio)-3 ,4-dihydro-2H- benzo[e] [l ,2]oxaborinine-8-carboxylic acid (5)
Figure imgf000079_0001
5
[0217] Compound 5 was prepared following similar procedure described in example 1 (steps 1 -6) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with 1 -methyl- 1H- tetrazole-5-thiol.
1H NMR (400 MHz, CD3OD) δ 7.70 - 7.78 (m, 1 H), 7.22 - 7.33 (m, 1 H), 6.78 - 6.90 (m, 1
H), 3.82 - 3.88 (m, 4H), 3.08 - 3.20 (m, 2H).
MS calcd for (CnHnBN404S): 306
MS (ESI, positive) found: (M +1): 307
MS (ESI, negative) found: (M+H20 -1): 323
Example 6: (R)-2-hydroxy-3-(phenylthio)-3,4-dihydro-2H-benzo[el [E21oxaborinine-8- carboxylic acid (6)
Figure imgf000079_0002
6 [0218] Compound 6 was prepared following similar procedure described example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with benzenethiol. 1H NMR (400 MHz, CD3OD) δ 7.70 - 7.81 (m, 1 H), 7.07 - 7.42 (m, 4 H), 6.75 - 6.95 (m, H), 2.72 - 3.24 (m, 3H).
MS calcd for (C15H13B04S): 300
MS (ESI, positive) found: (M +1): 301
MS (ESI, negative) found: (M+H20 -1): 317
Example 7 : (R)-3 -(5 -acetamido- 1 ,3 ,4-thiadiazol-2-ylthio)-2-hydroxy-3 ,4-dihydro-2H-
Figure imgf000080_0001
7
[0219] Compound 7 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with N-(5-mercapto- l,3,4-thiadiazol-2-yl)acetamide.
1H NMR (400 MHz, CD3OD) δ 7.77 (d, 1 H, J= 7.6 Hz), 7.34 (d, 1 H, J= 7.6 Hz), 6.94 (dd, 1 H, J= 7.6, 7.6 Hz), 3.76 (s, 1H), 3.03 - 3.30 (m, 2H), 2.20 (s, 3H).
MS calcd for (C13H12BN305S2): 365
MS (ESI, positive) found: (M +1): 366
MS (ESI, negative) found: (M-l): 364
Example 8: (R)-2-hvdroxy-3-(pyridin-3-ylthio -3,4-dihydro-2H-benzo[el [L21oxaborinine-8- carboxylic acid (8)
Figure imgf000081_0001
8
[0220] Compound 8 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with pyridine-3-thiol. 1H NMR (400 MHz, DMSO-ifc) δ 7.80 - 8.80 (m, 3 H), 7.55 - 7.70 (m, 2 H), 7.19 - 7.32 (m, 1 H), 6.74 - 6.85 (m, 1H), 2.48 - 3.16 (m, 3H).
MS calcd for (C14H12BN04S): 301
MS (ESI, positive) found: (M +1): 302
MS (ESI, negative) found: (M+H20-1): 318
Example 9 : (R)-3 -(3 -amino-3 -oxopropylthio)-2-hydroxy-3 ,4-dihydro-2H-
Figure imgf000081_0002
[0221] Compound 9 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 3- mercaptopropanamide .
1H NMR (400 MHz, CD3OD) δ 7.69 - 7.74 (m, 1 H), 7.30 - 7.35 (m, 1 H), 6.77 - 6.83 (m, 1
H), 2.40 - 3.10 (m, 7H).
MS calcd for (Ci2Hi4BN05S): 295
MS (ESI, positive) found: (M +1): 296
MS (ESI, negative) found: (M -1): 294 Example 10: (R)-2-hvdroxy-3-(l-iminoethylthio)-3,4-dihydro-2H-benzo[el[l,21oxaborinine- 8-carboxylic acid (10)
Figure imgf000082_0001
10
[0222] Compound 10 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with thioacetamide. 1H NMR (400 MHz, CD3OD) δ 1 1.0 (bs, 1H), 7.81 (d, 1 H, J= 8.0 Hz), 7.31 (d, 1 H, J= 7.6 Hz), 6.94 (dd, 1 H, J= 8.0, 8.0 Hz), 3.30 (s, 1H), 2.90 - 3.12 (m, 2H), 2.30 (s, 3H).
MS calcd for (CnH12BN04S): 265
MS (ESI, positive) found: (M +1): 266
MS (ESI, negative) found: (M-l): 264
Example 11 : (R)-2-hvdroxy-3-(thiazol-2-ylthio)-3,4-dihydro-2H-benzo[el[L21oxaborinine-8- carboxylic acid (11)
Figure imgf000082_0002
11
[0223] Compound 11 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with thiazole-2-thiol.
1H NMR (400 MHz, CD3OD) δ 7.78 (d, 0.5 H, J = 4.0 Hz), 7.60 - 7.65 (m, 1.5H), 4.78 - 7.50 (m, 1H), 7.23 (d, 1 H, J= 7.6 Hz), 6.84 (dd, 1 H, J= 8.0, 16.0 Hz), 3.79 - 3.90 (m, 1H), 3.15 - 3.36 (m, 1H), 2.89 - 2. 95 (m, 1H).
MS calcd for (C12H10BNO4S2): 307
MS (ESI, positive) found: (M +1): 308
MS (ESI, negative) found: (M-H20-1): 290 Example 12: (R)-3-(lH-l ,2,3 -triazol-4-ylthio)-2-hydroxy-3 ,4-dihydro-2H- benzo[e] [l ,2]oxaborinine-8-carboxylic acid (12)
Figure imgf000083_0001
12
[0224] Compound 12 was prepared following similar procedure described in example 1 (steps 1 -6) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with 1H-1 ,2,3- triazole-4-thiol.
1H NMR (400 MHz, CD3OD) δ 7.79 (s, 1H), 7.78 (dd, 1 H, J = 0.8, 8.0 Hz), 7.33 (d, 1 H, J = 7.6 Hz), 6.92 (dd, 1 H, J = 8.0, 8.0 Hz), 3.67 (t, 1H, J = 4.4 Hz), 3.23 (dd, 1 H, J = 5.2, 15.2 Hz), 2.95 (dd, 1 H, J= 3.6, 15.2 Hz).
MS calcd for (C11H10BN3O4S): 291
MS (ESI, positive) found: (M +1): 292
MS (ESI, negative) found: (M-l): 290
Example 13 : (R)-3 -(benzyloxy)-2-hydroxy-3 ,4-dihydro-2H-benzo [e] [ 1 ,2]oxaborinine-8- carboxylic acid (13)
Figure imgf000083_0002
13
[0225] (R)-3-(benzyloxy)-2-hydroxy-3,4-dihydro-2H-benzo[e] [1 ,2]oxaborinine-8- carboxylic acid (13) was prepared following similar procedure described in example 1 (steps 1 -5) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with benzyl alcohol to attain benzylated product with a procedure as described in EP 1550657.
[0226] Final deprotection (step 6) was done by isobutyl boronic acid following procedure described in step 7 of example 19. 1H NMR (400 MHz, CD3OD) δ 7.74 (d, 1 H, J= 8.0 Hz), 7.05 - 7.37 (m, 6H), 6.84 (dd, 1 H,
J= 4.0, 4.0 Hz), 4.26 - 4.60 (m, 2H), 3.55 (t, 1H, J = 6.4 Hz), 2.94 - 3.05 (m, 2H).
MS calcd for (Ci6Hi5B05): 298
MS (ESI, positive) found: (M +1): 299
Example 14 : (R)-3 -(4-amino-4H- 1 ,2,4-triazol-3 -ylthio)-2-hvdroxy-3 ,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (14)
Figure imgf000084_0001
14
[0227] Compound 14 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 4-amino-4H- l,2,4-triazole-3 -thiol.
1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.78 (dd, 1 H, J= 0.8, 8.0 Hz), 7.33 (d, 1 H, J = 7.6 Hz), 6.92 (dd, 1 H, J = 8.0, 8.0 Hz), 3.77 (t, 1H, J = 4.4 Hz), 3.23 (dd, 1 H, J = 5.2, 15.2 Hz).
MS calcd for (C11H11BN4O4S): 306
MS (ESI, positive) found: (M +1): 307
MS (ESI, negative) found: (M-l): 305
Example 15: (R)-2-hvdroxy-3-(4-methyl-4H-l,2.4-triazol-3-ylthio)-3,4-dihydro-2H- benzo[el[L21oxaborinine-8-carboxylic acid (15)
Figure imgf000084_0002
15 [0228] Compound 15 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 4-methyl-4H- l,2,4-triazole-3 -thiol.
1H-NMR(400 MHZ, CD3OD) δ 8.41 (s, 1H), 7.76 (d, 1H), 7.33 (d, 1H), 6.92 (t, 1H), 3.92 (dd, 1H), 3.52 (s, 3H), 3.25 (dd, 1H), 3.05 (dd, 1H).
MS calcd for (Ci2Hi2BN304S) 305
MS (ESI, positive) found: (M+l): 306
Example 16: (R)-2-hvdroxy-3-(methylthio)-3,4-dihydro-2H-benzo[el[l,21oxaborinine-8- carboxylic acid (16)
Figure imgf000085_0001
16
[0229] Compound 16 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l,3,4-thiadiazole in step 5 with methyl thiol. Ή- NMR(400 MHz, CD3OD) δ 7.73 (d, 1H), 7.33 (d, 1H), 6.82 (t, 1H), 2.85 - 3.00 (m, 2H), 2.49 (m, 1H), 2.06 (s, 3H).
MS calcd for (C10HnBO4S) 238
MS (ESI, negative) found: (2M-1): 475
Example 17 : (R)-2-hydroxy-3 -methoxy-3 ,4-dihydro-2H-benzo [e] [ 1 ,2]oxaborinine-8- carboxylic acid (17)
Figure imgf000085_0002
[0230] Compound 17 was prepared following similar procedure described in example 1 replacing 2-mercapto-l,3,4-thiadiazole in step 5 with methanol as in step 6 of example 19. Deprotection was done by isobutyl boron ic acid following procedure described in step 7 of example 19. 1H-NMR(400 MHz, CD3OD) δ 7.74 (d, IH), 7.34 (d, IH), 6.82 (t, IH), 3.38 (s, IH), 3.33 (s,
3H), 2.95 - 3.20 (m, 2H).
MS calcd for (C10HnBO5) 222
MS (ESI, negative) found: (2M-1): 443
Example 18 : (R)-3 -(azetidin-3 -yloxy)- 2-hydroxy-3 ,4-dihydro-2H-benzo [e] [1,2] oxaborinine-
8-carboxylic acid (18)
Figure imgf000086_0001
18
[0231] Compound 18 was prepared following similar procedure described in example 1 replacing 2-mercapto-l,3,4-thiadiazole in step 5 with N-Boc-3-hydroxy-azetidine as in step 6 of example 19. Deprotection was done by isobutyl boron ie acid following procedure described in step 7 of example 19.
1H-NMR(400 MHz, CD3OD) δ 7.73 - 7.78 (m, IH), 7.32 - 7.34 (m, IH), 6.77 - 6.89 (m,
IH), 3.70 - 4.70 (m, 6H), 2.90 - 3.20 (m, 2H).
MS calcd for (C12H14BNO5) 263
MS (ESI, negative) found: (2M-1): 525
Example 19 : (R)-7-fluoro-2-hydroxy-3 -methoxy-3 ,4-dihydro-2H-benzo |e] [ 1 ,2] oxaborinine-
8-carbox lic acid (19)
Figure imgf000087_0001
Step 1 : Synthesis of 19B
[0232] To a solution of 2-bromo-5-fluorophenol (19A) (13.5 g, 71 mmol) and Boc20 (18.5 g, 85 mmol) in DCM (300 mL) at r.t. was added DMAP (439 mg, 3.6 mmol), the mixture was stirred at r.t. for 0.5 h, concentrated to dryness, and purified by silica gel chromatography to afford compound 19B (20.1 g, 97%).
1H NMR (400 MHz, CDC13) δ 7.54 (m, 1 H), 6.98 (m, 1 H), 6.89 (m, 1 H), 1.56 (s, 9H).
Step 2: Synthesis of 19C
[0233] To a solution of compound 19B (21.7 g, 74.6 mmol) in THF (150 mL) at - 78 °C was added freshly prepared LDA solution (140 mL, 82.1 mmol), the mixture was stirred at -78 °C for 1 h, then warmed up slowly to r.t., quenched with 1 N HC1 (aq., 200 mL), extracted with EtOAc, washed with water and brine, dried over Na2S04, filtered and the filtrate was evaporated to dryness to afford compound 19C (17.9 g, 83%) which was used directly to the next step without further purification.
1H NMR (400 MHz, CDC13) δ 12.23 (s, 1 H), 7.59 (m, 1 H), 6.53 (m, 1 H), 1.61 (s, 9H). Step 3: Synthesis of 19D
[0234] To a solution of compound 19C (17.99 g, 62 mmol) and Boc20 (20.2 g, 92.7 mmol) in DCM (200 mL) at r.t. was added DMAP (400 mg, 3.1 mmol), the mixture was stirred at r.t. overnight, evaporated to dryness, purified by silica gel chromatography to afford compound 19D (19.1 g, 79%).
1H NMR (400 MHz, CDC13) δ 7.59 (m, 1 H), 6.93 (m, 1 H), 1.56 (s, 9H),9 , 1.52 (s, 9H).
Step 4: Synthesis of 19F
[0235] To a mixture of Zn powder (10.8 g, 166 mmol) and compound 19E (WO2013/56163) (362 mg, 1.3 mmol) in anhydrous THF (60 mL) was added DIBAL-H (2 mL, 3 mmol, 1.5 M in toluene) at r.t., the mixture was stirred at room temperature for 5 min, then more compound 19E (17.7 g, 65 mmol) in anhydrous THF (60 mL) was added drop- wise into the mixture over 20 min, the reaction mixture was warmed up to 50 °C and stirred at this temperature for 1 h, then the clear solution on the up-layer was transferred into a mixture of compound 19D (17.3 g, 44 mmol) and Pd(t-Bu3P)2 (558 mg, 1.1 mmol) in THF (60 mL), the mixture was stirred at r.t. under N2 for 1 h, concentrated, and purified by silica gel chromatography directly to afford the titled compound 19F (18.5 g, 83%).
1H NMR (400 MHz, CDC13) δ 7.27-7.39 (m, 1 H), 6.88-6.92 (m, 1 H), 4.25-4.27 (m, 1 H), 2.26-2.32 (m, 1 H), 2.20 (m, 3 H), 2.00-2.03 (m, 1 H), 1.81-1.88 (m, 2 H), 1.56 (s, 9 H), 1.54 (s, 9 H), 1.38 (s, 3 H), 1.27 (s, 3 H), 1.16-1.19 (d, 1 H), 0.82 (s, 3 H).
Step 5: Synthesis of 19G
[0236] To a solution of DCM (4.73 mL, 73.4 mmol) in anhydrous THF (400 mL) at -100 °C was added drop-wise n-BuLi (2.5 M in hexane, 21 mL, 51.2 mmol) over 1 h, the mixture was stirred at this temperature for 30 min, then a solution of compound 19F (18.5 g, 36.7 mmol) in anhydrous THF (100 mL) was added drop-wise into this mixture at -100 °C over 30 min, the mixture was slowly warmed up to r.t. and stirred at r.t. overnight, evaporated to dryness, and purified by silica gel chromatography to afford the titled compound 19G (16.3 g, 80%). 1H NMR (400 MHz, CDC13) δ 7.35-7.39 (m, 1 H), 6.92-6.96 (m, 1 H), 4.35-4.37 (m, 1 H), 3.61-3.65 (m, 1 H), 3.13-3.19 (m, 1 H), 2.94-3.00 (m, 1 H), 2.33-2.36 (m, 1 H), 2.30-2.31 (m, 1 H), 2.18-2.20 (m, 1 H), 1.89-1.93 (m, 2 H), 1.56 (s, 9 H), 1.54 (s, 9 H), 1.38 (s, 3 H), 1.28 (s, 3 H), 1.08 (d, 1H), 0.82 (s, 3 H).
Step 6: Synthesis of 19H
[0237] To the solution of compound 19G (490 mg, 0.89 mmol) in DMF (6 mL) was added MeOH (43 mg, 1.33 mmol), followed by K2C03 (490 mg, 3.55 mmol). The resulting mixture was stirred at 50 °C for one hour before it was diluted with EtOAc/hexanes and washed with saturated NH4C1 and water. The organic layer was concentrated to dryness and purified by column chromatography (100% hexane~20% EtOAc-hexane) to obtain the titled compound 19H (250 mg, 51% yield) as slightly yellow oil.
MS calcd for (C29H42BF08): 548
MS (ESI, positive) found: (M+l): 549
MS (ESI, negative) found: (M-l): 547
Step 7: Synthesis of 19
[0238] To the solution of compound 19H (240 mg, 0.44 mmol) in THF (2 mL) was added isobutylboronic acid (89 mg, 0.88 mmol), followed by concentrate HC1 (2 mL). The resulting solution was stirred at room temperature for 2 hour before it was concentrated to dryness. The residue was purified by purified by prep-HPLC (CI 8, acetonitrile and water as mobile phases, 0.1 % formic acid) to obtain the titled compound 19 (50 mg) as white solid. 1H-NMR(400 MHz, CD3OD) δ 7.24 (dd, 1H), 6.56 (dd, 1H), 3.36 (s, 3H), 3.05 (m, 1H), 2.92 (m, 2H).
MS calcd for (C10H10BFO5): 240
MS (ESI, positive) found: (M+l): 241
Example 20 : (R)-3-(4-amino-4H-l,2,4-triazol-3-ylthio)-7-fluoro-2-hydroxy-3,4-dihydro-2H- benzo[el[L21oxaborinine-8-carboxylic acid (20) [0239] Compound (20) was prepared from 19G (example 19) following methods described in steps 5 and 6 of ex H- 1 ,2,4-triazole-3-thiol.
Figure imgf000090_0001
20
1H-NMR(400 MHz, CD3OD) δ 8.34 (s, 1H), 7.14 (dd, 1H), 6.57 (dd, 1H), 3.70 (s, 1H), 3.17
(dd, 1H), 2.94(dd, 1H).
MS calcd for (C1 1H10BFN4O4S) 324
MS (ESI, negative) found: (M -1): 323
Example 21 : (R)-(isopropoxycarbonyloxy)methyl 2-hydroxy-3-(4-methyl-4H-l,2,4-triazol-3- ylthio)-3,4-dihydro-2H-benzo[el[l,21oxaborinine-8-carboxylate (21)
Figure imgf000090_0002
21
[0240] To the solution of acid 15 (0.5 mmol) in DMF (5 mL) was added chloromethyl isopropyl carbonate (1 mmol), followed by K2C03 (0.75 mmol). The resulting mixture was stirred at 50 °C for 18 hours and brought to room temperature and concentrated. The residue was purified by purified by prep-HPLC (CI 8, acetonitrile and water as mobile phases, 0.1% formic acid) to obtain the titled compound.
1H-NMR(400 MHz, CD3OD) δ 8.33 (s, 1H), 7.47 (d, 1H), 7.22 (d, 1H), 6.78 (t, 1H), 5.89 (dd, 2H), 3.70 (m, 1H), 3.52 (s, 3H), 3.17 (dd, 1H), 2.93 (dd, 1H), 1.28 (d, 6H).
MS calcd for (C17H20BN3O7S) 421
MS (ESI, positive) found: (M +Na): 444 Example 22: 3-(2-amino-2-oxoethyl)-2-hvdroxy-3,4-dihydro-2H-benzo[el[l,21oxaborinine-8- carbox lic acid (22)
Figure imgf000091_0001
Step 1 : Synthesis of compound 22B
[0241] To the mixture of TFAA (225 mL) and TFA (370 mL) was added compound 22 A (45 g, 292 mmol) slowly at -10 °C, followed by the addition of acetone (60 g, 1.03 mmol) in TFA(77 mL) over 1 h. After being stirred at -4 °C for 3 h, the solution was warmed up to room temperature and stirred for 2 days before it was concentrated in vacuo to dryness. The residue was dissolved in EtOAc, washed with NaHCOs solution, dried over Na2S04. Column chromatography (hexanes/ethyl acetate/DCM, v/v/v, 20/1/20) gave the titled compound 22B (28 g, 49% yield) as slightly yellow oil.
Step 2: Synthesis of compound 22C
[0242] To the solution of compound 22B (28 g, 144.2 mmol) and triethylamine (73 g, 721 mmol) in dichloromethane (300 mL) at -78 °C was added Tf20 (81.3 g, 288.4 mmol, 2 eq). The resulting mixture was warmed up to 0 °C slowly and stirred at 0 °C for 1 hour before it was quenched with water. The mixture was extracted with DCM and dried over Na2S04. After concentrated to dryness, the residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/40) to give the titled compound 22C (44 g, 94%) as a slightly yellow oil.
1H-NMR(400 MHz, CDC13) δ 7.99 (d, 1H), 7.50 (d, 1H), 7.17 (t, 1H), 1.78 (s, 6H).
Step 3 : Synthesis of compound 22D
[0243] The mixture of compound 22C (6.55 g, 20 mmol), potassium vinyltrifluoroborate (3.22 g, 24 mmol), triethylamine (5.6 mL, 40 mmol) and PdCl2(dppf) (820 mg, 1 mmol) in 2-propanol (150 mL) was degassed and filled with nitrogen (3 times) and refluxed for 15 hours. The reaction mixture was cooled down and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/6 to 1/3) to give the titled compound 22D (4.1 g, 75%) as a slightly yellow solid.
1H-NMR(400 MHZ, CDC13) δ 7.86 (d, 1H), 7.72 (d, 1H), 7.18 (t, 1H), 6.86 (dd, 1H), 5.82 (d, 1H), 5.39 (d, 1H), 1.77 (s, 6H).
Step 4: Synthesis of compound 22E
[0244] To t-BuOH (160 mL) was added PdCl2(MeCN)2 (130 mg, 0.5 mmol) and 1 ,4-benzoquinone (2.5 g, 23 mmol) at 85 °C, followed by water (0.36 mL, 20 mmol) and compound 22D (4.1 g, 20 mmol). The reaction mixture was stirred at 85 °C for about 30 minutes until TLC showed the disappearance of 22D. The reaction mixture was cooled down and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/3 to 1/2) to give the titled compound 22E (3.15 g, 70%>) as yellow solid.
1H-NMR(400 MHz, CDC13) δ 9.75 (s, 1H), 7.92 (d, 1H), 7.42 (d, 1H), 7.11 (t, 1H), 3.73 (s, 1H), 1.72 (s, 6H).
Step 5: Synthesis of compound 22F
[0245] To the solution of compound 22E (2.51 g, 11.4 mmol) in THF (40 mL) was added (tert-Butoxycarbonylmefhylene) triphenylphosphorane (5.15 g, 13.7 mmol). The reaction mixture was refluxed for 1.5 hours before it was cooled down and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/40 to 1/20) to give the titled compound 22F (2.73 g, 75%) as yellow solid.
1H-NMR(400 MHz, CDC13) δ 7.88 (d, 1H), 7.39 (d, 1H), 7.08 (t, 1H), 6.92 (m, 1H), 5.70 (d, 1H), 3.47 (dd, 2H), 1.73 (s, 6H), 1.45 (s, 9H).
Step 6: Synthesis of compound 22G
[0246] To the solution of compound 22F (2.0 g, 6.3 mmol) in THF (10 mL) was added bis(pinacolato)diboron (2.4 g, 9.4 mmol), 4-picoline (58.7 mg, 0.63 mmol), followed by CuS04 (16 mg, 0.063 mmol) in water (19 mL). The reaction mixture was stirred at room temperature for overnight before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/40 to 1/20) to give the titled compound 22G (0.94 g, 33%) as yellow solid.
MS calcd for (C24H35B07): 446
MS (ESI, positive) found: (M+l): 447
Step 7: Synthesis of compound 22H
[0247] The solution of compound 22G (720 mg, 1.6 mmol) and (+)-pinanediol (412 mg, 2.4 mmol) in THF (15 mL) was stirred at room temperature for overnight before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/40 to 1/20) to give the titled compound 22H (756 mg, 95%) as yellow solid.
MS calcd for (C28H39B07): 498
MS (ESI, positive) found: (M+l): 499
Step 8: Synthesis of compound 221
[0248] To the solution of compound 22H (756 mg, 1.5 mmol) in DCM (10 mL) was added TFA (10 mL, 90 %> aqueous). The solution was stirred at room temperature for 1 hour before it was concentrated to dryness. The residue is the crude titled compound 221 (749 mg) as yellow oil, which was used for next step without further purification.
MS calcd for (C24H31B07): 442
MS (ESI, positive) found: (M+l): 443 Step 9: Synthesis of compound 22 J
[0249] To the solution of compound 221 (100 mg, 0.23 mmol) in DMF (4.5 mL) was added CDI (48 mg, 0.30 mmol). The solution was stirred at 36 °C for 1 hour and then cooled to room temperature. Ammonia gas was bubbled in. After 2 hour at room temperature, the reaction mixture was concentrated and purified by column chromatography (ethyl acetate/hexanes, v/v, 1/10 to 1/1) to give the titled compound 22J (81 mg, 81%) as yellow solid.
MS calcd for (C24H32BNO6): 441
MS (ESI, positive) found: (M+l): 442
Step 10: Synthesis of compound 22
[0250] To the mixture of compound 22 J (81 mg, 0.18 mmol) and triethylsilane (0.7 mL) was added TFA (6.5 mL, 90 % aqueous). The solution was stirred at 50 °C for 1.5 hour and then cooled to room temperature. The reaction mixture was concentrated to dryness and purified by prep-HPLC (CI 8, acetonitrile and water as mobile phases, 0.1 % formic acid) to obtain the titled compound 22 (8.8 mg) as white solid.
1H-NMR(400 MHZ, CD3OD) δ 7.82 (d, 1H), 7.33 (d, 1H), 6.93 (t, 1H), 2.86 - 2.99 (m, 2H), 2.53 - 2.58 (m, 1H), 2.22 - 2.28 (m, 1H), 1.61 - 1.65 (m, 1H).
MS calcd for (CnHi2BN05): 249
MS (ESI, positive) found: (M+l): 250
MS (ESI, negative) found: (M-l): 248
Example 23: (R)-3-(5-amino-l,3,4-thiadiazol-2-ylthio)-7-fluoro-2-hydroxy-3,4-dihydro-2H- benzo[el[L21oxaborinine-8-carboxylic acid (23)
[0251] Compound 23 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 2-amino-5-mercapto-L3,4- thiadiazole.
Figure imgf000095_0001
23
1H NMR (400 MHz, CD3OD) δ 7.15 (dd, 1 H), 6.61 (dd, IH), 3.56, (s, IH), 3.16 (dd, 1 H), 2.94 (dd, IH).
MS calcd for (C11H9BFN3O4S2): 341
MS (ESI, positive) found: (M+l): 342
MS (ESI, negative) found: (M-l): 340
Example 24: (R)-7-fluoro-2-hydroxy-3-(4-methyl-4H-l ,2,4-triazol-3-ylthio)-3,4-dihydro-2H- benzo[el[E21oxaborinine-8-carboxylic acid (24)
[0252] Compound 24 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 4-methyl-3-mercapto- 1,2,4- triazole.
Figure imgf000095_0002
24
1H NMR (400 MHz, CD3OD) δ 8.38 (s, IH), 7.13 (dd, 1 H), 6.57 (dd, IH), 3.78, (s, IH), 3.57 (s, 3H), 3.16 (dd, 1 H), 2.94 (dd, IH).
MS calcd for (C12H11BFN3O4S): 323
MS (ESI, positive) found: (M+l): 324
MS (ESI, negative) found: (M-l): 322
Example 25. (R)-3-(4-amino-4H-l,2,4-triazol-3-ylthio -2-hvdroxy-7-(methylthio)-3,4-
Figure imgf000096_0001
Step 1 : Synthesis of compound 25B
[0253] To the mixture of compound 25 A (100 g, 0.64 mol) and allylbromide (232 g, 1.92 mol) in DMF (500 mL) was added K2C03 (265 g, 1.92 mol). The resulting mixture was stirred at room temperature for 16 hours before it was concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound 25B (162 g) as a yellow oil. Step 2: Synthesis of compound 25C
[0254] Compound 25B (162 g, 0.64 mol) was heated up to 200 °C for 8 hours under nitrogen. Column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) gave the titled compound 25C (153 g) as yellow oil.
Step 3 : Synthesis of compound 25D
[0255] To the solution of 25C (153 g, 0.64 mol) in THF (1.2 L) was added Pd(PPh3)4 (22 g, 19.2 mmol) and morpholine (557 g, 6.4 mmol). The resulting solution was stirred at room temperature for two days. The reaction mixture was concentrated to dryness and purified by column chromatography (ethyl acetate/hexanes, v/v, 1/20-1/8) to obtain the titled compound 25D as slightly yellow oil.
1H-NMR(400 MHZ, CDC13) δ 11.50 (bs, 1H), 7.45 - 7.70 (m, 1H), 7.25 - 7.31 (m, 1H), 6.55 - 6.62 (m, 1H), 5.93 - 6.01 (m, 1H), 5.08 (d, 1H), 3.38 (s, 2H).
Step 4: Synthesis of Compound 25E
[0256] To the solution of compound 25D (95 g, 0.48 mol) in THF (1.0 T) was added Boc20 (418 g, 1.92 mol), DMAP (2.9 g, 24 mmol) and lBuOH (1.0L). The resulting solution was stirred at 60 °C overnight before it was concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound 25E as slightly yellow oil.
1H-NMR(400 MHz, CDC13) δ 7.20 - 7.26 (m, 1H), 6.92 - 6.97 (m, 1H), 5.85 - 5.90 (m, 1H), 5.05 - 5.11 (m, 2H), 3.30 (d, 2H), 1.57 (s, 9H), 1.53 (s, 9H).
Step 5 : Synthesis of Compound 25F
[0257] The solution of 25E (109 g, 0.31 mol) and PdCl2(MeCN)2 (4.0 g, 15.5 mmol) in toluene (500 mL) was heated at 100 °C for 3 hours. After concentration, the residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound 25Γ as colorless oil, which contains some Boc-depleted side- product. 1H-NMR(400 MHz, CDC13) δ 7.44 - 7.49 (m, 1H), 6.92 - 6.97 (m, 1H), 6.34 - 6.39 (m, 1H), 6.16 - 6.20 (m, 1H), 1.87 (d, 3H), 3.30 (d, 2H), 1.57 (s, 9H), 1.53 (s, 9H).
Step 6: Synthesis of Compound 25G
[0258] To the solution of 25F (27 g, 77 mmol, contains some Boc-depleted side product) in MeOH (100 mL) and DCM (500 mL) was bubbled ozone gas (generated is situ from oxygene) at -78 °C until light blue color appeared. Nitrogen gas was bubbled in to remove the blue color and then Me2S (50 mL) was added in. The resulting solution was slowly warmed up to room temperature overnight. After concentration, the residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/50-1/20) to obtain the titled compound 25G ( containing some Boc-depleted side product) as slightly yellow oil. 1H-NMR(400 MHZ, CDCI3) δ 10.10 (s, 1H), 7.95 (dd, 1H), 7.14 (dd, 1H), 1.59 (s, 9H), 1.57 (s, 9H).
Step 7: Synthesis of Compound 25H
[0259] To the solution of 25G (19 g, 56 mmol, contains some Boc-depleted side product) in DMF (150 mL) was added NaSMe (1 1.8 g, 168 mmol). The resulting solution was stirred at 80 °C overnight, cooled to r.t., concentrated to small volume, and the pH was adjust to 5 with 1 N HCl solution, extracted with EtOAc, washed with water and brine, evaporated to dryness, the residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/20-1/10) to obtain the titled compound 25H as slightly yellow oil. 1H-NMR(400 MHZ, CDCI3) δ 12.03 (s, 1H), 10.14 (s, 1H), 7.67 (d, 1H), 6.79 (d, 1H), 2.48 (s, 3H), 1.65 (s, 9H).
Step 8: Synthesis of Compound 251
[0260] To the solution of compound 25H (9.0 g, 34 mmol) in THF (50 mL) was added Boc20 (7.4 g, 34 mol), DMAP (210 mg, 1.7 mmol) and lBuOH (50 mL). The resulting solution was stirred at 60 °C overnight before it was concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound 251 as slightly yellow oil. 1H-NMR(400 MHz, CDC13) δ 10.00 (s, 1H), 7.82 (d, 1H), 7.21 (d, 1H), 2.52 (s, 3H), 1.65 (s, 9H), 1.61 (s, 9H).
Step 9: Synthesis of Compound 25 J
[0261] To the solution of compound 251 (2.95 g, 8.0 mmol) in anhydrous THF (30 mL) was added NaBH4 (240 mg, 6.4 mmol). The resulting solution was stirred at room temperature for 40 minutes before it was quenched with saturated NH4CI solution. The reaction mixture was extracted with EtOAc three times, after concentration in vacuo, the residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/20-1/5) to give the titled compound 25J (1.5 g, 51% yield) as colorless oil.
1H-NMR(400 MHz, CDC13) δ 7.47 (d, 1H), 7.20 (d, 1H), 4.55 (s, 2H), 2.47 (s, 3H), 1.65 (s, 9H), 1.61 (s, 9H).
Step 10: Synthesis of Compound 25K
[0262] To the solution of compound 25J (1.5 g, 4.0 mmol) in DCM (15 mL) was added CBr4 (1.99 g, 6.0 mmol), followed by PPh3 (1.57 g, 6.0 mmol). The resulting reaction mixture was stirred at room temperature for one hour before it was concentration in vacuo to dryness. The residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound 25K as yellow solid.
1H-NMR(400 MHz, CDC13) δ 7.40 (d, 1H), 7.13 (d, 1H), 4.41 (s, 2H), 2.46 (s, 3H), 1.60 (s, 9H), 1.55 (s, 9H).
Step 11 : Synthesis of Compound 25L
[0263] The mixture of compound 25K (1.4 g, 3.2 mmol), bis(pinanediolato)diboron (1.03 g, 2.88 mmol), PdCi2(dppf) (130 mg, 0.16 mmol) and KOAc (940 mg, 9.6 mmol) in dioxane (10 mL) was flushed with nitrogen (3 times) and then stirred at 100 °C for 10 hours before it was concentration in vacuo to dryness. The residue was purified by flash column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/100) to give the titled compound 25L as slightly yellow oil.
MS calcd for (C28H41B07S): 532 MS (ESI, positive) found: (M+l): 533
Step 12: Synthesis of Compound 25M
[0264] To a solution of CH2C12 (0.18 mL, 2.9 mmol) in THF (20 mL) at -100 °C was added 2.5 M n-butyl lithium in hexane (0.8 mL, 2.03 mmol) slowly under nitrogen and down the inside wall of the flask, maintaining the temperature below -90 °C. The reaction mixture was stirred at -100 °C for another 30 minutes before the addition of compound 25L (0.77 g, 1.45 mmol) in THF (10 mL) at -90 °C and then the reaction was allowed to warm to room temperature where it was stirred for 16 h. The reaction was concentrated in vacuo directly to dryness and purified by column chromatography (100% hexane~20% EtOAc- hexane) to obtain the titled compound 25M as slightly yellow oil.
MS calcd for (C29H42BC107S): 580
MS (ESI, positive) found: (M+l): 581
[0265] Compound (25) was prepared from compound 25M following methods described in steps 5 and 6 of example 1 utilizing 4~amino-4H~ 1 ,2,4-triazole-3-thiol.
1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.15 (d, 1 H), 6.81 (d, 1H), 3.74, (s, 1H), 3.18 (dd, 1 H), 2.94 (dd, 1H), 2.35 (s, 3H).
MS calcd for (Ci2Hi3BN404S2): 352
MS (ESI, positive) found: (M+l): 353
MS (ESI, negative) found: (M-l): 351
Example 26: (R -3-(4-amino-4H-L2,4-triazol-3-ylthio)-2-hvdroxy-7-methoxy-3,4-dihydro- -benzo[e][l,2]oxaborinine-8-carboxylic acid (26)
Figure imgf000101_0001
Step 1: Synthesis of 26B
[0266] To a solution of 2, 6-dimethoxybenzoic acid (26A) (50 g, 0.275 mol) in CHC13 (1 L) at 0 °C was added dropwise bromine (14.4 mL, 0.263 mol). The reaction mixture was stirred at 25 °C for 30 hours, before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 26B (32.5 g, 48 %) as white solid.
Step 2: Synthesis of 26C
[0267] To the solution of compound 26B (32.5 g, 0.132 mol) in THF (200 mL) was added Boc20 (1 14.7 g, 0.526 mol), DMAP (4.8 g, 0.04 mol) and tBuOH (400 mL). The resulting solution was stirred at 60 oC for 6 hours before it was concentrated in vacuo. The residue was quickly passed through a silica gel column (ethyl acetate/hexanes) to give the corresponding t-butyl ester. To the solution of this ester and Boc20 (17 g, 0.078 mol) in DCM (300 mL) was added DMAP (475 mg, 3.89 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 26C (52.1 g, 98 %) as white solid. Step 3: Synthesis of 26D
[0268] To a mixture of Zn powder (20 g, 0.302 mol) and compound 19E (100 mg, 0.37 mmol) in anhydrous THF (100 mL) was added DIBAL-H (2.45 mL, 6.05 mmol, 1.5 M in toluene) at room temperature. The mixture was stirred at room temperature for 5 min, then more compound 19E (33 g, 0.121 mol) in anhydrous THF (100 mL) was added dropwise into the mixture over 20 min. The reaction mixture was warmed up to 50 °C and stirred at this temperature for 1 hour before it was settled down at room temperature. The top layer of clear solution was transferred into a mixture of compound 26C (20 g, 50 mmol) and Pd(t-Bu3P)2 (917 mg, 1.79 mmol) in THF (300 mL) at room temperature under N2. After stirring at room temperature for 1 hour, the reaction mixture was concentrated, and purified by column chromatography (ethyl acetate/hexanes) to afford compound 26D (21 g, 81 %) as light yellow solid.
Step 4: Synthesis of 26E
[0269] To a solution of dichloromethane (4.2 mL, 0.066 mol) in anhydrous THF (200 mL), was added dropwise n-butyllithium (2.5 M in hexane, 18.5 mL, 0.046 mol) along the wall of the flask over 1 h at -100 °C (cooled with liquid nitrogen and methanol), while keeping the internal temperature below -90 °C. After the addition, the mixture was stirred at -100 °C for 30 min before slow addition of the solution of compound 26D (17 g, 0.033 mol) in anhydrous THF (60 mL) over 1 h at -100 °C. The reaction mixture was slowly warmed up to room temperature over a period of 6 hours and stirred overnight. The solvent was evaporated and the residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 26E (16.5 g, 88 %) as light yellow solid.
Step 5: Synthesis of 26G
[0270] Compound 26G was prepared following similar procedure described in step 5 of example 1 replacing 2-mercapto-l,3,4-thiadiazole in step 5 with 4-amino-4H- 1,2,4- triazole-3 -thiol (26F). Step 6: Synthesis of 26
[0271] Compound 26 was prepared starting from 26G following similar procedure described in step 6 of example 1.
1H NMR (300 MHz, CD3OD) δ 8.42 (s, IH), 6.65 (d, IH), 6.32 (d, IH), 3.84 (s, 3H), 3.02
(dd, 2H), 2.63 (dd, IH).
MS calcd for (Ci2Hi3BN405S): 336
MS (ESI, positive) found: (M+l): 337
MS (ESI, negative) found: (M-l): 335
Example 27: (R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-2-hydroxy-7-methoxy-3,4-dihydro- 2H-benzo[el[E21oxaborinine-8-carbox lic acid (27)
Figure imgf000103_0001
27
[0272] Compound 27 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 5-amino-l,3,4- thiadiazole-2-thiol.
1H NMR (300 MHz, CD3OD) δ 6.85 (d, IH), 6.25 (d, IH), 3.74 (s, 3H), 3.05 (dd, IH), 2.85 (dd, 2H).
MS calcd for (Ci2Hi2BN305S2): 353
MS (ESI, positive) found: (M+l): 354
MS (ESI, negative) found: (M-l): 352 Example 28: (R -2-hvdroxy-7-methoxy-3-(4-methyl-4H-l,2,4-triazol-3-ylthio -3,4-dihydro- 2H-benzo[e][l,2]oxaborinine-8-carbox lic acid (28)
Figure imgf000104_0001
28
[0273] 58] Compound 28 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 4-methyl-4H- l,2,4-triazole-3 -thiol.
1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.05 (d, 1H), 6.48 (d, 1H), 3.85 (m, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.15 (dd, 1H), 2.85 (dd, 1H).
7.23 (d, 1H), 6.78 (d, 1H), 3.53 (t, 1H), 3.21 (dd, 1H), 2.95 (dd, 1H), 2.45 (s, 3H).
MS calcd for (C13H14BN305S): 335
MS (ESI, positive) found: (M+l): 336
MS (ESI, negative) found: (M-l): N/A
Example 29: (R)-2-hvdroxy-3-(4-methyl-4H-l,2,4-triazol-3-ylthio)-7-(methylthio)-3,4- dihvdro-2H-benzo[e][l,2]oxaborinine-8-carbox lic acid (29)
Figure imgf000104_0002
29
[0274] Compound 29 was prepared following the procedure described in Example 25 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol with 4-methyl-4H-l,2,4-triazole-3- thiol. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, IH), 7.15 (d, IH), 6.82 (d, IH), 3.83 (s, IH), 3.53 (s, 3H), 3.17 (d, IH), 2.96 (d, IH), 2.36 (d, 3H).
MS calcd for (C13H14BN3O4S2): 351
MS (ESI, positive) found: (M+l): 352
MS (ESI, negative) found: (M-l): N/A
Example 30: (R)-3-(5-amino-E3,4-thiadiazol-2-ylthio)-2-hvdroxy-7-(methylthio)-3,4- dihvdro-2H-benzo[e][l,2]oxaborinin -8-carbox lic acid (30)
Figure imgf000105_0001
30
[0275] Compound 30 was prepared following the procedure described in Example 25 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol with 5-amino-l,3,4-thiadiazole-2- thiol.
1H NMR (400 MHz, CD3OD) δ 7.23 (d, IH), 6.85 (d, IH), 3.65 (s, IH), 3.30 (m, IH), 2.95 (d, IH), 2.45 (s, 3H).
MS calcd for (C12H12BN3O4S3): 369
MS (ESI, positive) found: (M+l): 370
MS (ESI, negative) found: (M-l): 368
Example 31 : (R -3-(5-amino-l J,4-thiadiazol-2-ylthio)-2-hvdroxy-7-methyl-3,4-dihydro-2H- benzo e][l,2]oxaborinine-8-carboxylic acid (31)
Figure imgf000106_0001
Step 1: Synthesis of 31C
[0276] To a solution of compound 31 A (84 g, 1.198 mol) and compound 31B (87.5 g, 1.198 mol) in benzene (500 mL) was stirred at r.t. for 2h under N2, Then heated in a Dean-Stark apparatus until H20 formation ceases(ca. 2 h). The mixture was cooled to r.t. The mixture was washed with water (500 mL) and dried over MgS04, filtered and concentrated and the residue was distilled to afford compound 31C (45.76 g, 30%).
Step 2: Synthesis of 31E
[0277] To a solution of compound 31C (45.76 g, 0.366 mol) and compound 31D (42.47 g, 0.366 mol) in benzene (800 mL) was added TsOH (1.39 g, 7.322 mmol) at room temperature, and stirred at room temperature for 72 h under N2. The mixture was washed with water (500 mL) and dried over MgS04. The organic extract was filtered and concentrated, purified by silica gel chromatography to afford compound 31E (20 g, 32.5 %). Step 3: Synthesis of 31F
[0278] To a solution of compound 31E (20 g, 119.048 mmol) in AcOH(100 ml) was added dropwise Br2 at 0 °C. The mixture was stirred at 100 °C for 24 h under N2, cooled to r.t. and concentrated. The residue was purified by distillation to afford compound 31F (20.3 g, 70 %).
Step 4: Synthesis of 31G
[0279] To a solution of compound 31F (20 g, 81.6 mmol) and Boc20 (17.8 g, 81.6 mmol) in DCM (200 mL) was added DMAP (500 mg, 4.1 mmol) at room temperature. The mixture was stirred at room temperature for 3 h, then evaporated to dryness. The residue was purified by silica gel chromatography to afford compound 31G (22 g, 78 %).
Step 5: Synthesis of 31H
[0280] To a solution of 31G (1.5 g, 4.35 mmol) and Pd^Bus (66.7 mg, 0.13 mmol) in THF (20 mL) was added zinc reagent of 19E (freshly prepared as step 4 of Example 19) (5.65 mmol) at room temperature. The mixture was stirred at room temperature overnight, then evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 31H (0.82 g, 40.2 %).
Step 6: Synthesis of 311
[0281] To a solution of dichloromethane (0.304 g, 3.58 mmol) in anhydrous THF (20 mL) in a three-neck flask at -100 °C, cooled with liquid nitrogen and methanol was added dropwise n-butyllithium (1 mL, 2.5 mmol), through the wall of the flask over 0.5 h while keeping the internal temperature of the flask below -90 °C. After the addition, the mixture was stirred at this temperature for 30 min, To the mixture at -100 °C was added dropwise a solution of compound 31H (0.82 g, 1.79 mmol) in anhydrous THF (10 mL) over 0.5 h. After the addition, the mixture was slowly warmed up to room temperature, and stirred overnight. The solvent was evaporated to dryness to give a residue, which was purified by silica gel chromatography (PE: EA, 5: 1) to afford compound 311 (0.74 g, 81.6 %). Step 7: Synthesis of 31K
[0282] To a solution of compound 311 (0.3 g, 0.59 mmol) and compound 31J (0.12 mg, 0.889 mmol) in DCM/DMF (5 mL/2 mL) was added TEA (0.12 mg, 1.19 mmol) at room temperature. The mixture was stirred at room temperature overnight, then evaporated to 3 mL, extracted with EA, washed with brine, dried over NaS04, filtered. The filtrate was evaporated to dryness, purified by silica gel chromatography to afford compound 31K (0.35 g, 97.8 %).
Step 8: Synthesis of 31
[0283] A solution of compound 31K (200 mg) in 6 N HC1 /dioxane (3 mL/2 mL) was stirred at 100 °C for 2 h. The mixture was then evaporated to dryness and purified by prep-HPLC to afford 31 (5.6 mg).
1H NMR (400 MHz, CD30D) δ 7.04 (d, 1H), 6.71 (d, 1H), 3.57 (t, 1H), 3.20 (dd, 1H), 2.92
(d, 1H), 2.37 (m, 3H).
MS calcd for (C12H12BN3O4S2): 337
MS (ESI, positive) found: (M+l): 338
MS (ESI, negative) found: (M-l): 336
Example 32: (R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-2-hydroxy-5,7-dimethoxy-3,4- dih dro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (32)
Figure imgf000109_0001
32G 32H 32
Step 1: Synthesis of 32B (Can. J. Chem., 1989, 67, 335-344)
[0284] To a solution of compound 32A (5 g, 32.4 mmol) in DCM (50 mL) was added dropwise a solution of Br2 (10.4 g, 64.8 mmol) in DCM (20 mL) at 0 °C and the mixture was stirred at 0 °C for 1 h. To the mixture was then added a solution of Na2S203 (5.1 g, 32.4 mmol) in water (20 mL), and extracted with EtOAc, washed with saturated NaHC03 and brine. The extract was dried over Na2S04, filtered and concentrated to afford compound 32B (10 g, 99 %).
Step 2: Synthesis of 32C
[0285] To a solution of compound 32B (10 g, 32.15 mmol) and Boc20 (7 g, 32.15 mmol) in DCM (100 mL) was added DMAP (196 mg, 1.61 mmol) at room temperature. The mixture was stirred at room temperature for 3 h, then evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 32C (7.1 g, 65.3%). Step 3: Synthesis of 32D
[0286] To a solution of compound 32C (6.85 g, 16.63 mmol) in anhydrous THF (100 mL) was added dropwise n-BuLi (6.65 mL, 16.63 mmol) at -78 °C under N2. The mixture was stirred at -78 °C for 15 min, then warmed up to room temperature. Reaction mixture was diluted with EtOAc (100 mL), washed with 0.5 N HC1 (50mL) and brine, dried over NaS04. The organic extract was filtered and concentrated to afford compound 32D (5.5 g, 99%).
Step 4: Synthesis of 32E
[0287] To a solution of compound 32D (5.5 g, 16.6 mmol) and Boc20 (5.4 g, 24.8 mmol) in DCM (100 mL) was added DMAP (202 mg, 1.66 mmol) at room temperature. The mixture was stirred at room temperature for 3 h, then evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 32E (6.2 g, 85.6%).
Step 5: Synthesis of 32F
[0288] To a solution of compound 32E and Pd(PtBu3)2 (40 mg, 0.45 mmol) in THF (50 mL) was added zinc reagent of 19E (prepared as step 4 of Example 19) (25.5 mmol) at room temperature. The mixture was stirred at room temperature overnight, then evaporated to dryness. The crude product purified by silica gel chromatography to afford compound 32F (7.2 g, 78.3%).
Step 6: Synthesis of 32G
[0289] To a solution of dichloromethane (1.1 g, 12.7 mmol) in anhydrous THF (50 mL) in a three-neck flask at -100 °C, cooled with liquid nitrogen and methanol, was added dropwise n-butyllithium (3.6 mL, 8.88 mmol) through the wall of the flask over 0.5 h while keeping the internal temperature of the flask below -90 °C. After the addition, the mixture was stirred at this temperature for 30 min, To the mixture at -100 °C was added dropwise a solution of compound 32F (3 g, 6.34 mmol) in anhydrous THF (10 mL) over 0.5 h. After the addition, the mixture was slowly warmed up to room temperature and stirred overnight. The reaction solvent was evaporated to dryness to give a residue, which was purified by silica gel chromatography (PE: EA, 5: 1) to afford the compound 32G (2.4 g, 72.7%).
Step 7: Synthesis of 32H
[0290] To a solution of compound 32G (1.2 g, 2.3 mmol) and compound 31 J (367 mg, 2.8 mmol) in DCM/DMF (10 mL/3 mL) was added TEA (349 mg, 3.5 mmol) at room temperature. The mixture was stirred at room temperature overnight, then concentrated. The mixture was extracted with EA, washed with brine, dried over NaS04, filtered and evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 32H (210 mg, 16.5%).
Step 8: Synthesis of 32
[0291] A solution of compound 32H (210 mg) in TFA(90%) /TES (5 mL/1 mL) was stirred at room temperature for 2 h. The reaction was then evaporated to dryness and purified by pre-HPLC to afford 32 (32 mg, 25.4%).
1H NMR (400 MHz, CD30D) δ.6.26 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.54 (s, 1H), 3.23 (s,
1H), 2.75 (dd, 1H).
MS calcd for (C13H14BN3O6S2): 383
MS (ESI, positive) found: (M+l): 384
MS (ESI, negative) found: (M-l): 382
Example 33: (R)-3-(5-amino-l,3,4-thiadiazol-2-ylthio)-5,7-difluoro-2-hydroxy-3,4-dihydro-
2H-benzo[el[E21oxaborinine-8-carbox lic acid (33)
Figure imgf000111_0001
33
[0292] Compound 33 was prepared from 2,4-Difluoro-6-hydroxybenzoic acid (WO 2009129938) following the procedure described in Example 26 except replacing 4- amino-4H-l,2,4-triazole-3 -thiol in step 5 with 5-amino-l,3,4-thiadiazole-2-thiol. 1H NMR (400 MHz, CD3OD) δ 6.55 (t, 1H), 3.60 (t, 1H), 3.21 (dd, 1H), 2.95 (dd, 1H).
MS calcd for
Figure imgf000112_0001
359
MS (ESI, positive) found: (M+l): 360
MS (ESI, negative) found: (M-l): 358
Example 34: (3R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-2-hvdroxy-7-(methylsulfinyl)-3,4- dih dro-2H-benzo[el[E21oxaborinine-8-carboxylic acid (34)
Figure imgf000112_0002
Step 1: Synthesis of 34 A
[0293] To a solution of compound 25M (from Example 25) (2.5 g, 4.69 mmol) in DCM (100 mL) at room temperature was added oxone (14.4 g, 46.94 mmol). The mixture was stirred at 35 °C for 48 h, then filtrated and concentrated to dryness. The residue was purified by silica gel chromatography to afford compound 34A (1 g, 38.9%).
Step 2: Synthesis of 34B
[0294] To a solution of compound 34 A (210 mg, 0.35 mmol) and compound 31 J (71 mg, 0.53 mmol) in DCM/DMF (2 mL/1 mL) at room temperature was added TEA (70 mg, 0.7 mmol) and the mixture was stirred at room temperature overnight. The mixture was then evaporated to 1 mL, extracted with EA, washed with brine and dried over Na2S04. The organic extract was filtered and evaporated to dryness and purified by silica gel chromatography to afford compound 34B (150 mg, 61.5%).
Step 3: Synthesis of 34B
[0295] A solution of compound 34B (150 mg) in 90% aq.TFA (3 mL) was stirred at room temperature for 2 h. The reaction mixture was then evaporated to dryness and purified by pre-HPLC to afford 34 (18 mg, 21.7%).
1H NMR (400 MHz, CD3OD) δ 7.65 (d, IH), 7.60 (d, IH), 5.23 (d, IH), 3.72 (s, IH), 3.30 (m, lH), 3.15 (d, 1H), 2.82 (dd, 3H).
MS calcd for (C12H12BN3O5S3): 385
MS (ESI, positive) found: (M+l): 386
MS (ESI, negative) found: (M-l): 384
Example 35 : (R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-2-hvdroxy-7-(methoxymethyl)-3,4- dihvdro-2H-benzo[el[E21oxaborinine-8-carboxylic acid (35)
Figure imgf000113_0001
Step 1: Synthesis of 35 A
[0296] To a solution of compound 31G (1.1 g, 3.19 mmol) and BPO (0.077 g, 0.319 mmol) in CC14 (100 mL) at room temperature was added NBS (0.851 g, 4.78 mmol). The mixture was stirred at 100 °C overnight, then concentrated to dryness. The residue was purified by silica gel chromatography to afford compound 35A (1.3 g, 97 %).
Step 2: Synthesis of 35B
[0297] To a solution of compound 35A (1.3 g, 3.081 mmol) and MeONa (199 mg, 3.697 mmol) in MeOH (10 mL) was stirred at 80 °C for 4 h. The reaction mixture was then evaporated to dryness and purified by silica gel chromatography to afford compound 35B (700 mg, 60.9 %).
Step 3: Synthesis of 35C
[0298] To a solution of compound 35B (0.7 g, 2.01 mmol) and Pd^Bus (61.5 mg, 0.12 mmol) in THF (20 mL) was added zinc reagent of 19E (freshly prepared as in step 4 of Example 19) (3.01 mmol) at room temperature. The mixture was stirred at room temperature overnight, then evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 35C (600 mg, 61.2 %).
Step 4: Synthesis of 35D
[0299] To a solution of dichloromethane (0.209 g, 2.46 mmol) in anhydrous THF (10 mL) in a three-neck flask at -100 °C, cooled with liquid nitrogen and methanol, was added dropwise n-butyllithium (0.74 mL, 1.84 mmol) through the wall of the flask over 0.5 h while keeping the internal temperature of the flask below -90 °C. After the addition, the mixture was stirred at this temperature for 30 min, To the mixture at -100 °C was added dropwise a solution of compound 35C (0.6 g, 1.23 mmol) in anhydrous THF (10 mL) over 0.5 h. After the addition, the mixture was slowly warmed up to room temperature, and stirred overnight. The reaction solvent was evaporated to dryness to give a residue, which was purified by silica gel chromatography (PE: EA, 5: 1) to afford the compound 35D (530 mg, 80.3 %). Step 5: Synthesis of 35E
[0300] To a solution of compound 35D (520 mg, 0.97 mmol) and compound 31 J (193.5 mg, 1.45 mmol) in DCM/DMF (10 mL/5 mL) was added TEA (0.3 ml, 1.94 mmol) at room temperature. The mixture was stirred at room temperature overnight, then evaporated to 3 mL. The reaction was diluted with EtOAc, washed with brine and dried over NaS04. The organic extract was filtered, evaporated to dryness, and purified by silica gel chromatography to afford compound 35E (600 mg, 97.7 %).
Step 6: Synthesis of 35
[0301] A solution of compound 35E (200 mg) in 6 N HC1 /dioxane (4 mL/2 mL) was stirred at 100 °C for 2 h. The reaction mixture was then evaporated to dryness and purified by pre-HPLC to afford 35 (17.1 mg).
IH NMR (400 MHz, CD30D) δ 7.17 (d, IH), 6.99 (d, IH), 4.59 (s, 2H), 3.59 (t, IH), 3.39 (s, 3H), 3.22 (dd, 2H), 2.93 (dd, 2H).
MS calcd for (C13H14BN3O5S2): 367
MS (ESI, positive) found: (M+l): 368
MS (ESI, negative) found: (M-l): 366
Example 36: (R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-7-chloro-2-hvdroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (36)
Figure imgf000116_0001
36A 36B 36C 36D ™ PBu3)2
Figure imgf000116_0002
36
Step 1: Synthesis of 36B
[0302] To a solution of compound 36A (5 g, 24.1 mol) and Boc20 (6.61 g, 31.33 mol) in DCM (50 mL) at rt was added DMAP (0.147 g, 1.205mol).The mixture was stirred at rt for 24 h and concentrated to dryness. The crude product was purified by silica gel chromatography to afford compound 36B (7 g, 94.6%).
Step 2: Synthesis of 36C
[0303] To a solution of compound 36B (500 mg, 1.634 mmol) in THF (5 mL) at - 78 °C was added freshly prepared LDA solution (0.72 mL, 1.797 mmol). The mixture was stirred at -78 °C for 1 h, then warmed up slowly to rt. The reaction was then quenched with 1 N HCl (aq., 5 mL), extracted with EtOAc, washed with water and brine and dried over Na2S04. The extract was filtered and the filtrate was evaporated to dryness to afford compound 36C (484 mg, 80.1%). The crude product was used directly to the next step without further purification. Step 3: Synthesis of 36D
[0304] To a solution of compound 36C (484 mg, 1.57 mol) and Boc20 (445.6 mg, 2.044 mol) in DCM (4 mL) at rt was added DMAP (9.6 mg, 0.0786 mmol). The mixture was stirred at r.t. overnight and evaporated to dryness. The residue was purified by silica gel chromatography to afford compound 36D (598.6 mg, 93.6%).
Step 4: Synthesis of 36E
[0305] To a mixture of Zn powder (1.06 g, 16.3 mol) and compound 19E (0.5 g, 0.00183 mol) in anhydrous THF (2 mL) was added DIBAL-H (0.217 mL, 0.325 mmol, 1.5 M in toluene) at rt, the mixture was stirred for 5 min, then more compound 19E (1.274 g, 0.0047 mol) in anhydrous THF (18 mL) was added dropwise into the mixture over 20 min. The reaction mixture was warmed up to 50 °C and stirred at this temperature for 1 h. The resulting clear solution of the top layer was transferred into a solution of compound 36D (596 mg, 1.47 mol) and Pd(t-Bu3P)2 (74.98 mg, 0.15 mmol) in THF (5 mL). The mixture was then stirred at rt under N2 for 1 h and concentrated. The crude product was purified by silica gel chromatography directly to afford the compound 36E (460 mg, 62.2%).
Step 5: Synthesis of 36F
[0306] To a solution of dichloromethane (0.12 mL, 153 mg, 0.624 mmol, 2.0 eq) in anhydrous THF (4 mL) in a three-neck flask at -100 °C, cooled with liquid nitrogen and methanol, was added dropwise n-butyllithium (2.5 M in hexane, 0.54 mL, 1.35 mmol, 1.5 eq) through the wall of the flask over 1 h while keeping the internal temperature of the flask below -90 °C. After the addition, the mixture was stirred at this temperature for 30 min. To the mixture at -100 °C was added dropwise a solution of compound 36E (468 mg, 0.899 mmol, 1.0 eq) in anhydrous THF (8 mL) over 1 h. After the addition, the mixture was slowly warmed up to room temperature, and stirred overnight. The reaction solvent was evaporated to dryness to get crude compound 36F (440 mg, 85.9%). Step 6: Synthesis of 36g
[0307] To a solution of compound 36Γ (440 mg, 0.7732 mmol) in DCM (5 mL)/DMF(5 mL) was added 5-amino-l,3,4-thiadiazole-2-thiol (113.12 mg, 0.85 mol), TEA(156.2 mg, 0.1.54 mmol), the mixture was stirred at room temperature for 16 h before it was concentrated in vacuo. The residue was purified by column chromatography (PE/EA, v/v, 1/10-1/2) to afford the compound of 36G (369.6 mg, 71.7 %).
Step 7: Synthesis of 36
[0308] A solution of compound 36G (369 mg, 0.554 mmol) in TFA (90%)/TES (6 mL/0.5 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure. The residual oil was purified by pre-HPLC to afford the compound of 36 (17.1 mg).
1H NMR (400 MHz, CD3OD) δ 7.02 (d, 1H), 6.81 (d, 1H), 3.54 (d, 1H), 3.30 (dd, 1H), 2.93 (dd, 1H).
MS calcd for (C11H9BCIN3O4S2): 357
MS (ESI, positive) found: (M+l): 358
MS (ESI, negative) found: (M-l): 356
Example 37: (R)-3-(5-amino-L3,4-thiadiazol-2-ylthio)-6,7-difluoro-2-hvdroxy-3,4-dihydro-
2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (37)
Figure imgf000118_0001
37
[0309] Compound 37 was made starting from 3,4-difluorophenol following procedures described in Example 38.
1H NMR (400 MHz, CD3OD) δ 7.15 (t, 1H), 3.52 (t, 1H), 3.25 (dd, 1H), 2.85 (dd, 1H).
MS calcd for (C11H8BF2N3O4S2): 359 MS (ESI, positive) found: (M+l): 360
MS (ESI, negative) found: (M-l): 358
Example 38 : (R)-3 -(5 -amino- 1 ,3 ,4-thiadiazol-2-ylthio)-5 ,6,7-trifluoro-2-hydroxy-3 ,4- dihvdro-2H-benzo[el[E21oxaborinine-8-carboxylic acid (38)
Figure imgf000119_0001
Step 1: Synthesis of 38B
[0310] To a solution of compound 38A (6.5 g, 60.19 mmol) in DCM (24 mL) was added Boc20 (6.5 g, 71.41 mmol) and DMAP (6.5 g, 71.41 mmol) at room temperature. The mixture was stirred at rt overnight. The reaction was then concentrated and purified by silica gel chromatography to afford the compound 38B (3.3 g, 33.6 %).
Step 2: Synthesis of 38C
[0311] To a solution of compound 38B (3.3 g, 13.3 mmol) in THF (25 mL) at -78 °C was added freshly prepared LDA solution (5.85 mL, 14.6 mmol). The mixture was stirred at -78 °C for 1 h, then warmed up slowly to rt. The reaction was quenched with 1 N HCl (aq., 5 mL), extracted with EtOAc, washed with water and dried. The extract was filtered and the filtrate was evaporated to dryness to afford compound 38C (3.05 g, 92%). The crude product was used directly in the next step without further purification.
Step 3: Synthesis of 38D
[0312] To a solution of compound 38C (3 g, 12.1 mmol) and NBS (2.26 g, 12.70 mmol) in DCM (50 mL) was added DIA (0.34 mL, 2.42 mmol) at 0 °C under N2. The mixture was stirred at room temperature for 2 h, then washed with water, brine and dried over Na2S04. The extract was filtered and evaporated to dryness and crude was purified by silica gel chromatography to afford the compound 38D (4 g, 100%).
Step 4: Synthesis of 38E
[0313] To a solution of compound 38D (4 g, 12.23 mmol) in DCM (50 mL) was added Boc20 (3.47 g, 15.9 mmol) and DMAP (75 mg, 0.61 mmol) at room temperature. The reaction was stirred at room temperature for overnight. The mixture was concentrated and purified by silica gel chromatography to afford the compound 38E (3.7 g, 71.0 %).
Step 5: Synthesis of 38F
[0314] To a solution of compound 38E (303 mg, 0.71 mmol) and Pd(PlBu3)2 (18.1mg, 0.04 mmol) in anhydrous THF (10 mL) was added zinc reagent of 19E (freshly prepared as in step 4 of Example 19) (1.06 mmol) at room temperature. The mixture was stirred at room temperature overnight, then evaporated to dryness. The crude product was purified by silica gel chromatography to afford the compound 38F (330 mg, 86.1 %).
Step 6 Synthesis of 38G
[0315] To a solution of dichloromethane (104 mg, 1.22 mmol) in anhydrous THF (3 mL) in a three-neck flask at -100 °C, cooled with liquid nitrogen and methanol, was added dropwise n-butyllithium (0.37 mL, 0.92 mmol), through the wall of the flask over 0.5 h while keeping the internal temperature of the flask below -90 °C. After the addition, the mixture was stirred at this temperature for 30 min, To the mixture at -100 °C was added dropwise a solution of compound 38F (330 mg, 0.61 mmol) in anhydrous THF (3 mL) over 0.5 h. After the addition, the mixture was slowly warmed up to room temperature, and stirred overnight. The reaction solvent was evaporated to dryness, the residue was dissolved in DCM and washed with water and brine, dried over Na2S04, filtered and concentrated to afford the compound 38G (290 mg, 80.7 %).
Step 7: Synthesis of 38H
[0316] To a solution of compound 38G (290 mg, 0.49 mmol) in DCM (5 mL) was added compound 31 J (66 mg, 0.49 mmol) and TEA (0.1 mL, 0.74 mmol) at room temperature. The reaction was stirred at room temperature overnight. The mixture was then diluted with DCM, washed with water, brine and dried over Na2S04. The extract was filtered and evaporated to dryness, purified by silica gel chromatography to afford the compound 38H (114 mg, 33.7%).
Step 8: Synthesis of 38
[0317] To a solution of compound 38H (109 mg, 0.16 mmol) in 90%TFA (5 mL) was added TES (0.2 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The mixture was then evaporated to dryness and purified by pre-HPLC to afford the compound 38 (6.3 mg).
1H NMR (400 MHz, CD3OD) δ 3.56 (t, 1H), 3.30 (s, 1H), 2.93 (dd, 1H).
MS calcd for (CnH7BF3N304S2): 377
MS (ESI, positive) found: (M+l): 378
MS (ESI, negative) found: (M-l): 376
Example 39 : (R)-3 -( 1 H- 1 ,2,3 -triazol-4-ylthio)-2-hydroxy-7-methoxy-3 ,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (39)
H
Figure imgf000122_0001
39
[0318] Compound 39 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with lH-l,2,3-triazole-4- thiol.
1H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.02 (d, 1H), 6.48 (d, 1H), 3.85 (s, 3H), 3.75 (t, 1H), 3.15 (dd, 1H), 2.70 (dd, 2H).
MS calcd for (C12H12BN305S): 321
MS (ESI, positive) found: (M+l): 322
MS (ESI, negative) found: (M-l): 320
Examples 40 and 41 : (R -3-(l-(3-carboxypropyl -lH-L2,4-triazol-3-ylthio)-2-hydroxy-7- methoxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (40) and (R)-3-(4-(3- carboxypropyl)-4H-l,2,4-triazol-3-ylthio)-2-hvdroxy-7-methoxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (41)
Figure imgf000123_0001
Step 1: Synthesis of 40B
[0319] To a solution of compound 40A (2 g, 19.78 mmol) and TrCl (6.05 g, 22.76 mmol) in DCM (20 ml) was added TEA (6.0 g, 59.34 mmol). The mixture was stirred at 30 °C for 24 h. The reaction was quenched with water (20 mL) and then extracted with DCM. The extract was washed with water, brine and dried over Na2S04. The organic layer was filtered, evaporated to dryness, and the crude product was purified by silica gel chromatography to afford compound 40B (2.6 g, 38.8%).
Step 2: Synthesis of 40D and 40E
[0320] To a solution of compound 40B (2.48 g, 7.23 mmol) and compound 40C (2.62 g, 9.4 mmol) in DMF (20 mL) was added K2C03 (1.99 g, 14.46 mmol) under N2. The reaction mixture was stirred at 25 °C for 24 h. The reaction was diluted with and then extracted with hexane:EtOAc (1 : 1) mixture. The mixture was washed with water, brine and dried over Na2S04. The extract was filtered and evaporated to dryness, purified by silica gel chromatography to afford compound 40D (1.165 g, 36.4%>), and compound 40E (0.98 g, 30.6%).
Step 3: Synthesis of 40Γ and 40G
[0321] A solution of compound 40D (1.165 g, 2.6 mmol) in 90% TFA/TES (10 mL/1 mL) was stirred at 25 °C for 2 h, evaporated to dryness, purified by silica gel chromatography to afford compound 40F (550 mg, 98%).
A solution of compound 40E (0.98 g, 2.2 mmol) in 90% TFA/TES (10 mL/1 mL) was stirred at 25 °C for 2 h, evaporated to dryness, purified by silica gel chromatography to afford compound 40G (420 mg, 95.5%).
Step 4: Synthesis of 40H and 401
[0322] To a solution of compound 40F (181 mg, 0.90 mmol) and compound 26E (463 mg, 0.82 mmol) in DCM (5 mL) was added TEA (273 mg, 2.7 mmol). The mixture was stirred at 25 °C for 24 h and evaporated to dryness. The crude was purified by silica gel chromatography to afford compound 40H (330 mg, 55%), To a solution of compound 40G (168.5 mg, 0.84 mmol) and compound 26E (430 mg, 0.76 mmol) in DCM (5 mL) was added TEA (254 mg, 2.5 mmol). The mixture was stirred at 25 °C for 24 h, evaporated to dryness. The crude was purified by silica gel chromatography to afford compound 401 (201 mg, 39.8%).
Step 5: Synthesis of 40 and 41
[0323] A solution of compound 40H (325 mg, 0.45 mmol) in 3 N HC1 (3 mL) and 1 ,4-dioxane (3 mL) was stirred at 100 °C for 1 h. The mixture was then evaporated to dryness and purified by pre-HPLC to afford 40 (19.4 mg).
1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.01 (d, 1H), 6.43 (d, 1H), 4.02 (t, 2H), 3.81 (d, 1H), 3.79 (s, 3H), 3.11 (dd, 1H), 2.85 (dd, 1H), 2.17 (t, 2H), 2.02 (t, 2H).
MS calcd for (Ci6Hi8BN307S): 407
MS (ESI, positive) found: (M+l): 408
MS (ESI, negative) found: (M-l): 406
[0324] A solution of compound 401 (200 mg, 0.27 mmol) in 3 N HC1 (3 mL) and 1 ,4-dioxane (3 mL) was stirred at 100 °C for 1 h. The mixture was then evaporated to dryness and purified by pre-HPLC to afford 41 (39.4 mg).
1H NMR (400 MHz, CD3OD) δ 9.07 (s, 1H), 7.01 (d, 1H), 6.43 (d, 1H), 4.26 (t, 2H), 3.74 (s, 3H), 3.52 (t, 1H), 3.05 (dd, 1H), 2.80 (dd, 2H), 2.30-2.09 (m, 4H).
MS calcd for (C16H18BN307S): 407
MS (ESI, positive) found: (M+l): 408
MS (ESI, negative) found: (M-l): 406
Example 42 : (R)-3 -(5 -amino- 1 ,3 ,4-thiadiazol-2-ylthio)-6-chloro-2-hydroxy-7-methoxy-3 A-
Figure imgf000126_0001
42E 42
Step 1: Synthesis of 42 A
[0325] To a solution of compound 26C (from Example 26) (6 g, 14.93 mmol) in CHCI3 (100 mL) at room temperature was added SO2CI2 (10 g, 74.63 mmol). The mixture was stirred at 40 °C in the glass tube reactor for 12 h and then cooled to room temperature. The precipitated product was filtered to afford pure compound 42A (2.4 g, 57.4 %).
Step 2: Synthesis of 42B
[0326] To a solution of compound 42A (2.4 g, 8.54 mmol) and B0C2O (7.45 g, 34.16 mmol) in tert-BuOH/THF (30 mL/30 mL) at room temperature was added DMAP (104 mg, 0.85 mmol). The reaction was stirred at 65 °C overnight. The mixture was then cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography to afford compound 42B (3.4 g, 94.1%). Step 3: Synthesis of 42C
[0327] To a solution of compound 42B (3.4 g, 7.78 mmol) and Ρά(ΡιΒ¾)2 (400 mg, 0.78 mmol) in THF (100 mL) at room temperature was added zinc reagent of 19E (freshly prepared as in step 4 of Example 19) (10.11 mmol). The mixture was stirred at room temperature overnight, then evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 42C (3.1 g, 72.3%).
Step 4: Synthesis of 42D
[0328] To a solution of dichloromethane (0.96 g, 11.25 mmol) in anhydrous THF (40 mL) in a three-neck flask at -100 °C, cooled with liquid nitrogen and methanol, was added dropwise n-butyllithium (3.2 mL, 7.88 mmol), through the wall of the flask over 0.5 h while keeping the internal temperature of the flask below -90 °C. After the addition, the mixture was stirred at this temperature for 30 min, To the mixture at -100 °C was added dropwise a solution of compound 42C (3.1 g, 5.63 mmol) in anhydrous THF (20 mL) over 0.5 h. After the addition, the mixture was slowly warmed up to room temperature and stirred overnight. The reaction solvent was evaporated to dryness to give a residue, which was purified by silica gel chromatography (PE: EA, 25: 1) to afford the compound 42D (2.5 g, 74.2%).
Step 5: Synthesis of 42E
[0329] To a solution of compound 42D (400 mg, 0.67 mmol) and compound 31 J (133 mg, 1.0 mmol) in DCM/DMF (3 mL/1 mL) was added TEA (70 mg, 0.7 mmol) at room temperature. The reaction was stirred at room temperature overnight and then evaporated to 1 mL. The mixture was then extracted with EtOAc, washed with brine and dried over Na2S04. The organic extract was filtered and evaporated to dryness. The resulting crude product was purified by silica gel chromatography to afford compound 42E (330 mg, 70.8%).
Step 6: Synthesis of 42
[0330] A solution of compound 42E (200 mg, 0.287mmol) in TFA(90% aq.)/TES (4 mL/1 mL) was stirred at room temperature for 2 h. The reaction was then evaporated to dryness. The crude product was purified by pre-HPLC to afford 42 (32 mg). 1H NMR (400 MHz, CD3OD) δ 7.1 1 (s, 1H), 3.82 (s, 3H), 3.53 (t, 1H), 3.14 (dd, 1H), 2.88 (dd, 1H).
MS calcd for (Ci2HnBCl 305S2): 387
MS (ESI, positive) found: (M+l): 388
MS (ESI, negative) found: (M-l): 386
Example 43 : (R)-3 -(2-(5 -amino- 1 ,3 ,4-thiadiazol-2-yl)ethylthio)-2-hydroxy-7-methoxy-3 A- dih dro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (43)
Figure imgf000128_0001
Step 1: Synthesis of 43C
[0331] To a solution of compound 43A (6.5 g, 60.19 mmol) in sulfuric acid (24 mL) was added compound 43B (6.5 g, 71.41 mmol) at rt. The reaction was stirred at 110 °C for 1 h. The mixture was then cooled to rt and poured into ice-water and neutralized with ammonia. The resulting precipitate was filtered, rinsed with water and dried under reduced pressure to afford the compound 43C (3.3 g, 33.6 %). Step 2: Synthesis of 43D
[0332] To a solution of compound 43C (1 g, 6.11 mmol) in DMF (10 mL) was added AcSK (2.1 g, 18.33 mmol) at room temperature. The reaction was stirred at room temperature overnight. The mixture was then concentrated and crude product was purified by silica gel chromatography to afford compound 43D (720 mg, 58.0%).
Step 3: Synthesis of 43E
[0333] To a solution of compound 43D (110 mg, 0.54 mmol) in MeOH/water (2.5 mL/5 mL) was added NaOH (43 mg, 1.08 mmol) at rt. The mixture was stirred at rt for lh and MeOH was removed under vacuum. The water layer was lyophilized to afford compound 43E. The crude 43E was directly used in next step without further purification.
Step 4: Synthesis of 43F
[0334] To a solution of compound 43E and compound 26E (306 mg, 0.54 mmol) in DCM/DMF (5 mL/0.5 mL) was added TEA (0.1 1 mL, 0.81 mmol) at room temperature. The reaction was stirred at room temperature overnight. The mixture was then washed with water, brine and dried over Na2S04. The extract was filtered and evaporated to dryness. The crude product was purified by silica gel chromatography to afford compound 43F (245 mg, 65.6% overall two steps).
Step 5: Synthesis of 43
[0335] To a solution of compound 43F (214 mg, 0.31 mmol) and z'-BuB(OH)2 (63.3 mg, 0.62 mmol) in THF (3 mL) was added conc.HCl (3 mL) at room temperature. The reaction was stirred at room temperature for 1 h and concentrated to dryness. The crude product was purified by pre-HPLC to afford 43 (10 mg).
1H NMR (400 MHz, CD3OD) δ 7.20-7.00 (m, 1 H), 6.50-6.45 (m, 1H), 3.75 (s, 3H), 3.15-
2.50 (m, 6H), 2.11 (m, 1H).
MS calcd for (Ci4Hi6BN305S2): 381
MS (ESI, positive) found: (M+l): 382
MS (ESI, negative) found: (M-l): N/A Example 44: (R)-3-(5-amino-l ,3,4-thiadiazol-2-ylthio)-2 ,7-dihydroxy-3,4-dihydro-2H- benzo[e][l,2]oxaborinine-8-carboxylic acid (44)
Figure imgf000130_0001
Step 1: Synthesis of 44B
[0336] To a solution of 44A (10 g, 0.065 mol) in DCM (300 mL) at -78 oC was added DIA (3.28 g, 0.033 mol), and NBS (12.7 g, 0.071 mol). The reaction mixture was stirred at room temperature for 16 hours before it was concentrated to dryness. The residue was diluted with 1 N HC1 (500 mL) at 0 oC. The precipitate was filtered to afford compound 44B (10.5 g, 69.4 %) as white solid.
Step 2: Synthesis of 44C
[0337] To a solution of compound 44B (10.5 g, 0.047 mol) in THF (50 mL) was added Boc20 (61.8 g, 0.283 mol), DMAP (0.576 g, 0.005 mol) and lBuOH (25 mL). The resulting solution was stirred at 60 °C for 16 hours before it was concentrated in vacuo. The residue was then passed through a silica gel column (ethyl acetate/hexanes, v/v, 1/200-1/50) to afford compound 44C (17.1 g, 74%) as colorless oil. Step 3: Synthesis of 44D
[0338] To a mixture of Zn powder (7.02 g, 0.107 mol) and compound 19E (100 mg, 0.37 mmol) in anhydrous THF (60 mL) was added DIBAL-H (1.5 mL, 2.15 mmol, 1.5 M in toluene) at room temperature. The mixture was stirred at room temperature for 5 min, then more compound 19E (12 g, 0.043 mmol) in anhydrous THF (60 mL) was added dropwise into the mixture over 20 min. The reaction mixture was warmed to 50 oC and stirred at this temperature for 1 hour before cooling to room temperature. The top layer of clear solution was transferred into a mixture of compound 44C (8.9 g, 18.2 mmol) and Pd(tBu3P)2 (279 mg, 5.46 mmol) in THF (120 mL) at room temperature under N2. After stirring at room temperature for 1 hour, the reaction mixture was concentrated, and purified by column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/50) to afford compound 44D (9.5 g, 86 %) as colorless oil.
Step 4: Synthesis of 44E
[0339] To a solution of dichloromethane (2.68 g, 0.032 mol) in anhydrous THF (100 mL) was added dropwise n-butyllithium (2.5 M in hexane, 7.6 mL, 0.019 mol) along the wall of the flask over 1 h at -100 °C (cooled with liquid nitrogen and methanol), while keeping the internal temperature below -90 °C. After the addition, the mixture was stirred at -100 °C for 30 min before slow addition of the solution of compound 44D (9.5 g, 0.016 mol) in anhydrous THF (60 mL) over 1 h at -100 °C. The reaction mixture was slowly warmed up to room temperature over a period of 6 hours and stirred overnight. The solvent was evaporated and the residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/200-1/50) to afford compound 44E (9.1 g, 88 %) as yellow oil.
Step 5: Synthesis of 44F
[0340] To a solution of compound 44E (9.1 g, 0.014 mol) in DCM (100 mL) was added 5-amino-l,3,4-thiadiazole-2-thiol (31J) (2.1 g, 0.016 mol) and TEA (2.06 g, 0.020 mol). The mixture was stirred at room temperature for 16 h before it was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/DCM, v/v, 1/10-1/2) to afford compound 44F (9.1 g, 87 %) as white solid. Step 6: Synthesis of 44G
[0341] To a solution of compound 44Γ (3 g, 4 mmol) in anhydrous THF (30 n L) was added pyrrolidine (285 mg, 4 mmol). The mixture was stirred at r.t. for 3 h before it was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/DCM, v/v, 1/10-1/2) to afford compound 44G (2.25 g, 87 %) as white solid.
Step 7: Synthesis of 44
[0342] A solution of compound 44G (170 mg, 0.263 mmol) in TFA (90%)/TES (6 mL/0.5 mL) was stirred at room temperature overnight before it was evaporated to dryness. The residue oil was purified by pre-HPTC to afford 44 (1 1 mg).
1H NMR (400 MHz, CD3OD) δ 7.17 (t, 1 H), 6.45 (d, IH), 3.65 (m, IH), 3.16 (dd, IH), 2.90 (dd, IH).
MS calcd for (CnH10BN3O5S2): 339
MS (ESI, positive) found: (M+l): 340
MS (ESI, negative) found: (M-l): 338
Example 45: (R)-7-fluoro-2-hvdroxy-3-(thiazol-2-ylthio)-3,4-dihydro-2H- benzo[el [E21oxaborinine-8-carboxylic acid (45)
Figure imgf000132_0001
45
[0343] Compound (45) was prepared from 19G (example 19) following methods described in steps 5 and 6 of example 1 utilizing 2-mercaptothioI in step 5
1H NMR (400 MHz, CD3OD) δ 7.78(d, 1 H), 7.52 (d, IH), 7.23 (t, IH), 6.53 (t, IH), 3.74 (t, IH), 3.43-3.23 (m, IH), 2.85-2.80 (m, IH).
MS calcd for (CnHgBFNC^): 325
MS (ESI, positive) found: (M+l): 326
MS (ESI, negative) found: (M-l): 324 Example 46 : (R)-3 -(azetidin-3 -ylthioV 7-fluoro-2-hydroxy-3 ,4-dihydro-2H- benzo[el[E21oxaborinine-8-carboxylic acid (46)
Figure imgf000133_0001
46
[0344] Compound (46) was prepared from 19G (example 19) following methods described in steps 5 and 6 of example 1 utilizing N-Boc-3-mercapto-azetidine in step 5.
1H NMR (400 MHz, CD3OD) δ 7.18-7.05 (m, 1 H), 6.52 (q, IH), 4.38-4.05 (m, 2H), 4.03- 3.92 (m, IH), 3.78-3.65 (m, 2H), 3.15-2.63 (m, 2H), 2.53-2.42 (m, IH).
MS calcd for (C12H13BFN04S): 297
MS (ESI, positive) found: (M+l): 298
MS (ESI, negative) found: (M-l): 296
Example 47: (R)-2-hvdroxy-7-methoxy-3-(thiazol-2-ylthio)-3,4-dihydro-2H- benzo[el[E21oxaborinine-8-carboxylic acid (47)
Figure imgf000133_0002
47
[0345] Compound 47 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3-thiol in step 5 with 2-mercaptofhiazole. 1H NMR (400 MHz, CD3OD) δ 7.62 (d, 1 H), 7.52 (d, IH), 7.0 (d, IH), 6.42 (d, IH), 3.72 (s, 3H), 3.2-3.0 (m, 2H), 2.8 (m, 2H).
MS calcd for (Ci3Hi2BN05S2): 337
MS (ESI, positive) found: (M+l): 338 MS (ESI, negative) found: (M-l): N/A
Example 48j (3R)-7-fluoro-2-hvdroxy-3-(thiadiazol-5-ylsulfanyl)-3,4-dihydro-E2- benzoxaborinine-8-carboxylic acid (
Figure imgf000134_0001
[0346] Compound 48 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 5 -mercapto- 1 ,2,3 -thiadiazole (US4758557).
1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 7.22-7.15 (m, 1H), 6.58-6.54 (m, 1H), 3.30- 3.05 (m, 3H).
MS calcd for (CnHgBFNiC Si): 326
MS (ESI, positive) found: (2M+1): 653
MS (ESI, negative) found: (2M-1): 651
Example 49: (3R)-3-(2-amino-2-oxo-ethyl)sulfanyl-7-fluoro-2-hvdroxy-3,4-dihydro-l ,2- benzoxaborinine-8-carboxylic acid (49)
Figure imgf000134_0002
49
[0347] Compound 49 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 2-mercaptoacetamide (US4758557).
1H NMR (400 MHz, CD3OD): δ 7.07 (m, 1H), 6.52 (m, 1H), 3.58 (m, 1H), 3.22 - 3.13 (m, 2H), 2.99 (m, 1H), 2.64 (m, 1H).
MS calcd for (CnHnBFN05S): 299 MS (ESI, positive) found: (M+l):300
MS (ESI, negative) found: (M-l): 298
Example 50: (3R)-3 - [2-(5 -amino- 1 ,3 ,4-thiadiazol-2-yl)ethylsulfanyl] -7-fluoro-2-hydroxy-3 ,4- dihydro- l,2-benzoxaborinine-8-carboxylic acid (50)
Figure imgf000135_0001
50
[0348] Compound 50 was prepared following methods described in Example 43 except replacing 26E in step 4 with 19G of Example 19.
1H NMR (400 MHz, CD3OD): δ 7.28-7.20 (m, 1H), 6.55-3.45 (m, 1H), 3.60-1.77 (m, 7H). MS calcd for (¾Η13ΒΡΝ30482): 369
MS (ESI, positive) found: (M+l): 370
Example 51 : (3R)-3 -(cvanomethylsulfanyl)-7-fluoro-2-hydroxy-3 ,4-dihydro- 1 ,2- benzoxaborinine-8-carboxylic acid
Figure imgf000135_0002
[0349] Compound 51 was prepared following methods described Example 19 replacing MeOI l-potassium carbonate in step 6 with mercaptoacetonitrile sodium salt ( WO K) 135504).
1H NMR (400 MHz, CD3OD): δ 7.30-7.22 (m, 1H), 6.50-6.35 (m, 1H), 3.75-3.60 (m, 1H), 3.22- 3.13 (m, 2H), 2.90 (m, 1H), 2.64 (m, 1H).
MS calcd for (CnH9BFN04S): 281
MS (ESI, positive) found: (M+l): 282 MS (ESI, negative) found: (M-l): 280
Example 52: (3R)-3-(2-aminothiazol-5-yl sulfanyl-7-fluoro-2-hvdroxy-3,4-dihydro-E2- benzoxaborinine-8-carboxylic aci
Figure imgf000136_0001
52
[0350] Compound 49 was prepared from 19G (Example 19) following methods described in step 5 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 2- aminothiazole-5-thiol.
[0351] Final deprotection was done by isobutyl boronic acid following procedure described in step 7 of example 19.
1H NMR (400 MHz, CD3OD): δ 7.31-6.96 (m, 2H), 6.57-6.51 (m, 1H), 3.13-2.77 (m, 3H). MS calcd for (CnH^BFNaC^): 340
MS (ESI, positive) found: (M+l): 341
MS (ESI, negative) found: (M-l): 339
Example 53: (3R)-3-(5-carbamoylthiazol-2-yl)sulfanyl-7-fluoro-2-hvdroxy-3,4-dihydro-E2- benzoxaborinine-8-carboxylic acid (53)
Figure imgf000136_0002
[0352] Compound 53 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 and replacing 2-mercapto-l,3,4-thiadiazole with 2- sulfanylthiazole-5-carboxamide.
1H NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.11 (t, J = 7.2 Hz, 1H), 6.59 (t, J = 8.4 Hz, 1H), 3.77-3.74 (m, 1H), 3.21-3.16 (m, 1H), 2.98-2.94 (m, 1H). MS calcd for (C13H10BFN2O5S2): 368
MS (ESI, positive) found: (M+l): 369
Example 54: (3R)-3-(4-carbamoylthiazol-2-yl)sulfanyl-7-fluoro-2-hydroxy-3,4-dihydro-l ,2- benzoxaborinine-8-carboxylic acid (54)
Figure imgf000137_0001
54
[0353] Compound 54 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 2-sulfanylthiazole-4-carboxamide as described in Sanghvi et. al., J Heterocyclic Chem. , 1988 , 25, (623-633), which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 8.13 (s, 1H), 7.11 (t, J = 7.2 Hz, 1H), 6.59 (t, J = 8.8 Hz, 1H), 3.81-3.80 (m, 1H), 3.31-3.18 (m, 1H), 2.98-2.94 (m, 1H).
MS calcd for (C13H10BFN2O5S2): 368
MS (ESI, positive) found: (M+l): 369
MS (ESI, negative) found: (M-l): 367
Example 55 : (3R)-7-fluoro-2-hydroxy-3 - [ [5 -(trifluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl] sulfanyl] - 3,4-dihvdro-l,2-benzoxaborinine-8-carboxylic acid (55)
Figure imgf000137_0002
55 [0354] Compound 55 was prepared from 19G (Example 19) following methods described in step 5 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with 5- (trifluoromethyl)-l,3,4-thiadiazole-2-thiol as described in PCT publication WO 2010/03081 1. Wagman et al., which is incorporated herein by reference in its entirety..
[0355] Final deprotection was done by isobutyl boronic acid following procedure described in step 7 of example 19.
1H NMR (400 MHz, CD3OD): δ 7.1 1 (t, J = 7.2 Hz, 1H), 6.58 (t, J = 8.8 Hz, 1H), 3.74-3.72 (m, 1H), 3.23-3.18 (m, 1H), 3.04-2.99 (m, 1H).
MS calcd for (C12H7BF4N204S2): 394
MS (ESI, positive) found: (M+l): 395
Example 56: (3R)-3-(4-carbamoyl-2-methyl-pyrazol-3-yl)sulfan l-7-fluoro-2-hydroxy-3,4-
Figure imgf000138_0001
dihydro- 1 ,2-benzoxaborinine-8-carboxylic acid (56)
[0356] Compound 56 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with l-methyl-5-sulfanyl-pyrazole-4-carboxamide.
1H NMR (400 MHz, CD3OD): δ 7.87 (s, 1H), 7.11-7.09 (m, 1H), 6.52-6.47 (m, 1H), 3.96- 3.78 (m, 1H), 3.39 (s, 3H), 3.29-2.81 (m, 1H), 0.84-0.81 (m, 1H).
MS calcd for (Ci4Hi3BFN305S): 365
MS (ESI, positive) found: (M+l): 366
MS (ESI, negative) found: (M-l): 364
Example 57: (3R)-3 - [5 -(aminomethyl)thiazol-2-yl] sulfanyl-7-fluoro-2-hydroxy-3 ,4-dihydro- l,2-benzoxaborinine-8-carboxylic acid (57)
Figure imgf000139_0001
[0357] Compound 57 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 and replacing 2-mercapto-l,3,4-thiadiazole with 5- (aminomethyl)thiazole-2-thiol in step 5.
1H NMR (400 MHz, CD3OD): δ 7.77 (s, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.55 (t, J = 8.8 Hz, 1H), 4.36-4.31 (m, 2H), 3.76-3.74 (m, 1H), 3.18-3.13 (m, 1H), 2.96-2.91 (m, 1H).
MS calcd for (CBH^BF^C^): 354
MS (ESI, positive) found: (M+l): 355
MS (ESI, negative) found: (M-l): 353
Example 58: (3R)-7-fluoro-3-(5-formamidothiazol-2-yl)sulfanyl-2-hydroxy-3,4-dihydro-l,2-
Figure imgf000139_0002
[0358] Compound 58 was prepared from 19G (Example 19) following method described in step 5 of Example 1 by replacing 2-mercapto-l,3,4-thiadiazole with 5- am i not h iazo 1 e-2-t h i o 1 (US2013/317021) followed by formylation o the resulting compound with N-formylbenzotriazole as described in Katritzky. Synthesis, 1995 (5); 503-505, which is incorporated herein by reference in its entirety. [0359] The final deprotection was done by following the method described in step 6 of Example 1.
1H NMR (300 MHz, CD3OD): δ 8.27 (s, 1H), 7.48 (s, 1H), 7.11 (t, J= 7.2 Hz, 1H), 6.60 (t, J = 8.4 Hz, 1H), 3.89-3.87 (m, 1H), 2.93-2.88 (m, 2H).
MS calcd for (C13H10BFN2O5S2): 368
MS (ESI, positive) found: (M+l): 369
MS (ESI, negative) found: (M-l): 397
Example 59: (3R)-7-fluoro-2-hvdroxy-3-(E3,4-thiadiazol-2-ylsulfanyl)-3,4-dihydro-E2- benzoxaborinine-8-carboxylic acid (59)
Figure imgf000140_0001
59
[0360] Compound 59 was prepared from 19G (Example 19) following methods described in steps 5 and 6 of Example 1 except replacing 2-mercapto-l,3,4-thiadiazole with l,3,4-thiadiazole-2-thiol in step 5.
Ή NMR (400 MHz, CD3OD): 5 9.23 (s, 1H), 7.12 (t, J= 7.2 Hz, 1H), 6.57 (t, J= 9.2 Hz, 1H), 3.76 (s, 1H), 3.21-2.95 (m, 2H).
MS calcd for (CiiHsBF^C^): 326
MS (ESI, positive) found: (M+l): 327
Example 60: (3R)-2-hydroxy-7-methoxy-3-(thiadiazol-5-ylsulfanyl)-3,4-dihydro-E2- benzoxaborinine-8-carboxylic acid (60)
Figure imgf000140_0002
60 [0361] Compound 60 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 5-mercapto-l,2,3- thiadiazole as described in US Patent No. 4758557, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 7.19-7.06 (m, 1H), 6.54-6.39 (m, 1H), 3.85- 3.30 (m, 3H), 3.14-2.85 (m, 3H).
MS calcd for (C12HnBN205S2): 338
MS (ESI, positive) found: (2M+1): 677
MS (ESI, negative) found: (2M-1): 675
Example 61 : (3R)-3-(4-carbamoylthiazol-2-yl)sulfanyl-2-hvdroxy-7-methoxy-3,4-dihydro-
E2-benzoxaborinine-8-carboxylic acid (61)
Figure imgf000141_0001
61
[0362] Compound 61 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 2-sulfanylthiazole-5- carboxamide.
1H NMR (400 MHz, CD3OD): δ 8.11 (s, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.48 (d, J= 8.4 Hz, 1H), 3.77 (s, 3H), 3.31-3.29 (m, 2H), 2.91-2.88 (m, 1H).
MS calcd for (C14H13BN206S2): 380
MS (ESI, positive) found: (M+l): 381
Example 62: (3R)-2-hvdroxy-7-methoxy-3-(l ,3,4-thiadiazol-2-ylsulfanyl)-3,4-dihydro-l ,2- benzoxaborinine-8-carboxylic acid (62)
Figure imgf000142_0001
[0363] Compound 62 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with l,3,4-thiadiazole-2-thiol. 1H NMR (300 MHz, CD3OD): δ 9.10 (s, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.57 (s, 3H), 3.01-2.95 (m, 1H), 2.75-2.66 (m, 2H).
MS calcd for (C12HnBN205S2): 338
MS (ESI, positive) found: (M+1-H20): 321
Example 63 : (3R)-3-[(5-acetamido-l ,3,4-thiadiazol-2-yl)sulfanyl]-2-hydroxy-7-methoxy-3,4- dihvdro-l,2-benzoxaborinine-8-carboxylic acid (63)
Figure imgf000142_0002
[0364] Compound 63 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with N-(5-sulfanyl-l,3,4- thiadiazol-2-yl)acetamide as described in J. Med Chem., 1986, 29, 1488-1494, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.03 (d, J= 8.4 Hz, 1H), 6.46 (d, J= 8 Hz, 1H), 3.75 (s, 3H), 3.62-3.60 (m, 1H), 3.17-3.14 (m, 1H), 2.89-2.85 (m, 1H), 2.22 (s, 3H).
MS calcd for (C14H14BN306S2): 395
MS (ESI, positive) found: (M+l): 396 MS (ESI, negative) found: (M-l): 394
Example 64: (3R)-3-[[4-amino-5-(trifluoromethyl)-l,2,4-triazol-3-yl]sulfanyl]-2-hvdroxy-7- methoxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (64)
Figure imgf000143_0001
64
[0365] Compound 64 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 4-amino-5- (trifluoromethyl)-l,2,4-triazole-3 -thiol as described in J. Med. Chem., 1971 , 14, 335-338, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.02 (d, J= 8.4 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 3.89-3.67 (m, 4H), 3.19-3.13 (m, 1H), 2.92-2.87 (m, 1H).
MS calcd for (Ci3Hi2BF3N405S): 404
MS (ESI, positive) found: (M+l): 405
MS (ESI, negative) found: (M-l): 403
Example 65: (3R)-3 - [ 1 -(4,5-dihydrothiazol-2-yl)azetidin-3 -yl] sulfanyl-2-hydroxy-7-methoxy-
Figure imgf000143_0002
[0366] Compound 65 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3-thiol in step 5 with l-(4,5-dihydrothiazol-2- yl)azetidine-3 -thiol as described in J Antibiot., 2006, 59, 241 - 247, which is incorporated herein by reference in its entirety.
•H NMR (300 MHz, CD3OD): δ 6.76 (d, 1H), 6.25 (d, 1H), 4.55 (m, 1H), 4.30-4.15 (m, 2H), 3.80-3.55 (m, 8H), 3.28-3.15 (m, 2H), 2.65-2.52 (m, 1H), 2.56-2.44 (m, 1H). MS calcd for
Figure imgf000144_0001
394
MS (ESI, positive) found: (M+l): 395
Example 66: (3R)-3-[[4-amino-5-(aminomethyl)-l,2,4-triazol-3-yl]sulfanyl]-2-hvdroxy-7- methoxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (66)
Figure imgf000144_0002
66
[0367] Compound 66 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 4-amino-5- (aminomethyl)-l,2,4-triazole-3 -thiol as described in J. Indian. 'he . Soc, 1984, 61, 713- 714. which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.04 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 4.32 (s, 2H), 3.74-3.69 (m, 1H), 3.61 (m, 3H), 3.18-3.13 (m, 1H), 2.90-2.86 (m, 1H).
MS calcd for (Ci3Hi6BN505S): 365
MS (ESI, positive) found: (M+l): 366
Example 67: (3R)-3-[[5-(2-amino-2-imino-ethyl)sulfanyl-E3,4-thiadiazol-2-yllsulfanyll-2- hydroxy-7-methoxy-3.4-dihydro- 1.2-benzoxaborinine-8-carboxylic acid (67)
Figure imgf000144_0003
67
[0368] Compound 67 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 2-[(5-sulfanyl-l,3,4- t h i ad i azo 1 -2 -y 1 ) su 1 fany 1 j acetam i d i ne as described in US Patent No. 4971963. which is incorporated herein by reference in its entirety. 1H NMR (400 MHz, CD3OD): δ 7.05 (d, J = 8.8 Hz, 1H), 6.48 (d, J = 8 Hz, 1H), 4.36-4.31 (m, 2H), 3.82 (s, 3H), 3.76-3.69 (m, 1H), 3.18-3.14 (m, 1H), 2.94-2.89 (m, 1H).
MS calcd for (C14H15BN405S3): 426
MS (ESI, positive) found: (M+l): 427
Figure imgf000145_0001
103691 Compound 68 was prepared as described in Example 107 except replacing 107B with tert-butyl 4-[2-[(5-sulfanyl-l,3,4-thiadiazol-2-yl)sulfanyl]ethyl]piperazine-l- carboxylate, which was made from 107 A and tert-butyl 4-(2-bromoethyl)piperazine-l- carboxylate (described in PCT Publication WO2013/64919, incorporated herein by reference in its entirety) as in step 1 of Example 107.
1H NMR (400 MHz, CD3OD): δ 7.05 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.71-3.53 (m, 3H), 3.41 (m, 4H), 3.27-3.14 (m, 7H), 2.93-2.89 (m, 1H).
MS calcd for (C18H23BN405S3): 482
MS (ESI, positive) found: (M+l): 483
Example 69: (3R)-2-hvdroxy-7-methoxy-3-thiazol-5-ylsulfanyl-3,4-dihydro-l,2- benzoxaborinine-8-carboxylic acid (69)
Figure imgf000145_0002
[0370] Compound 69 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with thiazole-5 -thiol as described in US Patent No. 5028601, which is incorporated herein by reference in its entirety. 1H NMR (400 MHz, CD3OD): δ 8.91 (s, 1H), 7.48 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.26 (d, J= 8.4 Hz, 1H), 3.74 (s, 3H), 2.95-2.91 (m, 1H), 2.59-2.15 (m, 2H).
MS calcd for (Ci3Hi2BN05S2): 337
MS (ESI, positive) found: (M+l): 338
Example 70: (3R)-2-hvdroxy-7-methoxy-3-(4H-l,2,4-triazol-3-ylsulfanyl)-3,4-dihydro-l,2- benzoxaborinine-8-carboxylic acid (70)
Figure imgf000146_0001
70
[0371] Compound 70 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 4H-l,2,4-triazole-3- thiol.
1H NMR (400 MHz, CD3OD): δ 8.48 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 1H), 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H).
MS calcd for (Ci2Hi2BN305S): 321
MS (ESI, positive) found: (M+l): 322
MS (ESI, negative) found: (M-l): 320
Example 71 : (3R)-3 - [ [4-amino-5 -(piperazin- 1 -ylmethyl)- 1 ,2,4-triazol-3 -yl] sulfanyl] -2- hydroxy-7-methoxy-3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylic acid (71)
Figure imgf000147_0001
[0372] Compound 71 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3-thiol in step 5 with tert-butyl 4-[(4-amino-5- sulfanyl-l,2,4-triazol-3-yl)methyl]piperazine-l-carboxylate. The thiol intermediate was made from
Figure imgf000147_0002
acid as described in J. Indian. ( hem. Soc, 1984, 61, 713-714, incorporated herein by reference in its entirety, and followed by reprotection with Boc group.
1H NMR (400 MHz, CD3OD): δ 7.07 (d, J = 8 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 3.91-3.69 (m, 6H), 3.31-3.17 (m, 5H), 2.91-2.83 (m, 5H).
MS calcd for (C17H23BN6O5S): 434
MS (ESI, positive) found: (M+l): 435
MS (ESI, negative) found: (M-l): 433
Example 72: (3R)-2-hydroxy-7-methoxy-3-(2-piperazin-l-ylethylsulfanyl)-3,4-dihydro-l,2- benzoxaborinine-8-carboxylic acid (72)
Figure imgf000147_0003
[0373] Compound 72 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 2-piperazin-l- ylethanethiol as described in PCT publication WO 2014/145686, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.06-7.05 (m, 1H), 6.43-6.42 (m, 1H), 3.95-3.84 (m, 4H), 3.62-3.11 (m, 6H), 3.07-2.94 (m, 2H), 2.93-2.44 (m, 6H).
MS calcd for (C16H23BN205S): 366
MS (ESI, positive) found: (M+l): 367
Example 73 : (3R)-3-[[4-(4-aminobutyl)-l ,2,4-triazol-3-yl]sulfanyl]-2-hydroxy-7-methoxy-
Figure imgf000148_0001
73
[0374] Compound 73 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3-thiol in step 5 with tert-butyl N-[4-(3- sulfanyl-l,2,4-triazol-4-yl)butyl]carbamate (prepared starting from tert-butyl N-[4-
Figure imgf000148_0002
as described in Chem. Pharm. Bull, 1988, 36, 2968-2976, which is incorporated herein by reference in its entirety).
1H NMR (400 MHz, CD3OD): δ 8.46 (s, 1H), 6.54 (d, J= 8 Hz, 1H), 6.23 (d, J= 8.4 Hz, 1H), 3.81-3.70 (m, 2H), 3.59 (s, 3H), 3.15-3.03 (m, 2H), 2.98-2.43 (m, 3H), 1.63-1.28 (m, 4H). MS calcd for (C16H21BN405S): 392
MS (ESI, positive) found: (M+l): 393
Example 74: (3R)-3-[(3-amino-l ,2,4-thiadiazol-5-yl)sulfanyl]-2-hydroxy-7-methoxy-3,4- dihvdro-l,2-benzoxaborinine-8-carboxylic acid (74)
Figure imgf000149_0001
74
[0375] Compound 74 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with tert-butyl N-(5-sulfanyl- 1.2.4-thiadia/.ol-3-yl (carbamate as described in Tetrahedron Lett., 2006. 47, 8039-8042, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.03 (d, J= 8.8 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 3.82-3.76
(m, 4H), 3.32-3.19 (m, 2H).
MS calcd for (Ci2Hi2BN305S2): 353
MS (ESI, positive) found: (M+l): 354
Example 75: (3R)-2-hvdroxy-7-methoxy-3-(E2,4-thiadiazol-5-ylsulfanyl)-3,4-dihydro-E2- benzoxaborinine-8-carboxylic ac
Figure imgf000149_0002
75
[0376] Compound 75 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with l,2,4-thiadiazole-5- thiolas described in PCT publication WO2005/26139. which is incorporated herein b reference in its entirety.
1H NMR (400 MHz, CD30D): δ 8.55 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 3.82-3.74 (m, 4H), 3.22-3.11 (m, 1H), 2.91-2.86 (m, 1H).
MS calcd for (C12HnBN205S2): 338
MS (ESI, positive) found: (M+l): 339
MS (ESI, negative) found: (M-l): 337
Example 76 : (3R)-2-hydroxy-7-methoxy-3 -( 1 -sulfamoylazetidin-3 -yl)sulfanyl-3.4-dihydro-
1.2-benzoxaborinine-8-carboxylic acid (76)
Figure imgf000150_0001
76
[0377] Compound 76 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with (4-nitrophenyl)methyl N-(3-sulfanylazetidin-l-yl)sulfonylcarbamate. The deprotection of p-nitrobenzyl carbamate was done as described in PCT publication WO 2011/097958, which is incorporated herein by reference in its entirety. Final deprotection to 76 was done following procedures as in step 7 of Example 19 and step 6 of Example 1 consecutively and isolated as sodium salt.
1H NMR (400 MHz, CD30D): δ 6.73 (d, J= 8.8 Hz, 1H), 6.26 (d, J= 8.4 Hz, 1H), 3.93-3.92 (m, 2H), 3.73-3.72 (m, 6H), 3.53-3.51 (m, 2H), 3.31-3.29 (m, 1H).
MS calcd for (C13H17BN207S2): 388
MS (ESI, positive) found: (M+l): 389
MS (ESI, negative) found: (M-l): 387
Example 77: (3R)-3-(2-aminothiazol-5-yl)sulfanyl-2-hvdroxy-7-methoxy-3,4-dihydro-E2- benzoxaborinine- 8 -carboxylic acid (77)
Figure imgf000150_0002
77
[0378] Compound 77 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3-thiol in step 5 with 2-aminothiazole-5-thiol as described in J. Med. Chem., 2004. 47, 1719-1728, which is incorporated herein by reference in its entirety. 1H NMR (400 MHz, CD3OD, mixture of isomers) δ 7.30 - 7.15 (m, IH), 7.10 - 6.93 (m, IH), 6.45 - 6.41 (m, IH), 3.86 - 3.77 (m, 3H), 3.38 - 3.33 (m, IH), 3.10 - 2.90 (m, IH), 2.80 - 2.65 (m, IH).
MS calcd for (C13H13BN2O5S2): 352
MS (ESI, positive) found: (M+l): 353
MS (ESI, negative) found: (M-l): 351
Example 78 : (3R)-3 - [ [5 -(3 -aminoazetidin- 1 -yl)- 1 ,3 ,4-thiadiazol-2-yl] sulfanyl] -2-hydroxy-7- methoxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (78)
Figure imgf000151_0001
[0379] Compound 78 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- butyl N-(azetidin-3 -yl)carbamate.
1H NMR (400 MHz, CD30D): δ 7.03 (d, IH), 6.48 (d, IH), 4.57 (dd, IH), 4.54 (dd, IH), 4.28 (m, IH), 4.20 (dd, IH), 4.15 (dd, IH), 3.78 (s, 3H), 3.60 (m, IH), 3.15 (dd, IH), 2.85 (dd, IH).
MS calcd for (C15H17BN4O5S2): 408
MS (ESI, positive) found: (M+l): 409
Example 79: (3R)-7-(2-aminoethoxy)-3-[(5-amino-l,3,4-thiadiazol-2-yl)sulfanyll-2-hydroxy- 3,4-dihydro-L2-benzoxaborinine-8-carboxylic acid (79)
Figure imgf000151_0002
Step 1 : Synthesis of 79 A [0380] To a solution of compound 44G (305 mg, 0.472) and tert-butyl N-(2- bromoethyl (carbamate as described in J. Org. Chem., 1988, 53, 2226-2232, which is incorporated herein by reference in its entirety (264 mg, 1.18 mmol), potassium carbonate (228 mg, 1.65 mmol) in DMF (2 mL) was stirred at 35 °C overnight under nitrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 79A (175 mg, 47%).
1H NMR (400 MHz, CDC13): δ 9.40 (br. s, 1H), 7.20 (d, J= 8.4 Hz, 1H), 6.73 (d, J= 8.8 Hz, 1H), 4.46-4.35 (m, 1H), 4.14-4.03 (m, 2H), 3.66-3.64 (m, 2H), 3.25-3.21 (m, 1H), 3.20-3.17 (m, 1H), 2.35-2.32 (m, 2H), 2.29-2.27 (m, 2H), 1.91-1.81 (m, 2H), 1.53 (s, 9H), 1.51 (s, 9H), 1.43 (s, 9H), 1.33 (s, 3H), 1.31 (s, 3H), 1.30-1.07 (m, 1H), 0.85 (s, 3H).
Step 2: Synthesis of 79
[0381] To a solution of 79A (170 mg, 0.215 mmol) in 90% TFA/TES (v/v, 6 mL/0.5 mL) was stirred at rt for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC to give 79 (22.1 mg, 27%).
1H NMR (400 MHz, CD30D): δ 7.14 (d, J= 8.4 Hz, 1H), 6.58 (d, J= 8.4 Hz, 1H), 5.55 (m, 2H), 4.26-4.24 (m, 2H), 3.55-3.53 (m, 1H), 3.17-3.11 (m, 1H), 2.91-2.86 (m, 1H).
MS calcd for (C13H15BN405S2): 382
MS (ESI, positive) found: (M+l): 383
MS (ESI, negative) found: (M-l): 381
Example 80: (3R)-7-(2-amino-2-oxo-ethoxy)-3-[(5-amino-L3,4-thiadiazol-2-yl)sulfanyll-2- hvdroxy-3,4-dihvdro-L2-benzoxaborinine-8-carboxylic acid (80)
Figure imgf000152_0001
80 [0382] Compound 80 was prepared following the procedures described in Example 79 replacing tert-butyl N-(2-bromoethyl)carbamate in step 1 with 2- bromoacetamide.
•H NMR (400 MHz, CD30D): δ 7.14 (d, J = 8 Hz, 1H), 6.50 (d, J = 8 Hz, 1H), 4.50 (s, 2H), 3.57-3.55 (m, 1H), 3.17-3.12 (m, 1H), 2.91-2.86 (m, 1H).
MS calcd for (C13H13BN4O6S2): 396
MS (ESI, positive) found: (M+l): 397
MS (ESI, negative) found: (M-l): 395
Example 81 : (3R)-3-[(5-amino-l ,3,4-thiadiazol-2-yl)sulfanyl]-7-[2-(azetidin-3-ylamino)-2- oxo-ethoxy]-2-hydroxy-3,4-dihydro-l ,2-benzoxaborinine-8-carboxylic acid (81)
Figure imgf000153_0001
81
[0383] Compound 81 was prepared following the procedures described in Example 79 replacing tert-butyl N-(2-bromoethyl)carbamate in step 1 with tert-butyl 3-[(2- bromoacetyl)amino]azetidine- 1 -carboxylate.
1H NMR (400 MHz, CD30D): δ 7.20 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 4.73 (s, 2H), 4.34-4.18 (m, 5H), 3.59-3.57 (m, 1H), 3.17-2.89 (m, 2H).
MS calcd for (C16H18BN506S2): 451
MS (ESI, positive) found: (M+l): 452
MS (ESI, negative) found: (M-l): 450
Example 82 : (3R)-3 - [(3 -amino- 1 H- 1 ,2,4-triazol-5 -yQsulfanyl] -2-hydroxy-7-methoxy-3 ,4- dihvdro-l ,2-benzoxaborinine-8-carboxylic acid (82)
Figure imgf000154_0001
82
[0384] Compound 82 was prepared following the procedure described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 5-amino-4H-l,2,4- triazole-3-thiol.
1H NMR (400 MHz, CD30D): δ 7.01 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.55-3.53 (m, 1H), 3.08-3.03 (m, 1H), 2.77-2.72 (m, 1H).
MS calcd for (C12H13BN4O5S): 336
MS (ESI, positive) found: (M+l): 337
MS (ESI, negative) found: (M-l): 335
Figure imgf000154_0002
Step 1 : Synthesis of 83 B
[0385] To a mixture of compound 83A (synthesized from 44C by treatment of pyrrolidine in THF as in the preparation of 44G) (150 mg, 0.386 mmol), potassium carbonate
(60 mg, 0.386 mmol) in DMF (5 mL) was added iodoethane (60 mg, 0.386 mmol). The reaction mixture was stirred at rt for 1 h. Then the mixture was filtered and the filtrate was concentrated under pressure. The residue was dissolved in dichloromethane, washed with water and brine. The combined organic layer was dried over sodium sulfate, evaporated to dryness to provide compound 83B (160 mg, 99%).
1H NMR (400 MHz, CDC13): δ 7.48 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 1.54 (s, 9H), 1.53 (s, 9H), 1.37 (t, J= 6.8 Hz, 3H).
[0386] Compound 83 was prepared in steps 2-5 from 83B following the procedures described in steps 3-6 of Example 26 except replacing 4-amino-4H-l,2,4-triazole- 3 -thiol in step 5 with 5-amino-l,3,4-thiadiazole-2-thiol.
1H NMR (400 MHz, CD30D): δ 6.64 (d, J= 8.4 Hz, 1H), 6.22 (d, J= 8.4 Hz, 1H), 3.97 (q, J = 6.4 Hz, 2H), 3.09-3.05 (m, 1H), 2.84-2.76 (m, 2H), 1.32 (t, J= 6.8 Hz, 3H).
MS calcd for (Ci3Hi4BN305S2): 367
MS (ESI, positive) found: (M+l): 368
MS (ESI, negative) found: (M-l): 366
Example 84: (3R)-3-[(5-amino-l,3,4-thiadiazol-2-yl)sulfanyl]-7-(difluoromethoxy)-2- hydroxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (84)
Figure imgf000155_0001
84
[0387] Compound 84 was prepared following the procedures described in Example 83 except replacing iodoethane in step 1 with bromo(difluoro)methane.
1H NMR (300 MHz, CD30D): δ 7.08 (d, 1H), 6.95-6.40 (m, 2H), 3.53-3.42 (m, 1H), 3.19- 3.06 (m, 1H), 2.93-2.85 (m, 1H).
MS calcd for (C^H^BFaNsOsSa): 389
MS (ESI, positive) found: (M+1-H20): 372
Example 85: (3R)-2-hvdroxy-7-isopropoxy-3-(l,3,4-thiadiazol-2-ylsulfanyl)-3,4-dihydro-l,2- benzoxaborinine-8-carboxylic acid (85)
Figure imgf000156_0001
[0388] Compound 85A was prepared following the procedures described for 44G of Example 44 except replacing 5-amino-l,3,4-thiadiazole-2-thiol (31J) with 1,3,4- thiadiazole-2-thiol in step 5.
Step 1 : Synthesis of 85B:
[0389] Compound 85B was prepared from 85A following the procedure described in step 1 of Example 79 replacing tert-butyl N-(2-bromoethyl)carbamate with 2-iodopropane and potassium carbonate with potassium t-butoxide.
Step 2: Synthesis of 85:
[0390] Deprotection of 85B to 85 was done following the method described in step 2 of Example 79.
1H NMR (400 MHz, CD3OD): δ 9.19 (s, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.44 (d, J= 8 Hz, 1H), 4.51-4.47 (m, 1H), 3.72-3.71 (m, 1H), 3.18-3.14 (m, 1H), 2.91-2.89 (m, 1H), 1.25-1.23 (m, 6H).
MS calcd for (C14H15BN2O5S2): 366
MS (ESI, positive) found: (M+l): 367
MS (ESI, negative) found: (M-l): 365
Example 86: (3R)-7-(cyanomethoxy)-2-hydroxy-3-(l,3,4-thiadiazol-2-ylsulfanyl)-3,4-
Figure imgf000156_0002
86 [0391] Compound 86 was prepared using similar methods described in Example 85 except replacing 2-iodopropane in step 1 with 2-bromoacetonitrile and potassium t- butoxide with sodium hydride.
1H NMR (400 MHz, CD3OD): δ 9.23 (s, 1H), 7.12 (d, J= 8.4 Hz, 1H), 6.58 (d, J= 8 Hz, 1H), 4.92-4.89 (m, 2H), 3.76-3.74 (m, 1H), 3.31-3.17 (m, 1H), 2.98-2.94 (m, 1H).
MS calcd for (C13H10BN3O5S2): 363
MS (ESI, positive) found: (M+l): 364
MS (ESI, negative) found: (M-l): 362
Example 87: (3R)-7-(2-fluoroethoxy)-2-hydroxy-3-(l ,3,4-thiadiazol-2-ylsulfanyl)-3,4- dihvdro-l,2-benzoxaborinine-8-carboxylic acid (87)
Figure imgf000157_0001
[0392] Compound 87 was prepared following the procedures described in Example 83 except replacing iodoethane in step 1 with 1 -bromo-2-fluoro-ethane and 5- amino-l,3,4-thiadiazole-2-thiol (31J) with l,3,4-thiadiazole-2-thiol in step 4.
1H NMR (400 MHz, D20) δ 9.23 (s, 1H), 6.79 (d, J = 8 Hz, 1H), 6.35 (d, J = 8 Hz, 1H), 4.78-4.65 (m, 2H), 4.24-4.14 (m, 2H), 3.14-2.84 (m, 3H).
MS calcd for (Ci3Hi2BFN205S2): 370
MS (ESI, positive) found: (M+l): 371
MS (ESI, negative) found: (M-l): 369
Example 88: (3R)-2-hvdroxy-7-isobutoxy-3-(E3,4-thiadiazol-2-ylsulfanyl)-3,4-dihydro-E2- benzoxaborinine-8-carboxylic acid (88)
Figure imgf000158_0001
88
[0393] Compound 88 was prepared using similar methods described in Example 85 except replacing 2-iodopropane in step 1 with 1 -bromo-2-methyl-propane and potassium t-butoxide in DMF with KOH in DMSO.
1H NMR (400 MHz, CD3OD): δ 9.29 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 3.71-3.67 (m, 3H), 3.25-3.15 (m, H), 1.03-0.99 (m, 6H).
MS calcd for (C15H17BN2O5S2): 380
MS (ESI, positive) found: (M+l): 381
MS (ESI, negative) found: (M-l): 379
Example 89: (3R)-2-hvdroxy-7-(2-methoxyethoxy)-3-(l ,3,4-thiadiazol-2-ylsulfanyl)-3,4- dihvdro-l,2-benzoxaborinine-8-carboxylic acid (89)
Figure imgf000158_0002
89
[0394] Compound 89 was prepared using similar methods described in Example 85 except replacing 2-iodopropane in step 1 with l-iodo-2-methoxy-ethane.
1H NMR (400 MHz, CD30D): δ 9.19 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 6.45 (d, J = 8 Hz, 1H), 4.07-4.04 (m, 2H), 3.72-3.66 (m, 3H), 338-3.31 (m, 3H), 3.19-3.14 (m, 1H), 2.92-2.90 (m, 1H).
MS calcd for (C14H15BN2O6S2): 382
MS (ESI, positive) found: (M+l): 383
MS (ESI, negative) found: (M-l): 381 Example 90: (3R)-3-[(5-amino-l,3,4-thiadiazol-2-yl)sulfanyl]-7-(2,2-difluoroethoxy)-2- hydroxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (90)
Figure imgf000159_0001
90
[0395] Compound 87 was prepared following the procedures described in Example 83 except replacing iodoethane in step 1 with 2-bromo-l,l-difluoro-ethane.
1H NMR (300 MHz, CD30D): δ 7.05 (d, IH), 6.59-6.42 (d, IH), 6.35-5.86 (m, IH), 4.22- 4.18 (m, 2H), 3.54-3.42 (m, IH), 3.24-3.08 (m, IH), 2.95-2.79 (m, IH).
MS calcd for (C13H12BF2N3O5S2): 403
MS (ESI, positive) found: (M+l):404
Example 91 : (3R)-7-(2,2-difluoroethoxy)-2-hydroxy-3-(l,3,4-thiadiazol-2-ylsulfanyl)-3,4-
Figure imgf000159_0002
91
Compound 91 was prepared following the procedures described in Example 83 except replacing iodoethane in step 1 with 2-bromo-l,l-difluoro-ethane and 5 -amino- 1,3,4- thiadiazole-2-thiol (31 J) with l,3,4-thiadiazole-2-thiol in step 4.
1H NMR (300 MHz, CD3OD): δ 9.22 (s, IH), 7.03 (d, J= 9 Hz, IH), 6.48 (d, J= 8.1 Hz, IH), 6.08 (dd, d, J = 55.5, 4.2 Hz, IH), 4.21-4.11 (m, 2H), 3.74-3.72 (m, IH), 3.24-3.14 (m, IH), 2.95-2.89 (m, IH).
MS calcd for (CnHnBFaNaOjSa): 388
MS (ESI, positive) found: (M+l): 389 Example 92: (3R)-7-(cvclopropylmethoxy -2-hydroxy-3-(l ,3,4-thiadiazol-2-ylsulfanyl -3,4- dihydro-L2-benzoxaborinine-8-carboxylic acid (92)
Figure imgf000160_0001
[0396] Compound 92 was prepared using similar methods described in Example 85 except replacing 2-iodopropane in step 1 with bromomethylcyclopropane.
1H NMR (400 MHz, CD30D): δ 9.19 (s, 1H), 6.98 (d, J = 8 Hz, 1H), 6.41 (d, J = 8 Hz, 1H), 3.82-3.71 (m, 3H), 3.18-3.14 (m, 1H), 2.92-2.87 (m, 1H), 1.18-1.16 (m, 1H), 0.56-0.29 (m, 4H).
MS calcd for (C15H15BN2O5S2): 378
MS (ESI, positive) found: (M+l): 379
MS (ESI, negative) found: (M-l): 377
Figure imgf000160_0002
93
[0397] Compound 92 was prepared using similar methods described in Example 85 except replacing 2-iodopropane in step 1 with 2-(bromomethyl)-l ,3,4-thiadiazole and potassium t-butoxide with cesium carbonate.
1H NMR (400 MHz, CD30D): δ 9.46 (s, 1H), 9.21 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 5.52 (m, 2H), 3.73 (m, 1H), 3.18 (dd, J = 15.6, 4.4 Hz, 1H), 2.93 (dd, J = 15.6, 2.8 Hz, 1H).
MS calcd for (C14HnBN405S3): 422 MS (ESI, positive) found: (M+l): 423
Example 94: (3R)-7-(difluoromethoxy)-2-hydroxy-3-(l ,3,4-fhiadiazol-2-ylsulfanyl)-3,4- dihvdro-l,2-benzoxaborinine-8-carboxylic acid (94)
Figure imgf000161_0001
[0398] Compound 94 was prepared following the procedures described in Example 83 except replacing iodoethane in step 1 with bromo(difluoro)mefhane and 5- amino-l,3,4-thiadiazole-2-thiol (31J) with l,3,4-thiadiazole-2-thiol in step 4.
1H NMR (300 MHz, CD30D): δ 9.22 (s, 1H), 7.1 1-6.42 (m, 3H), 3.35-2.85 (m, 3H).
MS calcd for (C12H9BF2N2O5S2): 374
MS (ESI, positive) found: (M+l): 375
Example 95 : (3 R)-2-hvdroxy-7-(2-methylsulfanylethoxy)-3 -(1,3 ,4-fhiadiazol-2-ylsulfanyl)- 3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (95)
Figure imgf000161_0002
[0399] Compound 92 was prepared using similar methods described in Example 85 except replacing 2-iodopropane in step 1 with l-iodo-2-methylsulfanyl-ethane.
1H NMR (400 MHz, CD3OD): δ 9.29 (s, 1H), 7.01 (d, J= 8 Hz, 1H), 6.45 (d, J= 6.8 Hz, 1H), 4.14-4.08 (m, 2H), 3.74-3.72 (m, 1H), 3.26-3.15 (m, 2H), 2.81-2.77 (m, 2H), 2.15-2.03 (m, 3H).
MS calcd for (C14H15BN2O5S3): 398
MS (ESI, positive) found: (M+l): 399
MS (ESI, negative) found: (M-l): 397 Example 96: (3R)-3-[[5-(azetidin-3-ylamino)-l ,3,4-thiadiazol-2-yl]sulfanyl]-2-hydroxy-7-
Figure imgf000162_0001
Step 1 : Synthesis of 96B
[0400] To a mixture of compound 96A (5.0 g, 29.03 mmol) and TEA (5 mL, 35.87 mmol) in ethanol (20 mL) was added CS2 (2 mL, 33.10 mmol) while maintaining the temperature between 20 °C to 25 °C. After stirring for 1.5h. Methyl iodide (2 mL, 32.11 mmol) was added and stirred overnight. The reaction was complete as monitored by LCMS. The solvent was removed under reduced pressure. Then the residue was diluted with ethyl acetate and water, the organic phase was collected, dried, concentrated in vacuo to provide compound 96B (8.1 g, 100%) as a yellow solid.
Step 2: Synthesis of 96C
[0401] To a mixture of compound 96B (8.1 g, 29.03 mmol), NH2NH2'H20 (4 mL, 82.46 mmol) in ethanol (20 mL) was stirred at 80 °C overnight. The mixture was concentrated under reduced pressure. Then the residue was taken up in ethyl acetate and the organic layer was washed with water, dried, filtered and concentrated in vacuo to give compound 96C (6.2 g, 87% for two steps) as a white solid.
Step 3: Synthesis of 96D
[0402] To a mixture of compound 96C (6.2 g, 25.17 mmol), CS2 (3 mL, 49.64 mmol), Na2C03 (1.4 g, 13.21 mmol) in EtOH (20 mL) was stirred at 80 °C overnight. LC-MS analysis showed the complete consumption of starting material. The mixture was then concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo to provide compound 96D (4.0 g, 55%) as a white solid.
Step 4: Synthesis of 96E
[0403] To a mixture of compound 96D (1.021 g, 3.54 mmol) and compound 26E (2.0 g, 3.54 mmol) in DCM (10 mL) was added TEA (715.08 mg, 7.08 mmol) and stirred at rt overnight. The reaction was concentrated under pressure and the residue was purified by column chromatography (PE/EA = 10: 1 to 1 :2) to give compound 96E (2.3 g, 79%).
Step 5 : Synthesis of 96
[0404] A solution of compound 96E (1.2 g, 1.47 mmol) in TFA/TES (v/v, 6 mL/2 mL) was stirred at 30 °C overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The aqueous solution was washed with diethyl ether (3 x 10 mL)and lyophilized to afford 96 (82 mg, 14%) as a white solid.
1H NMR (300 MHz, CD3OD): δ 7.05 (d, J = 6.3 Hz, 1H), 6.49 (d, J = 6 Hz, 1H), 4.86-4.59 (m, 2H), 4.48-4.39 (m, 3H), 3.76 (s, 3H), 3.74 (s, 1H), 3.16-3.12 (m, 1H), 2.92-2.88 (m, 1H). MS calcd for (C15H17BN405S2): 408
MS (ESI, positive) found: (M+l): 409
MS (ESI, negative) found: (M-l): 407
Example 97: (3R)-3-[[5-(2-aminoethylamino)-l,3,4-thiadiazol-2-yllsulfanyll-2-hydroxy-7- methoxy-3,4-dihvdro-l,2-benzoxaborinine-8-carboxylic acid (97)
Figure imgf000163_0001
97
[0405] Compound 97 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- butyl N-( 2-aminoethyl (carbamate as described in ,/. Org. Chem., 1997 , 62, 411-416, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.04 (d, J= 8 Hz, 1H), 6.47 (d, J= 8 Hz, 1H), 3.76 (s, 3H), 3.75-3.55 (m, 3H), 3.36-3.11 (m, 3H), 2.88-2.85 (m, 1H).
MS calcd for (C14H17BN405S2): 396
MS (ESI, positive) found: (M+l): 397
MS (ESI, negative) found: (M-l): 395
Example 98 : (3R)-2-hvdroxy-7-methoxy-3-[[5-(2-piperazin- 1 -ylethylamino)- 1 ,3,4-thiadiazol-
2-yllsulfanyll-3,4-dihvdro-E2-benzoxaborinine-8-carboxylic acid (98)
Figure imgf000164_0001
[0406] Compound 98 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step lwith tert- butyl 4-( 2-aminoethyl )piperazine- l -earboxylate as described in US Patent No. 6395737, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.06 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.87 (m, 1H), 3.77 (s, 3H), 3.66 - 3.50 (m, 2H), 3.44 (m, 2H), 3.30 - 2.98 (m, 6H), 2.89 - 2.58 (m, 4H).
MS calcd for
Figure imgf000164_0002
465
MS (ESI, positive) found: (M+l): 466
MS (ESI, negative) found: (M-l): 464 Example 99 : (3R)-3 - [ [5 -(azetidin-3 -ylamino)- 1 ,3 ,4-thiadiazol-2-yl] sulfanyl] -2-hydroxy-3 ,4- dihydro- 1 ,2-benzoxaborinine-8-carboxylic acid (99)
Figure imgf000165_0001
99
[0407] Compound 99 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with 108C.
1H NMR (400 MHz, CD3OD): δ 7.79 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 4.64-4.60 (m, 1H), 4.43-4.32 (m, 4H), 3.85-3.84 (m, 1H), 3.31 -3.05 (m, 2H). MS calcd for (C14H15BN404S2): 378
MS (ESI, positive) found: (M+l): 379
MS (ESI, negative) found: (M-l): 377
Example 100: (3R)-3 - [ [5-(3 -aminopropylamino)- 1 ,3.4-thiadiazol-2-yl] sulfanyl] -2-hydroxy-7- methoxy-3,4-dihydro-E2-benzoxaborinine-8-carboxylic acid (100)
Figure imgf000165_0002
100
[0408] Compound 100 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- buty l N-(2-aminopropy l (carbamate as described in J. Org. Chem., 1997 , 62, 41 1 -41 6. which is incorporated herein by reference in its entirety. 1H NMR (400 MHz, CD3OD): δ 7.05 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.63 (m, 1H), 3.60 - 3.50 (m, 1H), 3.40 - 3.35 (m, 1H), 3.14 (dd, J= 15.6, 4.8 Hz, 1H), 3.07 (t, J= 7.2 Hz, 2H), 2.86 (d, J= 15.6 Hz, 1H), 2.19 - 2.00 (m, 2H).
MS calcd for (C15H19BN4O5S2): 410
MS (ESI, positive) found: (M+l): 41 1
MS (ESI, negative) found: (M-l): 409
Figure imgf000166_0001
101
[0409] Compound 101 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- butyl N- [2- [2-(tert-butoxycarbonylamino)ethylamino] ethyl] carbamate as described in Org.
Lett., 2000 , 2, 21 17-2120, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.00 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.88 -
3.59 (m, 9H), 3.83 (s, 3H), 3.12 (dd, J= 15.6, 4.4 Hz, 1H), 2.88 (d, J= 15.6 Hz, 1H).
MS calcd for (C16H22BN5O5S2): 439
MS (ESI, positive) found: (M+l): 440
MS (ESI, negative) found: (M-l): 438
Example 102: (3R)-3-[[5-[[2-amino-l-(aminomethyl)ethyl]amino]-l,3,4-thiadiazol-2- yllsulfanyll-2-hvdroxy-7-methoxy-3,4-dihvdro-E2-benzoxaborinine-8-carboxylic acid (102)
Figure imgf000167_0001
102
Compound 102 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96A) in step 1 with tert-butyl N-[2- amino-3-(tert-butoxycarbonylamino)propyl] carbamate as described in J med. Chem., 2005 , 48, 7781-7788, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, D20) δ 6.78 (d, J= 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.08 (m, 1H), 3.73 (s, 3H), 3.62 (d, J= 2.0 Hz, 1H), 3.15 - 2.96 (m, 5H), 2.76 (dd, J= 15.6, 6.0 Hz, 1H). MS calcd for (Ci5H2oBN505S2): 425
MS (ESI, positive) found: (M+l): 426
MS (ESI, negative) found: (M-l): 424
Figure imgf000167_0002
103
[0410] Compound 103 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- butyl ( .S')-3 -am i nopy rro lidine- 1 -carboxy late as described in PCT publication WO
2005/020975, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.04 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.45 (m, 1H), 3.76 (s, 3H), 3.63 - 3.48 (m, 4H), 3.40 - 3.35 (m, 1H), 3.13 (dd, J = 15.6, 5.2 Hz, 1H), 2.88 (d, J= 14.4 Hz, 1H), 2.42 - 2.38 (m, 1H), 2.27 - 2.22 (m, 1H).
MS calcd for
Figure imgf000167_0003
422 MS (ESI, positive) found: (M+l): 423
MS (ESI, negative) found: (M-l): 421
Example 104: (3R)-2-hydroxy-7-methoxy-3-[[5-(4-piperidylamino)-l ,3,4-thiadiazol-2- yl] sulfanyl] -3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylic acid ( 104)
Figure imgf000168_0001
104
[0411] Compound 104 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- butyl 4-aminopiperidine- 1 -carboxylate as described in PCT publication WO 2006/115353, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.05 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.95 - 3.90 (m, 1H), 3.83 (s, 3H), 3.77 - 3.73 (m, 1H), 3.61 - 3.59 (m, 2H), 3.23 - 3.10 (m, 3H), 2.88 (d, J= 15.2 Hz, 1H), 2.41 - 2.26 (m, 2H), 1.85 - 1.76 (m, 2H).
MS calcd for (Ci7H21BN405S2): 436
MS (ESI, positive) found: (M+l): 437
MS (ESI, negative) found: (M-l): 435
Example 105: (3R)-3-[[5 - [2-(azetidin-3 -ylamino)ethylamino] - 1 ,3 ,4-thiadiazol-2-yl] sulfanyl] -
Figure imgf000168_0002
105
[0412] Compound 105 was prepared following the procedures described in Example 96 replacing tert-butyl 3-aminoazetidine-l-carboxylate (96 A) in step 1 with tert- butyl 3-(2-aminoethylamino)azetidine-l-carboxylate as described in US Patent No. 5846965, which is incorporated herein by reference in its entirety.
1H NMR (400 MHz, CD3OD): δ 7.06 (d, J = 8.4 Hz, IH), 6.50 (d, J = 8.0 Hz, IH), 4.54 - 4.42 (m, 4H), 3.76 (s, 3H), 3.73 - 3.60 (m, 3H), 3.39 - 3.36 (m, 2H), 3.14 (dd, J = 16.0, 4.4 Hz, IH), 2.90 (d, J= 15.6 Hz, IH).
MS calcd for (C17H22BN5O5S2): 451
MS (ESI, positive) found: (M+l): 452
MS (ESI, negative) found: (M-l): 450
Example 106: (3R)-3-[(5-guanidino-l,3,4-thiadiazol-2-yl)sulfanyl]-2-hydroxy-7-methoxy-
Figure imgf000169_0001
Step 1 : Synthesis of 106B
[0413] Compound 106B was prepared from the penultimate precursor of Example 27 by treating with N,N'-bis(tert-butoxycarbonyl)-thiourea as described in J Med. Chem., 2008, 51. 3304 - 3312, which is incorporated herein by reference in its entirety.
Step 2: Synthesis of 106
[0414] Compound 106B was deprotected under the conditions described in step 6 of Example 1.
1H NMR (400 MHz, CD3OD): δ 7.05 (d, IH), 6.48 (d, IH), 3.76 (s, 3H), 3.61 (m, IH),
3.17(dd, 1H), 2.90 (dd, IH).
MS calcd for (C13H14BN5O5S2): 395
MS (ESI, positive) found: (M+l): 396
MS (ESI, negative) found: (M-l): 394
Example 107: (3R)-3-[[5-(2-aminoethylsulfanyl)-l ,3,4-thiadiazol-2-yl]sulfanyl]-2-hydroxy-7- methoxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (107)
Figure imgf000170_0001
Step 1 : Synthesis of 107B
[0415] To a solution of compound 107A (1 g, 6.6 mmol) in ethanol (10 mL) was added KOH (410 mg, 7.26 mmol). The resulting mixture was stirred at 70 °C for lh and tert- butyl N-(2-bromocthyl (carbamate as described in J. Org. Chem., 1988. 53. 2226-2232, which is incorporated herein by reference in its entirety, ( 1 .6 g, 7.26 mmol. 1.1 eq) was then added to the reaction. The mixture was stirred at 70 °C for additional 2h. The reaction was cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was purified by column chromatography (EA/Hexanes = 1 :3 to 1 :1) to give compound 107B (1.63 g, 84%).
1H NMR (300 MHz, CDC13): δ 3.42 (t, 2H), 3.15 (t, 2H), 1.45(s, 9H).
[0416] Compound 107 synthesized following the procedures described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 107B.
1H NMR (300 MHz, CD3OD+ DMSO-d6) δ 6.51 (d, J= 8.1 Hz, 1H), 6.07 (d, J= 8.1 Hz, 1H), 4.15 (d, J = 6.9 Hz, 1H), 3.55 (s, 3H), 3.20-3.08 (m, 2H), 3.04-2.92 (m, 1H), 2.80-2.65 (m, 3H).
MS calcd for (Ci4Hi6BN305S3): 413
MS (ESI, positive) found: (M+l): 414
Example 108: (3R)-3 - [[5-(azetidin-3-ylsulfanyl)- 1.3.4-thiadiazol-2-yll sulfanyl] -2-hydroxy-7- methoxy-3.4-dihydro-1.2-benzoxaborinine-8-carboxylic acid (108)
Figure imgf000170_0002
108
Step 1 : Synthesis of 108B [0417] To a solution of compound 108A (2.0 g, 11.55 mmol) in dichloromethane (10 mL) was added MsCl (1.455 g, 12.70 mmol) followed by TEA (1.519 g, 15.01 mmol). The mixture was stirred at rt overnight. The reaction was quenched with water and extracted with additional dichloromethane. The organic layer was washed, dried and concentrated to dryness to afford compound 108B (2.8 g, 96%) as a white solid.
1H NMR (400 MHz, CDC13): δ 5.22-5.18 (m, 1H), 4.30-4.25 (m, 2H), 4.12-4.08 (m, 2H), 3.06 (s, 3H), 1.45 (s, 9H).
Step 2: Synthesis of 108C
[0418] To a solution of compound 108B (200 mg, 0.80 mmol) in DMF (3 mL) were added l,3,4-thiadiazole-2,5-dithiol (179 mg, 1.20 mmol) and K2C03 (110 mg, 0.80 mmol). The mixture was stirred at rt overnight. The reaction was then heated to 100 °C for 2h. The mixture cooled to rt and acidified with aq. citric acid. The mixture was diluted with ethyl acetate, washed with water dried and concentrated. The residue was purified by column chromatography (PE/EA = 50:1 to 3:1) to give compound 108C (100 mg, 41%).
1H NMR (400 MHz, CDC13): δ 11.32 (br. s, 1H), 4.43 (m, 2H), 4.30-4.27 (m, 1H), 3.95-3.91 (m, 2H), 1.45 (s, 9H).
[0419] Compound 108 was synthesized following the procedures described in Example 26 except replacing 4-amino-4H-l,2,4-triazole-3 -thiol in step 5 with 108C.
1H NMR (400 MHz, CD3OD): δ 7.05 (d, J= 8.4 Hz, 1H), 6.49 (d, J= 8.4 Hz, 1H), 4.78-4.63 (m, 1H), 4.61-4.57 (m, 2H), 4.46-4.38 (m, 2H), 3.76 (s, 3H), 3.59 (s, 1H), 3.19-3.14 (m, 1H), 2.95-2.91 (m, 1H).
MS calcd for (Ci5Hi6BN305S3): 425
MS (ESI, positive) found: (M+l): 426
Example 109: (3R)-3-[[5-[2-amino-l-(aminomethyl)ethyl]sulfanyl-l,3,4-thiadiazol-2- yl] sulfanyl] -2-hydroxy-7-methoxy-3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylic acid ( 109)
Figure imgf000171_0001
109 [0420] Compound 109 was prepared as described in Example 107 replacing 107B with tert-butyl N-[3-(tert-butoxycarbonylamino)-2-[(5-sulfanyl-l ,3,4-thiadiazol-2- yl)sulfanyl]propyl] carbamate, which was made from 107 A and tert-butyl N-[2-bromo-3-(tert- butoxycarbonylamino)propyl]carbamate (described in US 2011/257406, incorporated herein by reference in its entirety) as in step 1 of Example 107.
1H NMR (400 MHz, CD3OD): δ 7.06 (d, J= 8 Hz, 1H), 6.49 (d, J= 8 Hz, 1H), 4.25-3.98 (m, 1H), 3.96-3.84 (m, 2H), 3.78 (s, 3H), 3.71-3.37 (m, 3H), 3.31-2.93 (m, 2H).
MS calcd for (Ci5Hi9BN405S3): 442
MS (ESI, positive) found: (M+l): 443
MS (ESI, negative) found: (M-l): 441
Figure imgf000172_0001
110
[0421] Compound 110 was prepared as described in Example 107 replacing 107B with 5-(2-morpholinoethylsulfanyl)-l,3,4-thiadiazole-2-thiol, which was made from 107A and 4-(2-bromoethyl)morpholine (described in PCT publication WO 2013/160810, incorporated herein by reference in its entirety) as in step 1 of Example 107.
1H NMR (400 MHz, CD3OD): δ 7.05 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 3.81-3.74 (m, 7H), 3.64-3.53 (m, 6H), 3.19-3.14 (m, 1H), 2.95-2.91 (m, 1H).
MS calcd for (Ci8H22BN306S3): 483
MS (ESI, positive) found: (M+l): 484
MS (ESI, negative) found: (M-l): 482 Example 1 1 1 : (3R)-3-rr5-r(5-amino-l,3,4-thiadiazol-2-vnsulfanyll-l,3,4-thiadiazol-2- yllsulfanyll-2-hvdroxy-7-methoxy-3,4-dihvdro-l,2-benzoxaborinine-8-carboxylic acid (111)
Figure imgf000173_0001
111
[0422] Compound 111 was prepared as described in Example 107 replacing 107B with tert-butyl N-[5-[(5-sulfanyl-l,3,4-thiadiazol-2-yl)sulfanyl]-l,3,4-thiadiazol-2- yl]carbamate, which was made from 107A and tert-butyl N-(5-bromo-l,3,4-thiadiazol-2- yl (carbamate as in step 1 of Example 107.
1H NMR (400 MHz, CD3OD): δ 7.02 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.72-3.63 (m, 1H), 3.30-3.12 (m, 1H), 2.98-2.86 (m, 1H).
MS calcd for (C14H12BN5O5S4): 469
MS (ESI, positive) found: (M+l): 470
Example 1 12: (3R)-2-hvdroxy-7-methoxy-3-[[5-(4-piperidylsulfanyl)-l,3,4-thiadiazol-2-
Figure imgf000173_0002
112
[0423] Compound 112 was prepared as described in Example 107 replacing 107B with tert-butyl 4-[(5-sulfanyl-l,3,4-thiadiazol-2-yl)sulfanyl]piperidine-l-carboxylate, which was made from 107A and tert-butyl 4-bromopiperidine- 1 -earboxy late (described in PCT publication WO 2004/084898, incorporated herein by reference in its entirety) as in step 1 o
Example 107. 1H NMR (400 MHz, CD3OD): δ 7.06 (d, J= 8.4 Hz, 1H), 6.49 (d, J= 8.8 Hz, 1H), 4.01 -3.97 (m, 1H), 3.76-3.74 (m, 4H), 3.51-3.46 (m, 2H), 3.18-3.14 (m, 3H), 2.95-2.81 (m, 1H), 2.45- 2.43 (m, 2H), 2.09-1.98 (m, 2H).
MS calcd for (C17H20BN3O5S3): 453
MS (ESI, positive) found: (M+l): 454
MS (ESI, negative) found: (M-l): 452
Example 1 13 : (3R)-3-[[5-(3-aminopropylsulfanyl)-l ,3,4-thiadiazol-2-yl]sulfanyl]-2-hydroxy-
Figure imgf000174_0001
113
[0424] Compound 113 was prepared as described in Example 107 replacing 107B with tert-butyl N-[3-[(5-sulfanyl-l ,3,4-thiadiazol-2-yl)sulfanyl]propyl]carbamate, which was made from 107A and 3-(tert-butoxycarbonylamino)propyl methanesulfonate (described in PCT publication WO2013166319, incorporated herein by reference in its entirety) as in step 1 of Example 107.
1H NMR (400 MHz, CD3OD): δ 7.07 (d, J= 8.0 Hz, 1H), 6.49 (d, J= 8.4 Hz, 1H), 3.76-3.73 (m, 4H), 3.55-3.49 (m, 1H), 3.30-3.18 (m, 4H), 2.91-2.90 (m, 1H), 2.27-2.22 (m, 2H).
MS calcd for (C15H18BN305S3): 427
MS (ESI, positive) found: (M+l): 428
MS (ESI, negative) found: (M-l): 426 Example 1 14: (3R)-3-[(5-amino-L3,4-thiadiazol-2-yl sulfanyll-6-fluoro-2-hvdroxy-7- methoxy-3,4-dihvdro-l,2-benzoxaborinine-8-carboxylic acid (114)
Figure imgf000175_0001
114
[0425] Compound 114 was prepared following procedures described in Example 38 except replacing 3,4,5-trifluorophenol (38A) with 4-fluoro-3-methoxyphenol.
1H NMR (300 MHz, CD3OD): δ 6.93 (d, 1H), 3.84 (s, 3H), 3.52-3.48 (m, 1H), 3.25-3.04 (m, 1H), 2.83-2.76 (m, 1H).
MS calcd for (C12HnBFN305S2): 371
MS (ESI, positive) found: (M+l): 372
MS (ESI, negative) found: (M-l): 370
Example 1 15: (3R)-3-[(5-amino-E3,4-thiadiazol-2-yl)sulfanyll-2-hvdroxy-4,8-dihydro-3H- oxaborinino[6,5-f|benzimidazole-9-carboxylic acid (115)
Figure imgf000175_0002
115A 115B
Step 1 : Synthesis of 115B
[0426] To a solution of 115A as described in PCT publication WO 2009/134850, incorporated herein by reference in its entirety, (3.0 g, 10.52 mmol, 1.0 eq) in acetic a id (30 mL) was added hydrobromic acid (30 mL). The reaction mixture was stirred at 110 °C overnight. Then the mixture was filtered and the solid was dried under vacuum to give 115B (3.2 g, 100%).
1H NMR (400 MHz, DMSO-t 6): δ 9.01 (s, 1H), 8.08 (s, 1H).
[0427] Formation of di-Boc protected t-butyl ester of 115B and conversion to 115 in steps 2-6 was done following methods described in steps 2-6 of Example 26. 1H NMR (400 MHz, CD3OD): δ δ 9.1 1 (s, 1H), 7.81 (s. 1H), 5.48 (s, 1H), 3.75 (s, 1H), 3.45- 3.05 (m, 2H).
MS calcd for (Ci2HioBN504S2): 363
MS (ESI, positive) found: (M+l): 364
MS (ESI, negative) found: (M-l): 362
Example 1 16: (3R)-3-[[5-(2-aminoethylsulfanyl)-E3,4-thiadiazol-2-yllsulfanyll-2-hydroxy- 3,4-dihvdro-E2-benzoxaborinine-8-carboxylic acid (1 16)
Figure imgf000176_0001
116
[0428] Compound 116 was prepared following similar procedure described in example 1 (steps 1-6) replacing 2-mercapto-l ,3,4-thiadiazole in step 5 with thiol 107B.
1H NMR (400 MHz, CD3OD): δ 7.79 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 3.88-3.87 (m, 1H), 3.76-3.69 (m, 1H), 3.46-3.08 (m, 5H).
MS calcd for (CnHnBNsC Ss): 383
MS (ESI, positive) found: (M+l): 384
MS (ESI, negative) found: (M-l): 382
Example 117: (3R -3-[[5-(2-aminoethoxy -l,3,4-thiadiazol-2-yllsulfanyll-2-hydroxy-7- methoxy-3,4-dihvdro-l,2-benzoxaborinine-8-carboxylic acid (117)
CS2, KOH, Mel ) Y S Ν2Η Ή20, EtOH NHNH CS2, Na2C03, EtOH
BocHN ^ ^ BocHN'
BocHN
DMSO Ύ s
117A 117B 117C
HS
Figure imgf000177_0001
Step 1 : Synthesis of 117B
[0429] To a mixture of compound 117A (2.0 g, 12.4 mmol), KOH (1.40 g, 24.8 mmol) in DMSO (12 mL) was added CS2 (1 mL, 16.5 mmol) dropwise. After stirring for 1.5 h. Mel (1 mL, 16.1 mmol) was added and stirred for another 1.5 h. Then the mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water, dried, filtered and concentrated in vacuo to give compound 117B (2.1 g, 67%).
Step 2: Synthesis of 117C
[0430] To a solution of compound 117B (2.0 g, 7.96 mmol) in EtOH (20 mL) at 0 °C was added Ν2Η4Ή20 (387 mL, 7.96 mmol). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water and extracted with ethyl acetate (2x100 mL). The combined organic extract was washed with water, dried, filtered and concentrated to afford compound 117C (2.06 g, 100%).
Step 3: Synthesis of 117D
[0431] To a solution of compound 117C (58 mg, 0.247 mmol) in ethanol (2 mL) was added CS2 (18 mL, 0.796 mmol, 1.2 eq) followed by Na2C03 (13 mg, 0.124 mmol, 0.5 eq). The resulting mixture was heated to reflux overnight. Then the mixture was concentrated under pressure and the residue was dissolved in ethyl acetate, treated with aq citric acid to pH 3-5. The organic layer was washed by water, dried, filtered and evaporated to dryness to afford compound 117D (50 mg, 73%). Step 4: Synthesis of 117E
[0432] To a mixture of compound 117D (160 mg, 0.578 mmol) and compound 5 (330 mg, 0.58 mmol) in dichloromethane (5 mL) was added TEA (240 mL, 1.733 mmol). The mixture was stirred at rt overnight. Then the mixture was concentrated and the residue was purified by column chromatography to give compound 117E (150 mg, 32%).
Step 5: Synthesis of 117
[0433] To a solution of compound 117E (140 mg, 0.17 mmol) in 90% TFA/TES (v/v, 5 mL/0.6 mL) was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. Then the residue was dissolved in water and washed with ether (3 x 5 mL). The aqueous layer was lyophilized to afford 117 (40 mg, 58%) as white solid.
1H NMR (400 MHz, CD3OD): δ 7.04 (d, J= 8.8 Hz, 1H), 6.47 (d, J= 8.4 Hz, 1H), 4.81-4.79 (m, 2H), 3.74 (s, 3H), 3.58-3.52 (m, 3H), 3.16-3.11 (m, 1H), 2.91-2.86 (m, 1H).
MS calcd for (C14H16BN306S2): 397
MS (ESI, positive) found: (M+l): 398
Example 118: (3R)-3-[[5-(azetidin-3-ylamino)-l,3,4-thiadiazol-2-yl]sulfanyl]-7-ethoxy-2- hydroxy-3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (118)
Figure imgf000178_0001
Step 1 : Synthesis of 118B
[0434] To a solution of compound 118 A (270 mg, 0.337 mmol) in DMF (3 mL) were added iodoethane (105 mg, 0.674 mmol) and t-BuOK (75 mg, 0.668 mmol). The resulting mixture was stirred at rt for 1 h. The reaction was quenched by water and the aqueous layer was extracted with ethyl acetate. Then the organic layer was washed with brine, dried and evaporated to dryness. The residue was purified by prep-TLC (DCM/MeOH = 20: 1) to afford compound 118B (80 mg, 29%) as light yellow solid.
Step 2: Synthesis of 118 [0435] To a solution of compound 118B (75 mg, 0.09 mmol) in 90% TFA/TES (v/v, 4 mL/0.5 mL) was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The aqueous solution was washed with ether and lyophilized to afford 118 (38 mg, 99%) as a white solid.
1H NMR (400 MHz, CD3OD): δ 7.02 (d, J= 8.4 Hz, 1H), 6.46 (d, J= 8.4 Hz, 1H), 4.68-4.61 (m, 2H), 4.59-4.36 (m, 3H), 4.03-3.97 (m, 2H), 3.74-3.73 (m, 1H), 3.16-3.14 (m, 1H), 2.92- 2.88 (m, 1H), 1.32 (t, J= 7.2 Hz, 3H).
MS calcd for (C16H19BN4O5S2): 422
MS (ESI, positive) found: (M+l): 423
MS (ESI, negative) found: (M-l): 421
Example 119: (3R)-3-[(5-amino-l,3,4-thiadiazol-2-yl)sulfanyl]-2-hydroxy-7-(triazol-l-yl)- 3,4-dihydro-l,2-benzoxaborinine-8-carboxylic acid (119)
Figure imgf000179_0001
119 Step 1 : Synthesis of 119B
[0436] The mixture of compound 119A (900 mg, 3.14 mmol), NaN3 (406 g, 6.29 mmol), Cul (60 mg, 0.314 mmol), sodium L-ascorbate (31 mg, 0.157 mmol) and Ν,Ν'- dimethylethylenediamine (42 mg, 0.471 mmol) in EtOH:H20 (7:3, 15 mL) was stirred at 80 °C for 2 hours in nitrogen atmosphere. After cooling down, the mixture was diluted with ethyl acetate and washed with 0.1N HC1. The aqueous layers was further extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was purified by column chromatography (EA/Hexanes = 1 :15 to 1 : 10) to give compound 119B (730 mg, 92%).
1H NMR (300 MHz, CDC13): δ 11.61 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 2.21 (s, 3H), 1.63 (s, 9H).
Step 2: Synthesis of compound 119C
[0437] To a solution of compound 119B (7.0 g, 28.1 mmol) in dichloromethane (100 mL) were added Boc20 (6.2 g, 28.1 mmol) and DMAP (342 mg, 2.8 mmol). The resulting mixture was stirred at rt for 30 minutes. Then the mixture was concentrated and the residue was purified by column chromatography (PE/EA = 100: 1 to 10:1) to give compound 119 C (9.5 g, 93%).
1H NMR (400 MHz, CDC13): δ 7.25 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 2.18 (s, 3H), 1.57 (s, 9H), 1.53 (s, 9H).
Step 3: Synthesis of compound 119D
[0438] To a stirred mixture of compound 119C (9.8 g, 28.05 mmol), NBS (5.0 g, 28.05 mmol), BPO (678 mg, 2.8 mmol) in CC14 (100 mL) was heated to reflux for 12 h. TLC analysis showed the incomplete consumption of raw material, then another batch of NBS (5.0 g, 28.05 mmol) and BPO (678 mg, 2.8 mmol) were added. The mixture was stirred for additional 12 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA = 100: 1 to 10: 1) to give pure compound 119D (10 g).
1H NMR (400 MHz, CDC13): δ 8.11 (d, J = 6.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.40 (s, 2H), 1.57 (s, 9H), 1.53 (s, 9H). Step 4: Synthesis of compound 119E
[0439] To a stirred mixture of compound 119D (10 g, 23.13 mmol), compound bis(pinanediolato)diboran (9.94 g, 27.76 mmol), PdCl2(dppf) (944 mg, 1.15 mmol), KOAc (6.81 g, 69.39 mmol) in dioxane (100 mL) was degassed with nitrogen. The resulting mixture was heated to 90 °C overnight. Then the solvent was removed under reduced pressure and diluted with water and ethyl acetate, the aqueous layers was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated to dryness in vacuo. The residue was purified by column chromatography (PE/EA = 100:1 to 20:1) to give compound 119E (2.3 g, 15% for two steps).
1H NMR (400 MHz, CDC13): δ 7.34 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.27-4.24 (m, 1H), 2.30-2.27 (m, 1H), 2.17 (s, 2H), 2.01 (t, J= 5.2 Hz, 1H), 1.89-1.81 (m, 2H), 1.57 (s, 9H), 1.53 (s, 9H), 1.37 (s, 3H), 1.27 (s, 3H), 1.17 (d, J= 10.8 Hz, 1H), 0.84 (s, 3H).
Step 5: Synthesis of compound 119F
[0440] To a 3 -neck round-bottom flask, purged and maintained in inert atmosphere of nitrogen, was placed a solution of dichloromethane (927 mg, 10.9 mmol) in anhydrous THF (50 mL). The solution was cooled to -100 °C and n-BuLi (2.5 M, 3.1 mL, 7.85 mmol) was added slowly along the flask wall over 10 minutes. After stirring for 20 minutes, compound 119E (2.3 g, 4.36 mmol) in anhydrous THF (30 mL) was added dropwise over 10 minutes. The resulting mixture was warmed slowly to rt and stirred at that temperature for overnight. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate, washed with water brine and dried in vacuo to give crude compound 119F (2.7 g, 100%).
1H NMR (400 MHz, CDC13): δ 7.41 (d, J= 8.4 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 3.65 (t, J = 8.4 Hz, 1H), 3.18-3.12 (m, 1H), 2.97-2.91 (m, 1H), 2.34-2.31 (m, 1H), 2.21-2.17 (m, 1H), 2.08-2.04 (m, 1H), 1.91-1.85 (m, 2H), 1.57 (s, 9H), 1.53 (s, 9H), 1.41 (s, 3H), 1.31 (s, 3H), 1.29-1.22 (m, 3H), 1.08 (d, 1H), 0.85 (s, 3H).
Step 6: Synthesis of compound 119G
[0441] To a solution of compound 119F (2.5 g, 4.34 mmol) in dichloromethane (30 mL) were added compound 5-amino-l,3,4-thiadiazole-2-thiol (751 mg, 5.64 mmol) and TEA (878 mg, 8.7 mmol). The resulting mixture was stirred at rt for 2 h. Then the mixture was quenched with water, separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure to provide compound 119G (1.9 g, 65%).
1H NMR (400 MHz, CDC13): δ 7.35 (d, J = 8.4 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H), 5.23 (br. s, 2H), 4.32 (d, J= 7.6 Hz, 1H), 3.26-3.22 (m, 2H), 2.90-2.82 (m, 1H), 2.40-2.31 (m, 1H), 2.30- 2.04 (m, 1H), 1.99-1.97 (m, 1H), 1.86-1.84 (m, 2H), 1.57 (s, 9H), 1.52 (s, 9H), 1.46 (s, 3H), 1.43 (d, J= 10.4 Hz, 1H), 1.25 (s, 3H), 0.85 (s, 3H).
Step 7: Synthesis of compound 119H
[0442] To a mixture of compound 119G (1.9 g, 2.83 mmol), Boc20 (740 mg, 3.4 mmol), DMAP (35 mg, 0.283 mmol) and TEA (572 mg, 5.66 mmol) in dichloromethane (20 mL) was stirred at rt for 1 h. The mixture was concentrated and the residue was purified by column chromatography (PE/EA = 10: 1 to 3: 1) to give compound 119H (1.9 g, 87%).
Step 8: Synthesis of compound 1191
[0443] To a mixture of compound 119H (200 mg, 0.26 mmol), ethynyltrimethylsilane (51 mg, 0.52 mmol), Cul (49 mg, 0.26 mmol) in 1,4-dioxane (4 mL) was stirred at 80 °C overnight in a seal tube under nitrogen. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude 1191 (250 mg) which was used directly to next step without purification.
Step 9: Synthesis of compound 119J
[0444] To a solution of compound 1191 (250 mg, 0.26 mmol) in THF (2 mL) was added TBAF (1.0 M in THF, 1.04 mL, 1.04 mmol). The mixture was stirred at 35 °C overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. Then the solution was washed with water, dried and evaporated to give crude 119J (300 mg).
Step 10: Synthesis of compound 119
[0445] To a solution of compound 119J (300 mg, 0.26 mmol, 1.0 eq) in 90% TFA/TES (v/v, 5 mL/1 mL) was stirred at 30 °C for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC to give 119(14 mg).
1H NMR (400 MHz, CD3OD): δ 8.18 (s, 1H), 7.82 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.97 (d, J= 7.6 Hz, 1H), 3.62-3.59 (m, 1H), 3.28-3.25(m, 1H), 3.07-3.02 (m, 1H). MS calcd for (C13HnBN604S2): 390
MS (ESI, positive) found: (M+l): 391
MS (ESI, negative) found: (M-l): 389
Example 120: (3R)-3-[(5-amino-E3,4-thiadiazol-2-yl)sulfanyll-2-hydroxy-7-
(methanesulfonamido)-3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylic acid ( 120)
Figure imgf000183_0001
120A 120B
Figure imgf000183_0002
120
Step 1 : Synthesis of compound 120A
[0446] A solution of compound 119H (500 mg, 0.65 mmol) in methanol (5 mL) was added 10% Pd/C (25 mg). The reaction mixture was stirred at rt overnight under hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 120A (317 mg, 66%).
Step 2: Synthesis of compound 120B
[0447] To a solution of compound 120A (150 mg, 0.2 mmol) in pyridine (3 mL) was added MsCl (691 mg, 6.03 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 120B (10 mg, 6%).
Step 3: Synthesis of compound 120 [0448] To a solution of compound 120B (225 mg, 0.27 mmol, 1.0 eq) in 90% TEA/TES (10 mL) was stirred at rt for 2 h. The mixture was concentrated and the residue was purified by pre-HPLC to give 120 (10 mg, 9%).
1H NMR (400 MHz, CD3OD): δ 7.31 (d, J= 8 Hz, 1H), 7.22 (d, J= 8 Hz, 1H), 3.67-3.66 (m, 1H), 3.31-3.17 (m, 1H), 3.03 (s, 3H), 2.99-2.95 (m, 1H).
MS calcd for (Ci2Hi3BN406S3): 416
MS (ESI, positive) found: (M+l): 417
MS (ESI, negative) found: (M-l): 415
General procedure (A) for prodrug formation:
[0449] To a solution of sodium salt of 62 (10 mmol) (prepared by treating 62 in MeCN-water with IN NaOH to pH7.6-8 and lyophilization) in anhydrous DMF (50 mL) was added prodrug precursor (20 mmol, 2 eq) followed by 0.2 eq of potassium carbonate. The mixture was stirred at 50 °C for overnight. The reaction was cooled to room temperature and DMF was concentrated under reduced pressure. The resulting mixture was diluted with 300 mL EtOAc and washed with 0.2 N HC1, water, dried and concentrated. Prep-HPLC (CI 8, acetonitrile and water as mobile phases, 0.1% formic acid) of crude product and lyophilization provided pure prodrug as a white solid.
General procedure (B) for prodrug formation:
[0450] To the solution of Compound 62 (1 mmol) in DMF (5 mL) was added prodrug precursor (2 mmol), followed by K2C03 (1.5 mmol). The resulting mixture was stirred at 50 °C for 18 h. The reaction was cooled to room temperature and DMF was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc and washed with 0.2 N HC1, water, dried and concentrated. Purification of the residue by prep- HPLC (CI 8, acetonitrile and water as mobile phases, 0.1% formic acid) and lyophilization gave prodrug as white solid.
Example 121 : 2-methylpropanoyloxymethyl (3R)-2-hvdroxy-7-methoxy-3-(L3,4-thiadiazol- 2-ylsulfanyl)-3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylate (121
Figure imgf000185_0001
121
[0451] Compound 121 was prepared following procedure A for prodrug formation and using chloromethyl isobutyrate as the prodrug precursor.
1H NMR (300 MHz, CD3OD): δ 9.20 (s, 1H), 7.04 (d, J= 9 Hz, 1H), 6.42 (d, J= 8.4 Hz, 1H), 5.89 (d, J= 6.3 Hz, 1H), 5.81 (d, J = 5.7 Hz, 1H), 3.74-3.69 (m, 4H), 3.15 (dd, J = 15.3, 5.1 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 2.69-2.60 (m, 1H), 1.19 (d, J = 6.9 Hz , 6H).
MS calcd for
Figure imgf000185_0002
438
MS (ESI, negative) found: (M-l): 437
Example 122: isopropoxycarbonyloxymethyl (3R)-2-hydroxy-7-methoxy-3-(l,3,4-thiadiazol-
Figure imgf000185_0003
122
[0452] Compound 122 was prepared following procedure A for prodrug formation and using chloromethyl isopropyl carbonate as the prodrug precursor.
1H NMR (300 MHz, CD3OD): δ 9.21 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.87 (d, J= 5.7 Hz, 1H), 5.81 (d, J= 5.7 Hz, 1H), 3.71-3.70 (m, 4H), 3.35-3.30 (m, 1H), 3.15 (dd, J= 14.7, 4.8 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 1.32 (d, J = 6.3 Hz , 6H). MS calcd for (CiyHigB^C^): 454
MS (ESI, negative) found: (M-l): 453 Example 123: acetoxymethyl (3R -2-hydroxy-7-methoxy-3-(l,3,4-thiadiazol-2-ylsulfanyl - 3,4-dihydro-L2-benzoxaborinine-8-carboxylate (123)
Figure imgf000186_0001
123
[0453] Compound 123 was prepared following procedure B for prodrug formation and using chloromethyl acetate as the prodrug precursor.
1H NMR (300 MHz, CD3OD): δ 9.20 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.87 (d, J = 5.7 Hz, 1H), 5.81 (d, J = 6 Hz, 1H), 3.72-3.71 (m, 4H), 3.15 (dd, J = 15.9, 4.5 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 2.14 (t, 3H).
MS calcd for (C15H15BN207S2): 410
MS (ESI, negative) found: (M-l): 409
Example 124: ethoxycarbonyloxymethyl (3R)-2-hydroxy-7-methoxy-3-(l,3,4-thiadiazol-2- ylsulfanyl)-3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylate ( 124)
Figure imgf000186_0002
124
[0454] Compound 124 was prepared following procedure B for prodrug formation and using chloromethyl ethyl carbonate as the prodrug precursor.
1H NMR (300 MHz, CD3OD): δ 9.20 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.7 Hz, 1H), 5.87 (q, J = 5.7 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H). 3.71-3.70 (m, 4H), 3.15 (dd, J = 15, 3.9 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H).
MS calcd for (Ci6Hi7BN208S2): 440
MS (ESI, negative) found: (M-l): 439 Example 125: 2,2-dimethylpropanoyloxymethyl (3R)-2-hydroxy-7-methoxy-3-(L3,4- thiadiazol-2-ylsulfanyl)-3,4-dihydro-l,2-benzoxaborinine-8-carboxylate (125)
Figure imgf000187_0001
125
[0455] Compound 125 was prepared following procedure B for prodrug formation and using chloromethyl pivalate as the prodrug precursor.
1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.89 (d, J= 5.7 Hz, 1H), 5.82 (d, J= 5.7 Hz, 1H), 3.69-3.68 (m, 4H), 3.15 (dd, J= 15.6, 4.8 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 1.23 (s, 9H).
MS calcd for (Cig^B^C^): 452
MS (ESI, negative) found: (M-l): 451
Example 126: butanoyloxymethyl (3R)-2-hydroxy-7-methoxy-3-(l,3,4-thiadiazol-2- ylsulfanyl)-3 ,4-dihydro- 1 ,2-benzoxaborinine-8-carboxylate ( 126)
Figure imgf000187_0002
126
[0456] Compound 126 was prepared following procedure A for prodrug formation and using chloromethyl butanoate as the prodrug precursor.
[045η 1H NMR (300 MHz, CD3OD): δ 9.20 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 8.1 Hz, 1H), 5.89 (d, J = 5.7 Hz, 1H), 5.82 (d, J = 5.7 Hz, 1H), 3.70-3.69 (m, 4H), 3.15 (dd, J= 12, 4.8 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 2.42 (t, J = 7.2 Hz, 2H), 1.69 (m, 2H), 0.97 (t, J= 7.5 Hz, 3H). MS calcd for (C17H19BN2O7S2): 438
MS (ESI, negative) found: (M-l): 437
Example 127: propanoyloxymethyl (3R)-2-hydroxy-7-methoxy-3-(l,3,4-thiadiazol-2-
Figure imgf000188_0001
127
[0458] Compound 127 was prepared following procedure B for prodrug formation and using chloromethyl propionate as the prodrug precursor.
1H NMR (300 MHz, CD3OD): δ 9.19 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 9.0 Hz, 1H), 5.89 (d, J= 5.7 Hz, 1H), 5.82 (d, J= 5.7 Hz, 1H), 3.71-3.70 (m, 4H), 3.15 (dd, J= 15.6, 4.5 Hz, 1H), 2.89 (dd, J = 15.6, 2.7 Hz, 1H), 2.46 (q, J = 7.8 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H).
MS calcd for (C16H17BN207S2): 424
MS (ESI, negative) found: (M-l): 423
Example 128: Inhibition of carbapenemase activity of NDM-1
[0459] Kj values of inhibition of NDM-1 were determined spectrophotometrically, using imipenem as a substrate for all compounds or using three different carbapenems, imipenem, tebipenem and biapenem for . NDM-1 preparation was diluted at 1/512, 1/256 and 1/64 ratios (for imipenem, tebipenem and biapenem/meropenem, respectively) and mixed with various concentrations of beta-lactamase inhibitors (BLIs) in reaction buffer (50 mM sodium phosphate pH7.0, 0.1 mg/ml bovine serum albumin) and incubated for 10 min at 37C. 100 uM of substrate was added and absorbance profiles were recorded at 294 nm every 1 min for lh at 37C. K; values were calculated by method of Waley SG (Biochem J. 1982 Sep l ;205(3):631-3). EDTA was used as a positive control. The results of these experiments are presented in Table 1. These experiments demonstrated that several described compounds are potent inhibitors of NDM-1
TABLE 1. Activity of BLIs (Κ,, μΜ) to inhibit cleavage of carbapenems by NDM-1
Figure imgf000189_0001
25 X ND ND ND
26 X ND ND ND
27 Y X Υ Υ
28 X ND ND ND
29 Y ND ND ND
30 Υ X Υ Υ
31 ζ ND ND ND
32 Υ ND ND ND
33 ζ ND ND ND
34 Υ ND ND ND
35 Υ ND ND ND
36 Υ ND ND ND
37 Υ ND ND ND
38 ζ ND ND ND
39 ζ ND ND ND
40 ζ ND ND ND
41 X ND ND ND
42 X ND ND ND
43 X ND ND ND
44 X ND ND ND
45 Υ ND ND ND
46 ζ ND ND ND
47 ζ ND ND ND
48 ζ ND ND ND
49 ζ ND ND ND
50 ζ ND ND ND
51 ζ ND ND ND
52 ζ ND ND ND
53 ζ ND ND ND
54 ζ ND ND ND
55 ζ ND ND ND
56 ζ ND ND ND 57 Y ND ND ND
58 Z ND ND ND
59 Z ND ND ND
60 z ND ND ND
61 z ND ND ND
62 z ND ND Y
63 z ND ND ND
64 z ND ND ND
65 z ND ND ND
66 Y ND ND ND
67 X ND ND ND
68 z ND ND ND
69 z ND ND ND
70 Y ND ND ND
71 Y ND ND ND
72 z ND ND ND
73 Y ND ND ND
74 z ND ND ND
75 z ND ND ND
76 z ND ND ND
79 z ND ND ND
80 z ND ND ND
81 z ND ND ND
82 X ND ND ND
83 X ND ND ND
84 Y ND ND ND
85 z ND ND ND
86 z ND ND ND
87 z ND ND ND
88 Y ND ND ND
89 Y ND ND ND
90 Y ND ND ND
91 Y ND ND ND
92 Y ND ND ND
93 z ND ND ND
94 z ND ND ND
95 Y ND ND ND
96 X ND ND ND
97 X ND ND ND
98 Y ND ND ND
99 X ND ND ND 100 X ND ND ND
101 X ND ND ND
102 X ND ND ND
103 X ND ND ND
104 X ND ND ND
105 X ND ND ND
106 z ND ND ND
107 X ND ND ND
108 Y ND ND ND
109 X ND ND ND
110 z ND ND ND
1 1 1 z ND ND ND
112 Y ND ND ND
1 13 X ND ND ND
114 Y ND ND ND
1 15 z ND ND ND
116 X ND ND ND
1 17 X ND ND ND
118 z ND ND ND
1 19 X ND ND ND
120 X ND ND ND
EDTA Y Y Y Y
X = Less than 0.010 μΜ
Y = 0.010 μΜ ΐο Ο.Ι μΜ
Z = Greater than 0.1 μΜ
ND = Not determined
Example 129: Inhibition of activity of VIM- 1
[0460] IC50 values of inhibition of VIM-1 were determined spectrophotometrically using nitrocefin (NCF) as reporter substrate. ECM6711 strain carrying pUCP24- VIM-1 plasmid was grown at 37C to reach OD600=0.6-0.8. Cell suspension was centrifuged for 10 min at 4000g, supernatant was collected, diluted at 1/64 ratio, mixed with various concentrations of BLIs in reaction buffer and incubated for 10 min at 37C. 200 uM NCF was added and absorbance profiles were recorded at 490 nm every 30 seconds for 30 min at 37C. IC50 values were calculated as a concentration of BLIs that reduces the rate of NCF degradation by VIM-1 supernatant by 50%. EDTA was used as a positive control. The results of these experiments are presented in Table 2. These experiments demonstrated that several described compounds are potent inhibitors of VIM-1. TABLE 2. Activity of BLIs (IC50, μΜ) to inhibit cleavage of Nitrocefin by VIM-1
Figure imgf000193_0001
28 X
29 X
30 X
31 Y
32 Y
33 Υ
34 X
35 X
36 Υ
37 Υ
38 Υ
39 X
40 Υ
41 X
42 X
43 X
44 X
45 Υ
46 Υ
47 X
48 Υ
49 Υ
50 X
51 Υ
52 X
53 X
54 X
55 Υ
56 Υ
57 X
58 X
59 X
60 X 61 X
62 X
63 X
64 X
65 Y
66 X
67 X
68 X
69 X
70 X
71 X
72 X
73 X
74 X
75 X
76 Y
79 Υ
80 X
81 Υ
82 X
83 X
84 X
85 X
86 X
87 X
88 X
89 X
90 X
91 X
92 X
93 X
94 X
95 X
96 X
97 X
98 X
99 X
100 X
101 X
102 X
103 X 104 X
105 X
106 X
107 X
108 X
109 X
110 X
111 X
112 X
113 X
114 X
115 X
116 X
117 X
118 X
119 X
120 X
EDTA X
X = IC50 of less than 1.0 μΜ
Y = IC50 of 1.0 μΜ and above
Example 130: Inhibition of carbapenemase activity of class A, B and D carbapenemases
[0461] Kj values of inhibition of purified class A (KPC-2), B (NDM-1) and D (OXA-48) carbapenemases were determined spectrophotometrically using either imipenem (for NDM-1) or biapenem (for KPC-2 and OXA-48) as substrates. Purified enzymes (6 nM and 145 nM for KPC-2 and OXA-48, respectively, 1/512 of NDM-1 enzyme preparation) were mixed with various concentrations of inhibitors in reaction buffer and incubated for 10 min at room temperature. 100 μΜ of substrate was added and absorbance profiles were recorded at 294 nm every 1 min for 1 hour at 37C. Kj values were calculated by method of Waley SG (Biochem J. 1982 Sep l ;205(3):631-3). The results of these experiments are presented in Table 3. These experiments demonstrated that the described compounds are inhibitors with activity towards carbapenemases from various classes. TABLE 3. Activity of BLIs (Ki, μΜ) to inhibit cleavage of carbapenems by purified class A, B and D carbapenemases
Figure imgf000197_0001
27 Y Y Y
28 ND ND X
29 ND ND Y
30 Y Y Y
31 ND ND z
32 ND ND Y
33 ND ND Y
34 ND ND Y
35 ND ND Y
36 ND ND Y
37 ND ND Y
38 ND ND z
39 ND ND z
40 ND ND z
41 ND ND X
42 ND ND X
43 ND ND X
44 ND ND X
45 ND ND Y
46 ND ND z
47 ND ND Y
48 ND ND z
49 ND ND z
50 ND ND z
51 ND ND z
52 ND ND z
53 ND ND z
54 ND ND z
55 ND ND z
56 ND ND z
57 ND ND Y
58 ND ND z
59 ND ND z 60 ND ND Z
61 ND ND Z
62 0.0039 0.0056 z
63 ND ND z
64 ND ND z
65 ND ND z
66 ND ND Y
67 ND ND X
68 ND ND z
69 ND ND z
70 ND ND Y
71 ND ND Y
72 ND ND z
73 ND ND Y
74 ND ND z
75 ND ND z
76 ND ND z
79 ND ND z
80 ND ND z
81 ND ND z
82 ND ND X
83 ND ND X
84 ND ND Y
85 ND ND z
86 ND ND z
87 ND ND Y
88 ND ND Y
89 ND ND Y
90 ND ND Y
91 ND ND Y
92 ND ND Y
93 ND ND z
94 ND ND z
95 ND ND Y
96 ND ND X
97 ND ND X
98 ND ND Y
99 ND ND X
100 ND ND X
101 ND ND X
102 ND ND X 103 ND ND X
104 ND ND X
105 ND ND X
106 ND ND z
107 ND ND X
108 ND ND Y
109 ND ND X
110 ND ND z
111 ND ND z
112 ND ND Y
113 ND ND X
114 ND ND Y
115 ND ND z
116 ND ND X
117 ND ND X
118 ND ND z
119 ND ND X
120 ND ND X
X = Less than 0.01 μΜ
Y = 0.01 μΜ to 0.1 μΜ
Z = Greater than 0.1 μΜ
ND = Not Determined
[0462] For several compounds, the Ki of inhibition of multiple carbapenems by KPC-2 (Table 4) and OXA-48 (Table 5) were determined.
TABLE 4. Activity of BLIs (Κ,, μΜ) to inhibit cleavage of carbapenems by KPC-2
Figure imgf000200_0001
Y = 0.010 μΜ to 0.1 μΜ
Ζ = Greater than 0.1 μΜ
ND = Not Determined
TABLE 5. Activity of BLIs (Κ,, μΜ) to inhibit cleavage of carbapenems by OXA-48
Figure imgf000201_0001
Example 131 : Inhibition of Activity of Various Beta-Lactamases
[0463] Ki values of inhibition of multiple purified class A, C and D enzymes were determined spectrophotometrically using nitrocefin as reporter substrate. Purified enzymes were mixed with various concentrations of inhibitors in reaction buffer and incubated for 10 min at room temperature. Nitrocefin was added and substrate cleavage profiles were recorded at 490 nm every 10 sec for 10 min. The results of these experiments are presented in Table 6. These experiments confirmed that the described compounds are inhibitors with a broad- spectrum of activity towards various β-lactamases.
TABLE 6. Activity of BLIs (Ki, μΜ) to inhibit cleavage of nitrocefin by purified class A, C and D enzymes Ki
i Ki Ki Ki
Ki (SHV- Ki (P99/Am
(CTX- (TEM- (CMY- (OXA- 12, (KPC-2, pC of
Compound M-14, 10, 2, 48,
NCF), NCF), ECL,
NCF), NCF), NCF), NCF), μΜ μΜ NCF),
μΜ μΜ μΜ μΜ μΜ
1 X X X Y X X X
2 Y X Z Y Y Y X
3 X Y z X X X X
4 X X Y Y X X X
5 X X X X X X X
6 X X X X X X X
7 X X Y Y X X X
8 X X X X X X X
9 X Y z X X X X
10 X X X Y X X X
1 1 Y X Y Y X X X
12 X X X Y X ND X
13 X X X X X ND X
14 X X Y Y X ND X
15 X X Y Y X X X
16 X Y Y X X ND X
17 X X X X X ND X
18 Y X Y Y Y ND X
19 X X X X X ND X
20 X X X Y Y ND Y
22 X X X X X X X X X X X X ND X
X X X Υ Υ ND X
X X X Υ Υ ND X
X X X Υ Υ ND X
X X X X Υ ND X
X X X Υ Υ ND X
X X Y Υ Υ ND X
X X X X X ND X
X X X Υ Υ ND X
X X Y X X ND X
X X Υ Υ X ND X
X X X Υ X ND X
X X X X Υ ND X
X X X X ζ ND X
X X X X ζ ND X
X X Υ ζ Υ ND X
X X X X Υ ND X
X X X X X ND X
X X X X X ND X
X X X Υ Υ ND X
X X X X X ND X
X X X X X ND X
X X X Υ ζ ND X
X X X Υ ζ ND X
X X X Υ Υ ND X
ND
X X Υ Υ ζ X X X X X Υ ND X
X X X X X ND X
X X X X ND X
ζ
X X X X Υ ND X
X X X X Υ ND X
X X X X Υ ND X
Y Υ Υ Υ Υ ND X
Y Υ X Υ ζ ND X
X X Υ Υ ζ ND X
X X X Υ Υ ND X
X X X X Υ ND X
X X X X ND X
ζ
X X X X Υ ND X
X X X X Υ ND X
X X X Υ X ND X
X X Υ Υ ζ ND X
X X X X ζ ND X
X X Υ Υ ζ ND Υ
X X X Υ Υ ND X
X X Υ Υ Υ ND X
X X X X Υ ND X
X X X Υ Υ ND X
X X Υ Υ ζ ND Υ
X X X X Υ ND X
X X Υ Υ ζ ND X
X X X X Υ ND X 75 X X X X Y ND X
76 X ND X Y Y ND X
79 X X Y z Y ND X
80 X X X Y Y ND X
81 X X Y z Y ND X
82 X X X Y Y ND X
83 X X X Y Y ND X
84 X X Y Y Y ND X
85 X X X Y Y ND X
86 X X Y Y z ND X
87 X X Y Y Y ND X
88 X X Y Y Y ND X
89 X X Y Y z ND X
90 X X Y X z ND X
91 X X Y Y Y ND X
92 X ND Y Y Y ND X
93 X ND Y Y Y ND X
94 X ND Y Y z ND X
95 X ND X Y Y ND X
96 X X X Y Y ND X
97 X X X Y Y ND X
98 X X X Y Y ND X
99 X X Y Y X ND X
100 X X Y Y X ND X
101 X X Y Y z ND X
102 X X z z z ND Y 103 X X X Y Y ND X
104 X X X X Y ND X
105 X X X Y Y ND X
106 X ND X Y X ND X
107 X X Y Y Y ND X
108 X X Y Y Y ND X
109 X X Y Y Y ND X
110 X X X X Y ND X
111 X X X Y Y ND z
112 X X X X X ND X
113 X X X X X ND X
114 X X X Y Y ND X
115 X X X Y X ND X
116 X X X X X ND X
117 X X X Y Y ND X
118 X X Y Y Y ND X
119 X Y Y z Y ND X
120 X ND X Y X ND X
Tazobactam X X X z z Y Y
Clavulanic
X X X z z z z acid
X = Less than 0.1 μΜ
Y = 0.1 μΜ to 1 μΜ
Z = Greater than 1 μΜ
ND = Not Determined
Example 132: Potentiation of Imipenem by Compound 1 against E. coli strains expressing cloned NDM-1 and VIM-1 [0464] Carbapenem popentiation activity of Compound 1 was first assessed as its ability to decrease MIC of imipenem of engineered strains of E. coli containing plasmids carrying either NDM-1 or VIM-1 genes. Both NDM-1 and VIM-1 expressing strains had increased MIC for imipenem as compared to the strain that contained the vector plasmid alone (Table7). In the presence of Compound 1 at fixed 4 μg/ml or 8 μg/ml, imipenem MIC of NDM-1 and VIM-1 producing strains was decreased to the level of the strain containing empty vector (Table7).
TABLE 7. Imipenem Potentiation Activity of Compound 1 against the Strains of E. coli Expressing Cloned NDM-1 or VIM-1 Metallo-Beta-lactamases
Figure imgf000207_0001
Example 133: Potentiation of carbapenems by Compound 1 against clinical isolates strains expressing various class A, B and D carbapenemases
[0465] The panel of clinical isolates expressing class A, B and D carbapenemases alone or in combination with other beta-lactamases was used to evaluate carbapenem potentiation activity of Compound 1. MIC for biapenem, doripenem, imipenem and meropenem of these strains was determined either alone or in the presence of Compound 1 at fixed 5 μg/ml in the growth media. The results are present in Table 8. Compound 1 significantly reduced carbapenem MIC of all the strains expressing various carbapenemases. TABLE 8. Carbapenem Potentiation Activity of Compound 1 against Clinical Isolates
Expressing Class A, B and D Carbapenemases
Figure imgf000208_0001
KPC-2,
Klebsiella CTX-M- 15,
KP1087 Z X z Y Y X z Y pneumoniae SHV-11,
TEM- 1
TEM, SHV,
Klebsiella
KP 1086 CTX-M- 15, z X z Y z Y z Y pneumoniae
OXA-48
X = MIC of less than 1 μg/mL
Y = MIC of 1 μ§/Ώ , to 10 μ§/Ώ ,
Z = MIC of greater than 10 μ Ληί
Example 134: Potentiation of Biapenem against clinical isolates strains expressing various class A, B and D carbapenemases
[0466] The same panel of clinical strains was used to evaluate biapenem potentiation activity of two other compounds, Compound 3 and Compound 4. The results are present in Table 9. The results indicate that several compounds are capable to potentiate biapenem against clinical strains expressing various carbapenemases.
TABLE 9. Biapenem Potentiation Activity of several BLIs against Clinical Isolates
Expressing Class A, B and D Carbapenemases
Figure imgf000209_0001
pneumoniae
Klebsiella VIM- 1 , SHV-
KP1059 Z Y Y Y
pneumoniae 1 1
Klebsiella VIM- 1 , SHV-
KP1054 z X X X
pneumoniae 1 1
Klebsiella KPC-2, SHV-
KP1064 z X Y X
pneumoniae 1 1, TEM-1
Klebsiella KPC-3, SHV-
KP1074 z Y Y Y
pneumoniae 1 1, TEM
Klebsiella KPC-3, SHV-
KP1084 z Y Y Y
pneumoniae 1 1, TEM-1
Klebsiella KPC-2, TEM-
KP1004 z X X X
pneumoniae 1, SHV-1 1
PC-2, CTX-
Klebsiella
KP1087 M-15, SHV- z X Y X
pneumoniae
1 1 , TEM- 1
TEM, SHV,
Klebsiella
KP 1086 CTX-M-15, z X Y X
pneumoniae
OXA-48
X = MIC of less than 1 μg/mL
Y = MIC of 1 μ§/Ώ , to 10 μ§/Ώ ,
Ζ = MIC of greater than 10 μ Ληί
Example 135. Potentiation of Meropenem and Imipenem by Compound 14 against the strains of Enterobacteriaceae overexpressing various carbapenemases
[0467] The larger panel of clinical isolates expressing class A and B carbapenemases alone or in combination with other beta-lactamases was used to evaluate carbapenem potentiation activity of Compound 14. Several strains simultaneously expressing both class A and class B carbapenemases, which were constructed using conjugation, were also included in the panel. MIC for imipenem and meropenem of these strains was determined either alone or in the presence of Compound 14 at a fixed concentration of 4 μg/ml in the growth media. The results are present in Table 10 below. As shown in the table, Compound 14 significantly reduced carbapenem MIC of the strains expressing various carbapenemases, including those strains that expressed class A and class B enzymes simultaneously.
Table 10. Meropenem and Imipemen Potentiation Activity of Compound 14 against the strains of Enterobacteriaceaea producing various carbapenemases
Figure imgf000211_0001
coli
Klebsiella z
KP1097 IMP-1 SHV Y Y X pneumoniae
Klebsiella z
KP1098 IMP-26 TEM SHV z Y Y pneumoniae
Enterobacter Y
ECL1082 VIM-1 X z X cloacae
Escherichia z
EC1068 VIM-1 X Y X coli
Enterobacter Y
ECL1026 KPC X Y X cloacae
Enterobacter Y
ECL1036 KPC X Y X cloacae
Enterobacter Y
ECL1055 KPC X Y X cloacae
Klebsiella z
KPM1 123 KPC-2 TEM SHV X z X pneumoniae
Enterobacter z
ECLM1013 NDM, KPC X z X cloacae
Enterobacter z
ECLM1014 NDM, KPC X Y X cloacae
Enterobacter z
ECLM1015 NDM, KPC X z X cloacae
Enterobacter z
ECLM1016 NDM, KPC X z X cloacae
Enterobacter z
ECLM1017 VIM, KPC X z X cloacae
Enterobacter z
ECLM1018 VIM, KPC X z Y cloacae
Enterobacter z
ECLM1019 VIM, KPC X z X cloacae
Klebsiella z
KP1004 X z X pneumoniae KPC TEM SHV
Klebsiella Y
KP1061 X z X pneumoniae KPC TEM SHV
KP 1064 Klebsiella KPC TEM SHV z Y z X pneumoniae
Klebsiella Z
KP1070 X z X pneumoniae KPC TEM SHV
Klebsiella z
KP1084 Y z Y pneumoniae KPC-3, SHV-1 1, TEM-1
Klebsiella z X z X
KPM1097 NDM, KPC
pneumoniae
Klebsiella z
KPM1099 NDM, KPC Y z Y pneumoniae
Klebsiella z
KPM1 107 NDM, KPC X z X pneumoniae
Klebsiella z
KPM1 108 NDM, KPC z z Y pneumoniae
Klebsiella z
KPM1 109 NDM, KPC Y z X pneumoniae
Klebsiella z
KPM1 1 10 NDM, KPC X z X pneumoniae
Klebsiella z
KPM1 1 1 1 NDM, KPC X z X pneumoniae
Klebsiella z
KPM1 122 NDM, VIM Y z Y pneumoniae
X = MIC of less than 1 μg/mL
Y = MIC of 1 μ§/Ώ , to 10 μ§/Ώ ,
Z = MIC of greater than 10 μ-g/mL
Example 136. Potentiation of Meropenem and Imipenem by Compound 27 against the strains of Enterobacteriaceae overexpressing various carbapenemases
[0468] The large panel of clinical isolates expressing class A, D and B carbapenemases alone or in combination with other beta-lactamases (104 strains) was used to evaluate carbapenem potentiation activity of Compound 27. MIC for meropenem, doripenem, ertapenem and cefepime of these strains was determined either alone or in the presence of Compound 27 at a fixed concentration of 4 μg/ml in the growth media. The results are present in Table 11 below. As shown in the table, Compound 27 significantly reduced antibiotics MIC of the strains expressing various carbapenemases. Table 11. Antibiotics Potentiation Activity of Compound 27 against the strains of
Enterobacteriaceaea producing various carbapenemases
Figure imgf000214_0001
TEM- l(2b);
Enterobacter CTX-M-
ECL1090 Y X Y X Y X z Y cloacae 22;
ACT-type;
IMP-8;
SHV- 12(2be);
Citrobacter
CF1022 TEM- Y X Y X Y X z X freundii
OSBL(2b)
; IMP-8;
Proteus DHA-1 ;
PM 1026 Z X z Y Y X Y X mirabilis IMP-26;
SHV- OSBL(2b)
; TEM-
Klebsiella
KP1 180 OSBL(2b) Y X Y X Y X z X pneumoniae
; CTX-M- 15; DHA- 1 ; IMP-26;
SHV- OSBL(2b)
Klebsiella
KP1 181 ; CTX-M- Y X Y X Y X z X pneumoniae
15; IMP- 26;
SHV-
Klebsiella
KP1 184 OSBL(2b) Y X Y X Y X Y X pneumoniae
; IMP-1 ;
SHV- OSBL(2b)
Klebsiella
KP1 185 ; TEM- Z Y z X z Y z Y pneumoniae
OSBL(2b)
; IMP-4; Citrobacter
CF1012 PC-2 Y X Y X z X z X freundii
Enterobacte KPC-2,
ECL1026 Y X Y X z X Y X r cloacae TEM-1
Enterobacte KPC-3,
ECL1036 Y X Y X Y X z X r cloacae TEM-1
Enterobacte KPC-3,
ECL1055 Y X Y X z X z X r cloacae TEM
KPC-3,
Klebsiella
KP1061 SHV-11, Z X z X z X z X pneumoniae
TEM-1
KPC-2,
Klebsiella
KP1070 SHV-11, Z X Y X z X Y X pneumoniae
TEM-1
KPC-3,
Enterobacte
ECL1059 SHV-12, Y X Y X Y X Y X r cloacae
TEM-1
KPC-2,
Klebsiella
KX1017 OXA-2, Y X Y X z X z X oxytoca
SHV-30
KPC-2,
Klebsiella
KX1018 SHV-40, Y X Y X Y X Y X oxytoca
OXY-1
Klebsiella KPC-2,
KP1082 Y X Y X z X z X pneumoniae SHV-1
KPC-3,
Klebsiella
KP1083 SHV-1, Y X Y X z X z X pneumoniae
TEM-1
KPC-3,
Klebsiella
KP1088 SHV-11, Y X Y X z X z X pneumoniae
TEM-1
KPM120 Klebsiella KPC SHV Y X Y X z X z X 2 pneumoniae TEM
KPM120 Klebsiella KPC SHV
Y X Y X Y X Y X
3 pneumoniae TEM
KPC-2
Klebsiella
KP1095 TEM-1 Y X Y X Y X Y X pneumoniae
SHV-1
KPC-2
Klebsiella
KP1096 TEM-181 Y X Y X z X Y X pneumoniae
SHV-11
Klebsiella
KP1 104 KPC TEM Z X z X z X z X pneumoniae
Klebsiella KPC TEM
KP1 105 Z X Y X z X z X pneumoniae SHV
Klebsiella KPC TEM
KP1002 Y X Y X Y X Y X pneumoniae SHV
Klebsiella KPC TEM
KP1003 Y X Y X z X z X pneumoniae SHV
Escherichia
EC 1007 KPC-3 X X X X X X Y X coli
KPC-2,
Klebsiella
KP1004 TEM-1, Z X Y X z X z X pneumoniae
SHV-11
Klebsiella
P1008 KPC-2 Y X X X Y X Y X pneumoniae
KPM1 12 Klebsiella KPC-2
Z X Y X z X z X 3 pneumoniae TEM SHV
Klebsiella KPC-2,
X1019 Y X Y X z X z X oxytoca OXA-2
KPC-3,
Enterobacte
ECL1058 SHV-11, Z X z X z Y z X r cloacae
TEM-1
ECL1061 Enterobacte KPC-3, Z X Y X z Y z Y r cloacae Hyper
AmpC
expression
KPC-3,
Klebsiella
KP1084 SHV-11, Z Y z Y z z z Y pneumoniae
TEM-1
KPC-2,
Klebsiella CTX-M-
KP1087 Z Y z Y z Y z Y pneumoniae 15, SHV- 1 1, TEM-1
Klebsiella KPC TEM
KP1001 Z Y z Y z z z Y pneumoniae SI IV
KPC-2,
Klebsiella
KP1064 SHV-11, Z Y z Y z z z Y pneumoniae
TEM-1
KPC-3,
Klebsiella
KP1074 SHV-11, Z z z Y z z z z pneumoniae
TEM
Escherichia NDM-1,
EC1061 Z X z X z X z X coli CMY-6
NDM-1,
Enterobacte TEM-1,
ECL1057 Z z z z z z z z r cloacae CTX-M- 15
NDM-1,
TEM-1,
Klebsiella SHV-11,
KP1081 Z X z X z Y z Y pneumoniae CMY-6,
CTX-M- 15
NDM-1,
Escherichia
EC 1064 CMY-6, Z Y z Y z z z z coli
CTX-M- 15
NDM-1
KPM134 Klebsiella SI IV
z X z X z X z X 7 pneumoniae CTX-M- 15
CTX-M-
Enterobacte 15; ACT-
ECL1084 z X z X z X z X r cloacae 16; NDM- i;
Klebsiella
P1 161 NDM-1 ; z X z X z X z X pneumoniae
SHV- 31(2be);
TEM-
Enterobacte
ECL1085 l(2b); z X z X z X z X r cloacae
CTX-M- 15; NDM- i;
SHV- l l(2b);
Klebsiella
KP1 170 CTX-M- z X z X z X z X pneumoniae
15; NDM- i;
CTX-M-
Escherichia
EC 1069 27; NDM- z X z X z X z X coli
i;
SHV- OSBL(2b)
; TEM-
Klebsiella
KP1 177 OSBL(2b) z X z X z X z X pneumoniae
; CTX-M- 15; NDM- i; TEM-
Escherichia OSBL(2b)
EC 1070 Z X z X z X z X coli ; CMY-42;
NDM-5;
SHV- 31(2be);
TEM-
Enterobacter OSBL(2b)
ECL1097 Z X z X z X z X cloacae ; CTX-M- 15; ACT- 31 ; NDM- i;
SHV- OSBL(2b)
; TEM-
Klebsiella
KP1 178 OSBL(2b) z X z X z X z X pneumoniae
; CTX-M- 15; NDM- i;
SHV- 12(2be);
TEM-
Klebsiella
KP1 179 OSBL(2b) z X z X z X z X pneumoniae
; CTX-M- 15; NDM- 7;
TEM- OSBL(2b)
Enterobacter
ECL1098 ; DHA-1 ; z X z X z X z X cloacae
ACT- 16;
NDM-1 ;
Citrobacter SHV-
CF1023 z X z X z X z X freundii 12(2be); TEM- OSBL(2b)
; CTX-M- 3; CMY- 34; NDM- i;
SHV- OSBL(2b)
; TEM-
Klebsiella
KP1183 OSBL(2b) Z X z X z X z X pneumoniae
; CTX-M- 15;NDM- i;
Escherichia CTX-M-3;
EC 1072 Z X z X z X z Y coli NDM-1;
CTX-M-
Klebsiella
KP1186 15;NDM- Z X z X z X z Y pneumoniae
i;
SHV- 55(2be);
TEM-
Klebsiella
KP1187 OSBL(2b) Z X z X z X z X pneumoniae
; CTX-M- 15;NDM- i;
SHV- OSBL(2b)
Klebsiella
KP1188 ; CTX-M- Z Y z Y z Y z Y pneumoniae
15;NDM- i;
TEM-
Klebsiella
KP1189 OSBL(2b) Z X z X z X z X pneumoniae
; CTX-M- 15; CTX-
M-27;
NDM-1 ;
Enterobacter
ECL1004 NMC-A Y X Y X z X X X cloacae
OXA-181,
Klebsiella CTX-M-
KP1089 Y X Y X z X z Y pneumoniae 15, TEM,
SI IV
OXA-48,
Escherichia
EC 1062 CTX-M- X X X X Y X z X coli
15
OXA-48,
Klebsiella CTX-M-
KP1086 Z Y z Y z z z z pneumoniae 15, TEM,
SI IV
Enterobacte SHV-5,
EA1019 Z X z X z X z Y r aerogenes VIM-1
Enterobacte
ECL1045 VIM-1 Y X Y Y z Y z Y r cloacae
Klebsiella VIM-1,
P1054 Z X z X Y X z X pneumoniae SHV-11
Klebsiella VIM-1,
KP1059 z Y z Y z Y z Y pneumoniae SHV-11
Klebsiella VIM-1,
P1065 Y X Y X Y X z X pneumoniae SHV-11
KPM134 Klebsiella
VIM-1 Y X Y X Y X z X 4 pneumoniae
KPM134 Klebsiella VIM-1
z X z X Y X z X 5 pneumoniae SI IV
Enterobacte
ECL1082 VIM-1 z X z X Y X z Y r cloacae Escherichia
EC 1068 VIM-1 Z X z X z X z Y coli
Serratia
SMI 023 VIM-4; z Y z Y z Y Y Y marcescens
SHV-
Klebsiella
KP1164 12(2be); z X z X z X z X pneumoniae
VIM-1;
SHV- ll(2b);
Klebsiella
KP1165 CTX-M- z z z z z z z z pneumoniae
15; VIM- 27;
SHV-
Klebsiella
KP1166 5(2be); z Y z Y z Y z z pneumoniae
VIM-26;
SHV-
Klebsiella
KP1167 12(2be); X X X X Y X z X pneumoniae
VIM-1;
TEM-
Proteus l(2b);
PM1024 Y X z X Y X z X mirabilis CMY-16;
VIM-1;
CMY-
Citrobacter
CF1021 type; Y X Y X Y X z X freundii
VIM-1;
SHV-
Klebsiella
KP1169 ll(2b); z X z X Y X z X pneumoniae
VIM-1;
SHV-
Klebsiella 31(2be);
P1172 Y X z X Y X z X pneumoniae DHA-1;
VIM-1;
ECL1087 Enterobacter VIM-1; z X z X z X z Y cloacae
TEM- l(2b);
Enterobacter CTX-M-
ECL1088 Z X z X z X z Y cloacae 14; ACT- type;
VIM-1 ;
SHV-
Klebsiella
KP1 175 OSBL(2b) Z X z X z X z X pneumoniae
; VIM-1 ;
Enterobacter
ECL1091 VIM-1 ; Z X z Y Y X z Y cloacae
TEM-
Enterobacter OSBL(2b)
ECL1092 Y X Y X Y X z X cloacae ; ACT-32;
VIM-1 ;
TEM-
Enterobacter OSBL(2b)
ECL1093 Y X Y X Y X z X cloacae ; ACT-32;
VIM-1 ;
Enterobacter
ECL1094 VIM-1 ; Z X z X z Y z Y cloacae
Proteus
PM 1027 VIM-5; Z X Y X z X X X mirabilis
VIM-1,
Klebsiella
KP1014 TEM, Y X z Y Y X z X pneumoniae
SI IV
VIM-31;
Enterobacter
ECL1086 OXA- Y X Y X z Y Y Y cloacae
48(c)
CMY-4;
Enterobacter
ECL1096 VIM-4; Y X Y X z X z X cloacae
OXA- 48(c)
X = MIC of less than 1 μg/mL "M" means Meropenem Y = MIC of 1 μg/mL to 10 μg/mL "D" means Doripenem
Z = MIC of greater than 10 μg/mL "E" means Ertapenem
"C" means Cefepime
[0469] The largest panel of clinical isolates expressing class A, D and B carbapenemases alone or in combination with other beta-lactamases (169 strains) was used to evaluate carbapenem potentiation activity of Compounds 97 and 62. MIC for meropenem and tebipenem of these strains were determined either alone or in the presence of Compounds 97 or 62, respectively, at a fixed concentration of 8 ^ιηΐ in the growth media. The results are present in Table 12 below. As shown in the table, both compounds significantly reduced antibiotics MIC of the strains expressing various carbapenemases.
Table 12. Meropenem or Tebipenem Potentiation Activity of Compounds 97 respectively, against the strains of Enterobacteriaceaea producing carbapenemases
Figure imgf000225_0001
Klebsiella VIM-1,
KP1059 Z X z z pneumoniae SHV-11
KPC-3,
Klebsiella
KP1061 TEM-l , Z X z X pneumoniae
SHV-1 1
KPC-2,
Klebsiella
KP1064 TEM-l, Z Y z Y pneumoniae
SHV-11
Klebsiella VIM-1 ,
KP1065 Y X Y X pneumoniae SHV-1 1
KPC-2,
Klebsiella
KP1070 SHV-11, z X z X pneumoniae
TEM-l
KPC-3,
Klebsiella
KP1074 SHV-1 1 , z Y z Y pneumoniae
TEM
NDM-1,
Enterobacte
ECL1057 TEM-l, z Y z z r cloacae
CTX-M-15
Escherichia NDM-1,
EC1061 z X z X coli CMY-6
NDM-1,
TEM-l,
Klebsiella
KP1081 SHV-11, z X z X pneumoniae
CMY-6,
CTX-M-15
Enterobacte
ECL1004 NMC-A z X z X r cloacae
Escherichia
EC 1007 KPC-3 Y X Y X coli
KPC-2,
Klebsiella
KP1004 TEM-l , z X z X pneumoniae
SHV-1 1
Klebsiella
KP1008 KPC-2 Y X z X pneumoniae Klebsiella Vim-1, TEM,
KP1014 Z X X pneumoniae SHV z
Klebsiella
KP1015 VIM-1 , SHV
pneumoniae z Y z z
KPC-2,
Klebsiella CTX-M-15,
KP1087
pneumoniae SHV-1 1 , z X z Y
TEM-1
Klebsiella KPC-2,
KX1019 Y X z X oxytoca OXA-2
KPC-2,
Klebsiella
KX1017 OXA-2, Y X
oxytoca z X
SHV-30
Klebsiella KPC-2,
KP1082 X pneumoniae SHV-1 z X z
KPC-2,
Klebsiella
KX1018 SHV-40, Y X
oxytoca z X
OXY-1
KPC-3,
Klebsiella
KP1083 SHV-1, X
pneumoniae z z X
TEM-1
KPC-3,
Enterobacte
ECL1058 SHV-1 1 , Y X X r cloacae z
TEM-1
KPC-3,
Klebsiella
KP1084 SHV-1 1 ,
pneumoniae z Y z Y
TEM-1
KPC-3,
Klebsiella
KP1088 SHV-11, X
pneumoniae z z X
TEM-1
KPC-3,
Enterobacte
ECL1059 SHV-12, Y X Y X r cloacae
TEM-1
TEM, SHV,
Klebsiella
KP1086 CTX-M-15, z Y z Y pneumoniae
OXA-48 NDM-1,
Escherichia
EC 1064 CMY-6, Z Y
coli z Y
CTX-M-15
TEM, SHV,
Klebsiella
KP1089 CTX-M-15, Y X Y X pneumoniae
OXA-181
KPC-3,
Enterobacte
ECL1061 Hyper AmpC Y X z X r cloacae
expression
SHV-11,
Klebsiella
KP1092 SHV- 12,
pneumoniae z z z z
TEM-1, KPC
Klebsiella KPC-2 TEM
PM 1 123 z X pneumoniae SHV z X
Enterobacte
ECL1079 KPC TEM
r cloacae z z z z
Klebsiella KPC-3 TEM
KP1093 Y
pneumoniae SHV-1 1 z z z
Klebsiella KPC-2 TEM-
KP1094
pneumoniae 1 LEN-17 z z z z
Klebsiella KPC-2 TEM-
KP1095 Y X
pneumoniae 1 SHV-1 z X
Klebsiella KPC-2 TEM-
KP1096
pneumoniae 181 SHV-11 z z z z
Klebsiella KPC SHV
PM 1202 X pneumoniae TEM z X z
Klebsiella KPC SHV
KPM1203 Y X
pneumoniae TEM z X Klebsiella
KPM1344 VIM-1 Y X Y X pneumoniae
Klebsiella
PM 1345 VIM-1 SHV X Y X pneumoniae z
NDM-1 TEM
Klebsiella
KPM1346 SHV CTX- pneumoniae z Y z z
M-15 CMY
Klebsiella NDM-1 SHV
PM 1347 X z X pneumoniae CTX-M-15 z
Escherichai IMP-1 CMY-
EC 1065 Y X Y X coli 2
Klebsiella
KP1097 IMP-1 SHV
pneumoniae z X Y X
Klebsiella IMP-26 TEM
P1098 Y pneumoniae SHV z Y z
Klebsiella
KP1099 KPC-2 SHV Y
pneumoniae z z z
Klebsiella PC-3 TEM
KP1 100
pneumoniae SHV z Y z z
Klebsiella KPC-2 TEM
KP1 101 Y
pneumoniae SHV z z Y
Klebsiella KPC-3 TEM
P1 102
pneumoniae SHV z Y z z
Enterobacte
ECL1082 VIM-1 Y X Y X r cloacae
Klebsiella
KP1 104 KPC, TEM z X z X pneumoniae Klebsiella KPC, SHV,
KP1 105 Z X X pneumoniae TEM z
Klebsiella KPC TEM
KP1001
pneumoniae SHV z Y z Y
Klebsiella KPC TEM
KP1002 z X pneumoniae SHV z X
Klebsiella KPC TEM
KP1003
pneumoniae SHV z X z X
Escherichia
EC1068 VIM-1 z X Y X coli
Citrobacter CMY-type;
CF1021 Y X Y X freundii VIM-1 ;
SHV-
12(2be);
Citrobacter
CF1022 TEM- Y X Y X freundii
OSBL(2b);
IMP-8;
SHV-
12(2be);
TEM-
Citrobacter
CF1023 OSBL(2b);
freundii z X z X
CTX-M-3;
CMY-34;
NDM-1 ;
Escherichia CTX-M-27;
EC 1069 X
coli NDM-1 ; z z X
TEM-
Escherichia OSBL(2b);
EC1070 X X coli CMY-42; z z
NDM-5;
Escherichia CTX-M-3;
EC 1072
coli NDM-1 ; z X z X
CTX-M-15;
Enterobacte
ECL1084 ACT- 16;
r cloacae z X z X
NDM-1 ;
SHV-
31(2be);
Enterobacte
ECL1085 TEM- 1 (2b);
r cloacae z X z X
CTX-M-15;
NDM-1 ;
ECL1087 Enterobacte VIM-1 ; z X Y X
Figure imgf000231_0001
SHV-
Klebsiella 28(2be);
KP1160 Z X Y X pneumoniae CTX-M-15;
IMP-26;
Klebsiella
KP1161 NDM-1;
pneumoniae z X z X
SHV-l(2b);
Klebsiella
P1162 CTX-M-15; Y
pneumoniae z z z
IMP-4;
SHV-ll(2b);
Klebsiella MOX-1;
KP1163
pneumoniae KPC-2; z Y z z
VIM-1;
SHV-
Klebsiella
KP1164 12(2be);
pneumoniae z X z X
VIM-1;
SHV-ll(2b);
Klebsiella
P1165 CTX-M-15; Y
pneumoniae z z z
VIM-27;
Klebsiella SHV-5(2be);
KP1166 X
pneumoniae VIM-26; z z z
SHV-ll(2b);
Klebsiella
P1168 CTX-M-15;
pneumoniae z Y z z
VIM-27;
Klebsiella SHV-ll(2b);
KP1169 X pneumoniae VIM-1; z X Y
SHV-ll(2b);
Klebsiella
P1170 CTX-M-15; X pneumoniae z X z
NDM-1;
SHV-
Klebsiella 31(2be);
KP1172 Y X pneumoniae DHA-1; z X
VIM-1;
TEM-
Klebsiella 33(2br);
KP1173 Y X Y X pneumoniae CTX-M-15;
IMP-1
Figure imgf000233_0001
SHV- OSBL(2b);
Klebsiella TEM-
KP1183 Z X
pneumoniae OSBL(2b); z X
CTX-M-15;
NDM-1;
SHV-
Klebsiella
KP1184 OSBL(2b); Y X Y X pneumoniae
IMP-1;
SHV- OSBL(2b);
Klebsiella
P1185 TEM- pneumoniae z X z Y
OSBL(2b);
IMP-4;
Klebsiella CTX-M-15;
P1186
pneumoniae NDM-1; z X z X
SHV- 55(2be);
Klebsiella TEM-
KP1187 X pneumoniae OSBL(2b); z X z
CTX-M-15;
NDM-1;
SHV-
Klebsiella OSBL(2b);
KP1188 Y X z Y pneumoniae CTX-M-15;
NDM-1;
TEM- OSBL(2b);
Klebsiella
KP1189 CTX-M-15;
eumoniae z X z X pn
CTX-M-27;
NDM-1;
TEM-l(2b);
Proteus
PM1024 CMY-16;
bilis z X z X mira
VIM-1;
SHV-5(2be);
TEM-
Proteus
PM1025 OSBL(2b); Y X Y X mirabilis
VEB-2;
VIM-1;
Proteus DHA-1;
PM1026
mirabilis IMP-26; z X Y Y
Proteus
PM1027 VIM-5; X z X mirabilis z
Serratia
SM1023 VIM-4; Y marcescens z X z
SMI 024 Serratia TEM-l(2b); Y X Y Y marcescens IMP-47;
Klebsiella PC-4 VIM- ΡΠ90 Z Z z z pneumoniae 4 TEM SHV
Klebsiella
KP1191 KPC-2 Z Y z Y pneumoniae
Klebsiella KPC-2 TEM
P1192 Z Z z z pneumoniae SHV
Klebsiella KPC-3 TEM
KP1193 Z Y z Y pneumoniae SHV
Klebsiella PC TEM
P1194 Z Z z z pneumoniae SHV
Klebsiella KPC TEM
KP1195 Z Z z z pneumoniae CTX-M-15
KPC TEM
Klebsiella
KP1196 SHV CTX- Z Y z z pneumoniae
M-15 CMY
Klebsiella KPC-3, VIM-
KP1197 Z Y z z pneumoniae 1 TEM SHV
Klebsiella KPC-3, VIM- P1198 Z Y z Y pneumoniae 1 TEM SHV
Klebsiella KPC-3 TEM
KP1199 Z z z z pneumoniae SHV
Klebsiella KPC-3 TEM
P1200 Z z z z pneumoniae SHV Klebsiella KPC SHV
KP1210 Z X Z X pneumoniae TEM
KPC SHV
Klebsiella
KP121 1 TEM CTX- Z Y Z Y pneumoniae
M-15
KPC SHV
Klebsiella
KP1212 TEM CTX- Z Y Z z pneumoniae
M-15
KPC SHV
Klebsiella
KP1213 TEM CTX- Z X Z X pneumoniae
M-15
Klebsiella KPC SHV
KP1214 Z Y z z pneumoniae TEM + 1.9kb
Klebsiella
KP1215 KPC SHV Z Y z z pneumoniae
Klebsiella KPC SHV
KP1216 Z Y z Y pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
KP1217 Z Y z Y pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
KP1218 Z Y z Y pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
KP1219 Z X z X pneumoniae TEM + 1.9kb Klebsiella KPC SHV
KP1220 Z Y z Y pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
KP1221 Z Y z Y pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
KP1222 Z X z X pneumoniae TEM IMP
Klebsiella KPC SHV
KP1223 Z z z z pneumoniae TEM
Klebsiella KPC SHV
KP1224 Z z z z pneumoniae TEM
KPC SHV
Klebsiella
KP1225 TEM + 1.9kb Z X z X pneumoniae
CMY
Klebsiella KPC SHV
KP1226 Z Y z z pneumoniae TEM + 1.9kb
KPC SHV
Klebsiella
KP1227 TEM CTX- Z X z X pneumoniae
M-15
OXA-48
Klebsiella
KP1228 TEM SHV Y X Y X pneumoniae
CTX-M-15
OXA-48
Klebsiella
KP1229 TEM SHV z X z X pneumoniae
CTX-M-15
OXA-48
Klebsiella
KP1230 TEM SHV Y X Y X pneumoniae
CTX-M-15
OXA-48
Klebsiella
KP1231 TEM SHV Y X Y X pneumoniae
CTX-M-15 OXA-48
Klebsiella
KP1232 TEM SHV Z Y z Y pneumoniae
CTX-M-15
OXA-48
Klebsiella
KP1234 TEM SHV Z Y z Y pneumoniae
CTX-M-15
OXA-48
Klebsiella
KP1236 TEM SHV Z Y z Y pneumoniae
CTX-M-15
OXA-48
Klebsiella
KP1237 TEM SHV Z Y z Y pneumoniae
CTX-M-15
Klebsiella OXA-48
KP1239 Z Y z Y pneumoniae SHV
OXA-181
Klebsiella
KP1240 SHV CTX- Z X Y X pneumoniae
M-15
OXA-181
Klebsiella
KP1241 TEM SHV Z Y z Y pneumoniae
CTX-M-15
Escherichia
EC1073 OXA-48 Z Y z Y coli
Escherichia KPC-2,
EC 1074 Z X z
coli SHV- 12
KPC-2,
Klebsiella
KP1242 SHV- 12 Z X z
pneumoniae
TEM
Klebsiella KPC-2 SHV
KP1243 Z Y z
pneumoniae VIM-1
Klebsiella KPC SHV
KP1244 Z z z z pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
P1245 Z X z X pneumoniae TEM + 1.9kb
Klebsiella KPC SHV
KP1246 Z X z X pneumoniae TEM + 1.9kb
Klebsiella IMP TEM
P1247 Z Y z Y pneumoniae SHV
OXA-232
Klebsiella
KP1248 SHV CTX- Z Y z Y pneumoniae
M-15 Klebsiella OXA-232
KP1249 Z Y Z Y
pneumoniae SI IV
NDM-1 TEM
Klebsiella
KP1250 SHV SMY-2 Z X Z X pneumoniae
CTX-M-15
Escherichia NDM-1
EC1076 Z X z X
coli CMY-2
Klebsiella KPC TEM
KP1252 Z Y z X
pneumoniae SHV
X = MIC of less than 1
Z
Figure imgf000239_0001
= MIC of greater than 10
"M" means Meropenem
"T" means Tebipenem
Example 137: Serum Stability of Prodrugs
[0470] Prodrug strategy is one of the ways to achieve or increase oral bioavailability for therapeutic drugs. Compound 62 was used as a template for various ester prodrugs. After a prodrug molecule is absorbed into systemic circulation, it should be hydrolyzed in the blood in order to release the active form. Hydrolysis of several prodrugs by rat and human serum were evaluated.
[0471] For all stability experiments the test compounds were treated with rat or human serum in Eppendorf tubes. Typically, 980 μΐ of serum was prewarmed at 37 degrees for 2 minutes and then 20 μΐ of a compound (at 1 mg/ml, 50x) was added to it to get a final concentration of 20 μg/ml and immediately mixed. Duplicate samples were tested. The tubes were sampled immediately (100 μΐ) and then placed back in a 37 degree water bath and samples were taken at designated times and transferred directly into Eppendorf tubes containing 400 μΐ of precipitant solution (a 4.00 μg/mL solution of a standard compound, RPX7479, in 10% water, 45% methanol and 45%) acetonitrile). After vortexing for 30 seconds, the tube was centrifuged in a microcentrifuge for 10 minutes at 15K rpm. Next, 100 μΐ of the supernatant was combined with 600 μΐ of water and injected on TC-MS using 0.1 % formic acid in water for mobile phase A and 0.1 % formic acid in methanol for mobile phase B on an ACE 5 CI 8 2.1x100mm column with a 10 μΕ injection. The flow rate and gradient were adjusted as needed to give the desired resolution and run time. The pH of the mobile phase was adjusted if needed to improve the chromatography.
[0472] The time course of both the disappearance of a prodrug and the appearance of the active form of that prodrug is presented in Table 13 and Table 14. The active metabolites for all of the listed prodrugs are corresponding parent drugs
TABTE 13. Time-course of prodrug hydrolysis by human serum
Figure imgf000240_0001
[0473] The data showed that different prodrugs differ significantly in serum stability. Compound 123 appeared to be completely converted to active metabolite over the course of 4 hour experiment.
Example 138: Oral Pharmacokinetics of Prodrugs of Compound 62
[0474] The prodrugs of compound 62, including compounds 121, 122, 123, 124, 125, 126 and 127 were tested for their oral pharmacokinetics. Rats (n= 3 per compound) were administered a single oral dose. Oral doses were administered as a single dose. Plasma (~ 0.3 mL) samples were collected from each rat at designated time points up to 24 hours. Blood samples were centrifuged within 5 min of collection at 12000 g for 5 min to obtain plasma. The plasma samples were stored at -80°C until analyzed. Data were analyzed using WinNonlin and the results are presented in Table 15.
TABTE 15. Bioavailability of Prodrugs of Compound 62
Figure imgf000241_0001
[0475] Although the invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound havin the structure of Formula (I):
Figure imgf000242_0001
(I)
or pharmaceutically acceptable salts thereof, wherein:
A is selected from the group consisting of C3-i0 carbocyclyl, C -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl;
Xa is -C(ReRf)-, -0-, -S-, -S(O)-, -S(0)2-, or -NR1-;
Ra is selected from the group consisting of -H, halogen, optionally substituted -C1-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C,-6 alkyl, -NR'R2, -N(0R3)R2, optionally substituted -S-C1-6 alkyl, - C(0)NR1R2, -S(0)2NR1R2, CN, optionally substituted -S(0)-C1-6 alkyl, optionally substituted -S(0)2-Ci_6 alkyl, and a carboxylic acid isoster;
Rb is selected from the group consisting of -H, halogen, optionally substituted -C1-6 alkyl, -OH, -C(0)OR, optionally substituted -O-Ci-6 alkyl, -NR!R2, -N(OR3)R2, optionally substituted -S-C1-6 alkyl, -C(0)NR1R2, - S(0)2NR'R2, -CN, optionally substituted -S(0)-C1-6 alkyl, optionally substituted -S(0)2-Ci- alkyl, and a carboxylic acid isoster, and
Rc is selected from the group consisting of-OH, optionally substituted -0-C1-6 alkyl -NR^2, and -N(OR3)R2, or
Rb and Rc together with intervening atoms form a 5-8 membered boron ester ring, optionally comprising additional 1-3 heteroatoms selected from Oxygen (O), Sulfur(S) or Nitrogen(N);
Rd is selected from the group consisting of -OH, optionally substituted -O-Ci-6 alkyl -NR'R2, and -N(OR3)R2, or when Rb and Rc do not together form a 5-8 membered boron ester ring, then optionally Rc and Rd together with intervening atoms form a 5-15 membered boron ester or amide ring, optionally comprising additional 1-3 heteroatoms selected from O, S, and N;
Y is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, - CH2- and -NR2-;
G is selected from the group consisting of -NR^2, -N3, -C(0)NR1R2, - S(0)2NR'R2, -BR3, -OR3, -CH2NR1C(0)R5, -C(=NOR3)-X, C(=NOR3)-Z, - C(0)OR3, -C(0)NR1(OR3), -NR^OR3), -NR1C(0)R5, -NR1C(0)NR2Rla, - NR'C(0)OR3, -NR' S(0)2R3, -NR'S(0)2NR2Rla, -NR'NR 3, C(0)NR1NR2Rla, -S(0)2NR1NR2Rla, -C(=NR1)R5, -C(=NR1)NR2Rla, - NR'CR5(=NR2), -NR'C(=NR2)NRlaR2a, -CN, CM0 alkyl optionally substituted by one or more R10, C2-ioalkenyl optionally substituted by one or more R10, C2-1oalkynyl optionally substituted by one or more R10, C3-7 carbocyclyl optionally substituted by one or more R10, 3-10 membered heterocyclyl optionally substituted by one or more R10, C6-ioaryl optionally substituted by one or more R10, 5-10 membered heteroaryl optionally substituted by one or more R10,
Figure imgf000243_0001
optionally substituted by one or more R10, Ci- alkylene-3-10 membered heterocyclyl optionally substituted by one or more R10, Ci^alkylene-Ce-ioaryl optionally substituted by one or more R10, and Ci- alkylene-5-10 membered heteroaryl optionally substituted by one or more R10;
Re and RF are each independently selected from the group consisting of -H, C1-6 alkyl, -OH, -OCi-6alkyl, -SCi-6alkyl, C3-1ocycloalkyl, C2-1oalkenyl, C2-,0alkynyl, -NR1C(0)R5, -NR1S(0)2R3, -C(0)R5, -C(0)OR3, alkylaryl, optionally substituted C6-10 aryl, optionally substituted -0-C6-ioaryl, -CN, optionally substituted 5-10 membered heteroaryl, optionally substituted -O-heteroaryl, optionally substituted 3-10 membered heterocyclyl, -S(0)R3' -S(0)2R3, -R1-0-C(0)OR3, or Re and Rf together with the carbon to which they are attached form a C3-8 cycloalkyl or a 4-8 membered heterocyclyl;
7 7
R is present 1 to 5 times and each R is independently selected from the group consisitng of -H, -OH, halogen, -CH3, -CF3, Ci-C6 alkenyl, C -C alkynyl, C]-C6 heteroalkyl, C3-C7 carbocyclyl, 3-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, C C6 alkoxy(Ci-C6)alkyl, aryloxy, sulfhydryl (mercapto), and -(CH2)m-Y'-(CH2)pM', or
two adjacent R7 together with any intervening atoms form a 5-10 membered heteroaryl;
m and p are independently 0 to 3;
Y' is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, - CR5R6-, and -NR1-;
1 2
M' is selected from the group consisting of -C(0)NR R ; - C(0)NR'OR3; -NR'C(0)R5; -NR'C(0)NR2Rl a; -NR'C(0)OR3; -NR' S(0)2R3; -NR1S(0)2NR2Rla; -C(=NR1)R5; -C(=NR1)NR2Rla; -NR1CR5(=NR2); - NR'C(=NR2)NRl aR2a; NR'R2; -S03R3; -CN; Cm alkyl optionally substituted
3 1 2 with 0-2 substituents selected from the group consisting, -OR , -NR R , halogen, -C(0)NR'R2, and -NR'C(0)R5; C3-IO cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C1 -4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C6-IO aryl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR1C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR , - NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5;
X is hydrogen or optionally substituted Ci-galkyl; Z is selected from optionally substituted C3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
R is selected from the group consisting of -H, -C1 -9alkyl, -CR5R6OC(0)C1 -9alkyl, -CR5R6OC(0)OC1 -9alkyl,
CR6R7OC(O)C6-i0aryl, CR6R7OC(O)OC6-i0aryl, and
Figure imgf000245_0001
each R1, R2, Rla and R2a are independently selected from the group consisting of -H, optionally substituted -Ci-ioalkyl, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
R is hydrogen, optionally substituted Ci-ioalkyl, -optionally substituted Ci.ioalkyl-COOH, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
each R5, R6, R8 and R9 are independently selected from the group consisting of -H, -OH, -NH2, -optionally substituted alkoxyl, optionally substituted -Ci.i0alkyl, optionally substituted C2-i0alkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
each n is independently 0-3;
each R10 is independently (CH2)0-6Rn ; and
each R11 is independently selected from C]-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C -C heteroalkyl; C3-C7 carbocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and Ci- C6 haloalkoxy; C3-C7-carbocyclyl-C1-C6-alkyl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and C]-C6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci-C6 alkoxy, C]-C6 haloalkyl, and C]-C6 haloalkoxy; 3-10 membered heterocyclyl-Ci-Ce-alkyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and Ci- C6 haloalkoxy; aryl optionally substituted with halo, amine, cyano, C -C alkyl, C]-C6 alkoxy, Ci-C6 haloalkyl, and C]-C6 haloalkoxy; aryl(C] -C6)alkyl optionally substituted with halo, amine, cyano, C -C alkyl, Ci-C6 alkoxy, Ci- C haloalkyl, and C]-C6 haloalkoxy; 5-10 membered heteroaryl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and Ci-C6 haloalkoxy; 5-10 membered heteroaryl(C] -C6)alkyl optionally substituted with halo, amine, cyano, C -C alkyl, Ci-C6 alkoxy, Ci- C haloalkyl, and C]-C6 haloalkoxy; Ci-6alkylene-C3.7carbocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and Ci-C6 haloalkoxy; Ci- alkylene-3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, C -C alkyl, Ci-C6 alkoxy, Ci- C haloalkyl, and C]-C6 haloalkoxy; Ci- alkylene-C6-ioaryl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C -C alkoxy, C -C haloalkyl, and Ci-C6 haloalkoxy; C]-6alkylene-5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C -C alkyl, Ci-C6 alkoxy, Ci- C haloalkyl, and Ci-C6 haloalkoxy; halo; cyano; hydroxy; C]-C6 alkoxy(Ci- C6)alkyl (ether); aryloxy; halo(Ci-C6)alkyl; halo(Ci-C6)alkoxy; amino; amino(Ci-C6)alkyl; nitro; O-carbamyl; N-carbamyl; O-thiocarbamyl; N- thiocarbamyl; C-amido; N-amido; S-sulfonamido; N-sulfonamido; C-carboxy; O-carboxy; acyl; cyanate; isocyanate; thiocyanato; isothiocyanato; sulfonyl; oxo; -OR3; -Ci-6alkylene-COOR3; -SR3; -C(0)NR'R2; -NR'R2; -NR'(CH2)O- 4COR5; -NR1(CH2)O-4C(=NR2)R5; -NR1-CH-[(CH2)0-4-NRlaR2a]2; -NR1- (CH2)1-5-R3; -NR'(CH2)1-4-NR, aR2a ; -NtCCH,)!.,^^ ],; -S(CH2)0- 4C(=NR1)R5; -S(CH2)1 -4-R3; -8(ΟΗ2)0-4^^2; -8-ϋΗ-[( Η2)0-4-ΝΛ2]2; - S[(CH2)1-4-NR'R ]2; -S(CH2)O-4-3-10 membered heterocyclyl; -S(CH2)0-4-3-10 membered heterocyclyl-NR R2; -S(CH2)0- -5-10 membered heteroaryl-NR^2;
-S(0)2NR1R2; and -O-Ci.galkylene-NR'R2.
2. The compound of claim 1, wherein:
G is selected from the group consisting of -NR'R2, -N3, -C(0)NR'R2, - S(0)2NR1R2, -SR3, -OR3, -CH2NR1C(0)R5, -C(=NOR3)-X, C(=NOR3)-Z, -C(0)OR3, -C(0)NR'(OR3), -NR'(0R3), -NR'Ct yiR5, -NR'C(0)NR Rl a, -NR'C(0)OR3, - NR1S(0)2R3, -NR1S(0)2NR2Rla, -NR^R 3, -C(0)NR1NR2Rla, -S(0)2NR1NR2Rla, -C(=NR')R5, -C(=NR')NR2Rla, -NR'CR5(=NR2), -NR1 C(=NR2)NR' aR2a, optionally substituted C1-10 alkyl, optionally substituted C2-ioalkenyl, optionally substituted C2- 10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C -ioaryl, optionally substituted 5-10 membered heteroaryl, optionally substituted
Figure imgf000247_0001
optionally substituted Ci- alkylene-5-10 membered heterocyclyl, optionally substituted C\. 6alkylene-C6-10aryl, and optionally substituted C1-6alkylene-5-10 membered heteroaryl;
R7 is present 1 to 5 times and each R7 is independently selected from the group consisitng of -H, -OH, halogen, -CF3, Ci-C6 alkenyl, C]-C6 alkynyl, C]-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C6 alkoxy(Ci-C )alkyl, aryloxy, sulfhydryl (mercapto), and - (CH2)m-Y'-(CH2)pM';
M' is selected from the group consisting of -C(0)NR1R2; -C(0)NR1OR3; - NR'C(0)R5; -NR'C(0)NR2Rla; -NR'C(0)OR3; -NR'SCO^R3; -NR1S(0)2NR2Rla; - C(=NR1)R5; -C(=NR1)NR2Rla; -NR1CR5(=NR2); -NR1C(=NR2)NRlaR2a; C,-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR , -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; C3-i0 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, - OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, - OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5;
R is selected from the group consisting of -H, -Ci-galkyl, -CR5R6OC(0)C1-
Figure imgf000248_0001
9alkyl, -CR5R6OC(0)OC,-9alkyl, and ;
each R1, R2, Rla and R a are independently selected from the group consisting of -H, optionally substituted -Ci.ioalkyl, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl; and
each R5, R6, R8 and R9 are independently selected from the group consisting of -H, -OH, -optionally substituted alkoxyl, optionally substituted -Ci-ioalkyl, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3- 7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C -ioaryl, and optionally substituted 5-10 membered heteroaryl.
3. The compound of claim 1 or 2, wherein G is selected from the group consisting of -NRJR2, -N3, -C(0)NR1R2, -S(0)2NR1R2, -SR3, -OR3, -CH2NR1C(0)R5, - C(=NOR3)-X, C(=NOR3)-Z, -C(0)OR3, -C(0)NR1(OR3), -NR'(OR3), -NR' C(0)R5, - NR1C(0)NR2Rla, -NR1C(0)OR3, -NR1S(0)2R3, -NR1S(0)2NR2Rla, -NR^R 3, - C(0)NR'NR2Rla, -S(0)2NR'NR Rl a, -C(=NR')R5, -C(=NR')NR2Rla, -NR'CR5(=NR2), - NR1C(=NR2)NRlaR2a, optionally substituted CM 0 alkyl, optionally substituted C2-i0alkenyl, optionally substituted C2-ioalkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl.
4. The compound of any one of claims 1 to 3, wherein each R11 is independently selected from Ci-C6 alkyl; haloCi-6alkyl; -OR3; -C1-6alkylene-COOR3; -SR3; halogen; -CO- C,-4alkyl; C(0)NR1R2; -NRJR2; -NR1(CH2)0-4COR5; -NR1(CH2)0-4C(=NR2)R5; -NR^CH- [(CH2)0-4-NRl aR a]2; -NR'- ^.s-R3; -NR,(CH2)i-4-NRl aR a; -N[(CH2)1-4-NR,R2]2; - S(CH2)o-4C(=NR1)R5; -S(CH2)1 -4-R3; -SCCH^-NR^2; -S-CH-KCH^-NR^2],; - S[(CH2)1-4-NR'R2]2; -S(CH2)O-4-3-10 membered heterocyclyl; -S(CH2)0-4-3-10 membered heterocyclyl-N^R2; -S(CH2)0-4-5-10 membered heteroaryl-N^R2; -SCO^NR^2; and -O-C,.
1 2
6alkylene-NR R ; C3-7 carbocylcyo optionally substituted with halo, amine, cyano, C C6 alkyl, C]-C6 alkoxy, C]-C6 haloalkyl, and C]-C6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C C6 alkoxy, C C6 haloalkyl, and C]-C6 haloalkoxy; 6 to 10 membered aryl optionally substituted with halo, amine, cyano, Ci-C6 alkyl, C C6 alkoxy, C C6 haloalkyl, and C C6 haloalkoxy; and 5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci-C alkoxy, C]-C6 haloalkyl, and Ci-C6 haloalkoxy.
5. The compound of any one of claims 1 to 4, wherein Y is -CH2-, -S(O)-, - S(0)2-, -0-, -NH-, or -S-.
6. The compound of any one of claims 1 to 5, wherein RD is -OH.
7. The compound of any one of claims 1 to 6, wherein Xa is -CH2-.
8. The compound of any one of claims 1 to 7, wherein RA is selected from the group consisting of -H, halogen, optionally substituted -C1-6 alkyl, -OH, -C(0)OR, optionally substituted -0-C,-6 alkyl, -NR!R2, -N(OR3)R2, optionally substituted -S-C1-6 alkyl, -C(0)NR'R2, -S(0)2NR'R2, CN, optionally substituted -S(0)-Ci-6 alkyl, and optionally substituted -S(0)2-C,-6 alkyl.
9. The compound of any one of claims 1 to 8, wherein RB is selected from the group consisting of -H, halogen, optionally substituted -Ci-6 alkyl, -OH, -C(0)OR, optionally substituted -0-Ci-6 alkyl, -NR'R2, -N(OR3)R2, optionally substituted -S-C1-6 alkyl, -C(0)NR1R2, -SCO^NR^2, -CN, optionally substituted -S(0)-C,-6 alkyl, and optionally substituted -S(0)2-Ci_6 alkyl.
10. The compound of any one of claims 1 to 9, wherein RB is-OH
11. The compound of any one of claims 1 to 10, wherein RC is -OH.
12. The compound of any one of claims 1 to 8 having the structure of Formula
(Γ):
Figure imgf000250_0001
( )
or pharmaceutically acceptable salts thereof.
13. The compound of any one of claims 1 to 5, having the structure of Formula (I-l) Formula (1-2):
Figure imgf000250_0002
(I-l) (1-2)
or pharmaceutically acceptable salts thereof, wherein:
J, L, and M are each independently selected from the group consisting of CR7 and N.
14. The compound of any one of claims 1 to 13, wherein the two adjacent R7 together with any intervening atoms form a 5-8 membered heteroaryl ring.
15. The compound of claim 14, wherein the two adjacent R7 together with any intervening atoms form an imidazole ring.
16. The compound of any one of claims 1 to 15, wherein R is H and R is H.
17. The compound of any one of claims 6 to 16, wherein:
Y is selected from the group consisting of -S-, -0-, -CH2-, and -NH-;
G is selected from the group consisting of -C(0)NR1R2; -C(0)NR1OR3; - NR'C(0)R5; -NR'C(0)NR2R2a; -NR'C(0)OR3; -NR'SiO^R3; -NR'S(0)2NR2Rla; - C(=NR!)R5; -C(=NR1)NR2Rla; -NR1CR5(=NR5); -NR1C(=NR2)NRlaR2a; C6-10aryl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, -OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of Q-4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; and 5-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of Q-4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and - NR1C(0)R5;
R is selected from a group consisting of -H, -Q.galkyl, -CR5R6OC(0)Ci_9alkyl,
Figure imgf000251_0001
and
each R1, R2, RL A, R2A, R3, R5 and R6 are independently selected from -H and -Ci-4alkyl; and
R7 is selected from the group consisting of -H, -C1-4alkyl, -OH, -OCi-4alkyl, and halogen.
18. The compound of any one of claims 6 to 16, wherein:
Y is selected from the group consisting of -S-, -0-, -CH2-, and -NH-;
G is selected from the group consisting of -C(0)NR'R2; -C(0)NROR3; - NR1C(0)R5; -NR1C(0)NR2R2A; -NR1C(0)OR3; -NR1S(0)2R3; -NR1S(0)2NR2RLA; - C(=NR')R5; -C(=NR')NR2RL A; -NR'CR5(=NR5); -NR1 C(=NR2)NR' AR2A; C6-i0aryl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, -OR3, -Ci-6alkylene-COOR3, -SR3, -NR'R2, halogen, -C(0)NR'R2, and - NR1C(0)R5; 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of Q-4 alkyl, -OR , -Ci-6alkylene-COOR , -SR , - NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; and 5-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of Q-4 alkyl, -OR3, -C,-6alkylene-COOR3, -SR3, -NR!R2, halogen, -C(0)NR1R2, and - NR'C(0)R5; R is selected from a group consisting of -H, -Chalky!, -CR5R6OC(0)Ci.9alkyl,
Figure imgf000252_0001
and
each R1, R2, Rla, R2a, R3, R5 and R6 are independently selected from -H and -Ci-4alkyl; and
R is selected from the group consisting of -H, -C]-4alkyl, - OH, -OCwalkyl, -SQ-4alkyl and halogen.
19. The compound of any one of claims 16 to 18, having the structure of Formula (la)
Figure imgf000252_0002
(la)
or pharmaceutically acceptable salts thereof.
20. The compound of any one of claims 16 to 18, having the structure of (lb):
Figure imgf000252_0003
(lb)
or pharmaceutically acceptable salts thereof.
21. The compound of any one of claims 16 to 18, having the structure of Formula (Ic)
Figure imgf000252_0004
(Ic)
or pharmaceutically acceptable salts thereof.
22. The compound of any one of claims 16 to 18, having the structure of (Id):
Figure imgf000253_0001
(Id)
or pharmaceutically acceptable salts thereof.
23. The compound of any one of claims 1-22, wherein Y is -CJ¾-, -O- or -S-.
24. The compound of any one of claims 1-22, wherein Y is -O- or -S-.
25. The compound of any one of claims 13-22, wherein:
Y is -O- or -S-;
G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of C1-4 alkyl, -OR ,
-C1-6alkylene-COOR3, -SR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5,
1 2 5
wherein R , R and R in G are independently selected from -H and -C1-4alkyl; and
J, L and M are CR7.
26. The compound of any one of claims 1-25, wherein n is 0 or 1.
27. The compound of any one of claims 1-26, wherein n is 0.
28. The compound of any one of claims 1-8 and 12-27, wherein the compound of formula (I) has the structure of formula Ie):
Figure imgf000253_0002
selected from H, F, CI, -CH3, -CF3, and -Y'-(CH2)PM'; and p is 0 or 1.
29. The compound of any one of claims 1-11, wherein the compound of formula (I) has the structure of formula (If):
Figure imgf000254_0001
(if)
or pharmaceutically acceptable salts thereof,
wherein n is 0;
R7 is selected from H, F, CI, -CH3, -CF3, and -Y'-(CH2)PM'; and p is 0 or 1.
30. The compound of any one of claims 1-29, wherein G is a 5-10 membered heteroaryl optionally substituted with one or more R10.
31. The compound of claim 30, wherein G is a thiadiazole optionally substituted with one or more R10.
32. The compound of claim 30, wherein G is a thiazole optionally substituted with one or more R10.
33. The compound of claim 30, wherein G is an imidazole optionally substituted with one or more R10.
34. The compound of claim 30, wherein G is a triazole optionally substituted with one or more R10.
35. The compound of any one of claims 1-29, wherein G is a 3-10 membered heterocyclyl optionally substituted with one or more R10.
36. The compound of claim 35, wherein G is an azetidine optionally substituted with one or more R10.
37. The compound of claim 36, wherein G is
Figure imgf000254_0002
38. The compound of claim 35, wherein G is a piperazine optionally substituted with one or more R10.
39. The compound of any one of claims 1-38, wherein R10 is R11.
40. The compound of any one of claims 1-38, wherein R10 is CH2Rn, (CH2)2Rn, (CH2)3Ru, or (CH2)4RU.
41. The compound of claim 35, wherein n is 2 and G is
Figure imgf000255_0001
42. The compound of any one of claims 1-29, wherein G is -CONH2.
43. The compound of any one of claims 1-29, wherein G is -CN.
44. The compound of any one of claims 1-29, wherein G is -CH3.
45. The compound of any one of claims 1-29, wherein G is thiadiazole.
46. The compound of any one of claims 1-29, wherein G is thiadiazole optionally substituted with -NRJR2 or -NR1C(0)R5, wherein R1, R2and R5 in G are independently -H or -Ci-4alkyl.
47. The compound of any one of claims 1-29, wherein G is triazole optionally substituted with -NR 1 R2 , wherein R 1 and R2 in G are independently -H or -Ci-4alkyl.
48. The compound of any one of claims 1-29, wherein G is triazole optionally substituted with a C1-4 alkyl.
49. The compound of any one of claims 1-29, wherein G is tetrazole optionally substituted with methyl.
50. The compound of any one of claims 1-29, wherein G is triazole optionally substituted with -Ci^alkylene-COOH.
51. The compound of claim 50, wherein G is triazole optionally substituted with - (CH2)3-COOH.
52. The compound of any one of claims 1-29, wherein G is pyridine.
53. The compound of any one of claims 1-29, wherein G is thiazole.
54. The compound of any one of claims 1-29, wherein G is phenyl.
55. The compound of any one of claims 1-29, wherein G is azetidine.
56. The compound of any one of claims 13-24, wherein:
Y is -S-;
n is 1 or 2;
G is -C(0)NR'R2; and
J, L and M are CR7.
57. The compound of any one of claims 13-23, wherein:
Y is -CH2-;
n is 0 to 2;
G is -C(0)NR'R2; and
J, L and M are CR7.
58. The compound of any one of claims 1 to 29, wherein the compound of formula (I) has the structure of formula Ig) or (Ih):
Figure imgf000256_0001
or pharmaceutically acceptable salts thereof, wherein n is 0;
1 2 3 4 12
each Z , Z , Z and Z are independently selected from N, NR , O, S, and CR12 provided that Z1 to Z4 are selected such that a five membered aromatic ring is formed;
12 11
each R is independently H or (CH2)o-5R ; and
1 1 3 each R is independently selected from Ci-C6 alkyl; haloCi-6alkyl; -OR ; -C\. 6alkylene-COOR3; -SR3; halogen; -CO-C,-4alkyl; C(0)NR1R2; -NR!R2; -NR1(CH2)0-
Figure imgf000256_0002
NR^CH^ -NR1^; -Ν[( Η2)1 -4-Ν^2]2; -S(CH2)0-4C(=NR1)R5; -S(CH2)1 -4-R3; - S(CH2)o-4-NR'R2; -S-CH-KCH^-NR'R2],; -StCCH^!^-NR^2],; -S(CH2)0-4-3-10
1 2
membered heterocyclyl; -S(CH2)o-4-3-10 membered heterocyclyl-NR R ; -S(CH2)o-4- 5-10 membered heteroaryl-NR'R2; -SCO)^^2; and -O-Ci-ealkylene-NR'R2; C3-7 carbocyclyl optionally substituted with halo, amine, cyano, Ci-C alkyl, C] -C6 alkoxy, Ci-C6 haloalkyl, and C C6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, amine, cyano, Ci-C alkyl, C] -C6 alkoxy, C] -C6 haloalkyl, and Ci-C6 haloalkoxy; 6 to 10 membered aryl optionally substituted with halo, amine, cyano, Ci-C alkyl, C] -C6 alkoxy, C] -C6 haloalkyl, and Ci-C haloalkoxy; and 5-10 membered heteroaryl optionally substituted with halo, amine, cyano, C]-C6 alkyl, Ci- C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy.
59. The compound of claim 58, wherein Z1 is S.
60. The compound of claim 58 or 59, wherein each Z 2 and Z 3 are independently N, NR12, or CR12.
61. The compound of any one of claims 58 to 60, wherein Z4 is N or CR12.
62. The compound of claim 58, wherein Z1 to Z4 are selected to form a five-
;
Figure imgf000257_0001
63. The compound of any one of claims 58 to 62, wherein R 12 is H.
64. The compound of any one of claims 58 to 62, wherein R 12 is R 11.
65. The compound of any one of claims 1 to 64, wherein R1 1 is -CF CHF2, or
CH2F.
66. The compound of claim 65, wherein R1 1 is CF3.
67. The compound of any one of claims 1 to 64, wherein R11 is Ci-C6 alkyl.
68. The compound of claim 67, wherein R1 1 is CH .
69. The compound of any one of claims 1 to 64, wherein R11 is a C1-4 alkyl optionally substituted with a 3-10 membered heterocyclyl.
70. The compound of claim 69, wherein R , 11 is -CH2-piperazine
71. The compound of any one of claims 1 to 64, wherein R1 ' is an optionally substituted C]-6alkylene-3-10 membered heterocyclyl.
72. TThhee ccoompound of claim 71, wherein R is azetidine optionally substituted with one or more NH2
N. -NH2
73. The compound of claim 71, wherein R is
74. The compound of any one of claims 1 to 64, wherein R11 is -(CH2)o-4NR1R2.
75. The compound of claim 74, wherein R1 1 is NH2, -CH2NH2, or -(CH2)4NH2.
76. The compound of claim 74, wherein R11 is NRJR2, R1 is H, and R2 is an optionally susbstituted -Ci-4alkyl or an optionally substituted 3-8 membered heterocyclyl.
77. The compound of claim 76, wherein R2 is azetidine.
I— NH
-t- CH
78. The compound of claim 76, wherein R2 is ^CH2^2 -N NiHP
79. The The compound of claim 76, wherein RN is
Figure imgf000258_0001
80. The compound of claim 76, wherein R2 is -(CH2)?-piperazine.
81 . The compound of claim 76, wherein R2 is pyrrolidine.
82. The compound of claim 76, wherein R2 is -(CH2)2-NH2 or -(CH2)3-NHi.
83. The compound of any one of claims 1 to 64, wherein R1 1 is -C(0)NR' R2.
84. The compound of claim 83, wherein R11 is -CONH2.
85. The compound of any one of claims 1 to 64, wherein R1 1 is -NR'C(0)R5.
86. The compound of claim 85, wherein R11 is-NHCOH or -NHCOCH3.
87. The compound of any one of claims 1 to 64, wherein RN is -N((CH2)0-4-
NR'R2);..
88. The compound of claim 87, wherein R1 1 is -N((CH2)2-NH2)2.
89. The compound of any one of claims 1 to 64, wherein R11 is -NR1-CH-[(CH2)o-
4-NRL ARZA]2.
90. The compound of claim 89, wherein R11 is -NHCH(CH2-NH2)2.
91. The compound of any one of claims 1 to 64, wherein RN is -NH(CH2)1 -4-
NR'R2.
92. The compound of claim 91 , wherein R1 1 is -NH(CH2)2-NH- azetidine.
93. The compound of any one of claims 1 to 64, wherein R11 is -NR1(CH2)o- 4C(=NR2)R5.
94. The compound of claim 93, wherein R11 is -NHC(=NH)NH2.
95. The compound of any one of claims 1 to 64, wherein RN is -S(CH2)0- 4C(=NR1)R5.
96. The compound of claim 95, wherein R11 is -SCH2C(=NH)NH2.
97. The compound of any one of claims 1 to 64, wherein R1 1 is -S(CH2)0-4-3-10 membered heterocyclyl.
98. The compound of claim 97, wherein R1 1 is -S(CH2)2-piperazine.
99. The compound of any one of claims 1 to 64, wherein R 11 is -S(0)2NR 1 R2.
100. The compound of claim 99, wherein R1 1 is -S(0)2NH2.
101. The compound of any one of claims 1 to 64, wherein R 11 is -S(CH 1 2
2)o-4-NR R .
102. The compound of claim 101, wherein R1 1 is -S(CH2)2NH2 or -S(CH2)3NH2.
103. The compound of any one of claims 1 to 64, wherein R 11 is -SR 3.
104. The compound of claim 103, wherein R is azetidine or piperidine.
105. The compound of any one of claims 1 to 64, wherein R11 is -S(CH2)i-4-3-10 membered heterocyclyl.
106. The compound of claim 105, wherein R11 is ~S(CH2)2-morpholine.
1 1 3
107. The compound of any one of claims 1 to 64, wherein R is -S(CH2)1-4-R .
108. The compound of claim 107, wherein R11 is-S(CH2)o-4-5-10 membered heteroaryl-NH2.
Figure imgf000259_0001
1 10. The compound of any one of claims 1 to 64, wherein R 11 is -OR 3.
111. The compound of claim 110, wherein R1 1 is -CXCH^-NR^2.
1 12. The compound of claim 1 1 1, wherein R11 is -0(CH2)2NH2.
113. The compound of any one of claims 1-112, wherein R7 is selected from the group consisting of-H, -OH, -C]-4alkyl, -0-C]-4alkyl, -S-C]-4alkyl, halogen, -CF3, and cyano.
114. The compound of any one of claims 1-112, wherein R7 is selected from the group consisting of F, CI, Me, -CF3, SMe, and -OMe.
115. The compound of any one of claims 1-112, wherein R7 is H.
η
1 16. The compound of any one of claims 1-112, wherein R is F.
117. The compound of any one of claims 1-112, wherein R7 is -OMe.
η
1 18. The compound of any one of claims 1-112, wherein R is -SMe.
119. The compound of any one of claims 1-112, wherein R7 is -S(0)Me.
120. The compound of any one of claims 1 -1 12, wherein R is present 1 to 3 times and each R7 is triazole.
121. The compound of any one of claims 1 -1 12, wherein:
R7 is present 1 to 3 times and each R7 is independently -(CH2)m-Y'-(CH2)pM'; m and p are independently 0 to 3;
Y' is selected from the group consisting of -S-, -O- and -NR1 -;
M' is selected from the group consisting of NR!R2, -S03R3, -CN, -
1 2
C(0)NR R ; -C1-4 alkyl optionally substituted with 1-2 substituents selected from the group consisting, -OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; C3-10 cycloalkyl optionally substituted with 1 -2 substituents selected from the group consisting of C, -4 alkyl, -OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; C6-10 aryl optionally substituted with 1-2 substituents selected from the group consisting of C alkyl, -OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 1-2 substituents selected from the group consisting of C, -4 alkyl, -OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 1-2 substituents selected from the group consisting of C, -4 alkyl, -OR3, -NR!R2, halogen, -C(0)NR1R2, and - NR' C(0)R5.
122. The compound of claim 121 , wherein R is present once.
123. The compound of claim 121 , wherein R7 is present twice.
124. The compound of any one of claims 121 to 123, wherein Y' is O.
125. The compound of any one of claims 121 to 123, wherein Y' is NH
126. The compound of any one of claims 121 to 123, wherein p is 0, 1 , or 2.
127. The compound of any one of claims 121 to 126, wherein M' is cyclopropyl, - S03CH3, SCH3, -NH2, or -CN.
128. The compound of any one of claims 121 to 126, wherein M' is Ci-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR , - NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5.
129. The compound of claim 128, wherein M' is CHF2, CF3, (CH2)2F, or (CH2)2OCH3,
130. The compound of any one of claims 121 to 126, wherein M' is CH3, CH2CH3, or CH(CH3)2CH2CH(CH3)2.
1 2
131. The compound of any one of claims 121 to 126, wherein M' is C(0)NR R .
132. The compound of claim 131 , wherein R1 is H and R1 is azetidine.
133. The compound of claim 131 , wherein R7 is
Figure imgf000261_0001
134. The compound of claim 131 , wherein R7 is -0(CH2)CONH2.
135. The compound of any one of claims 121 to 126, wherein M' is a 5 to 10 membered heteroaryl.
136. The compound of claim 135, wherein M' is thiadiazole.
137. The compound of any one of claims 1 -1 12, wherein
7 7
R is present 1 to 3 times and each R is independently selected from the group consisitng of -OH, halogen, -CF3, Ci-C6 alkenyl, C -C alkynyl, C C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C6 alkoxy(Ci-C6)alkyl, aryloxy, sulfhydryl (mercapto), and - (CH2)m-Y'-(CH2)pM' ;
m and p are independently 0 to 3;
Y' is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, -CR5R6-, and -NR1-;
M' is selected from the group consisting of -C(0)NR1R2; -C(0)NR1OR3; - NR'C(0)R5; -NR'C(0)NR2Rl a; -NR'C(0)OR3; -NR' SCO^R3; -NR1 S(0)2NR2Rl a; - C(=NR1)R5; -C(=NR1)NR2Rla; -NR1CR5(=NR2); -NR1C(=NR2)NRlaR2a; C,-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR , -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1 -4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; and with the proviso that the compound does not have the structure selected from the group consisting of
Figure imgf000262_0001
an ; 0r p armaceut ca y accepta e sa ts t ereo .
η
138. The compound of claim 120, wherein each R is independently selected from -
OH, -C1-4alkyl, -0-C1-4alkyl, -S-C1-4alkyl, -S(0)-C1-4alkyl, and halogen.
139. The compound of any one of Claims 1-13 and 19-138, wherein R is -CR5R6OC(0)Ci-9alkyl or -CR5R6OC(0)OCi-9alkyl.
140. The compound of any one of Claims 1-57, wherein M' is selected from the group consisting of -C(0)NR'R2; -C(0)NROR3; -NR'C(0)R5; -NR'C(0)NR2Rla; - NR1C(0)OR3; -NR1S(0)2R3; -NR1S(0)2NR2Rla; -C(=NR1)NR2Rla; -NR1CR5(=NR2); - NR'C(=NR2)NRlaR2a; aryl optionally substituted with 0-2 substituents selected from the group consisting of -OR3, -NR!R2, halogen, -C(0)NR1R2, and -NR1C(0)R5; heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of -OR3, -NRJR2, halogen, -C(0)NR1R2, and -NR1C(0)R5; and heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of -OR , -NR R , halogen, -C(0)NR1R2, and -NR1C(0)R5.
141. The compound of any one of Claims 1-140, wherein R 1 is H and R 2 is H.
142. The compound of claim 1, having the structure selected from the consistin of:
Figure imgf000263_0001
or pharmaceutically acceptable salts thereof.
143. The compound of claim 1, having the structure selected from the consisting of:
Figure imgf000263_0002
and O , or pharmaceutically acceptable salts thereof.
144. The compound of claim 1, having the structure selected from the group consisting of:
Figure imgf000264_0001
Figure imgf000264_0002
Figure imgf000265_0001
-264-
Figure imgf000266_0001
, or pharmaceutically acceptable salts thereof.
146. The compound of claim 1, having the structure selected from the group consisting of:
Figure imgf000266_0002
Figure imgf000267_0001
-266-
Figure imgf000268_0001
-267-
Figure imgf000269_0001
-268-
Figure imgf000270_0001
-269-
Figure imgf000271_0001
Figure imgf000271_0002
-270-
Figure imgf000272_0001
-271-
Figure imgf000273_0001
, or pharmaceutically acceptable salts thereof.
147. The compound of claim 1, with the proviso that the compound does not have the structure selected from the rou consisting of
Figure imgf000273_0002
Figure imgf000274_0001
Figure imgf000274_0002
, or pharmaceutically acceptable salts thereof.
148. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-147 and a pharmaceutically acceptable excipient.
149. The composition of claim 148, wherein the excipient is a monosaccharide or monosaccharide derivative.
150. The compound of claims 149, wherein the monosaccharide or monosaccharide derivative is meglumine.
151. The pharmaceutical composition of any one of claim 148 to 150, further comprising an additional medicament.
152. The composition of claim 151, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.
153. The composition of claim 152, wherein the additional medicament is a β- lactam antibacterial agent.
154. The composition of claim 153, wherein the β-lactam antibacterial agent is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, MetampiciUin, TalampiciUin), Epicillin, Carbenicillin (CarindaciUin), TicarciUin, TemociUin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Ceftazidime, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA- 101, PvWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ- 442831, RWJ-333441, or RWJ-333442.
155. The composition of claim 153, wherein the β-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Apapenem, or Panipenem.
156. The composition of claim 153, wherein the β-lactam antibacterial agent is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.
157. A method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof, a compound according any one of claims 1-144.
158. The method of claim 157, further comprising administering to the subject an additional medicament.
159. The method of claim 158, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent.
160. The method of claim 158, wherein the additional medicament is a β-lactam antibacterial agent.
161. The method of claim 160, wherein the β-lactam antibacterial agent is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, PhenoxymethylpeniciUin (V), Propicillin, Benzathine phenoxymethylpeniciUin, Pheneticillin, CloxaciUin (DicloxaciUin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Toracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA- 101, RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or RWJ-333442.
162. The method of claim 160, wherein the β-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or Panipenem.
163. The method of claim 160, wherein the β-lactam antibacterial agent is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.
164. The method of any one of Claims 157-163, wherein the subject is a mammal.
165. The method of claim 164, wherein the mammal is a human.
166. The method of any one of Claims 157-165, wherein the infection comprises a bacteria selected from Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellular e, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.
167. The method of any one of Claims 157-165, wherein the infection comprises a bacteria selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.
168. A chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative and a compound of any one of claims 1 to 147.
169. The chemical complex of claim 168, wherein the monosaccharide or monosaccharide derivative is meglumine.
170. The chemical complex of claim 168 or 169, wherein
R7 is present 1 to 3 times and each R7 is independently selected from the group consisitng of -OH, halogen, -CF3, Ci-C6 alkenyl, C]-C6 alkynyl, C]-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, Ci-C6 alkoxy(Ci-C )alkyl, aryloxy, sulfhydryl (mercapto), and - (CH2)m-Y'-(CH2)pM';
m and p are independently 0 to 3;
Y' is selected from the group consisting of -S-, -S(O)-, -S(0)2-, -0-, -CR5R6-, and -NR1-;
M' is selected from the group consisting of -C(0)NR'R2; -C(0)NROR3; - NR1C(0)R5; -NR1C(0)NR2RLA; -NR1C(0)OR3; -NR1S(0)2R3; -NR^CO^NR 3; - C(=NR')R5; -C(=NR')NR2RL A; -NR'CR5(=NR2); -NR1 C(=NR2)NR' AR2A; C alkyl optionally substituted with 0-2 substituents selected from the group consisting, -OR , -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; C6-IO aryl optionally substituted with 0-2 substituents selected from the group consisting of Ci-4 alkyl, - OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR'C(0)R5; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1 -4 alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of CM alkyl, -OR3, -NR'R2, halogen, -C(0)NR'R2, and -NR' C(0)R5; and with the proviso that the compound does not have the structure selected from the group consisting of
Figure imgf000279_0001
an ; 0r p armaceut ca y accepta e sa ts t ereo .
171. The chemical complex of any one of claims 168 to 170, with the proviso that com ound does not have the structure selected from the group consisting of
Figure imgf000279_0002
Figure imgf000280_0001
Figure imgf000280_0002
0r pharmaceutically acceptable salts thereof.
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