BORON CONTAINING COMPOUNDS AND THEIR USES

Cross-Reference to Related Applications

[0001] The present application claims the benefit of U.S. Provisional Application Serial No. 62/728,632, filed September ?, 2018, herein incorporated by reference in its entirety.

Technical Field

[0002] The present disclosure contemplates novel boron-containing compounds and their uses as active agents that exhibit pesticidal activity such as antimicrobial, insecticidal, arachnicidal, and/or antiparasitic activity. An agrochemical composition containing such a compound and its use in, animal health, agriculture, or horticulture is also contemplated. A method for promoting plant performance and/or controlling, reducing, preventing, ameliorating, or inhibiting microbes, insects, arachnids, and/or parasites on or in an animal, a plant, a plant part, plant propagation material, and/or harvested fruits or vegetables is also contemplated.

Background

[0003] Boron is an unique element due to its capacity to create powerfully effective compounds. While the use of boron as simple naturally occurring borates is well known, the construction and characterization of more complex rationally designed boron-containing synthetic compounds that have low toxicity and are effective has been relatively under investigated.

[0004] The creation and development of such boron-containing compounds is unpredictable even in the hands of experts. Additionally, boron’s ability to covalently bond with other molecules makes it challenging to work with. Boron-containing molecules traditionally have suffered in becoming commercially viable products due to these synthetic and pharmacological uncertainties.

[0005] Further complicating matters, the charge and geometry of benzoxaborole compounds are not static in some environments that the benzoxaborole is applied in; benzoxaboroles often exist in a dynamic equilibrium. Moreover, substitutions on the benzoxaborole can have profound effects on this dynamic equilibrium. Additionally, the boron atom’s empty p-orbital forms covalent bonds with Lewis bases that may potentially affect biological activity. These characteristics together make the development of benzoxaborole compounds that display biological activity an unpredictable and challenging endeavor.

[0006] Within the field of plant health, fungal, bacterial, insect, parasite, protozoa, virus, and nematode plant pathogens lead to a wide range of diseases (rusts, spots, downy mildews, blasts, blotches, stripes, rots, smuts, wilt, root knot nematode disease, fire blight, insects, etc.) across all crops, resulting in massive losses.

Current solutions are limited; currently available, conventional, and outdated chemical pesticides provide only a partial level of control (as with resistant cultivars), or add significant costs. While breeding for resistance traits to specific

crop/pathogen combinations in germplasm offers some hope in circumventing the problem, it is widely recognized that novel pesticides must be developed.

[0007] Pesticides, such as fungicides and insecticides, are costly to both purchase and use, as well as often being toxic and/or otherwise detrimental to off-target animals and/or vegetation near the site of application including runoff, affecting the watershed. Moreover, many pesticides such as fungicides and lose efficacy over time, concomitantly with pathogens becoming resistant to treatment. Nonetheless, agrochemical pesticides are important to control various diseases and minimize crop yield loss.

[0008] Parasitic infections in animals, including humans, are responsible for significant suffering and economic loss globally. Specifically, endoparasitic infections and in particular helminthiases caused by nematodes (roundworms including filarial worms) and flatworms (cestodes, or tapeworms and trematodes, or flukes), can inflict significant disease through infection of, and damage to various organ systems, for example, the gastrointestinal tract, the lymphatic system, various tissues, the liver, lungs, heart and the brain with sequelae that include neurological and metabolic dysfunction, nutritional deficiencies, delayed growth, loss of productivity, and death.

[0001] In agriculture and horticulture, some nematodes are considered beneficial; however, predatory nematodes, such as, for example, cutworms and root-knot nematodes, attack and damage various plant parts including leaves, stems and roots, inflicting significant economic losses to this industry as well. A very limited number of active agents have been developed recently that appear to address some of these shortcomings. However, there is still a pressing need for additional active agents with superior and/or varying attributes in terms of spectrum and activity, physical-chemical properties and drug-ability profile, mammalian safety, and more diverse and convenient treatment options to ensure long-term viability.

[0002] Accordingly, there is a need for compounds and compositions for plant and animal health.

Brief Summary

[0003] One embodiment of the present disclosure is a compound of formula (I):

wherein:

X ¹ is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, CN, unsubstituted C1-C3 hydrocarbyl, C1-C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl;

X is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine,

CN, unsubstituted C1 -C3 hydrocarbyl, C1 -C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl;

Z ¹ is oxygen or sulfur;

Y ¹ is selected from the group consisting of: oxygen, sulfur, and NH;

R ¹ is selected from the group consisting of: hydrogen, unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^1a substitutions, unsubstituted aryl, aryl having 1-5 R ^1a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^1a substitutions, unsubstituted heteroaryl, heteroaryl substituted with one or more R ^1a substitutions, unsubstituted heterocyclyl, and heterocyclyl substituted with one or more R ^1a substitutions;

each R ^1a independently is selected from the group consisting of CrCs hydrocarbyl, NH ₂ , OH, N0 ₂ , CN, C1-C2 haloalkyl, OR ⁶ , SR ⁶ , SOR ⁶ , SO2R ⁶ , NHC(0)OR ⁶ , NR ⁶ R ⁷ , C(0)OR ⁶ , unsubstituted aryl, C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, heteroaryl, and heterocyclyl;

R ⁶ and R ⁷ are independently selected from the group consisting of C1-C6 hydrocarbyl and substituted hydrocarbyl, or

R ⁶ and R ⁷ can be taken together with the nitrogen to which they are attached to form a ring of no more than 8 members; and

[0004] each of R ⁸ and R ⁹ independently is selected from the group consisting of: hydrogen, methyl, ethyl; or

R ⁸ and R ⁹ can be taken together to form a 3 - 6 membered ring,

or a salt, stereoisomer, enantiomer, or tautomer thereof. [0005] In one aspect, Y ¹ is oxygen or sulfur. In one aspect, if Y ¹ is NH, then Z ¹ is sulfur. In one aspect, Z ¹ or Y ¹ is sulfur. In one aspect, Z ¹ and Y ¹ are sulfur.

[0006] In one aspect, one of X ¹ or X ^1’ is hydrogen. In one aspect, X ¹ is fluorine, chlorine, bromine, CN, unsubstituted C1-C ₃ hydrocarbyl, C1-C ₃ hydrocarbyl having 1- 7 halogen substitutions, and cyclopropyl. In one aspect, X ¹ is fluorine, chlorine, or bromine. In one aspect, X ¹ is fluorine or chlorine. In one aspect, X ¹ is chlorine.

[0007] In one aspect, R ¹ is selected from the group consisting of: unsubstituted Cr C ₆ alkyl, C1-C ₆ alkyl substituted with one or more R ^1a substitutions, unsubstituted C2- C ₆ alkenyl, C2-C6 alkenyl substituted with one or more R ^1a substitutions,

unsubstituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with one or more R ^1a substitutions, unsubstituted phenyl, phenyl substituted with one or more R ^1a substitutions, unsubstitued benzyl, benzyl substituted with one or more R ^1a substitutions, unsubstituted heterocyclyl, and heterocyclyl substituted with one or more R ^1a substitutions. In one aspect, each R ^1a independently is selected from halogen, OH, SCH3, OCH3, NH2, CH3, and NHC(0)0-f-butyl. In one aspect, each R ^1a independently is selected from NH2, OH, NHC(0)OR ⁶ , NR ⁶ R ⁷ , C(0)OR ⁶ , fluorine, chlorine, and bromine. In one aspect, the number of R ^1a substitutions is three, two, or one.

[0008] In one aspect, Y ¹ is sulfur; Z ¹ is oxygen; and R ¹ is selected from the group consisting of: unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C3-C6 cy cl o hydrocarbyl, and C3-C6 cyclohydrocarbyl having 1-11 R ^1a substitutions.

[0009] In one aspect, Y ¹ is oxygen; Z ¹ is sulfur; and R ¹ is selected from the group consisting of: unsubstituted phenyl, aryl having 1-5 R ^1a substitutions, unsubstituted heteroaryl, and heteroaryl substituted with one or more R ^1a substitutions.

[0010] In one aspect, the compound is a compound of formula (la), (la-2), (la-3), or (1a-4):

[0011] In one aspect, each of X ¹ and X independently is selected from fluorine and chlorine. [0012] In one aspect, R ¹ is selected from the group consisting of: hydrogen, unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^1a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^1a substitutions, phenyl, and phenyl having 1-5 R ^1a substitutions.

[0013] In one aspect, each CrCs hydrocarbyl is selected from CrCs alkyl, C ₂ -C ₈ alkenyl, and C2-C8 alkynyl, and further wherein C1-8 alkyl may have 1 - 17 R ^1a substitutions, further wherein C2-8 alkenyl may have 1 - 15 R ^1a substitutions, and further wherein C2-8 alkynyl may have 1 - 9 R ^1a substitutions.

[0014] In one aspect, the compound is a compound of formula (la-2); X ¹ is selected from hydrogen, fluorine, and chlorine; X ¹ ’ is selected from hydrogen, fluorine, and chlorine; and R ¹ is C2-C8 hydrocarbyl having one R ^1a substitution where R ^1a is NH2 or NR ⁶ R ⁷ and each R ⁶ and R ⁷ independently is C1-C6 unsubstituted alkyl.

[0015] In one aspect, the compound is a compound of formula (lb) or (lb-2):

[0016] In one aspect, each of X ¹ and X independently is selected from fluorine and chlorine. In one aspect, R ¹ is selected from the group consisting of: hydrogen, unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^1a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^1a substitutions, phenyl, and phenyl having 1-5 R ^1a substitutions. In one aspect, each CrCs hydrocarbyl is selected from CrCs alkyl, C ₂ -C ₈ alkenyl, and C ₂ -C ₈ alkynyl, and further wherein Cre alkyl may have 1 - 17 R ^1a substitutions, further wherein C _2-8 alkenyl may have 1 - 15 R ^1a substitutions, and further wherein C _2-8 alkynyl may have 1 - 9 R ^1a substitutions.

[0017] In one aspect, the compound is a compound of formula (lc):

[0018] In one aspect, X ¹ is halogen; X is hydrogen; and R ¹ is unsubstituted CrCs hydrocarbyl, unsubstituted C3-C6 cyclohydrocarbyl, unsubstituted benzyl, or benzyl having 1 or 2 R ^1a substitutions. In one aspect, each R ^1a substitution is a halogen.

[0019] In one aspect, the compound is a compound of formula (Id):

[0020] In one aspect, X ¹ is halogen; and R ¹ is selected from the group consisting of unsubstituted CrCs hydrocarbyl, unsubstituted C3-C6 cyclohydrocarbyl, unsubstituted benzyl, and benzyl having 1-2 R ^1a substitutions. In one aspect, R ¹ is CrCs alkyl. In one aspect, R ¹ is benzyl having 1 or 2 halogen substitutions.

[0021] One embodiment of the present disclosure includes a compound of formula (V):

[0022] wherein:

X ⁵ is selected from the group consisting of: hydrogen, chlorine, fluorine, bromine, CN, unsubstituted C1-C6 hydrocarbyl, C1-C6 hydrocarbyl having 1-13 R ^5a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^5a substitutions,

0(unsubstituted C1-C5 hydrocarbyl), 0(Ci-Cs hydrocarbyl having 1-11 R ^5a

substitutions), 0(unsubstituted C3-C6 cyclohydrocarbyl), and 0(03-0b

cyclohydrocarbyl having 1-11 R ^5a substitutions);

X ^5’ is selected from the group consisting of: hydrogen, chlorine, fluorine, bromine,

CN, unsubstituted C1-C6 hydrocarbyl, C1-C6 hydrocarbyl having 1-13 R ^5a

substitutions, C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^5a substitutions,

0(unsubstituted C1-C5 hydrocarbyl), 0(CrCs hydrocarbyl having 1-1 1 R ^5a

substitutions), 0(unsubstituted C3-C6 cyclohydrocarbyl), and C C3-C6

cyclohydrocarbyl having 1-11 R ^5a substitutions);

R5 is selected from the group consisting of: hydrogen, unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^5a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted aryl, aryl having 1-5 R ^5a substitutions, unsubstituted benzyl, benzyl substituted with 1- 7 R ^5a substitutions, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl;

Y ⁵ is selected from the group consisting of: oxygen, sulfur, and NH;

each R ^5a independently is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, NH ₂ , OH, CN, N0 ₂ , C1-C2 haloalkyl, OR ¹⁴ , SR ¹⁴ , SOR ¹⁴ , SO2R ¹⁴ , NHC(0)0R ¹⁴ , NR ¹⁴ R ¹⁵ , C(0)0R ¹⁴ , unsubstituted aryl, unsubstituted C ₃ -C ₆ cyclohydrocarbyl, substituted C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl; and

R ¹⁴ and R ¹⁵ are independently selected from the group consisting of: hydrocarbyl and substituted hydrocarbyl, or

R ¹⁴ and R ¹⁵ can be taken together with the nitrogen to which they are attached to form a ring of no more than 8 members;

or a salt, stereoisomer, enantiomer, or tautomer thereof.

[0023] In one aspect, R ₅ is selected from the group consisting of: unsubstituted Cr Cs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^5a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted aryl, aryl having 1-5 R ^5a substitutions, unsubstituted benzyl, benzyl substituted with 1- 7 R ^5a substitutions, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl.

[0024] In one aspect, the compound is a compound of formula (Va):

[0025] In one aspect, X ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine. In one aspect, X ^5’ is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine.

[0026] In one aspect, the compound is a compound of formula (Vb):

[0027] In one aspect, X ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C6 hydrocarbyl, and unsubstituted benzyl. In one aspect, X ^5’ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C6 hydrocarbyl, and unsubstituted benzyl. In one aspect, R ⁵ is CrCs hydrocarbyl.

[0028] In one aspect of the present disclosure, as applicable, each of X ¹ , X , X ⁵ , or X ^5’ independently is fluorine, chlorine, bromine, CN, unsubstituted C ₁ -C ₃ hydrocarbyl, C ₁ -C ₃ hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl.

[0029] In one aspect of the present disclosure, as applicable, each of X ¹ , X , X ⁵ , or X ^5’ independently is chlorine, fluorine, bromine, CN, unsubstituted C ₁ -C ₆ hydrocarbyl,

C1-C6 hydrocarbyl having 1-13 substitutions, unsubstituted C3-C6 cy cl o hydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 substitutions, unsubstituted benzyl, benzyl having 1-7 substitutions, 0(unsubstituted C ₁ -C ₅ hydrocarbyl), 0(Ci-Cs hydrocarbyl having 1-11 substitutions), 0(unsubstituted C3-C6 cyclohydrocarbyl), and 0(C3-C6 cyclohydrocarbyl having 1-11 substitutions).

[0030] In one aspect of the present disclosure, each CrCs hydrocarbyl is selected from CrCs alkyl, C ₂ -C ₈ alkenyl, and C ₂ -C ₈ alkynyl, and further wherein C _1-8 alkyl may have 1 - 17 R ^1a substitutions, further wherein C _2-8 alkenyl may have 1 - 15 R ^1a substitutions, and further wherein C _2-8 alkynyl may have 1 - 9 R ^1a substitutions.

[0031] In one aspect, each aryl is phenyl. In one aspect, heterocyclyl is piperidine or tetrahydropyran.

[0032] One embodiment of the present disclosure is a compound selected from the Table A herein provided, including a salt, stereoisomer, enantiomer, or tautomer thereof.

[0033] One embodiment of the present disclosure is a compound selected from the

Table B herein provided, including a salt, stereoisomer, enantiomer, or tautomer thereof.

[0034] One embodiment of the present disclosure includes a method for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen by applying an effective amount of a compound according to the present disclosure. In one aspect, the pathogen is selected from a group consisting of microbes, insects, arachnids, parasites, and any combination thereof. In one aspect, the pathogen is one or more microbe. In one aspect, an infestation relates to one or more of an animal, a plant, a plant part, plant propagation material, harvested fruits, and harvested vegetables.

[0035] One embodiment of the present disclosure includes a pesticidal, veterinary, or pharmaceutical composition comprising a compound according to the present disclosure and one or more acceptable excipient. In one aspect, such a composition includes one or more additional active agent.

[0036] Certain embodiments of the present disclosure includes compounds of formula (I) and (V), the compounds having anti-pathogenic (e.g., antifungal, antimicrobial, anti-insecticidal, anti-parasitic, anti-nematode, or combinations thereof) activity.

[0037] One embodiment includes compounds that exhibit control, for example, curative, inhibitive, ameliorative, and/or preventative activity of microbes, insects, arachnids, parasites, any combination thereof, and the like.

[0038] Surprisingly, the compounds described herein, when applied to animals, a plant, a plant part, plant proagation material, and/or harvested fruits or

vegetablesand/or plant’s locus of growth allows for effective control of pathogenic microorganisms, insects, nematodes, fungi, bacteria, and other phytopathogens.

[0039] A method of controlling, reducing, preventing, ameliorating, or inhibiting growth of a target microbes, insects, arachnids, parasites, and any combination thereof is also contemplated. In accordance with that method, a target microbes, insects, arachnids, parasites, and any combination thereof is contacted with an effective amount of the compounds described herein, and that contact is maintained for a period of time sufficient to control and/or inhibit growth of the target microbes, insects, arachnids, parasites, and any combination thereof. For example, that contact is carried out by administering the compounds described herein to the target microbes, insects, arachnids, parasites, and any combination thereof where the administration is topical, soil, seed treatment, foliar, or systemic. In some

embodiments, the administration is repeated.

[0040] In another aspect of the present disclosure, the compounds described herein are used for controlling, reducing, preventing, ameliorating, or inhibiting overall damage of plants and plant parts as well as losses in harvested fruits or vegetables caused by microbes, insects, arachnids, parasites, and any combination thereof. [0041] In a further aspect of the present disclosure, the compounds described herein are employed to control, reduce, prevent, ameliorate, or inhibit infection in animals caused by microbes, insects, arachnids, parasites, and any combination thereof.

[0042] Furthermore, in another aspect, the compounds described herein, increase the overall plant health.

[0043] Moreover, in yet another aspect, the compounds described herein, increase overall animal health.

[0044] Furthermore, the compounds described herein, have potent microbicidal activity and can be used for control of unwanted microorganisms, such as fungi and bacteria, in crop protection and in the protection of plant materials.

[0045] Wherein the compound of the disclosure is a fungicide, the compound can be used in crop protection for control of phytopathogenic fungi. They can include an outstanding efficacy against a broad spectrum of phytopathogenic fungi, including soil borne pathogens, which are in particular members of the classes

Plasmodiophoromycetes, Peronosporomycetes (Syn. Oomycetes), Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes, and Deuteromycetes (Syn. Fungi imperfecti). Some fungicides are systemically active and can be used in plant protection as foliar, seed dressing or soil fungicide. Furthermore, they are suitable for combating fungi, which inter alia infest wood or roots of plant.

[0046] Improved plant health refers to improved plant characteristics including: crop yield, more developed root system (improved root growth), improved root size maintenance, improved root effectiveness, tillering increase, increase in plant height, bigger leaf blade, less dead basal leaves, stronger tillers, greener leaf color, photosynthetic activity, more productive tillers, enhanced plant vigor, and increased plant stand.

[0047] In one aspect, the disclosure includes a compound of formula (I):

wherein:

Xi is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, CN, C1-C3 hydrocarbyl, C1-C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl; Xi ^’ is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine,

CN, C ₁ -C ₃ hydrocarbyl, C ₁ -C ₃ hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl;

Zi is oxygen or sulfur;

Yi is selected from the group consisting of: oxygen, sulfur, and NH;

R ₁ is selected from the group consisting of: hydrogen, CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 Ri ^a substitutions, C ₃ -C ₆ cyclohydrocarbyl, C ₃ -C ₆

cyclohydrocarbyl having 1-11 Ri ^a substitutions, phenyl, aryl having 1-5 Ri ^a substitutions, benzyl having 0-7 Ri ^a substitutions, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;

each Ri ^a is independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, -NH ₂ , -OH, -NO ₂ , -CN, C ₁ -C ₂ haloalkyl, -OR ⁶ , -SR ⁶ , -SOR ⁶ , - SO ₂ R ⁶ , -NHC(0)OR ⁶ , -NR ⁶ R ⁷ , -C(0)OR ⁶ , phenyl, aryl, C ₃ -C ₆ cyclohydrocarbyl, substituted C ₃ -C ₆ cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, substituted heteroaryl, heteroaryl, substituted heterocyclyl, and heterocyclyl;

R ⁶ and R ⁷ are independently selected from the group consisting of:

hydrocarbyl and substituted hydrocarbyl group, or R ⁶ and R ⁷ can be taken together with or without the nitrogen to which they are attached to form a ring of no more than 8 members; and

R ⁸ and R ⁹ are independently selected from the group consisting of: hydrogen, methyl, ethyl , or R8 and R9 can be taken together to form a 3 - 6 membered ring, or a salt, stereoisomer, enantiomer, or tautomer thereof.

[0048] In yet another aspect, the disclosure includes a compound of formula (V):

wherein:

X ₅ is selected from the group consisting of: hydrogen, chlorine, fluorine, bromine, CN, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyl having 1-13 R ₅ ^a substitutions, C ₃ -C ₆

cyclohydrocarbyl, C ₃ -C ₆ cyclohydrocarbyl having 1-11 R ₅ ^a substitutions, benzyl having 0-7 Rs ^a substitutions, 0(Ci-Cs hydrocarbyl), 0(CrCs hydrocarbyl having 1-11 R ₅ ^a substitutions), 0(C ₃ -C ₆ cyclohydrocarbyl), and 0(Cz-Ce cyclohydrocarbyl having 1-11 R ₅ ^a substitutions);

X ₅ ' is selected from the group consisting of: hydrogen, chlorine, fluorine, bromine,

CN, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyl having 1-13 Rs ^a substitutions, C ₃ -C ₆ cyclohydrocarbyl, C ₃ -C ₆ cyclohydrocarbyl having 1-11 Rs ^a substitutions, benzyl having 0-7 R ₅ ^a substitutions, 0(CrCs hydrocarbyl), 0(CrCs hydrocarbyl having 1 - 1 1 R ₅ ^a substitutions), C C3-C6 cyclohydrocarbyl), and C C3-C6 cyclohydrocarbyl having 1-11 R ₅ ^a substitutions);

R5 is selected from the group consisting of: hydrogen, CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 Rs ^a substitutions, C3-C6 cyclohydrocarbyl, C3-C6

cyclohydrocarbyl having 1-11 Rs ^a substitutions, C2-C8 alkenyl, C2-C8 alkenyl having 1- 15 R ₅ ^a substitutions, C2-C6 alkynyl, C2-C6 alkynyl having 1-9 Rs ^a substitutions, phenyl, aryl having 1-5 Rs ^a substitutions, benzyl having 0-7 Rs ^a substitutions, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;

Y5 is selected from the group consisting of: oxygen, sulfur, and NH;

R ₅ ^a is selected independently from the group consisting of hydrocarbyl, substituted hydrocarbyl, -NH ₂ , -OH, -CN, -NO2, C1-C2 haloalkyl, -OR ¹⁴ , -SR ¹⁴ , -SOR ¹⁴ , -SO2R ¹⁴ , - NHC(0)OR ¹⁴ , -NR ¹⁴ R ¹⁵ , -C(0)OR ¹⁴ , phenyl, aryl, C3-C6 cyclohydrocarbyl, substituted C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, substituted heteroaryl, heteroaryl, substituted heterocyclyl, and heterocyclyl; and

R ¹⁴ and R ¹⁵ are independently selected from the group consisting of: hydrocarbyl and substituted hydrocarbyl group, or R ¹⁴ and R ¹⁵ can be taken together with or without the nitrogen to which they are attached to form a ring of no more than 8 members; or a salt, stereoisomer, enantiomer, or tautomer thereof.

[0049] In another aspect, the disclosure includes a method for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen by applying an effective amount of a compound according to any one of the above formulae, wherein the pathogen is selected from a group consisting of insects, nematodes, bacteria, microbes, fungi, protozoa, viruses, parasites, and any combinations thereof.

[0050] In another aspect, the disclosure includes a method for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen by applying a compound according to any one of the above formulae, wherein the pathogen is selected from a group consisting of insects, nematodes, bacteria, microbes, fungi, protozoa, viruses, parasites, and any combinations thereof.

[0051] In yet another aspect, the disclosure includes a method for controlling or preventing an infestation of the pathogen by treating an animal, a plant, a plant part, plant proagation material, and/or harvested fruits or vegetables with an effective amount of a compound according to any one of the above formulae.

[0052] In yet another aspect, the disclosure includes a method for controlling or preventing an infestation of the pathogen by treating an animal, a plant, a plant part, plant proagation material, and/or harvested fruits or vegetables with a compound according to any one of the above formulae.

[0053] The preceding is a simplified summary to provide an understanding of some embodiments of the present disclosure. This summary is neither an extensive nor exhaustive over-view of the present disclosure and its various embodiments. The summary presents selected concepts of the embodiments of the present disclosure in a simplified form as an introduction to the more detailed description presented below. As will be appreciated, other embodiments of the present disclosure are possible utilizing, alone or in combination, one or more of the embodiment, aspects, or features set forth above or described in detail below.

Brief Description of the Drawings

[0054] The foregoing and other aspects of the embodiments disclosed herein are best understood from the following detailed description when read in connection with the accompanying drawings. For the purposes of illustrating the embodiments disclosed herein, there is shown in the drawings embodiments that are presently preferred, it being understood, however, that the embodiments disclosed herein are not limited to the specific instrumentalities disclosed. Included in the drawings are the following figures:

[0055] FIGURE 1 , in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 1 are intended as general and do not necessarily align with the variable designations otherwise herein described.

[0056] FIGURE 2 represents a table of examples of biological activity of the boron containing compounds of the present disclosure.

[0057] FIGURES 3A and 3B represent tables of examples of in vivo biological activity of the boron containing compounds of the present disclosure.

[0058] FIGURE 4, in accordance with an embodiment of the present disclosure, illustrates a schematic representation of a synthetic scheme for making the boron containing compounds of the present disclosure. The variable designations in Figure 4 are intended as general and do not necessarily align with the variable designations otherwise herein described.

[0059] While embodiments of the present disclosure are described herein by way of example using several illustrative drawings, those skilled in the art will recognize the present disclosure is not limited to the embodiments or drawings described. It should be understood the drawings and the detailed description thereto are not intended to limit the present disclosure to the form disclosed, but to the contrary, the present disclosure is to cover all modification, equivalents and alternatives falling within the spirit and scope of embodiments of the present disclosure as recited by the appended claims.

[0060] The headings used herein are for organizational purposes only and are not meant to be used to limit the scope of the description or the claims. As used throughout this application, the word "may" is used in a permissive sense (i.e., meaning having the potential to), rather than the mandatory sense (i.e., meaning must). Similarly, the words“include”,“including”, and“includes” mean including but not limited to. To facilitate understanding, like reference numerals have been used, where possible, to designate like elements common to the figures.

Detailed Description

[0061] The description set forth below is intended as a description of various embodiments of the described subject matter and is not necessarily intended to represent the only embodiment(s). In certain instances, the description includes specific details for the purpose of providing an understanding of the described subject matter. However, it will be apparent to those skilled in the art that

embodiments may be practiced without the specific details as described.

DEFINITIONS

[0062] Any reference in the specification to“one embodiment” or“an embodiment” or “another embodiment” or a similar phrase means that a particular feature, structure, characteristic, operation, or function being described is included in at least one embodiment. Thus, any appearance of the phrases“in one embodiment” or“in an embodiment” in the specification is not necessarily referring to the same

embodiment. Further, the particular features, structures, characteristics, operations, or functions may be combined in any suitable manner in one or more embodiments, and it is intended that embodiments of the described subject matter can and do cover modifications and variations of the described embodiments. Particular aspects, as used herein, should be treated in a similar manner.

[0063] The phrases“at least one”,“one or more”, and“and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions“at least one of A, B, and C”,“at least one of A, B, or C”,

“one or more of A, B, and C”,“one or more of A, B, or C” and“A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together. [0064] The term“a” or“an” entity refers to one or more of that entity. As such, the terms“a” (or“an”),“one or more” and“at least one” may be used interchangeably herein. It is also to be noted that the terms“comprising”,“including”, and“having” may be used interchangeably.

[0065] A compound of this disclosure includes those described generally, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version,“Handbook of Chemistry and Physics", 75th Ed., CRC Press, New York, NY (1995). Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, CA (1999), and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York, NY (2001), “Plant Pathology”, 5 ^th Ed., Gore N Agrios, Elsevier Academic Press, Cambridge, MA (2005), the entire contents of which are hereby incorporated by reference.

[0066] The term“hydrocarbyl” refers to a monovalent moiety formed by removing a hydrogen atom from a hydrocarbon. The term‘hydrocarbyl’ includes alkyl groups, alkenyl groups, and alkynyl groups. A preferred“hydrocarbyl” group is an“alkyl” group. Representative hydrocarbyl groups are alkyl groups having 1 to 25 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, decyl, dodecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, and tricosyl, and the isomeric forms thereof such as iso-propyl, t-butyl, iso-butyl, sec-butyl, 1 ,1- dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethyl propyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethyl-butyl;

alkenyl groups having 2 to 25 carbon atoms, such as methenyl, ethenyl, 1-propenyl,

2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl and the isomeric forms thereof; alkynyl groups having 2 to 25 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,

3-pentynyl, 4-pentynyl, hexynyl, pentynyl, and octynyl, and the isomeric forms thereof. A hydrocarbyl group may also be substituted with a“cyclohydrocarbyl” group. Accordingly, groups such as 2-(cyclopropyl)-ethyl, cyclohexylmethyl, cyclopropylethyl, and cyclopropylmethyl, are contemplated hydrocarbyl groups.

[0067] In some embodiments, a“hydrocarbyl group” contains 1 to 6 members (Cr Ob), or for alkenyl or alkynyl groups 2 to 6 members (C2-C6). In other embodiments, the hydrocarbyl radical contains 1 to 3 members (C1-C3) , or for alkenyl or alkynyl groups 2 to 3 members (C2-C3) . In yet other embodiments, the hydrocarbyl radical may contain from 1 to 17 substitutions, or in another embodiment from 1 to 5 substitutions. The hydrocarbyl group may also contain one or more substitutions.

[0068] The term“cyclohydrocarbyl”, by itself or part of another substituent, unless otherwise stated, refers to a cyclic hydrocarbyl group which may be fully saturated, monounsaturated, or polyunsaturated but not aromatic, and includes C3-C15 hydrocarbons in a ring system. The cyclohydrocarbyl group may contain one or more substitutions. In one embodiment, the ring contains 3 to 6 members (C3-C6) .

[0069] In another embodiment, a cyclohydrocarbyl group may have from 1 to 11 substitutions, or in another embodiment from 2 to 6 substitutions. Examples of cyclohydrocarbyl groups include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, cyclohex- 1-enyl, cyclohex-3-enyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamant-1 -yl, adamant-2-yl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]-hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo-[5.1.0]octyl, spiro[2.6]nonyl,

bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl, and the like.

[0070] The term "aryl", unless otherwise stated, used alone or as part of a larger moiety as in“arylalkyl”, is an aromatic cyclohydrocarbyl group that is monocyclic or polycyclic containing up to three fused rings, preferably up to two fused rings, and more preferably, monocyclic. Examples of aryl groups include, but are not limited to phenyl, naphthyl, anthracenyl, and phenanthryl and substituted phenyl, naphthyl, anthracenyl, and phenanthryl groups.

[0071] Phenyl, naphthyl, substituted phenyl, and substituted naphthyl groups are preferred aryl groups, with unsubstituted phenyl and substituted phenyl groups being more preferred. In one embodiment, the ring system may have 1 to about 5 substitutions, or in another embodiment 2 to 3 substitutions are present on the ring system. In one embodiment, the ring system has 1 substitution.

[0072] The term“phenyl” as used herein is a CeHs group. The term“phenyl” may be abbreviated herein as“Ph”. “Phenyl” groups may be substituted. Similarly, the term “naphthyl” as used herein is a C10H7 group. “Naphthyl” groups may be substituted.

[0073] The term "heteroaryl", unless otherwise stated, used alone or as part of a larger or smaller moiety as in“aryl”, contain from one to four heteroatoms selected from nitrogen, oxygen, and sulfur, where the nitrogen and sulfur atoms are optionally oxidized, and one or several nitrogen atoms are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. [0074] A heteroaryl group may contain one ring or two fused rings. Non-limiting examples of heteroaryl groups include, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 1- imidizoyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,

4- pyrimidyl, 5-benzo-thiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,

5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. In one embodiment, examples of heteroaryl groups include pyridine, thiophene, thiazole, imidazole, benzimidazole, pyrazole, and oxazole.

[0075] The terms "arylalkyl" and "heteroarylalkyl" is meant to include those radicals in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth-1-yloxy)propyl, and the like). The term“benzyl” as used herein referes to a group in which a phenyl group is attached to a CH2 group (i.e. a CH2Ph group). The term substituted benzyl refers to a group in which either the CH ₂ linker or the phenyl group contains one or more substitutions. In one embodiment, the phenyl group may have 1 to 5 substitutions, or in another embodiment 2 to 3 substitutions.

[0076] Each of the above terms "hydrocarbyl", "cyclohydrocarbyl", "alkoxy", "aryl", "heteroaryl", "arylalkyl", and "heteroarylalkyl" may be present in substituted and unsubstituted forms of the indicated radical unless otherwise stated. The

"hydrocarbyl", "cyclohydrocarbyl", "alkoxy", "aryl", "heteroaryl", "arylalkyl", and "heteroarylalkyl" groups are optionally substituted by one or more groups that may be the same or different and which are, independently, selected from halogen, halohydrocarbyl which may be mono-, partially substituted, or completely substituted (e.g., in the form of CF ₃ , CF2CF3, CHF ₂ , CH ₂ F, and the like), R', OR', OH, SH, SR', N0 ₂ , CN, C(0)R', C(0)OR', OC(0)R', CON(R') ₂ , OC(0)N(R') ₂ , NH ₂ , NHR', N(R') ₂ , NHCOR', NHCOH, NHCONH ₂ , NHCONHR', NHCON(R') ₂ , NRCOR', NRCOH, NHCO2H, NHCO2R', CO2R', CO2H, CHO, CONH2, CONHR', CON(R') ₂ , S(0) ₂ H, S(0) ₂ R', SO2NH2, S(0)H, S(0)R', SO2NHR', S0 ₂ N(R') ₂ , NHS(0) ₂ H, NR'S(0) ₂ H, NHS(0) ₂ R', NR'S(0) ₂ R', and Si(R') ₃ . A saturated carbon atom of any such

"hydrocarbyl", "cyclohydrocarbyl", "alkoxy", "aryl", "heteroaryl", "arylalkyl", or

"heteroarylalkyl" groups may be optionally substituted as long as valency allows. For each of the foregoing, each occurrence of R' is, independently, selected from "hydrocarbyl", "cyclohydrocarbyl", "alkoxy", "aryl", "heteroaryl", "arylalkyl", and "heteroarylalkyl”.

[0077] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S). The heteroatoms oxygen and nitrogen are preferred.

[0078] The terms "alkoxy" refers to those groups attached to the remainder of the molecule via an oxygen atom. Suitable examples of alkoxy groups include, but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, and the like.

[0079] The term "halogen" or“halo” means fluorine, chlorine, bromine, or iodine.

The term "halohydrocarbyl" means a hydrocarbyl as defined above wherein one or more hydrogens is replaced with a halogen. A halohydrocarbyl group is typically a substituted alkyl substituent. Examples of such haloalkyl include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl, and the like. A haloalkyl is an alkyl as defined above wherein one or more hydrogen is replaced with a halogen. Thus, a“partially halogenated hydrocarbyl” group means a hydrocarbyl group in which some but not all hydrogens are replaced by a halogen. Illustrative partially fluorinated hydrocarbyl groups include difluoromethyl, 6,6,6- trifluorohexyl, and 2,3,-difluoropropyl. The term“fully halogenated hydrocarbyl” means a hydrocarbyl group wherein each hydrogen has been replaced by a halogen. Examples of such fully halogenated hydrocarbyl groups are perfluorohydrocarbyl groups such as trifluoromethyl, peril uorobutyl, perfluoroisopropyl, and perfluorohexyl. Preferred partially and fully halogenated hydrocarbyl groups are partially and fully fluorinated hydrocarbyl groups and partially and fully chlorinated hydrocarbyl groups.

[0080] The phrases“independently selected”,“independently” and their variants, when used in reference to two or more of the same substituent group are used herein to mean that that two or more groups may be the same or different. In addition, where one or more substituent positions are recited for such substituent(s), the position numbers and recited substituents(s) take precedence over“independently”.

[0081] The terms“pathogen” and“pest” are used interchangeably herein to broadly include any organism that may be harmful to the entity to which a contemplated compound or composition containing such a compound is administered. The term “pest” includes plant and animal pests. A“pathogen” or“pest” is intended to include a microbe, an insect, an arachnid, a virus, or a parasite, or other organism that may cause infection or disease directly or as a vector, as well as any combinations thereof. Plant pests are commonly nematodes, insects, arachnids, bacteria, viruses, or fungi, or combinations thereof. Animal pathogens or pests include similar types of pests, but usually do not include nematodes and do include helminths. Insect and arachnid pests of plants often eat one or more portions of a plant, a plant part, plant proagation material, and/or harvested fruits or vegetables. Additionally, biting insects are often pests in and of themselves, but may also be vectors for microbially-caused diseases such as malaria, plague, and Lyme disease.

[0082]“Phytopathogen” as used herein, is a pathogen affecting a plant, a plant part, plant propagation material, and/or harvested fruits or vegetables. Plant pathogens are commonly insects, arachnids, parasites, viruses, or microbes, or combinations thereof. Insect pests of plants often eat or suck fluids from one or more portions of a plant.

[0083] The phrase“True Fungi” is used herein means all members of the kingdom Fungi, including, but not limited to, yeasts, rusts, smuts, mildews, molds, and mushrooms, excepting members of Oomycota (Phytophthora infestens and

Plasmopara viticola). The term“fungi” or“fungus” is used to include all of the fungal organisms discussed herein, including the Oomycota.

[0084] The term“plant health” generally describes various sorts of characteristics of plants. For example, properties that may be mentioned are crop characteristics including: emergence, crop yields, protein content, oil content, starch content, root system, root growth, root size maintenance, stress tolerance (e.g. against drought, heat, salt, UV, water, cold), ethylene (production and/or reception), tillering, plant height, leaf blade size, number of basal leaves, tillers strength, leaf color, pigment content, photosynthetic activity, amount of input needed (such as fertilizers or water), seeds needed, tiller productivity, time to flowering, time to grain maturity, plant verse (lodging), shoot growth, plant vigor, plant stand, tolerance to biotic and abiotic stresses, natural defense mechanisms, and time to germination.

[0085] In general,“pesticidal” means the ability of a substance to increase mortality or inhibit the growth rate of plant and/or animal pests. The term is used herein, to describe the property of a substance to exhibit activity against microbes, viruses, insects, arachnids, parasites, and/or other pests. A substance that is pesticidal is a “pesticide”.

[0086] The term‘active agent’ or‘active ingredient’ or‘active compound’ means a contemplated compound.

[0087] By“effective” amount of a drug, active ingredient, pesticide, fungicide, nematicide, arachnicide, antiparasitic, antimicrobial, insecticide, formulation, composition, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A(n)“effective”,“topically effective”, “therapeutically effective”,“fungicidally effective”,“nematicidally effective”, “antimicrobially effective”,“arachnicidally effective”, or“insecti cidally effective” amount refers to the amount of drug needed to effect the desired biological result.

[0088] The term“control” or“controlling” refers to a composition that provides a curative and/or inhibitive activity of pests.

[0089] The term“composition” includes stereoisomers and agriculturally, pesticidally, or veterinary acceptable salts of the active agents disclosed herein. The compound of the disclosure included in the composition may be covalently attached to a carrier moiety, as described herein. Alternatively, any compound of the disclosure included in the composition is not covalently linked to a carrier moiety.

[0090] The terms which incorporate the phrase“acceptable salt”, including pharmaceutically (or veterinary) acceptable salt and agriculturally acceptable salt, are meant to include a salt of a compound of the disclosure which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein and the intended use. When compounds of the disclosure contain relatively acidic functionalities, base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert carrier. Examples of

agriculturally acceptable base addition salts include sodium, potassium, zinc, calcium, ammonium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, l-arginine, d-lysine, or l-lysine), or magnesium salt, or a similar salt. When compounds of the disclosure contain relatively basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,

monohydrogencarbonic, phosphoric, monohydrogen-phosphoric,

dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,

methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al.,“Pharmaceutical Salts”, J Pharm Sci 66:1-19 (1977)). Certain specific compounds of the disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0091] The term“acceptable carrier” or“acceptable vehicle” refers to any medium that provides the appropriate delivery of an effective amount of an active agent(s), fungicide, nematicide, insecticide, drug, formulation, or permeant, as defined herein, does not negatively interfere with the effectiveness of the biological activity of the active agent, fungicide, nematicide, insecticide, drug, formulation, or permeant, and that is sufficiently non-toxic to the host, whether agricultural, pharmaceutical, veterinary, or pesticidal to a locus that may be infected with pests, such as a plant, an animal, such as a mammal, or a building, or for the prevention of infection or infestation of such a locus with pests.

[0092] Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, emulsion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Additional information concerning carriers may be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), which is incorporated herein by reference.

[0093] The term "carrier" is used herein to denote a natural or synthetic, organic, or inorganic material that constitutes a portion of the diluent medium in which the active agent is dispersed or dissolved. This carrier is inert. In some embodiments, this carrier is inert and agriculturally acceptable, in particular to the plant being treated. The phrase“agriculturally acceptable” is utilized herein to be analogous to

“pharmaceutically acceptable” as used in pharmaceutical products to describe diluent media. A carrier may be solid (clays, natural or synthetic silicates, silica, resins, waxes, solid fertilizers, dusts and dispersible powders such as kaolinite, lactose, calcite, talc, kaolin, bentonite, or other absorptive polymers, and the like) or liquid (water, alcohols, ketones, petroleum fractions, aromatic or paraffinic hydrocarbons, chlorinated hydrocarbons, liquefied gases, and the like).

[0094] The term“acceptable excipient” is conventionally known to mean

agriculturally acceptable carriers, agriculturally acceptable diluents and/or

agriculturally acceptable vehicles used in formulating compositions effective for the desired use.

[0095]“Pharmaceutical compositions” includes stereoisomers and pharmaceutically acceptable salts of the active agents disclosed herein. The compound of the disclosure included in the composition may be covalently attached to a carrier moiety. Alternatively, any of the compounds of the disclosure included in the composition is not covalently linked to a carrier moiety.

[0096]“Agrochemical compositions” includes stereoisomers and pharmaceutically acceptable salts of the active agents disclosed herein. The compound of the disclosure included in the composition may be covalently attached to a carrier moiety. Alternatively, any of the compounds of the disclosure included in the composition is not covalently linked to a carrier moiety.

[0097] An "acceptable carrier," as used herein refers to excipients, for example, pharmaceutically, veterinary, or physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.

[0098] The term "hydrocarbon solvent" refers to one or more hydrocarbons which have solvency for mineral oil. Typically, the hydrocarbon solvent comprises at least one of normal or branched chain paraffins or olefins, cyclic hydrocarbons and aromatic hydrocarbons. Often, the hydrocarbon solvent is comprised of at least 50 wt. %, preferably at least 75 wt. % and most preferably at least 90 wt. % of normal or branched chain paraffins or olefins based on the weight of the hydrocarbon solvent.

In some embodiments, the hydrocarbon solvent is selected from the group consisting of isoparaffins and normal paraffins. In other embodiments, the hydrocarbon solvent is a normal paraffin. In one embodiment, the hydrocarbon solvent is petroleum ether. In still other embodiments, the hydrocarbon solvent comprises from 5 to 15 carbon atoms per molecule. In other embodiments, the hydrocarbon solvent comprises 7 to 10 carbon atoms per molecule. In addition, the hydrocarbon solvent does not require the presence of functional groups such as, for example, esters, alcohols or adds. In another embodiment, the hydrocarbon solvent is a mixture of petroleum ether and ethyl acetate. In yet other embodiments, that the hydrocarbon solvent contain less than about 5 wt. % and more preferably less than about 1 wt. % of oxygen-containing functional groups such as, for examples, esters, alcohols, acids, or mixtures thereof, based on the weight of the hydrocarbon solvent. [0099] The term“microbe” is intended to include any organism that is harmful to the entity to which a contemplated compound or composition containing such is administered. The term“microbe” is intended to include fungi and bacteria as well as any combinations thereof. The term“microbe” includes all bacteria and fungi.

[0100] The term“antimicrobial” means a compound that controls, reduces, prevents, ameliorates, or inhibits the growth of microbes.

[0101] “Fungicide” and“fungicidal” refers to the ability of a substance to control, reduce, prevent, ameliorate, or inhibit the growth rate of fungi.

[0102] The term“parasite” as used herein is intended to include protozoa, parasitic worms, helminths, trematodes, nematodes, flatworms, other endoparasites, epiparasites or hyperparasites, and ectoparasites that are harmful to plants or animals.

[0103] The term“antiparasitic” means a compound that controls, reduces, prevents, ameliorates, or inhibits the growth of parasites.

[0104]“Nematicides” and“nematicidal” refers to the ability of a substance to control, reduce, prevent, ameliorate, or inhibit the growth of nematodes. In general, the term “nematode” comprises eggs, larvae, juvenile, and mature forms of said organism.

[0105]“Insecticide” as well as the term“insecticidal” refers to the ability of a substance to control, reduce, prevent, ameliorate, or inhibit the growth of insects. As used herein, the term“insects” includes all organisms in the class“Insecta.” The term“pre-adult” refers to any form of an organism prior to the adult stage, including, for example, eggs, larvae, instars, and nymphs.

[0106] Arachnicides including“acaricides” and“acaricidals” refer to the ability of a substance to control, reduce, prevent, ameliorate, or inhibit the growth of

ectoparasites belonging to the class“Arachnida”, and particularly sub-class Acari.

The term“pre-adult” refers to any form of an organism prior to the adult stage, including, for example, eggs, larvae, instars, and nymphs.

[0107] The term“animal” generally includes commercial animals, livestock, companion animals, wild animals, and humans. In some embodiments, for any of the methods described herein, the animal is a mammal. In some embodiments, a mammal is a member selected from human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. In some embodiments, for any of the methods described herein, a mammal is a human.

[0108] The term“animal health” includes both“veterinary health” and“human health” and generally means the achievement and maintenance of healthful homeostasis of an animal, whether the animal be commercial, livestock, companion animal, wild, or human.

[0109]“Biological medium,” as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro“biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma, and blood. In vivo applications may be performed in animals and plants.

[0110] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0111] Chemical structures represented herein can be determined by those of skill in the art.

[0112] The presence of one or more possible asymmetric carbon atoms in a compound of the disclosure means that the compounds may occur in chiral isomeric forms, i.e., enantiomeric or diastereomeric forms. Also, atropisomers may occur as a result of restricted rotation about a single bond. The disclosed compound formulas are intended to include all those possible isomeric forms and mixtures thereof. The disclosed compounds are intended to include all possible tautomers (e.g. keto-enol tautomerism) where present. Accordingly, the present disclosure includes all possible tautomeric forms for the disclosed compounds.

[0113] embodiment of the present disclosure is a compound of formula (I)

wherein:

X ¹ is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, CN, unsubstituted C1-C3 hydrocarbyl, C1-C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl; X is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine,

CN, unsubstituted C1-C ₃ hydrocarbyl, C1-C ₃ hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl;

Z ¹ is oxygen or sulfur;

Y ¹ is selected from the group consisting of: oxygen, sulfur, and NH;

R ¹ is selected from the group consisting of: hydrogen, unsubstituted C Cs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C ₃ -C ₆ cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-1 1 R ^1a substitutions, unsubstituted aryl, aryl having 1-5 R ^1a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^1a substitutions, unsubstituted heteroaryl, heteroaryl substituted with one or more R ^1a substitutions, unsubstituted heterocyclyl, and heterocyclyl substituted with one or more R ^1a substitutions;

each R ^1a independently is selected from the group consisting of CrCs hydrocarbyl, NH ₂ , OH, N0 ₂ , CN, C1-C2 haloalkyl, OR ⁶ , SR ⁶ , SOR ⁶ , SO2R ⁶ , NHC(0)OR ⁶ , NR ⁶ R ⁷ , C(0)OR ⁶ , unsubstituted aryl, C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, heteroaryl, and heterocyclyl;

R ⁶ and R ⁷ are independently selected from the group consisting of Oi-Ob hydrocarbyl and substituted hydrocarbyl, or

R ⁶ and R ⁷ can be taken together with the nitrogen to which they are attached to form a ring of no more than 8 members; and

[01 14] each of R ⁸ and R ⁹ independently is selected from the group consisting of: hydrogen, methyl, ethyl; or

R ⁸ and R ⁹ can be taken together to form a 3 - 6 membered ring,

or a salt, stereoisomer, enantiomer, or tautomer thereof.

[01 15] In one aspect, Y ¹ is oxygen or sulfur. In one aspect, if Y ¹ is NH, then Z ¹ is sulfur. In one aspect, Z ¹ or Y ¹ is sulfur. In one aspect, Z ¹ and Y ¹ are sulfur.

[01 16] In one aspect, one of X ¹ or X is hydrogen. In one aspect, X ¹ is fluorine, chlorine, bromine, CN, unsubstituted C1-C ₃ hydrocarbyl, C1-C ₃ hydrocarbyl having 1- 7 halogen substitutions, and cyclopropyl. In one aspect, X ¹ is fluorine, chlorine, or bromine. In one aspect, X ¹ is fluorine or chlorine. In one aspect, X ¹ is chlorine.

[01 17] In one aspect, R ¹ is selected from the group consisting of: unsubstituted Cr C ₆ alkyl, C1-C ₆ alkyl substituted with one or more R ^1a substitutions, unsubstituted C2- C ₆ alkenyl, C2-C6 alkenyl substituted with one or more R ^1a substitutions,

unsubstituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with one or more R ^1a substitutions, unsubstituted phenyl, phenyl substituted with one or more R ^1a substitutions, unsubstitued benzyl, benzyl substituted with one or more R ^1a substitutions, unsubstituted heterocyclyl, and heterocyclyl substituted with one or more R ^1a substitutions. In one aspect, each R ^1a independently is selected from halogen, OH, SCH ₃ , OCH ₃ , NH ₂ , CH ₃ , and NHC(0)0-f-butyl. In one aspect, each R ^1a independently is selected from NH ₂ , OH, NHC(0)0R ⁶ , NR ⁶ R ⁷ , C(0)0R ⁶ , fluorine, chlorine, and bromine. In one aspect, the number of R ^1a substitutions is three, two, or one.

[0118] In one aspect, Y ¹ is sulfur; Z ¹ is oxygen; and R ¹ is selected from the group consisting of: unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted 0 ₃ -0b cy cl o hydrocarbyl, and 0 ₃ -0b cyclohydrocarbyl having 1-11 R ^1a substitutions.

[0119] In one aspect, Y ¹ is oxygen; Z ¹ is sulfur; and R ¹ is selected from the group consisting of: unsubstituted phenyl, aryl having 1-5 R ^1a substitutions, unsubstituted heteroaryl, and heteroaryl substituted with one or more R ^1a substitutions.

[0120] In one aspect, the compound is a compound of formula (la), (la-2), (la-3), or (1a-4):

[0121] In one aspect, each of X ¹ and X independently is selected from fluorine and chlorine.

[0122] In one aspect, R ¹ is selected from the group consisting of: hydrogen, unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C ₃ -C ₆ cyclohydrocarbyl, C ₃ -C ₆ cyclohydrocarbyl having 1-11 R ^1a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^1a substitutions, phenyl, and phenyl having 1-5 R ^1a substitutions.

[0123] In one aspect, each CrCs hydrocarbyl is selected from CrCs alkyl, C ₂ -C ₃ alkenyl, and C ₂ -C ₃ alkynyl, and further wherein C s alkyl may have 1 - 17 R ^1a substitutions, further wherein C _2-3 alkenyl may have 1 - 15 R ^1a substitutions, and further wherein C _2-3 alkynyl may have 1 - 9 R ^1a substitutions.

[0124] In one aspect, the compound is a compound of formula (la-2); X ¹ is selected from hydrogen, fluorine, and chlorine; X ¹ ’ is selected from hydrogen, fluorine, and chlorine; and R ¹ is C2-C8 hydrocarbyl having one R ^1a substitution where R ^1a is NH ₂ or NR ⁶ R ⁷ and each R ⁶ and R ⁷ independently is C1-C6 unsubstituted alkyl.

[0125] In one aspect, the compound is a compound of formula (lb) or (lb-2):

[0126] In one aspect, each of X ¹ and X independently is selected from fluorine and chlorine. In one aspect, R ¹ is selected from the group consisting of: hydrogen, unsubstituted CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^1a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^1a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^1a substitutions, phenyl, and phenyl having 1-5 R ^1a substitutions. In one aspect, each CrCs hydrocarbyl is selected from CrCs alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, and further wherein C1-8 alkyl may have 1 - 17 R ^1a substitutions, further wherein C2-8 alkenyl may have 1 - 15 R ^1a substitutions, and further wherein C2-8 alkynyl may have 1 - 9 R ^1a substitutions.

[0127] In one aspect, the compound is a compound of formula (lc):

[0128] In one aspect, X ¹ is halogen; X is hydrogen; and R ¹ is unsubstituted CrCs hydrocarbyl, unsubstituted C3-C6 cyclohydrocarbyl, unsubstituted benzyl, or benzyl having 1 or 2 R ^1a substitutions. In one aspect, each R ^1a substitution is a halogen.

[0129] In one aspect, the compound is a compound of formula (Id):

[0130] In one aspect, X ¹ is halogen; and R ¹ is selected from the group consisting of unsubstituted CrCs hydrocarbyl, unsubstituted C3-C6 cyclohydrocarbyl, unsubstituted benzyl, and benzyl having 1-2 R ^1a substitutions. In one aspect, R ¹ is CrCs alkyl. In one aspect, R ¹ is benzyl having 1 or 2 halogen substitutions. [0131] One embodiment of the present disclosure includes a compound of formula (V):

[0132] wherein:

X ⁵ is selected from the group consisting of: hydrogen, chlorine, fluorine, bromine, CN, unsubstituted C C ₆ hydrocarbyl, C C ₆ hydrocarbyl having 1-13 R ^5a substitutions, unsubstituted C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^5a substitutions,

0(unsubstituted C ₁ -C ₅ hydrocarbyl), 0(CrCs hydrocarbyl having 1-11 R ^5a

substitutions), 0(unsubstituted C3-C6 cyclohydrocarbyl), and 0(03-0b

cyclohydrocarbyl having 1-11 R ^5a substitutions);

X ^5’ is selected from the group consisting of: hydrogen, chlorine, fluorine, bromine,

CN, unsubstituted C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyl having 1-13 R ^5a

substitutions, C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted benzyl, benzyl having 1-7 R ^5a substitutions,

0(unsubstituted C ₁ -C ₅ hydrocarbyl), 0(Ci-Cs hydrocarbyl having 1-11 R ^5a

substitutions), 0(unsubstituted C3-C6 cyclohydrocarbyl), and 0(Cz-Ce

cyclohydrocarbyl having 1-11 R ^5a substitutions);

R5 is selected from the group consisting of: hydrogen, unsubstituted C Cs

hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^5a substitutions, unsubstituted C ₃ -C ₆ cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted aryl, aryl having 1-5 R ^5a substitutions, unsubstituted benzyl, benzyl substituted with 1- 7 R ^5a substitutions, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl;

Y ⁵ is selected from the group consisting of: oxygen, sulfur, and NH;

each R ^5a independently is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, NH ₂ , OH, CN, NO2, C1-C2 haloalkyl, OR ¹⁴ , SR ¹⁴ , SOR ¹⁴ , S0 ₂ R ¹⁴ , NHC(0)OR ¹⁴ , NR ¹⁴ R ¹⁵ , C(0)OR ¹⁴ , unsubstituted aryl, unsubstituted C ₃ -C ₆ cyclohydrocarbyl, substituted C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl; and R ¹⁴ and R ¹⁵ are independently selected from the group consisting of: hydrocarbyl and substituted hydrocarbyl, or

R ¹⁴ and R ¹⁵ can be taken together with the nitrogen to which they are attached to form a ring of no more than 8 members;

or a salt, stereoisomer, enantiomer, or tautomer thereof.

[0133] In one aspect, Rs is selected from the group consisting of: unsubstituted Cr Cs hydrocarbyl, CrCs hydrocarbyl having 1-17 R ^5a substitutions, unsubstituted C ₃ -C ₆ cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 R ^5a substitutions, unsubstituted aryl, aryl having 1-5 R ^5a substitutions, unsubstituted benzyl, benzyl substituted with 1- 7 R ^5a substitutions, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl.

[0134] In one aspect, the compound is a compound of formula (Va):

[0135] In one aspect, X ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine. In one aspect, X ^5’ is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine.

[0136] In one aspect, the compound is a compound of formula (Vb):

[0137] In one aspect, X ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C6 hydrocarbyl, and unsubstituted benzyl. In one aspect, X ^5’ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C6 hydrocarbyl, and unsubstituted benzyl. In one aspect, R ⁵ is CrCs hydrocarbyl.

[0138] In one aspect of the present disclosure, as applicable, each of X ¹ , X , X ⁵ , or X ^5’ independently is fluorine, chlorine, bromine, CN, unsubstituted C1-C3 hydrocarbyl, C1-C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl. [0139] In one aspect of the present disclosure, as applicable, each of X ¹ , X , X ⁵ , or X ^5’ independently is chlorine, fluorine, bromine, CN, unsubstituted C1-C6 hydrocarbyl, C1-C6 hydrocarbyl having 1-13 substitutions, unsubstituted C3-C6 cy cl o hydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 substitutions, unsubstituted benzyl, benzyl having 1-7 substitutions, 0(unsubstituted C1-C5 hydrocarbyl), 0(Ci-Cs hydrocarbyl having 1-11 substitutions), 0(unsubstituted C3-C6 cyclohydrocarbyl), and 0(C3-C6 cyclohydrocarbyl having 1-11 substitutions).

[0140] In one aspect of the present disclosure, each CrCs hydrocarbyl is selected from CrCs alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, and further wherein C1-8 alkyl may have 1 - 17 R ^1a substitutions, further wherein C2-8 alkenyl may have 1 - 15 R ^1a substitutions, and further wherein C2-8 alkynyl may have 1 - 9 R ^1a substitutions.

[0141] In one aspect, each aryl is phenyl.

[0142] One embodiment of the present disclosure is a compound selected from the Table A herein provided, including a salt, stereoisomer, enantiomer, or tautomer thereof.

[0143] One embodiment of the present disclosure is a compound selected from the Table B herein provided, including a salt, stereoisomer, enantiomer, or tautomer thereof.

[0144] One embodiment of the present disclosure includes a method for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen by applying an effective amount of a compound according to the present disclosure. In one aspect, the pathogen is selected from a group consisting of microbes, insects, arachnids, parasites, and any combination thereof. In one aspect, the pathogen is one or more microbe. In one aspect, an infestation relates to one or more of an animal, a plant, a plant part, plant propagation material, harvested fruits, and harvested vegetables.

[0145] One embodiment of the present disclosure includes a pesticidal, veterinary, or pharmaceutical composition comprising a compound according to the present disclosure and one or more acceptable excipient. In one aspect, such a composition includes one or more additional active agent.

[0146] In one aspect of the present disclosure is a compound of formula (I):

wherein: Xi is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, CN, C1-C3 hydrocarbyl, C1-C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl;

Xi ^’ is selected from the group consisting of: hydrogen, fluorine, chlorine, bromine,

CN, C1-C3 hydrocarbyl, C1-C3 hydrocarbyl having 1-7 halogen substitutions, and cyclopropyl;

Zi is oxygen or sulfur;

Yi is selected from the group consisting of: oxygen, sulfur, and NH;

R1 is selected from the group consisting of: hydrogen, CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 Ri ^a substitutions, C3-C6 cyclohydrocarbyl, C3-C6

cyclohydrocarbyl having 1-11 Ri ^a substitutions, phenyl, aryl having 1-5 Ri ^a substitutions, benzyl having 0-7 Ri ^a substitutions, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;

each Ri ^a is independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, -NH2, -OH, NO2, CN, C1-C2 haloalkyl, -OR ⁶ , -SR ⁶ , -SOR ⁶ , SO2R ⁶ , -NHC(0)OR ⁶ , -NR ⁶ R ⁷ , -C(0)OR ⁶ , phenyl, aryl, C ₃ -C ₆ cyclohydrocarbyl, substituted C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, substituted heteroaryl, heteroaryl, substituted heterocyclyl, and heterocyclyl;

R ⁶ and R ⁷ are independently selected from the group consisting of:

hydrocarbyl and substituted hydrocarbyl group, or R ⁶ and R ⁷ can be taken together with or without the nitrogen to which they are attached to form a ring of no more than 8 members; and

R ⁸ and R ⁹ are independently selected from the group consisting of: hydrogen, methyl, ethyl , or R ⁸ and R ⁹ can be taken together to form a 3 - 6 membered ring,

or a salt, stereoisomer, enantiomer, or tautomer thereof.

[0147] In one embodiment, Z1 or Y1 of the compound of formula (I) is sulfur.

[0148] In another embodiment, both Z1 and Y1 of the compound of formula (I) are sulfur.

[0149] In yet another embodiment of the compound of formula (I), Y1 is sulfur, Z1 is oxygen; and R1 is selected from the group consisting of CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 Ri ^a substitutions, C3-C6 cyclohydrocarbyl, and C3-C6 cyclohydrocarbyl having 1 - 1 1 Ri ^a substitutions.

[0150] In yet one other embodiment of the compound of formula (I), Y1 is oxygen, Z1 is sulfur; and R1 is selected from the group consisting of phenyl, aryl having 1-5 Ri ^a substitutions, heteroaryl, and substituted heteroaryl. [0151] In an embodiment of the present disclosure, the compound of formula (I) disclosed herein is formula (la):

wherein Ri is selected from the group consisting of hydrogen, CrCs hydrocarbyl, Ci- Cs hydrocarbyl having 1-17 Ri ^a substitutions, C3-C6 cyclohydrocarbyl, C3-C6 cyclohydrocarbyl having 1-11 Ri ^a substitutions, C2-C8 alkenyl, C2-C8 alkenyl having 1- 15 Ri ^a substitutions, C3-C6 alkynyl, and C3-C6 alkynyl having 1-9 Ri ^a substitutions; and each Ri ^a is independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, -NH ₂ , -OH, NO2, CN, C1-C2 haloalkyl, -OR ⁶ , -SR ⁶ , -SOR ⁶ , SO2R ⁶ , -NHC(0)0R ⁶ , -NR ⁶ R ⁷ , -C(0)0R ⁶ , phenyl, aryl, C ₃ -C ₆ cyclohydrocarbyl, substituted C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, substituted heteroaryl, heteroaryl, substituted heterocyclyl, and heterocyclyl

[0152] In one embodiment of the present disclosure, the compound of formula (I) disclosed herein is formula (lb):

R1 is selected from the group consisting of hydrogen, CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 Ri ^a substitutions, C3-C6 cyclohydrocarbyl, C3-C6

cyclohydrocarbyl having 1-11 Ri ^a substitutions, C2-C8 alkenyl, C2-C8 alkenyl having 1- 15 Ri ^a substitutions, C3-C6 alkynyl, and C3-C6 alkynyl having 1-9 Ri ^a substitutions; and

each Ri ^a is independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, -NH ₂ , -OH, NO ₂ , CN, C ₁ -C ₂ haloalkyl, -OR ⁶ , -SR ⁶ , -SOR ⁶ , SO ₂ R ⁶ , -NHC(0)OR ⁶ , -NR ⁶ R ⁷ , -C(0)OR ⁶ , phenyl, aryl, C ₃ -C ₆ cyclohydrocarbyl, substituted C3-C6 cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, substituted heteroaryl, heteroaryl, substituted heterocyclyl, and heterocyclyl.

[0153] ln_yet another embodiment of the present disclosure, the compound of formula (I), disclosed herein is formula (lc)

[0154] In one aspect of the present disclosure is a compound of formula (V):

wherein:

X ₅ is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, CN, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyl having 1-13 Rs ^a substitutions, C ₃ -C ₆

cyclohydrocarbyl, C ₃ -C ₆ cyclohydrocarbyl having 1-11 Rs ^a substitutions, benzyl having 0-7 R ₅ ^a substitutions, 0(CrCs hydrocarbyl), 0(CrCs hydrocarbyl having 1-11 R ₅ ^a substitutions), 0(C ₃ -C ₆ cyclohydrocarbyl), and C C ₃ -C ₆ cyclohydrocarbyl having 1-11 R ₅ ^a substitutions);

X ₅ ' is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, CN, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyl having 1-13 R ₅ ^a substitutions, C ₃ -C ₆

cyclohydrocarbyl, C ₃ -C ₆ cyclohydrocarbyl having 1-11 Rs ^a substitutions, benzyl having 0-7 Rs ^a substitutions, 0(Ci-Cs hydrocarbyl), 0(CrCs hydrocarbyl having 1-11 R ₅ ^a substitutions), 0(C ₃ -C ₆ cyclohydrocarbyl), and 0(Cz-Ce cyclohydrocarbyl having 1-11 R ₅ ^a substitutions);

R ₅ is selected from the group consisting of hydrogen, CrCs hydrocarbyl, CrCs hydrocarbyl having 1-17 Rs ^a substitutions, C ₃ -C ₆ cyclohydrocarbyl, C ₃ -C ₆

cyclohydrocarbyl having 1-11 Rs ^a substitutions, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkenyl having 1- 15 R ₅ ^a substitutions, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkynyl having 1-9 Rs ^a substitutions, phenyl, aryl having 1-5 Rs ^a substitutions, benzyl having 0-7 Rs ^a substitutions, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;

Y ₅ is selected from the group consisting of oxygen, sulfur, and NH;

R ₅ ^a is selected independently from the group consisting of hydrocarbyl, substituted hydrocarbyl, -NH ₂ , -OH, CN, N0 ₂ , C ₁ -C ₂ haloalkyl, -OR ¹⁴ , -SR ¹⁴ , -SOR ¹⁴ , SO ₂ R ¹⁴ , - NHC(0)OR ¹⁴ , -NR ¹⁴ R ¹⁵ , -C(0)OR ¹⁴ , phenyl, aryl, C ₃ -C ₆ cyclohydrocarbyl, substituted C ₃ -C ₆ cyclohydrocarbyl, fluorine, chlorine, bromine, iodine, substituted heteroaryl, heteroaryl, substituted heterocyclyl, and heterocyclyl; and

R ¹⁴ and R ¹⁵ are independently selected from the group consisting of: hydrocarbyl and substituted hydrocarbyl group, or R ¹⁴ and R ¹⁵ can be taken together with or without the nitrogen to which they are attached to form a ring of no more than 8 members; or a salt, stereoisomer, enantiomer, or tautomer thereof. .

[0155] In one embodiment of the present disclosure, the compound of formula (V) disclosed herein is formula (Va):

wherein:

X ₅ is selected from the group consisting of hydrogen, fluorine, chlorine and bromine, and

X ₅ ’ is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.

[0156] In one embodiment of the present disclosure, the compound of formula (V) disclosed herein is formula (Vb):

wherein:

X ₅ is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, Cr C ₆ hydrocarbyl, and benzyl;

X ₅ ’ is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, Cr C ₆ hydrocarbyl, and benzyl; and

R ₅ is hydrogen or CrCs hydrocarbyl.

[0157] Another embodiment of the present disclosure is a compound selected from Table A, which may also be found in Figure 2. In some embodiments, the compound selected from Table A is a salt, stereoisomer, enantiomer, or tautomer thereof.

Table A:











40

41

[0158] Another embodiment of the present disclosure is a compound selected from Table B. In some embodiments, the compound from Table B is a salt, stereoisomer, enantiomer, or tautomer thereof. Table B

44



 [0159] It is understood that when in aqueous media, the compounds of formula (I) or formula (V) according to the present disclosure may be present in a reversible equilibrium with water due the lewis acidic nature of the trigonal planar boron center (e.g. compounds A and B shown below). This dynamic equilibrium may important for the biological activity of the compounds of formula (I) and formula (V). All compounds in the present disclosure in this dynamic equilibrium are another aspect of the present invention.

[0160] In some embodiments, the compounds of the present disclosure are useful for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen. In some embodiments the pathogen is selected from a group consisting of at least one of microbes, insects, arachnids, parasites, or any combination thereof.

[0161] In some emobidments, a compound of the present disclosure is applied to an animal, a plant, a plant part, plant proagation material, and/or harvested fruits or vegetables or a combination thereof. Once applied, the compounds of the present disclosure are useful for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen. In some embodiments the pathogen is selected from a group consisting of microbes, insects, arachnids, parasites, and any combination thereof, or any combinations thereof.

[0162] In one embodiment, as shown in FIG. 1 and FIG. 4, of the present disclosure is provided a general process for preparing the compounds of the present disclosure.

[0163] According to another embodiment of the disclosure, there is provided an agrochemical composition comprising a compound of the present disclosure.

[0164] Another embodiment of the present disclosure includes an agrochemical composition comprising a compound of the present disclosure and

an agrochemically-acceptable diluent or carrier.

[0165] In yet another emobidment, the agrochemical composition comprising the compound of the present disclosure is applied to an animal, a plant, a plant part, plant proagation material, and/or harvested fruits or vegetables.

[0166] In some embodiments, the agrochemical composition comprises at least one additional active ingredient. In some embodiments, the compound of the present disclosure forms a syngergistic mixture with the at least one additional active ingredient. In other emodiments, at least one other compound of the present disclosure is the additional active ingredient.

Agrochemical Compositions

[0167] The compounds disclosed herein may be used in unmodified form or together with inerts conventionally employed in the art of formulation. The compounds disclosed herein can be prepared as a formulation that is an agrochemical composition. They may be formulated into emulsifiable concentrates, suspension concentrates, water dispersible concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, water- dispersible granules, soluble powders, dusts, granulates, seed treatments, and also encapsulations e.g. in polymeric substances. The methods of application, such as spraying, atomizing, dusting, scattering, coating, or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. Also contemplated in the present disclosure are conventional slow release formulations.

[0168] The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers,

micronutrient donors or other formulations for obtaining the intended effect(s). They may also contain surfactants (also known as surface-active agents). Exemplary surfactants include wetting and dispersing agents and other compounds that provide adjuvancy effects, e.g., the condensation product of formaldehyde with naphthalene sulphonate, an alkylarylsulphonate, a lignin sulphonate, a fatty alkyl sulphate, an ethoxylated alkylphenol, a trisiloxane ethoxylate, and an ethoxylated fatty alcohol.

[0169] Suitable diluent media, carriers and adjuvants (auxiliaries) can be solid or liquid and are substances useful in formulation technology, e.g., natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders, or fertilizers. Such diluent media are for example described in WO 97/33890, which is hereby incorporated by reference. Water-based (more than 50 weight percent water) diluent media are used illustratively herein.

[0170] Suitable carriers and adjuvants can be solid or liquid and are substances useful in formulation technology, for example: mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders, surfactants, and/or fertilizers.

[0171] Solid, particulate carriers that can be used, for example for dusts and dispersible powders, are calcite, talc, kaolin, diatomaceous earth, montmorillonite or attapulgite, and highly-disperse silica or absorptive polymers. Illustrative particulate, adsorptive carriers for granules include pumice, crushed brick, sepiolite or bentonite, montmorillonite-type clay, and exemplary nonsorbent carrier materials are calcite or dolomite. A particulate solid formulation can also be prepared by encapsulation of a compound of the invention or by a granulation process that utilizes one or more of the above diluents or an organic diluent such as microcrystalline cellulose, rice hulls, wheat middlings, saw dust and the like. Illustrative granules can be prepared as discussed in US Patents No. 4,936,901 , No. 3,708,573 and No. 4,672,065.

[0172] Suitable liquid carriers include: aromatic hydrocarbons, in particular the fractions C ₈ -C ₁₂ , such as xylene mixtures or substituted naphthalenes, phthalic esters such as dibutyl or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane, paraffins or limonene, alcohols and glycols as well as their ethers and esters, such as ethylene glycol monomethyl ether or benzyl alcohol, ketones such as cyclohexanone or isophorone, strongly polar solvents such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, and, if appropriate, epoxidized vegetable oils such as soybean oil, and water. If appropriate, the liquid carrier can be a naturally occurring essential oil, such as oils from citronella and lemon grass.

[0173] Suitable surface-active compounds are non-ionic, cationic and/or anionic surfactants having good emulsifying, and/or dispersing and wetting properties, depending on the water solubility and preffered formulation type of the compound of the invention. The term“surfactants” is also to be understood as meaning mixtures of two or more surface-active compounds.

[0174] The surfactants customarily employed in formulation technology are described, inter alia, in the following publications: McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Glen Rock, N.J., 1988; M. and J. Ash, Encyclopedia of Surfactants, Vol. I-III, Chemical Publishing Co., New York, 1980- 1981.

[0175] Among the suitable illustrative surfactants there can be mentioned, e.g., high molecular weight polymers, polyacrylic acid salts, lignosulphonic acid salts, phenolsulphonic or (mono- or di-alkyl)naphthalenesulphonic acid salts, laurylsulfate salts, polycondensates of ethylene oxide with lignosulphonic acid salts,

polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (in particular alkylphenols or arylphenols such as mono- and di-(polyoxyalkylene alkylphenol) phosphates, polyoxyalkylene alkylphenol carboxylates or polyoxyalkylene alkylphenol sulfates), salts of sulphosuccinic acid esters, taurine derivatives (in particular alkyltaurides), polycondensates of ethylene oxide with phosphated tristyrylphenols and polycondensates of ethylene oxide with phosphoric esters of alcohols or phenols. Additional suitable surfactants include: amine ethoxylates, alkylaryl sulphonates, alkylbenzene sulphonates, castor oil ethoxylates and polyethylene glycol derivatives of hydrogenated castor oil, sorbitan fatty acid ester ethoxylates, sorbitan fatty acid esters, non-ionic ethoxylates, branched and unbranched secondary alcohol ethoxylates, nonylphenol ethoxylates, and octylphenol ethoxylates. The presence of at least one surfactant is often where the inert vehicles are not readily soluble in water and the composition of the invention used for the administration is aqueous.

[0176] In general, a concentrated formulation comprising a compound of the invention includes about 0.01 to about 90% by weight compound of the invention, about 0 to about 35% agriculturally acceptable surfactant and 5 to 99.99% solid or liquid carriers and adjuvant(s).

[0177] The formulations preferably comprise between 0.00000001% and 98% by weight compound of the invention or, with particular preference, between 0.01 % and 95% by weight compound of the invention, more preferably between 0.5% and 90% by weight compound of the invention . Application takes place in a customary manner adapted to the application forms.

[0178] Suitable penetrants in the present context include all those substances which are typically used in order to enhance the penetration of active agrochemical compounds into plants. Penetrants in this context are defined in that, from the (generally aqueous) application liquor and/or from the spray coating, they are able to penetrate the cuticle of the plant and thereby increase the mobility of the active compounds in the cuticle. This property can be determined using the method described in the literature (Baur et al., 1997, Pesticide Science 51 , 131-152).

Examples include alcohol alkoxylates such as coconut fatty ethoxylate or isotridecyl ethoxylate, fatty acid esters such as rapeseed or soybean oil methyl esters, fatty amine alkoxylates such as tallowamine ethoxylate, or ammonium and/or

phosphonium salts such as ammonium sulphate or diammonium hydrogen phosphate, for example.

[0179] A contemplated formulation can also include at least one polymer that is a water-soluble or water-dispersible film-forming polymer that improves the adherence of the compound of the invention to plant propagation material.

[0180] In some embodiments, a coloring agent, such as a dye or pigment, is included in a the agrochemical composition so that an observer can immediately determine that the plant or plant propagation material has been treated. An agrochemical composition that includes a coloring agent is an embodiment of the disclosure, as such a composition can improve user and consumer safety. The coloring agent is also useful to indicate to the user the degree of uniformity of application of a composition. Generally, the coloring agent tends to have a melting point above 30°C., and therefore, is suspended in the composition. The coloring agent can also be a soluble compound.

[0181] As examples of coloring agents can be mentioned pigment red 48-2 (CAS- 7023-61-2), pigment blue 15 (CAS- 147- 14-8), pigment green 7 (CAS- 1328-53-6), pigment violet 23 (CAS-6358-30-1), pigment red 53-1 (CAS-5160-02-1), pigment red 57-1 (CAS 5281-04-9), pigment red 112 (CAS 6535-46-2) or similar coloring agents. A coloring agent is typically present at about 0.1 to about 10% by mass of an agrochemical formulation.

[0182] In typical use, a compound of the invention is formulated as a concentrate also known as a pre-mix composition (or concentrate, formulated compound, agrochemical composition), and the end user normally employs a diluted formulation for administration to the plants of interest. Such a diluted composition is often referred to as a tank-mix composition. A tank-mix composition is generally prepared by diluting a pre-mix agrochemical composition (concentrate) with a solvent such as water that can optionally also contain further auxiliaries. Generally, an aqueous tank- mix is used.

[0183] Particularly, formulations for crop protection may be applied as a spray, e.g. foliar, soil, etc .

[0184] In some embodiments, other biocidally active ingredients or compositions may be combined with the compounds of the disclosure and applied simultaneously or sequentially with the compounds of the disclosure. When applied simultaneously, these other biocidally active ingredients may be formulated together with the compounds of the disclosure or mixed in, for example as a tank mix. Examples of other biocidally active ingredients include fungicides, nematicides, insecticides, herbicides, bactericides, acaricides, and/or plant growth regulators, or any combinations thereof.

[0185] The compounds of the disclosure can be used in the form of agrochemical compositions that can be applied to the crop area of plant to be treated, alone, simultaneously, or in succession with further compounds. These further compounds can be, for example, fertilizers, micronutrient donors, or other compounds that influence the growth of plants.

[0186] The compounds of the disclosure may be used in fungicidal compositions for controlling or protecting again phytopathogenic microorganisms, where the fungicidal composition comprises as an active ingredient of at least one compound of the present disclosure in either the free form or in an agrochemically usable salt form. Biological Activity

[0187] In each case, the compounds of the disclosed disclosure are may be present in free form, as a hydrate, as a salt, as a stereoisomer, as an enantiomer, or a tautomeric form; e.g., as an agronomically usable or an agrochemically acceptable salt form.

[0188] The compounds and compositions disclosed herein provide a method for controlling, reducing, preventing, ameliorating, or inhibiting an infestation by a pathogen. The pathogen is selected from a group consisting of: microbes, insects, arachnids, parasites, and any combination thereof.

[0189] In general, bacterial pathogens may be classified as either gram-positive or gram-negative pathogens. Antibiotic compounds with activity against both gram positive and gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded as active against gram-positive and/or gram-negative bacterial pathogens.

[0190] Examples of gram-positive and gram-negative aerobic and anaerobic bacteria, include Staphylococci, Enterococci, Streptococci, Bacilli, Listeria,

Haemophilus, Moraxella, Mycobacteria, Staphylococci, Pseudomonas, and

Escherichia.

[0191] Examples of fungi include: one or more members of the phyla of Ascomycota, Oomycota, Basidiomycota, and the subphylum Mucoromycotina.

[0192] In one embodiment, activity of the compounds according to the disclosure corresponds to a mortality rate of at least 50-60% of the pests herein described, more preferably to a mortality rate over 90%, most preferably above 90%, above 91 %, above 92%, above 93%, about 94%, above 95%, above 96%, above 97%, above 98%, above 99%, or 100%.

[0193] The compositions herein disclosed, in some embodiments, are active against normally sensitive and resistant species and against all or some stages of development. Furthermore, a contemplated compound may have potent activity and may be used for control of unwanted pathogens (particularly fungi) for the protection of a plant, a plant part, plant propagation material, and/or harvested fruits or vegetables.

[0194] Where a contemplated compound is a fungicide, the compound may be used in crop protection for control of phytopathogenic fungi. A contemplated compound may exhibit outstanding efficacy against a broad spectrum of phytopathogenic fungi, including soil borne pathogens, which are in particular members of the classes Plasmodiophoromycetes, Peronosporomycetes (Syn. Oomycetes), Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes, and Deuteromycetes (Syn. Fungi imperfecti). Some fungicides are systemically active and may be used in plant protection as foliar, seed dressing or soil fungicide. Furthermore, they are suitable for combating fungi, which, inter alia, infest wood or roots of plant.

[0195] Examples of fungi include: one or more members of the phyla of Ascomycota, Oomycota, Basidiomycota, and the subphylum Mucoromycotina. The fungi of the division Ascomycota include, for example, subdivision Pezizomycotina and

Taphrinomycotina which include Dothideomycetes, Leotiomycetes, Sordariomycetes and Taphrinomycetes classes. The fungi of the phylum Ascomycota include, for example, subphyla selected from the group consisting of Dothideomycetes,

Leotiomycetes, and Sordariomycetes. The fungi of the division Basidiomycota include, for example, subdivisions Agaricomycotina, Pucciniomycotina, and

Ustilaginomycotina. In some embodiments, the one or more target fungi whose growth is to be controlled or inhibited is selected from one or more of the group consisting of Alternaria, Aspergillus, Bipolaris, Blumeria, Botrytis, Candida,

Cercospora, Cercosporidium, Claviceps, Cochliobolus, Colletotrichum, Corynespora, Dybotryon, Dilophospora, Erysiphe, Exserohilum, Fusarium, Leveillula, Magnaporthe, Melampsora, Microsphaera, Microsphaeropsis, Monilia, Monilinia, Mycosphaerella, Oidiopsis, Peronospora, Phaeosphaeria, Phakopsora, Phomopsis, Phymatotrichum, Phytophthora, Plasmopora, Podosphaera, Pseudoperonospora, Puccinia,

Pyrenophora, Pyricularia, Pythium, Rhizoctonia, Sclerophthora, Sclerotinia, Septoria, Setosphaeria, Uncinula, Ustilago, Venturia, Verticillium, and Zymoseptoria.

[0196] The compositions according to the disclosure demonstrate antipathogenic activity, good plant tolerance, low toxicity to plants and animals, while exhibiting minimal environmental impact. The compositions are suitable for protecting a plant, a plant part, plant proagation material, and/or harvested fruits or vegetables seeds, for increasing harvest yields, for improving the quality and/or vigor of the harvested material, and for controlling animal pests, in particular insects, nematodes, bacteria, microbes, fungi, protozoa, viruses, and parasites, which are encountered in agriculture, in horticulture, in animal husbandry, in forests, in gardens and leisure facilities, in protection of stored products and of materials, and in the hygiene sector. They can be employed as plant protection agents. [0197] They are active against normally sensitive and resistant species and against all or some stages of development. Where a contemplated compound is a parasite, the compound can be used as an antiparasiticide in animal health.

[0198] Exemplary animal parasites from the phyla Plathelminthes and Nematoda, include, for example, Ancylostoma duodenale, Ancylostoma ceylanicum, Acylostoma braziliensis, Ancylostoma spp., Ascaris spp., Brugia malayi, Brugia timori,

Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp., Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis,

Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa, Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni, Strongyloides stercoralis, Stronyloides spp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus spp., Trichuris trichiura, and Wuchereria bancrofti.

[0199] Where a contemplated compound is a parasite, the compound can be used as in crop protection for control of phytopathogenic nematodes. Such a compound can include an outstanding efficacy against a broad spectrum of phytopathogenic nematodes, including soil borne plant parasitic nematodes.

[0200] A contemplated compound can be active against a wide spectrum of nematodes; there are 16 to 20 different orders within the phylum Nematoda. Ten of these orders regularly occur in soil, including four orders, including Rhabditida, Tylenchida, Aphelenchida, and Dorylaimid. Further, plant parasites include many members of the order Tylenchida, and a few genera in the orders Aphelenchida and Dorylaimida.

[0201] Phytoparasitic pests from the phylum Nematoda, for example,

Aphelenchoides spp., Bursaphelenchus spp., Ditylenchus spp., Globodera spp., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus spp., Trichodorus spp., Tylenchulus spp., Xiphinema spp., Helicotylenchus spp., Tylenchorhynchus spp., Scutellonema spp., Paratrichodorus spp., Meloinema spp., Paraphelenchus spp., Aglenchus spp., Belonolaimus spp., Nacobbus spp.,

Rotylenchulus spp., Rotylenchus spp., Neotylenchus spp., Dolichodorus spp., Hoplolaimus spp., Punctodera spp., Criconemella spp., Quinisulcius spp.,

Hemicycliophora spp., Anguina spp., Subanguina spp., Hemicriconemoides spp., Psilenchus spp., Pseudohalenchus spp., Criconemoides spp., Cacopaurus spp., Hirschmaniella spp, Tetylenchus spp..

[0202] In one aspect of the invention, a contemplated compound exhibits efficacy against plant-parasitic nematodes selected from the group consisting of: root-knot nematodes (abbreviated herein as RKN, Meloidogyne spp.), soybean cyst nematodes (abbreviated herein as SCN, Heterodera glycines), cyst nematodes (Heterodera spp.), reniform nematodes ( Rotylenchulus reniformis), sting nematodes (Belonolaimus spp.), lance nematodes ( Hoplolaimus spp.), and lesion nematodes (Pratylenchus spp.).

[0203] Some of the contemplated compounds are systemically active and can be used in plant protection as a foliar nematicide, a seed dressing or a soil-applied nematicide. Furthermore, they are suitable for combating nematodes that infest roots, seed gall, seeds, stems, and/or foliar parts of plants.

[0204] Chemical treatment with a compound of the disclosure is the main method for controlling plant-parasitic nematodes. Application methods include fumigation, in furrow, seed treatment, pre- and post planting application through irrigation systems, granules, and broadcast sprays, and bare root dipping/drenching in the case of transplanted seedlings.

[0205] In another aspect, the invention includes compounds and methods for reducing, ameliorating, or inhibiting an infestation a pest from the phylum Arthropoda, and particularly of its classes Insecta and Arachnida. In some embodiments the insect or arachnid is an ectoparasite.

[0206] Examples of ectoparasites that infest non-human animals, without being limiting, are arthropod ectoparasites such as biting flies, blow flies, fleas, lice, other sucking insects or dipterous pests, and arachnid members such as ticks and mites. Examples of genera of such ectoparasites infecting animals and/or humans are Aedes, Amblyomma, Boophilus, Calliphora, Chorioptes, Cochliomyia,

Ctenocephalides, Culicoides, Damalinia, Demodex, Dermacentor, Dermanyssus, Dermatobia, Gasterophilus, Haematobia, Haematopinus, Haemaphysalis,

Hyalomma, Hypoderma, Ixodes, Linognathus, Lucilia, Melophagus, Oestrus, Otobius, Otodectes, Phlebotomus, Psorergates, Psoroptes, Rhipicephalus, Sarcoptes, Stomoxys, and Tabanus.

[0207] The activity against Arachnida, and particularly against the subclass Acari, especially against ticks of family Ixodidae (hard ticks) and family Arganidae (soft ticks), is one aspect of the disclosure. The subclass Acari also includes other parasites, such as mites (e.g. Chorioptes bovis, Cheyletiella spp., Dermanyssus gaffinae, Demodex canis, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp.) and ticks.

[0208] In the context of the present invention, ticks are understood to be members of the order Acarina. Well-known representatives are, for example, Boophilus,

Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes,

Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros and the like, which usually infest warm-blooded animals including farm animals, such as cattle, horses, pigs, sheep and goats, poultry such as chickens, turkeys and geese, fur-bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as pets such as cats and dogs, but they can also infest humans.

[0209] In another aspect, the invention includes compounds and methods for reducing, ameliorating, or controlling an infestation of an insect. In some

embodiments that insect is an endoparasite.

[0210] Further examples of pests from the phylum Anthropoda, especially from the class Arachnida, include, for example, Acarus spp., Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Amphitetranychus viennensis, Argas spp., Boophilus spp., Brevipalpus spp., Bryobia graminum, Bryobia praetiosa, Centruroides spp., Chorioptes spp., Dermanyssus gallinae, Dermatophagoides pteronyssinus,

Dermatophagoides farinae, Dermacentor spp., Eotetranychus spp., Epitrimerus pyri, Eutetranychus spp., Eriophyes spp., Glycyphagus domesticus, Halotydeus destructor, Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Latrodectus spp., Loxosceles spp., Metatetranychus spp., Neutrombicula autumnalis, Nuphersa spp., Oligonychus spp., Ornithodorus spp., Ornithonyssus spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Steneotarsonemus spp., Steneotarsonemus spinki, Tarsonemus spp., Tetranychus spp., Trombicula alfreddugesi, Vaejovis spp., Vasates lycopersicl·, from the class Chilopoda, for example, Geophilus spp., Scutigera spp.; from the order or the class Collembola, for example, Onychiurus armatus ; from the class Diplopoda, for example, Blaniulus spp.

[0211] Further examples include pests from the class Arachnida, especially from the subclass Acari (i.e. ticks). These pests may be from the family ixodidae and the family argasidae.

[0212] Further examples of pests include pests from the order Orthoptera or Saltatoria, for example, Acheta domesticus, Dichroplus spp., Gryllotalpa spp., Hieroglyphus spp., Locusta spp., Melanoplus spp., Schistocerca gregaria further examples of pests include pests from the order Phthiraptera, for example, Damalinia spp., Haematopinus spp., Linognathus spp., Pediculus spp., Ptirus pubis,

Trichodectes spp.] further examples of pests include pests from the order Psocoptera for example Lepinatus spp., Liposcelis spp.] further examples of pests include pests from the order Siphonaptera, for example, Ceratophyllus spp., Ctenocephalides spp., Pulex irritans, Tunga penetrans, Xenopsylla cheopsis] further examples of pests include pests from the order Thysanoptera, for example, Anaphothrips obscurus, Baliothrips biformis, Drepanothrips reuteri, Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothrips femoralis, Rhipiphorothrips cruentatus, Scirtothrips spp., Taeniothrips cardamomi, Thrips spp:,

[0213] Further examples of pests include pests from the order Zygentoma

(=Thysanura), for example, Ctenolepisma spp., Lepisma saccharina, Lepismodes inquilinus, Thermobia domestica] further examples of pests include pests from the class Symphyla, for example, Scutigerella spp.] further examples of pests include pests from from the phylum Mollusca, especially from the class Bivalvia, for example, Dreissena spp., and from the class Gastropoda, for example, Anion spp.,

Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Pomacea spp., Succinea spp.

[0214] A further example is the pest Aedes aegypti from the Insecta class, order Diptera. This mosquito is a vector for diseases such as Zika, dengue, chikungunya and yellow fever.

[0215] Other examples are from the class Insecta, e.g., from the order Blattodea, for example, Blattella asahinai, Blattella germanica, Blatta orientalis, Leucophaea maderae, Panchlora spp., Parcoblatta spp., Periplaneta spp., Supella longipalpa] from the order Coleoptera, for example, Acalymma vittatum, Acanthoscelides obtectus, Adoretus spp., Agelastica alni, Agriotes spp., Alphitobius diaperinus, Amphimallon solstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp., Anthrenus spp., Apion spp., Apogonia spp., Atomaria spp., Attagenus spp.,

Bruchidius obtectus, Bruchus spp., Cassida spp., Cerotoma trifurcata,

Ceutorrhynchus spp., Chaetocnema spp., Cleonus mendicus, Conoderus spp., Cosmopolites spp., Costelytra zealandica, Ctenicera spp., Curculio spp.,

Cryptolestes ferrugineus, Cryptorhynchus lapathi, Cylindrocopturus spp., Dermestes spp., Diabrotica spp., Dichocrocis spp., Dicladispa armigera, Diloboderus spp., Epilachna spp., Epitrix spp., Faustinus spp., Gibbium psylloides, Gnathocerus cornutus, Hellula undalis, Heteronychus arator, Heteronyx spp., Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, Hypomeces squamosus,

Hypothenemus spp., Lachnosterna consanguinea, Lasioderma serricorne, Latheticus oryzae, Lathridius spp., Lema spp., Leptinotarsa decemlineata, Leucoptera spp., Lissorhoptrus oryzophilus, Lixus spp., Luperodes spp., Lyctus spp., Megascelis spp., Melanotus spp., Meligethes aeneus, Melolontha spp., Migdolus spp., Monochamus spp., Naupactus xanthographus, Necrobia spp., Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Oryzaphagus oryzae, Otiorrhynchus spp., Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp., Phyllophaga helleri, Phyllotreta spp., Popillia japonica, Premnotrypes spp., Prostephanus truncatus, Psylliodes spp., Ptinus spp., Rhizobius ventralis, Rhizopertha dominica, Sitophilus spp., Sitophilus oryzae, Sphenophorus spp., Stegobium paniceum, Sternechus spp., Symphyletes spp., Tanymecus spp., Tenebrio molitor, Tenebrioides mauretanicus, Tribolium spp., Trogoderma spp., Tychius spp., Xylotrechus spp., Zabrus spp.; from the order Diptera, for example, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Asphondylia spp., Bactrocera spp., Bibio hortulanus, Calliphora erythrocephala, Calliphora vicina, Ceratitis capitata, Chironomus spp., Chrysomyia spp., Chrysops spp., Chrysozona pluvialis, Cochliomyia spp., Contarinia spp., Cordylobia anthropophaga, Cricotopus sylvestris, Culex spp., Culicoides spp., Culiseta spp., Cuterebra spp., Dacus oleae, Dasyneura spp., Delia spp., Dermatobia hominis, Drosophila spp., Echinocnemus spp., Fannia spp., Gasterophilus spp., Glossina spp., Haematopota spp., Hydrellia spp., Hydrellia griseola, Hylemya spp., Hippobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Lutzomyia spp., Mansonia spp., Musca spp., Oestrus spp., Oscinella frit, Paratanytarsus spp., Apedilum subcinctum, Pegomyia spp., Phlebotomus spp., Phorbia spp., Phormia spp., Piophila casei, Prodiplosis spp., Psila rosae, Rhagoletis spp., Sarcophaga spp., Simulium spp., Stomoxys spp., Tabanus spp., Tetanops spp., Tipula spp.; from the order Hemiptera, for example, Anasa tristis, Antestiopsis spp., Boisea spp., Blissus spp., Calocoris spp., Campylomma livida, Cavelerius spp., Cimex spp., Collaria spp., Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisa spp., Leptocorisa varicornis, Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae, Monalonion atratum, Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp., Psallus spp., Pseudacysta persea, Rhodnius spp., Sahlbergella singularis, Scaptocoris casta nea, Scotinophora spp., Stephanitis nashi, Tibraca spp., Aeneolamia spp., Aleyrodes proletella, Acizzia acaciaebaileyanae, Acizzia dodonaeae, Acizzia uncatoides, Acrogonia spp.,

Agonoscena spp., Aleurolobus barodensis, Aleurothrixus floccosus, Amrasca spp., Anuraphis cardui, Triatoma spp. ; [0216] Other examples are from the order Homoptera, for example, Acyrthosipon spp., Allocaridara malayensis, Aonidiella spp., Aphanostigma pin, Aphis spp., Arboridia apicalis, Arytainilla spp., Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani, Bemisia tabaci, Blastopsylla occidentalis, Boreioglycaspis meiaieucae, Brachycaudus helichrysi, Brachycolus spp., Brevicoryne brassicae, Cacopsylla spp., Calligypona marginata, Carneocephala fulgida, Ceratovacuna lanigera, Cercopidae spp., Ceroplastes spp., Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chondracris rosea, Chromaphis juglandicola,

Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus spp.,

Cryptomyzus ribis, Cryptoneossa spp., Ctenarytaina spp., Dalbulus spp., Dialeurodes citri, Diaphorina citri, Diaspis spp., Drosicha spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp., Eriosoma spp., Erythroneura spp., Eucalyptolyma spp., Euphyllura spp., Euscelis bilobatus, Ferrisia spp., Geococcus coffeae, Glycaspis spp.,

Heteropsylla cubana, Heteropsylla spinulosa, Homalodisca coagulata, Hyalopierus arundinis, lcerya spp., Idiocerus spp., Idioscopus spp., Laodelphax striatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi, Macrosiphum spp.,

Macrosteles facifrons, Mahanarva spp., Melanaphis sacchari, Metcalf iella spp., Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, Myzus spp., Nasonovia hbisnigri, Nephotettix spp., Nettigoniclla spectra, Nilaparvata lugens, Oncometopia spp., Orthezia praelonga, Oxya chinensis, Pachypsylla spp.,

Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp., Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodon humuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp., Prosopidopsylla flava, Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus spp., Psyllopsis spp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus spp., Quesada gigas,

Rastrococcus spp., Rhopalosiphum spp., Saissetia spp., Scaphoideus titan us, Schizaphis graminum, Selenaspidus articulatus, Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina, Siphoninus phillyreae, Tenalaphara malayensis, Tetragonocephela spp., Tinocallis caryaefoliae, Tomaspis spp.,

Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp., Unaspis spp., Viteus vitifolii, Zygina spp.] from the order Hymenoptera, for example,

Acromyrmex spp., Athalia spp., Atta spp., Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis, Sirex spp., Solenopsis invicta, Tapinoma spp., Urocerus spp., Vespa spp., Xeris spp.]

[0217] Other examples include non-insect pests, for example, from the order Isopoda, for example, Armadillidium vulgare, Oniscus asellus, Porcellio scaber, from the order Isoptera, for example, Coptotermes spp., Cornitermes cumulans,

Cryptotermes spp., Incisitermes spp., Microtermes obesi, Odontotermes spp., Reticulitermes spp.] from the order Lepidoptera, for example, Achroia grisella, Acronicta major, Adoxophyes spp., Aedia leucomelas, Agrotis spp., Alabama spp., Amyelois transitella, Anarsia spp., Anticarsia spp., Argyroploce spp., Barathra brassicae, Borbo cinnara, Bucculatrix thurberiella, Bupalus piniarius, Busseola spp., Cacoecia spp., Caloptilia theivora, Capua reticulana, Carpocapsa pomonella, Carposina niponensis, Cheimatobia brumata, Chilo spp., Choristoneura spp., Clysia ambiguella, Cnaphalocerus spp., Cnaphalocrocis medinalis, Cnephasia spp., Conopomorpha spp., Conotrachelus spp., Copitarsia spp., Cydia spp., Dalaca noctuides, Diaphania spp., Diatraea saccharalis, Earias spp., Ecdytolopha aurantium, Elasmopalpus lignosellus, Eldana saccharina, Ephestia spp., Epinotia spp., Epiphyas postvittana, Etiella spp., Eulia spp., Eupoecilia ambiguella, Euproctis spp., Euxoa spp., Feltia spp., Galleria mellonella, Gracillaria spp., Grapholitha spp., Hedylepta spp., Helicoverpa spp., Heliothis spp., Hofmannophila pseudospretella,

Homoeosoma spp., Homona spp., Hyponomeuta padella, Kakivoria flavofasciata, Laphygma spp., Laspeyresia molesta, Leucinodes orbonalis, Leucoptera spp., Lithocolletis spp., Lithophane antennata, Lobesia spp., Loxagrotis albicosta,

Lymantria spp., Lyonetia spp., Malacosoma neustria, Maruca testulalis, Mamstra brassicae, Melanitis leda, Mods spp., Monopis obviella, Mythimna separata,

Nemapogon cloacellus, Nymphula spp., Oiketicus spp., Oria spp., Orthaga spp., Ostrinia spp., Oulema oryzae, Panolis flammea, Parnara spp., Pectinophora spp., Perileucoptera spp., Phthorimaea spp., Phyllocnistis citrella, Phyllonorycter spp., Pieris spp., Platynota stultana, Plodia interpunctella, Plusia spp., Plutella xylostella, Prays spp., Prodenia spp., Protoparce spp., Pseudaletia spp., Pseudaletia unipuncta, Pseudoplusia includens, Pyrausta nubilalis, Rachi plusia nu, Schoenobius spp., Scirpophaga spp., Scirpophaga innotata, Scotia segetum, Sesamia spp., Sesamia inferens, Sparganothis spp., Spodoptera spp., Spodoptera praefica, Stathmopoda spp., Stomopteryx subsecivella, Synanthedon spp., Tecia solanivora, Thermesia gemmatalis, Nemapogon variatella, Tinea pellionella, Tineola bisselliella, Tortrix spp., Trichophaga tapetzella, Trichoplusia spp., Tryporyza incertulas, Tuta absoluta, Virachola spp. ;

[0218] Additional pests include those from the order Orthoptera, for example, Acrida turrita, Acheta domesticus, Dichroplus spp., Gryllotalpa spp., Hieroglyphus spp., Locusta spp., Melanoplus spp., Schistocerca gregaria] from the order Phthiraptera, for example, Damalinia spp.,] Haematopinus spp., Linognathus spp., Pedicuius spp., Ptirus pubis, Trichodectes spp.] from the order Psocoptera for example Lepinotus spp., Liposcelis spp; from the order Siphonaptera, for example, Ceratophyllus spp., Ctenocephalides spp., Pulex irritans, Tunga penetrans, Xenopsylla cheopsis ; from the order Thysanoptera, for example, Anaphothrips obscurus, Baliothrips biformis, Drepanothrips reuteri, Enneothrips flavens, Frankliniella spp., Heliothrips spp.,

Hercinothrips femoralis, Rhipiphorothrips cruentatus, Scirtothrips spp., Taeniothrips cardamomi ; from the order Zygentoma (=Thysanura), for example, Ctenolepisma spp., Lepisma saccharina, Lepismodes inquilinus, Thermobia domestica] from the class Symphyla, for example, Scutigerella spp.] and pests from the phylum Mollusca, especially from the class Bivalvia, for example, Dreissena spp., and from the class Gastropoda, for example, Anion spp., Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Pomacea spp., Succinea spp.

[0219] While the present disclosure includes these listings of pest species, any omission or mistaken characterization should not be limiting.

Examples

Part I: Experimental Procedures for Syntheses of 6-(Carbamate-related) - CBOs 6-amino-7-chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol

H ₂ , Pd/C

EtOAc, 25°C, 2 h

C, 1 .5 h

[0220] To a solution of (2-formylphenyl)boronic acid (10 g, 66.69 mmol, 1 eq) in THF (100 ml_) was added NaBH ₄ in portions (5.05 g, 133.39 mmol, 2 eq) at 0°C over 5 min. After addition, the mixture was stirred at 25°C for 1 hr. The reaction mixture was quenched by adding aq. HCI (2M) at 0°C until pH to 7, and then diluted with EtOAc (30 ml_) and extracted with EtOAc (30 ml_ x 3). The combined organic layers were washed with brine (30 ml_ x 3), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give benzo[c][1 ,2]oxaborol-1 (3H)-ol (7.7 g, 57.49 mmol, 86.2% yield) as a white solid. ¹ H NMR (CDCI _3, 400 MHz): d 7.78 (d, J = 7.2 Hz, 1 H), 7.53-7.49 (m, 1 H), 7.41-7.36 (m, 2 H), 5.75 (s, 1 H) and 5.15 (s, 2 H) ppm. To a solution of fuming HNO3 (70 ml_) was added benzo[c][1 ,2]oxaborol-1(3H)-ol (6.7 g, 50.02 mmol, 1 eq) at -30°C over 5 min. After addition, the mixture was stirred at - 30°C for 30 min. The reaction mixture was poured with stirring into water and ice (80 ml_) and stirred at 0°C for 40 min. Solid was precipitated. The solid was filtered and dried under vacuum to afford 1-hydroxy-6-nitro-3H-2, 1-benzoxaborole (6 g, 33.53 mmol, 67.0% yield, 100% purity) as a pale yellow solid. ¹ H NMR (DMSO-cfe _, 400 MHz): d 9.59 (s, 1 H), 8.57 (s, 1 H), 8.33 (dd, J = 8.4, 2.0 Hz, 1 H), 7.69 (d, J = 8.4 Hz,

1 H), 5.1 1 (s, 2 H) ppm. MS (ESI): mass calcd. For C ₇ H ₈ BN0 ₂ 149.06, m/z found 150.1 [M+H] ⁺ . Purity by HPLC: 100% (220 nm) and 100% (254 nm). To a solution of 1-hydroxy-6-nitro-3H-2, 1-benzoxaborole (950 mg, 5.31 mmol, 1 eq) in EtOAc (20 ml_) was added Pd/C (200 mg, 10%) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated to give crude product. The crude product was purified by re-crystallization from 20 ml_ of MTBE to give 6-aminobenzo[c][1 ,2]oxaborol-1 (3H)-ol (0.73 g, 4.90 mmol, 92.3% yield, 100% purity) as a pale yellow solid. ¹ H NMR (DMSO-cfe _, 400 MHz): d 8.90 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.87 (s, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2 H), 4.80 (s, 2 H) ppm. MS (ESI): mass calcd. For C ₇ H ₈ BN0 ₂ 149.06, m/z found

150.1 [M+H] ⁺ . Purity by HPLC: 100% (220 nm) and 100% (254 nm). To a solution of 6-aminobenzo[c][1 ,2]oxaborol-1 (3H)-ol (1 g, 6.71 mmol, 1 eq) in DMF (15 mL) was added NCS (0.95 g, 7.11 mmol, 1.06 eq) at 0°C. The mixture was stirred at 25°C for 1.5 hr. The reaction mixture was quenched by adding ice-water (50 mL) at 0°C, and then diluted and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by re

crystallization from MTBE (20 mL) to afford crude product (800 mg, brown solid).

Part of the crude product (270 mg, brown solid) was further purified by prep-TLC (Si0 ₂ , Ethyl acetate/MeOH=10/1) to give 6-amino-7-chlorobenzo[c][1 ,2]oxaborol- 1 (3H)-ol (44.6 mg, 96.3% purity) was obtained as a yellow solid. ¹ H NMR (DMSO-cfe _, 400 MHz): d 8.89 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 5.21 (s,

2 H), 4.82 (s, 2 H) ppm. MS (ESI): mass calcd. For C ₇ H ₇ BCIN0 ₂ 183.03, m/z found

184.2 [M+H] ⁺ . Purity by HPLC: 96.33% (220 nm).

1. Methyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

Methyl chloroformate

K ₂ C0 ₃ , DCM, rt to reflux

[0221] To a solution of 6-amino-7-chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol (350 mg, 1.9 mmol) and K ₂ CO ₃ (789 mg, 5.7 mmol) in DCM (10 ml_) was added methyl chloroformate (0.44 mL, 5.7 mmol) at room temperature. It was refluxed for 2 hours, cooled to room temperature and quenched with 2N HCI (5 mL). The organic layer was separated, dried over Na ₂ SC>4, filtered and evaporated to dryness under vacuum. Purification by prep-HPLC (0.5% TFA in MeCN) gave the title compound (34 mg, yield 4%) as an off-white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.15 (s, 1 H), 9.02 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2H), 3.66 (s, 3H) ppm. HPLC purity: 96.38% at 210 nm and 95.78% at 254 nm. MS: m/z = 242.0 (M+H) ⁺ .

2. Ethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamate

Ethyl chloroformate

K ₂ C0 ₃ , DCM, reflux

[0222] The title compound was synthesized by following the procedure described above. It was obtained as an off-white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.14 (s, 1 H), 8.95 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2 H),

4.1 1 (q, J = 6.8 Hz, 1 H), 1.24 (t, = 6.8 Hz, 1 H) ppm. HPLC purity: 96.9% at 210 nm and 91.3% at 254 nm. MS (M+H) ⁺ : m/z = 256.0.

3. n-Propyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate n-propyl chloroformate K ₂ C0 ₃ , DCM, rt to 40°C

[0223] The title compound was synthesized by following the procedure described above for the ethyl analog. It was obtained as white solid. ¹ HNMR (400 MHz, DMSO- de). d 9.15 (s, 1 H), 8.96 (s, 1 H), 7.61 (d, = 8.0 Hz, 1 H), 7.33 (d, = 8.1 Hz, 1 H), 4.97 (s, 2H), 4.02 (t, J = 6.7 Hz, 2H), 1.70-1.53 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 98.7% at 210 nm and 96.4% at 254 nm. MS (M+H) ⁺ : m/z = 270.0. 4. tert-Butyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamate

[0224] To a mixture of tert-butyl N-(1-hydroxy-3H-2,1-benzoxaborol-6-yl)carbamate (1 g, 4.01 mmol, leg) in DMF (10 mL) was added NCS (589.74 mg, 4.42 mmol, 1.1 eq) at 0°C. Then the mixture was stirred at 0-25°C for 2 hrs. HPLC checking showed most reactant consumed, and one major new peak formed. The mixture was poured into cold aq. Na ₂ SC>3 solution and extracted with EtOAc twice. The combined organic layers were washed with aq. NH ₄ CI solution, dried over Na ₂ S0 ₄ and concentrated to give crude product as light-yellow oil (1.2 g crude). A sample (100 mg) was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water(0.1 %TFA)-ACN];B%: 40%-50%, 10min) to give 36 mg pure product as a white solid. ¹ H NMR (DMSO-cfe, 400 MHz): 6 9.13 (s, 1 H), 8.59 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 4.95 (s, 2H), 1.45 (s, 9H) ppm. Purity by HPLC: 98.61 % (220 nm) and 99.67% (254 nm). MS (ESI): mass calcd. For Ci ₂ Hi ₅ BCIN0 ₄ , 283.08, m/z found 228.1 [M-56+H] ⁺ .

5. tert-Butyl (7-chloro-1 -hydroxy-3, 3-dimethyl-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate

[0225] To a mixture of methyl 2-bromobenzoate (20 g, 93.00 mmol, 13.07 mL, 1 eq) in THF (200 mL) was added dropwise MeMgBr (3 M, 65.10 mL, 2.1 eq) at 5°C under N ₂ . The mixture was stirred at 25°C for 2 h and then quenched with aqueous NH ₄ CI (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (150 mL), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0- 30% Ethyl acetate/Petroleum ethergradient, 80 mL/min) to afford 2-(2- bromophenyl)propan-2-ol (13 g, 60.44 mmol, 64.99% yield) as light-yellow oil. ¹ H NMR (CDCIs, 400 MHz): d 7.67 (d, J = 7.6 Hz, 1 H), 7.59 (d, J = 7.6 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.12 (t, = 7.6 Hz, 1 H), 1.77 (s, 6H) ppm. To a mixture of 2-(2- bromophenyl)propan-2-ol (12 g, 55.79 mmol, 1 eq) in THF (120 ml_) was added n- BuLi (2.5 M, 55.79 ml_, 2.5 eq) in one portion at -70°C. The mixture was stirred at - 70°C for 2 h. Then triisopropyl borate (20.99 g, 111.58 mmol, 25.65 ml_, 2 eq) was added to the mixture. The mixture was warmed to 20°C and stirred for 15 h. The residue was poured into ice-water (w/w = 1/1) (10 ml_) and adjust to pH 5. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0-100% Ethyl

acetate/Petroleum ethergradient, 100 mL/min) to afford 3,3-dimethylbenzo

[c][1 ,2]oxaborol-1 (3H)-ol (9 g, 55.56 mmol, 99.6% yield) as crude yellow oil. ¹ H NMR (CDCIs, 400 MHz): d 9.00 (s, 1 H), 7.67 (d, J = 7.2 Hz, 1 H), 7.47-7.41 (m, 2H), 7.33- 7.31 (m, 1 H), 1.45 (s, 6H) ppm. To a mixture of 3,3-dimethylbenzo[c][1 ,2]oxaborol- 1 (3H)-ol (9 g, 55.56 mmol, 1 eq) in H ₂ S0 ₄ (100 mL) was added HNOs (10.50 g, 166.67 mmol, 7.50 mL, 3 eq) at -20°C. The mixture was stirred at -15°C for 10 min. Ice-water (100 mL) was added to the mixture at -10°C and stirred for 10 min. It was filtered and then the solid was washed by petroleum ether (50 mL) to afford crude 3,3-dimethyl-6-nitrobenzo[c][1 ,2]oxaborol-1 (3H)-ol (8 g, 38.65 mmol, 69.6% yield) as yellow solid. 150 mg of crude product was purified by pre-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (10mM NH ₄ HC0 ₃ )-ACN]; B%: 10%-40%, 10.5 min) to afford the purified material of 3,3-dimethyl-6-nitrobenzo[c][1 ,2]oxaborol- 1 (3H)-ol (91 mg) as yellow solid. ¹ H NMR (DMSO-cfe, 400 MHz): d 9.47 (s, 1 H), 8.52 (d, J = 2.4 Hz, 1 H), 8.32 (dd, J = 8.4, 2.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 1.49 (s, 6H) ppm. MS (ESI): mass calcd. For C ₉ HI ₀ BNO ₄ 207.07, m/z found 206.1 [M-H]\ HPLC purity: 100% (220 nm) and 100% (254 nm). To a solution of 3,3-dimethyl-6- nitrobenzo[c][1 ,2]oxaborol-1 (3H)-ol (2 g, 9.66 mmol, 1 eq) in EtOAc (70 mL) was added Pd/C (0.5 g, 10% purity) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 20°C for 15 h. The reaction mixture was filtered, and the filtrate was concentrated to affrord 6-amino-3,3-dimethylbenzo[c][1 ,2] oxaborol-1 (3H)-ol (1.5 g, 8.47 mmol, 87.70% yield) as red solid. 100 mg of the crude product was purified by pre-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (10mM NH ₄ HC0 ₃ )- ACN]; B%: 10%-40%, 10.5 min) to afford 6-amino-3,3-dimethylbenzo[c][1 ,2]oxaborol- 1 (3H)-ol (51 mg) as yellow solid. ¹ H NMR (DMSO-cfe, 400 MHz): d 8.73 (s, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 6.67 (dd, J = 8.0, 2.4 Hz, 1 H), 4.95 (s, 2H), 1.37 (s, 6H) ppm. MS (ESI): mass calcd. For C ₉ Hi ₂ BN0 ₂ 177.10, m/z found 176.1 [M-H]-. HPLC: 99.4% (220 nm), 98.6% (254 nm). To a mixture of 6-amino-3,3- dimethylbenzo[c][1 ,2]oxaborol-1 (3H)-ol (1 g, 5.65 mmol, 1 eq) in t-BuOH (20 mL) was added (Boc) ₂ 0 (3.70 g, 16.95 mmol, 3.89 mL, 3 eq) in one portion at 20°C under N ₂ . The mixture was stirred at 50°C for 12 h and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent of 0-80% Ethyl acetate/Petroleum ethergradient: 30 mL/min) to afford tert-butyl (1-hydroxy-3,3-dimethyl-1 ,3-dihydrobenzo[c][1 ,2]oxaborol- 6- yl)carbamate (0.6 g, 2.17 mmol, 38.32% yield) as yellow oil. ¹ H NMR (CDCh, 400 MHz): d 7.60 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.53 (s, 1 H), 1.55 (s, 9H), 1.54 (s, 6H). To a mixture of tert-butyl (1 -hydroxy-3, 3-dimethyl-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamate (0.5 g, 1.80 mmol, 1 eq) in DMF (10 mL) was added NCS (240.93 mg, 1.80 mmol, 1 eq) in one portions at 0°C. The mixture was stirred at 50°C for 15 h and then poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuum to give 0.6 g crude product which was used to next step.

Part of that (0.1 g) was purified by pre-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (10mM NH ₄ HCC>3)-ACN]; B%: 35%-65%, 10.5 min) to afford tert-butyl (7-chloro- 1 -hydroxy-3, 3-di methyl- 1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate (10 mg) as a white solid. ¹ H NMR (DMSO-cfe, 400 MHz): d 8.98 (s, 1 H), 8.58 (s, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 1.46 (s, 9H), 1.45 (s, 6H). MS (ESI): mass calcd. For Ci ₄ Hi ₉ BCIN0 ₄ 311.11 , m/z found 310.0[M-H]\ HPLC purity: 100% (220 nm) and 100% (254 nm).

6. Phenyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0226] The title compound was synthesized by following the procedure described above for the ethyl analog. It was obtained as white solid. ¹ HNMR (400 MHz, MeOD): d 7.89 (d, J = 7.9 Hz, 1 H), 7.47-7.39 (m, 2H), 7.36-7.31 (m, 1 H), 7.29-7.18 (m, 3H), 5.06 (s, 2H) ppm. HPLC purity: 96.7% at 210 nm and 99.9% at 254 nm. MS (M+H) ⁺ : m/z = 303.9.

7. 4-Chlorophenyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0227] The title compound was synthesized by following the procedure described above for the ethyl analog. It was obtained as an off-white solid. ¹ HNMR (400 MHz, MeOD): d 7.87 (s, 1 H), 7.43 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1 H), 7.24 (d, J = 8.6 Hz, 2H), 5.06 (s, 2H) ppm. HPLC purity: 96.3% at 210 nm and 99.7% at 254 nm. MS (M+H) ⁺ : m/z = 337.9.

8. Isopropyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

Isopropyl chloroformate

K ₂ C0 ₃ , DCM, rt to reflux

[0228] The title compound was synthesized by following the procedure described above for the ethyl analog. It was obtained as an off-white solid. ¹ HNMR (400 MHz, DMSO-de): d 9.14 (s, 1 H), 8.85 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2H), 4.88 (m, 1 H), 1.24 (d, J = 6.4 Hz, 6H) ppm. HPLC purity: 96.94% at 210 nm and 92.36% at 254 nm. MS (M+H) ⁺ : m/z = 270.0.

9. Benzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0229] The title compound was synthesized by following the procedure described above for the ethyl analog. It was obtained as an off-white solid. ¹ HNMR (400 MHz, DMSO-de): d 9.22 (s, 1 H), 9.19 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.52-7.28 (m, 6H), 5.15 (s, 2H), 4.97 (s, 2H) ppm. HPLC purity: 99.9% at 210 nm and 95.3% at 254 nm. MS (M+H) ⁺ : m/z = 318.0.

10. 4-Fluorobenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0230] To a solution of (4-fluorophenyl)methanol (1.26 g, 10.0 mmol) and DIPEA (516 mg, 4.0 mmol) in DCM (25 ml_) was added dropwise a solution of triphosgene (1.2 g, 4.0 mmol) in DCM (10 ml_) at 0-5°C. It was stirred at 0°C for additional 30 min and at room temperature overnight. Then 6-amino-7-chlorobenzo[c][1 ,2]oxaborol- 1 (3H)-ol (250 mg, 1.40 mmol) was added to the reaction mixture in one portion at room temperature, followed by addition of K2CO3 (4.14 g, 30 mmol). The reaction was heated to 40°C for 30 min. LCMS indicated no starting materials left. The reaction mixture was cooled to below 0°C, quenched by addition of 5 mL of H2O, neutralized by 6N HCI to pH 3, and extracted with EtOAc (2 ^c 50 mL). Combined organics were washed with H2O, brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.5% TFA in MeCN) to give the title compound (155 mg, yield 33%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.16 (s, 1 H), 9.14 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.61-7.46 (m, 2H), 7.33 (d, J = 8.4 Hz, 1 H), 7.22 (t, J = 9.2 Hz, 2H), 5.13 (s, 2H), 4.96 (s, 2H) ppm. HPLC purity: 99.9% at 210 nm and 98.7% at 254 nm. MS (M-H)-: m/z =

334.1.

11. tert-Butyl 4-(((7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamoyl)oxy)piperidine-1-carboxylate

[0231] The title compound was synthesized by following the procedure like that described above for the 4-F-benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.14 (s, 1 H), 8.99 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.33 (d, J

= 8.1 Hz, 1 H), 4.96 (s, 2H), 4.90-4.60 (m, 1 H), 3.72-3.55 (m, 2H), 3.22-3.08 (m, 2H),

1.91-1.72 (m, 2H), 1.60-1.40 (m, 2H), 1.40 (s, 9H) ppm. HPLC purity: 95.4% at 210 nm. MS (M-H)-: m/z = 409.2.

12. Piperidin-4-yl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate hydrogen chloride

[0232] To a solution of the Boc-protected compound (300 mg, crude) in dioxane (10 ml_) was added 4N HCI (2 ml_, 8 mmol, 4N in dioxane) at room temperature. It was then stirred at room temperature for 1 hour. LCMS indicated the reaction was completed. It was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (0.5% TFA in MeCN) to give the title compound (64 mg, yield 25%) as a white foamy solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.19 (broad s, 3H), 9.16 (s, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 4.97 (s, 2H), 4.88 (m, 1 H), 3.38 (m, 1 H), 3.29-2.98 (m, 4H), 2.16-1.98 (m, 2H), 1.94-1.72 (m, 2H) ppm. HPLC purity: 99.9% at 210 nm and 98.7% at 254 nm. MS (M-H)-: m/z = 334.1. 13. 2,2,2-Trifluoroethyl (7-chloro-1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamate

[0233] To a solution of 6-amino-7-chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.6 mmol) and triethylamine (0.75 ml_, 5.3 mmol) in DCM (10 ml_) at 0°C was added triphosgene (190 mg, 0.64 mmol) in portions during a period of 10 min. After the addition was completed, the reaction mixture was warmed slowly to room

temperature with stirring for 1 hour. Trifluoroethanol (0.5 ml_, 6.9 mmol) was added in one portion. The reaction mixture was stirred at rt for another 1 hour and cooled to 0°C. It was quenched with 2N HCI (5 ml_), separated the organic layer, dried over Na2SC>4, filtered and evaporated to dryness under vacuum. The residue was purified by prep-HPLC (0.5% FA in MeCN) giving the title compound (44 mg, yield 9%) as an off-white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.63 (s, 1 H), 9.18 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 4.99 (s, 2 H), 4.78 (q, J = 9.2 Hz, 2H) ppm.

HPLC purity: 98.75% at 210 nm and 91.18% at 254 nm. MS (M-H)-: m/z = 308.1.

14. 4-Chlorobenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0234] The title compound was synthesized by following the procedure like that described above for the trifluoroethyl analog. It was obtained as an off-white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.20 (s, 1 H), 9.15 (s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.46 (s, 4H), 7.33 (d, J = 8.0 Hz, 1 H), 5.14 (s, 2 H), 4.97 (s, 2H) ppm. HPLC purity: 99.5% at 210 nm and 98.0% at 254 nm. MS (M-H)-: m/z = 350.0.

15. Cyclohexyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamate

[0235] The title compound was synthesized by following the procedure like that described above for the 4-F-benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.13 (s, 1 H), 8.87 (s, 1 H), 7.62 (d, = 8.0 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.97 (s, 2H), 4.68-4.55 (m, 1 H), 1.92-1.83 (m, 2H), 1.78-1.65 (m, 2H), 1.55-1.50 (m, 1 H), 1.46-1.18 (m, 5H) ppm. HPLC purity: 99.5% at 210 nm and 97.0% at 254 nm. MS (M-H)-: m/z = 308.2.

16. Tetrahydro-2H-pyran-4-yl (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamate _{2 3} , ,

[0236] The title compound was synthesized by following the procedure like that described above for the 4-F-benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.14 (s, 1 H), 8.99 (s, 1 H), 7.62 (d, = 8.1 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 4.97 (s, 2H), 4.88-4.74 (m, 1 H), 3.90-3.73 (m, 2H), 3.55-3.40 (m, 2H), 2.01-1.85 (m, 2H), 1.65 - 1.47 (m, 2H) ppm. HPLC purity: 99.8% at 210 nm and 99.2% at 254 nm. MS (M+H) ⁺ : m/z = 312.2.

17. 2-Methoxyethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0237] The title compound was synthesized by following the procedure like that described above for the 4-F-benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.13 (s, 1 H), 9.09 (s, 1 H), 7.60 (d, = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.96 (s, 2H), 4.21-4.15 (m, 2H), 3.58-3.54 (m, 2H), 3.28 (s, 3H) ppm. HPLC purity: 98.35% at 210 nm and 96.95% at 254 nm. MS (M+H) ⁺ : m/z = 286.3.

18. 2-((tert-butoxycarbonyl)amino)ethyl (7-chloro-1 -hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamate

[0238] The title compound was synthesized by following the procedure like that described above for the 4-F-benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.08 (s, 1 H), 8.93 (s, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 6.92 (s, 1 H), 4.96 (s, 2H), 4.04 (t, J = 5.7 Hz, 2H), 3.24-3.16 (m, 2H), 1.39 (s, 9H) ppm. HPLC purity: 98.8% at 210 nm and 98.6% at 254 nm. MS (M-H)-: m/z = 369.2.

19. 2-aminoethyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamate hydrogen chloride

[0239] To a solution of the Boc-protected compound (300 mg, crude) in dioxane (10 ml_) was added 4N HCI (2 ml_, 8 mmol, 4N in dioxane) at room temperature. It was then stirred at rt for 1 hour and concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC (0.5% TFA in MeCN) to give the title compound (75 mg, yield 30%) as a white foamy solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.19 (s, 1 H), 8.89 (s, 1 H), 7.90 (broad s, 3H), 7.76 (d, J = 8.1 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 4.97 (s, 2H), 4.26 (t, J = 5.4 Hz, 2H), 3.13 (t, J = 5.4 Hz, 2H) ppm. HPLC purity: 97.6% at 210 nm and 97.0% at 254 nm. MS (M+H) ⁺ : m/z = 271.2.

20. 2-Hydroxyethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0240] The title compound was synthesized by following the procedure like that described above for the 4-F-benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.13 (s, 1 H), 8.97 (s, 1 H), 7.64 (d, = 8.0 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.96 (s, 2H), 4.80 (t, J = 5.4 Hz, 1 H), 4.14-4.03 (m, 2H), 3.68-3.57 (m, 2H) ppm. HPLC purity: 99.6% at 210 nm and 98.6% at 254 nm. MS (M+H)-: m/z = 272.1.

21. Cyclopropyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0241] The title compound was synthesized by following the procedure like that described above for the trifluoroethyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-de): d 9.13 (s, 1 H), 9.00 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.96 (s, 2 H), 4.10-4.04 (m, 1 H) and 0.69-0.66 (m, 4H) ppm. HPLC purity: 97.8% at 210 nm and 98.2% at 254 nm. MS (M+H) ⁺ : m/z = 268.1.

22. 2-(Dimethylamino)ethyl (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate HCI

[0242] The title compound was prepared by reductive amination of 2-aminoethyl (7- chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamate with NaBH(OAc)3 and paraformaldehyde in acetic acid. Final purification was performed by prep-HPLC. ¹ HNMR (400 MHz, DMSO-cfe): d 9.70 (s, 1 H), 9.21 (s, 1 H), 9.1 1 (s, 1 H), 7.70 (d, J =

8.1 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 4.98 (s, 2H), 4.41-4.38 (m, 2H), 3.50-3.30 (m, 2H), 2.86 (s, 6H) ppm. HPLC purity: 98.9% at 210 nm and 99.3% at 254 nm. MS

(M+H) ⁺ : m/z = 299.0.

23. S-Benzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

Benzyl

mercaptan

DCM, rt

[0243] To a solution of 6-amino-7-chiorobenzo[c][1 ,2]oxaboroi-1 (3H)-ol (250 mg, 1.4 mmol) in DCM (2 mL) was added Et ₃ N (0.5 mL) followed by addition of triphosgene (240 mg, 0 8 mmol) at Q ^c C under inert atmosphere, and the mixture was warmed to 25 ^c C for 2 hours. Benzyl mercaptan (0.5 mL) was added to this solution, and the whole mixture was stirred for 2 hours. The reaction mixture was then quenched with 2N HCI. The organic layer was separated, and aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with

PE/EtOAc (10: 1 to 1 :1) to give the title compound (126 mg, yield 27%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.00 (s, 1 H), 9.19 (s, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.40-7.19 (m, 6H), 4.98 (s, 2H), 4.14 (s, 2H) ppm. HPLC purity: 96.8% at 210 nm and 97.6% at 254 nm. MS (M+H) ⁺ : m/z = 333.9.

24. S-Ethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate l

[0244] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a red solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.89 (s, 1 H), 9.18 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 2.85 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 95.6% at 210 nm and 94.8% at 254 nm. MS (M+H) ⁺ : m/z = 272.0.

25. S-Propyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate l

[0245] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.89 (s, 1 H), 9.18 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 2.84 (t, J = 7.1 Hz, 2H), 1.64-1.53 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm. HPLC purity: 98.0% at 210 nm and 98.4% at 254 nm. MS (M+H) ⁺ : m/z = 285.9.

26. S-lsopropyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate l

[0246] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (300 MHz, DMSO-cfe): d 9.85 (s, 1 H), 9.20 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1 H), 4.98 (s, 2H), 3.59-3.39 (m, 1 H), 1.29 (d, J = 6.8 Hz, 6H) ppm. HPLC purity: 95.9% at 210 nm and 99.4% at 254 nm. MS (M+H) ⁺ : m/z = 286.2. 27. S-phenyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate l

[0247] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.11 (s, 1 H), 9.19 (s, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.53 (dd, J = 6.5, 3.0 Hz, 2H), 7.46-7.41 (m, 3H), 7.35 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H) ppm. HPLC purity: 98.1 % at 210 nm and 99.4% at 254 nm. MS (M+H) ⁺ : m/z =

319.9.

28. S-(4-Fluorobenzyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl) carbamothioate

4-Fluorobenzyl

mercaptan

DCM, rt

[0248] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.01 (s, 1 H), 9.18 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.43-7.28 (m, 4H), 7.16-7.10 (m, 3H), 4.98 (s, 2H), 4.13 (s, 2H) ppm. HPLC purity: 95.7% at 210 nm and 96.8% at 254 nm. MS (M+H) ⁺ : m/z = 351.9.

29. S-(4-Chlorophenyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

4-Chloro

thiophenol

DCM, rt

[0249] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.21 (s, 1 H), 9.20 (s, 1 H), 7.62-7.43 (m, 5H), 7.36 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H) ppm. HPLC purity: 95.6% at 210 nm and 99.2% at 254 nm. MS (M+H) ⁺ : m/z = 353.9.

30. S-(2,2,2-Trifluoroethyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0250] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.37 (s, 1 H), 9.21 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 4.99 (s, 2H), 3.87 (q, J = 10.4 Hz, 2H) ppm. HPLC purity: 95.3% at 210 nm and 98.1% at 254 nm. MS (M+H) ⁺ : m/z = 326.2.

31. S-(2-hydroxyethyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0251] To a mixture of 2-mercaptoethan-1-ol (5 g, 64 mmol) and pyridinium p- toluenesulfonate (1.6 g , 6.4 mmol) in dichloromethane (100 ml) was added 3, 4- di hydro-2 H-pyran (5.8 g, 70 mmol) at 0°C, and the solution was stirred at room temperature for 1 hour. Brine was added to the mixture and the aqueous layer was extracted with EtOAc (3 ^c 50 ml_). The combined organic layer was washed with brine, evaporated. The residue was purified by silica gel chromatography (10% to 20% ethyl acetate in PE) to provide 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-thiol. ¹ HNMR (400 MHz, DMSO-cfe): 6 4.71-4.59 (m, 1 H), 3.96-3.82 (m, 2H), 3.64-3.47 (m, 2H), 3.00-2.57 (m, 2H), 1.79-1.42 (m, 7H) ppm. To a solution of 6-amino-7- chlorobenzo[c][1 ,2]oxaborol-1(3H)-o! (250 mg, 1 4 mmol) in DCM (2 mL) was added Et _;J N (0.5 mL) followed by triphosgene (240 mg, 0.8 mmol) at 0°C under inert atmosphere, and the mixture was heated to 25°C for 2 b. 2-((tetrahydra-2H-pyran-2- yl)oxy)ethane-1 -thiol (1 g, 6.1 mmol) was added to this solution, and the whole mixture was stirred for 2 h. The reaction mixture was then quenched by 2N HCI (5 mL). The organic layer was separated, and aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were concentrated under reduced pressure.

The residue was purified by silica chromatography eluting with PE/EtOAc (10:1 to 1 :1), and further purification by pre-HPLC (0.5% FA in MeCN) gave the final compound (40 mg, yield 10%) as a white solid. ¹ HNMR (300 MHz, DMSO-cfe): d 9.93 (s, 1 H), 9.17 (s, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 4.98 (s, 2H), 5.00-4.90 (m, 1 H), 3.60-3.45 (m, 2H), 2.94 (t, J = 5.9 Hz, 2H) ppm. HPLC purity: 97.7% at 210 nm and 98.3% at 254 nm. MS (M+H) ⁺ : m/z = 287.9.

32. S-(2-methoxyethyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

1. Thiourea, EtOH, reflux

2 N OH H 0 fl

[0252] A mixture of 2-chloroethyl methyl ether (5 g, 53 mmol) and thiourea (4 g, 53 mmol) in 95% ethanol (50 ml_) was refluxed under nitrogen overnight. The cooled ethanol solution was evaporated in vacuo to low volume at 45°C, and the residue dissolved in a solution of sodium hydroxide (3 g) in water (30 ml_). The solution was refluxed under nitrogen for 2 hours. The cooled solution was then acidified with 6N HCI and extracted with EtOAc (2 ^c 50 ml_). The combined organic extracts were evaporated in vacuo at 35°C, and the resulting product 2-methoxyethane-1-thiol (3.2 g, yield 64%) was used directly in the next step without further purification. The final title compound was prepared by reacting 2-methoxyethane-1-thiol with the intermediate 7-chloro-6-isocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol and following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.97 (s, 1 H), 9.17 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.26 (s, 3H), 3.03 (t, J = 6.5 Hz, 2H) ppm. HPLC purity: 96.6% at 210 nm and

95.7% at 254 nm. MS (M+H) ⁺ : m/z = 302.1.

33. tert-butyl (2-(((7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamoyl)thio) ethyl)carbamate

[0253] 2-Aminoethane-1-thiol reacted to B0C2O in the presence of DIPEA in DCM at rt to give tert-butyl (2-mercaptoethyl)carbamate . The final title compound was prepared by reacting tert-butyl (2-mercaptoethyl)carbamate with the intermediate 7- chloro-6-isocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol and following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.95 (s, 1 H), 9.17 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 3.11 (q, J = 6.3 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H), 1.38 (s, 9H) ppm. HPLC purity: 97.4% at 210 nm and 99.7% at 254 nm. MS (M-H)-: m/z = 385.2.

34. S-(2-Aminoethyl) (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1,2]oxaborol- 6-yl)carbamothioate hydrogen chloride

[0254] A solution of tert-butyl (2-(((7-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamoyl)thio)ethyl)carbamate (122 mg, 32 mmol) in HCI/dioxane (4N, 10 mL) was stirred at 25°C overnight. The solvent was evaporated under reduced pressure, and the resulting solid was purified by prep- HPLC (0.5% FA in MeCN) to give the product (25 mg, yield 27%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.17 (s, 1 H), 9.21 (s, 1 H), 7.91 (broad s, 3H), 7.57

(d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 3.11-2.93 (m, 4H) ppm. HPLC purity: 99.0% at 210 nm and 99.3% at 254 nm. MS (M+H) ⁺ : m/z = 287.0.

35. S-Methyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate

[0255] A mixture of 1 ,2-dimethyldisulfane (2 g, 21 mmol), Zn powder (6.5 g, 100 mmol) and AlC (13 g, 100 mmol) in MeCN/H20 (v/v = 2: 1 , 5 ml_) was heated to 25°C for 2 hours. Common intermediate 7-chloro-6-isocyanatobenzo[c][1 ,2]oxaborol· 1 (3H)-oi, prepared from 8-amino-7-cblQrQben2o[c][1 ,2]QxaboroM (3H)-oi (1.4 mmol) as previously described, in DCM (2 ml_) was added to this solution. And the whole mixture was stirred for 2 hours. The reaction mixture was then quenched by 2N HCI, and the organic layer was separated. The aqueous layer was extracted with EtOAc (25 ml_). The combined organic layers were concentrated under reduced pressure. Purification by prep-HPLC (0.5% FA in MeCN) gave the final product (32 mg, yield

9%) as white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.95 (s, 1 H), 9.17 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 2.28 (s, 3H) ppm. HPLC purity: 99.4% at 210 nm and 97.9% at 254 nm. MS (M-H)-: m/z = 256.0.

36. S-(4-chlorobenzyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl) carbamothioate

[0256] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid (yield 26%). ¹ HNMR (400 MHz, DMSO-cfe): d 10.03 (s, 1 H), 9.18 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.37 (s, 4H), 7.35 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 4.12 (s, 2H) ppm. HPLC purity: 95.5% at 210 nm and 99.0% at 254 nm. MS (M+H) ⁺ : m/z = 367.9.

37. S-Cyclohexyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate

[0257] The title compound was prepared by following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.85 (s, 1 H), 9.19 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 2.00-1.91 (m, 2H), 1.66-1.62 (m, 2H), 1.60-1.50 (m, 1 H), 1.50-1.30 (m, 4H), 1.30-1.20 (m, 2H) ppm. HPLC purity: 95.6% at 210 nm and 97.2% at 254 nm. MS (M+H) ⁺ : m/z = 326.1.

38. tert-Butyl 4-(((7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamoyl)thio)piperidine-1-carboxylate

[0258] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5 g, 25 mmol) and EΐbN (4.2 mL, 30 mmol) in 20 mL of anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (1.9 mL, 25 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours, diluted with DCM, washed with brine, dried over Na ₂ SC>4 and concentrated. The resulting residue was dissolved in 20 ml_ of DMF, treated with potassium thioacetate (4.3 g, 37 mmol) and the mixture was stirred at 65°C under a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3 ^c 50 ml_). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting product tert-butyl 4-(acetylthio)piperidine-1-carboxylate (4.2 g, yield 66%) was used directly in the next step without further purification. ¹ HNMR (400 MHz, DMSO-cfe): d 3.82-3.76 (m, 2H), 3.57-3.48 (m, 1 H), 3.04-2.94 (m, 2H), 2.25 (s, 3H), 1.87-1.77 (m,

2H), 1.54-1.42 (m, 2H), 1.38 (s, 9H) ppm. A methanol solution of sodium methoxide (1.1 g, 20 mmol) was added dropwise to a stirred solution of tert-butyl 4- (acetylthio)piperidine-l-carboxylate (4.2 g, 16 mmol) in 80 ml_ of anhydrous methanol at 0°C. After 1 hour at 0°C. The mixture was warmed to room temperature and then stirred for an additional 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (PE/EtOAc = 4: 1) to give tert-butyl 4-mercaptopiperidine-1-carboxylate (2.4 g, yield 68%). ¹ HNMR (400 MHz, DMSO-cfe): d 4.08-4.02 (m, 2H), 2.93-2.80 (m, 3H), 2.05-

1.96 (m, 2H), 1.90 (broad s, 1 H), 1.59-1.50 (m, 2H), 1.47 (s, 9H) ppm. The final title compound was prepared by reacting tert-butyl 4-mercaptopiperidine-1-carboxylate with the intermediate 7-chloro-6-isocyanatobenzo[c][1 ,2] oxaborol-1(3H)-ol and following the procedure like that described above for the synthesis of the benzyl analog. It was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 9.92 (s,

1 H), 9.19 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 3.77-3.74 (m, 2H), 3.60-3.46 (m, 1 H), 3.10-2.95 (m, 2H), 1.94-1.90 (m, 2H), 1.53-

1.43 (m, 2H), 1.40 (s, 9H) ppm. HPLC purity: 99.5% at 210 nm and 99.6% at 254 nm. MS (ESI ⁺ ): m/z = 449.2 (M+Na ⁺ ).

39. S-(Piperidin-4-yl) (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-

6-yl)carbamothioate hydrogen chloride

[0259] A solution of tert-butyl 4-(((7-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl) carbamoyl)thio)piperidine-1-carboxylate (142 mg, 33 mmol) in HCI/dioxane (4N, 10 ml_) was stirred at 25°C overnight. The solvent was evaporated under reduced pressure, and the resulting solid was purified by prep- HPLC (0.5% FA in MeCN) to give the solution containing the desired compound. Several drops of concentrated HCI were added and subsequent lyophilization generated the product (45 mg, yield 42%) as a white solid. ¹ HNMR (300 MHz, DMSO-cfe): d 10.06 (s, 1 H), 9.23 (s, 1 H), 8.90-8.65 (broad m, 2H), 7.52 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 1 H), 4.98 (s, 2H), 3.85-3.49 (m, 1 H), 3.46-3.24 (m, 2H), 3.21-2.90 (m, 2H), 2.15-2.05 (m, 2H), 1.85-1.65 (m, 2H) ppm. HPLC purity: 99.3% at 210 nm and 98.8% at 254 nm. MS (M+H) ⁺ : m/z = 327.1.

40. S-(1 -Methylpiperidin-4-yl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioate hydrogen chloride

[0260] Reductive amination of S-(piperidin-4-yl) (7-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioate with HCHO and HCOOH in water at 100°C gave the crude product, which was purified by prep-HPLC (0.5% FA in MeCN) to give the solution containing the desired compound. Several drops of concentrated HCI were added and subsequent lyophilization generated the product (45 mg, yield 42%) as a white solid. ¹ HNMR (300 MHz, DMSO-cfe): d 10.05 (s, 1 H), 9.61 (broad s, 1 H), 9.21 (broad s, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 1 H), 4.98 (s, 2H), 3.85-3.49 (m, 1 H), 3.50-3.30 (m, 2H), 3.21-3.00 (m, 2H), 2.80 (s, 3H), 2.20-2.10 (m, 2H), 2.00-1.70 (m, 2H) ppm. HPLC purity: 97.5% at 210 nm and 99.4% at 254 nm. MS (M+H) ⁺ : m/z = 341.0.

41. O-Methyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate

[0261] To a solution of 6-amino-7-chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol (1.0 g, 5.4mmol) and thiophosgene (1.23 ml_, 16.2 mmol) in anhydrous DCM (8 ml_) was added sodium hydroxide (0.65 g, 16.2 mmol) in portions at 0°C under N ₂ . After the addition was completed, the reaction mixture was warmed to rt. LCMS indicated the reaction was completed. It was cooled to 0°C, neutralized by 1 N HCI to pH = 5, and extracted with EtOAc (2 ^c 25 ml_). Combined organics were washed with H ₂ 0, brine, dried over Na ₂ S04 and filtered. The filtrate was concentrated under reduced pressure to afford the common intermediate 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol- 1 (3H)-ol (1.1 g, yield 91 %) as a pale yellow solid. ¹ H NMR (300 MHz, DMSO -d ₆ ): d

9.40 (br. s, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 5.00 (s, 2H) ppm. A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and MeOH (1 ml_, 4 mmol) in DMF (3 ml_) were stirred at room temperature. Potassium carbonate (897 mg, 6.5 mmol) was added in one portion, and the mixture was then stirred at 40°C for 18 hours. HPLC and LCMS indicated the reaction was completed. The mixture was diluted with EtOAc (10 mL) , washed with water (2 x 10 mL ) and brine (3 x 15 mL) , dried over Na ₂ S0 ₄ , and concentrated in vacuum. The residue was purified by prep-HPLC (0.5% TFA in MeCN) to give the desired product O-methyl (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate (93 mg, yield 28%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.82 (s, 1 H),

9.19 (s, 1 H), 7.55-7.40 (br. s, 1 H), 7.38(d, J = 8.0 Hz, 1 H), 4.99 (s, 2H), 3.93 (s, 3H) ppm. HPLC purity: 99.7% at 210 nm and 99.9% at 254 nm. MS: (M+H) ⁺ : m/z = 258.1. 42. O-Ethyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate

[0262] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) in EtOH (1.0 ml_) were refluxed for 18 hours. LCMS indicated the reaction was completed. EtOH was removed under reduced pressure. The residue was purified by prep-HPLC (0.5% FA in MeCN) to give the title compound (85 mg, yield 23%) as a white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) d 10.75 (s, 1 H), 9.19 (s, 1 H), 7.55-7.40 (br. s, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 4.99 (s, 2H), 4.45 (q, J = 7.0 Hz, 2H)), 1.40-1.10 (br. m, 3H) ppm. HPLC purity: 96.9% at 210 nm and 98.5% at 254 nm. MS (M+H) ⁺ : m/z = 272.0.

43. 0-(2,2,2-Trifluoroethyl) (7-chloro-1 -hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

CF CH OH [0263] To a solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and 2,2,2-trifluoroethanol (1 ml_, 4 mmol) in DMF (3 ml_) were added potassium carbonate (1.38 g, 10.0 mmol) in one portion at rt, and the mixture was then stirred at 40°C for 18 hours. LCMS indicated the reaction was completed. The mixture was diluted with EtOAc (10 ml_) , washed with water (2 ^c 10 ml_ ) and brine (3 x 15 ml_) , dried over Na ₂ S0 ₄ , and concentrated in vacuum. The residue was purified by prep-HPLC (0.5% TFA in MeCN) to give the desired product (93 mg, yield 28%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 11.45-11.28 (m, 1 H), 9.22 (s, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 5.27-5.06 (m, 2H), 5.01 (s, 2H) ppm. HPLC purity: 98.7% at 210 nm and 99.8% at 254 nm. MS: (M+H) ⁺ : m/z = 325.9. 44. O-lsopropyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

[0264] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) in i-PrOH (1.0 ml_) were refluxed for 18 hours. LCMS indicated the reaction was completed, and the isopropanol was removed under reduced pressure. The residue was purified by prep-HPLC (0.5% FA in MeCN) to give the title compound (90 mg, yield 24%) as a white solid. ¹ H NMR (400 MHz, DMSO-ck): d 10.66 (br. s, 1 H), 9.18 (s, 1 H), 7.55-7.40 (br. s, 1 H), 7.36 (d, J = 7.2 Hz, 1 H), 5.51- 5.41 (m, 1 H), 1.45-1.05 (br. m, 6H) ppm. HPLC purity: 91.5% at 210 nm and 96.4% at

254 nm. MS (M+H) ⁺ : m/z = 286.0.

45. 0-(2-Hydroxyethyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0265] To a solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and ethylene glycol (1 mL, 4 mmol) in DMF (3 mL) was added potassium carbonate (1.38 g, 10.0 mmol) in one portion at rt, and the mixture was then stirred at 40°C for 18 hours. LCMS indicated the reaction was completed. The mixture was diluted with EtOAc (10 mL), washed with water (2 ^c 10 mL ) and brine (3 x 15 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (0.5% TFA in MeCN) to give the desired product (36 mg, yield 9%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.81 (s, 1 H), 9.18 (s, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 4.99 (s, 2H), 4.98-4.60 (br. s, 1 H), 4.42 (t, J = 4.8 Hz, 2H), 3.80-3.50 (br. m, 2H) ppm. HPLC purity: 95.8% at 210 nm and 97.1 % at 254 nm. MS (M+H) ⁺ : m/z = 288.0.

46. 0-(2-Methoxyethyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0266] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) in 2-methoxyethan-1-ol (1.0 mL) were refluxed for 18 hours. Normal work-up procedure described above was used to generate the title compound (32 mg, yield 8%) as a white solid. ¹ H NMR (400 MHz, DMSO -cf _e ): d 10.88 (s, 1 H), 9.18 (s, 1 H), 7.55-7.40 (br. s, 2H), 7.37 (d, J = 7.6 Hz, 1 H), 4.99 (s, 2H), 4.59-4.46 (m, 2H), 3.71-3.48 (br. m, 2H), 3.32 (s, 3H) ppm. HPLC purity: 98.0% at 210 nm and 99.9% at 254 nm. MS: (M+H) ⁺ : m/z = 302.0.

47. O-Benzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

[0267] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and benzyl alcohol (0.3 ml_, 2.8 mmol) in DMF (0.5 ml_) were stirred at 80°C for 4 hours. Normal work-up procedure described above was used to generate the title compound (76 mg, 17%) as a white powder. ¹ HNMR (400 MHz, DMSO-cfe): d 10.94 (br. s, 1 H), 9.19 (s, 1 H), 7.71-7.15 (m, 7H), 5.51 (s, 2H), 4.99 (s, 2H) ppm. HPLC purity: 99.7% at 210 nm and 99.5% at 254 nm. MS (M-H)-: m/z = 332.0.

48. 0-(4-Fluorobenzyl) (7-chloro-1 -hydroxy-1 ,3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0268] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and (4-fluorophenyl)methanol (0.3 mL, 2.8 mmol) in DMF (0.5 mL) were stirred at 80°C for 4 h. Normal work-up procedure described above was used to generate the title compound (59 g, 13%) as a white solid. ¹ HNMR (400 MHz, DMSO-cfe): d 10.94 (br. s, 1 H), 9.19 (s, 1 H), 7.61-7.08 (br. m, 6H), 5.49 (s, 2H), 4.99 (s, 2H) ppm. HPLC purity: 98.7% at 210 nm and 99.5% at 254 nm. MS (M-H)-: m/z = 350.0.

49. O-Propyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

[0269] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) in n-propanol (1.0 mL) were refluxed for 18 h. Normal work-up procedure described above was followed to generate the title compound (160 mg, 42%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-de): d 10.77 (br. s, 1 H), 9.19 (s, 1 H), 7.55-7.40 (br. s, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 4.99 (s, 2H), 4.35 (br. s, 2H), 1.90-1.40 (br. m, 2H), 1.10-0.70 (br. m, 3H) ppm. HPLC purity: 99.9% at 210 nm and 99.9% at 254 nm. MS (M+H) ⁺ : m/z = 286.0.

50. 0-(4-Chlorobenzyl) (7-chloro-1 -hydroxy-1 ,3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0270] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and (4-chlorophenyl)methanol (0.3 mL, 2.8 mmol) in DMF (0.5 ml_) was stirred at 80°C for 4 h. Normal work-up procedure described above was followed to generate the title compound (38 mg, yield 8%) as a white solid. ¹ HNMR (400 MHz, DMSO-de): d 10.98 (br. s, 1 H), 9.20 (s, 1 H), 7.60-7.22 (br. m, 6H), 5.51 (br. s, 2H), 4.99 (s, 2H) ppm. HPLC purity: 99.9% at 210 nm and 99.7% at 254 nm. MS (M-H)-: m/z = 366.0.

51. 0-(4-Chlorophenyl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0271] To the mixture of 4-chlorophenol (1.28 g, 10 mmol) in 1 N aqueous NaOH (12 ml_) was added a solution of thiophosgene (1.72 g, 10 mmol) in CHCh OO ml_) dropwise, and the resulting mixture was stirred at 0°C for 1.5 h. After completed, the reaction was quenched with 1 N HCI (10 ml_). The organic layer was dried over Na ₂ SC>4, filtered and evaporated under reduced pressure resulting a yellow oil (2.05 g, crude), which was used in the next step without any further purification. 6-Amino-7- chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) in DMF (1 ml_) was mixed with 0-(4-chlorophenyl) carbonochloridothioate (1.02 g, 5 mmol). The reaction mixture was stirred at rt overnight. Normal work-up procedure described above was followed to generate the title compound (100 mg, yield 21 %). ¹ HNMR (400 MHz, DMSO-de): d 9.65 (s, 1 H), 9.39 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H) ppm. HPLC purity: 98.9% at 210 nm and 99.6% at 254 nm. MS (M+H) ⁺ : m/z = 354.0.

52. O-cyclohexyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

[0272] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and c-hexyl alcohol (0.3 ml_, 2.8 mmol) in DMF (0.5 ml_) was stirred at 80°C for 4 h. Normal work-up procedure described above was followed to generate the title compound (124 mg) as a white solid. ¹ HNMR (400 MHz, DMSO-d ₆ ): d 10.69 (br. s, 1 H), 9.19 (s, 1 H), 7.55-7.40 (br. s, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 5.30-5.20 (m, 1 H), 4.99 (s, 2H), 2.10-1.15 (br. m, 10H) ppm. HPLC purity: 98.7% at 210 nm and

99.5% at 254 nm. MS (M+H) ⁺ : m/z = 326.0.

53. 0-(Piperidin-4-yl) (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol- 6-yl)carbamothioate hydrogen chloride

[0273] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.3 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (0.6 g, 2.8 mmol) in DMF (0.5 ml_) was stirred at 80°C for 4 h. Normal work-up procedure described above was followed to generate tert-butyl 4-(((7-chloro-1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioyl)oxy)piperidine-1-carboxylate (100 mg) as a white solid. This Boc-protected compound was de-protected with HCI in dioxane (4N) to afford the title compound (60mg). ¹ HNMR (400 MHz, DMSO-d ₆ ): d 10.96 (br. s, 1 H), 9.22 (s, 1 H), 9.40-9.05 (br. s, 2H), 7.60-7.45 (br. s, 1 H), 7.38 (d, J = 7.6 Hz, 1 H), 5.55-5.40 (m, 1 H), 5.00 (s, 2H), 3.30-2.70 (br. m, 4H), 2.40-1 .70 (br. m, 4H) ppm. HPLC purity: 97.1 % at 210 nm and 99.3% at 254 nm. MS (M+H) ⁺ : m/z = 327.1 .

54. O-Phenyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

[0274] The title compound was prepared by following the procedure like that described for the synthesis of its 4-chlorophenyl analog. It was obtained as an off- white solid (40 mg). ¹ HNM R (400 MHz, DMSO-d ₆ ): d 1 1.48-1 1.42 (m, 1 H), 9.41 -9.24 (m, 1 H), 7.65-6.73 (m, 7H), 5.01 (s, 2H) ppm; ¹ HNMR (400 M Hz, DMSO-d ₆ with D ₂ 0): d 7.61 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 7.2 Hz, 2H), 6.80-6.75 (m, 3H), 5.00 (s, 2H) ppm. HPLC purity: 99.9% at 210 nm and 100% at 254 nm. MS (M+H) ⁺ : m/z = 320.0.

55. 0-(Tetrahydro-2H-pyran-4-yl) (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

microwave, 30 min

[0275] A solution of 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1 .3 mmol) and tetrahydro-2H-pyran-4-ol (0.6 mL) in DMF (0.5 mL) was heated at 120°C for 30 min under a microwave reaction system. Normal work-up procedure described above was followed to generate the title compound as an off-white solid (23 mg). ¹ HNMR (400 MHz, DMSO-cfe): d 10.87-10.80 (m, 1 H), 9.22 (s, 1 H), 7.60- 7.45 (br. s, 1 H), 7.38 (d, J = 7.6 Hz, 1 H), 5.46-5.40 (m, 1 H), 5.00 (s, 2H), 4.00-3.80 (br. s, 1 H), 3.60-3.35 (br. s, 3H), 2.10-1 .85 (br. m, 2H), 1.80-1 .40 (br. m, 2H) ppm. HPLC purity: 95.7% at 210 nm and 95.6% at 254 nm. MS (M+H) ⁺ : m/z = 328.1.

56. Ethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate [0276] To a solution of 6-amino-7-chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol (250 mg,

1.36 mmol) in EtOAc (10 mL) and Et ₃ N (1 mL) was added thiophosgene (188 mg,

1.60 mmol). It was stirred for 30 min at rt to give the common intermediate 7-chloro- 6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol. Then ethanethiol (422 mg, 6.8 mmol) was added in one portion and stirred for another 1 h. It was quenched by 6N HCI (3 mL) and extracted with EtOAc (2 ^c 20 mL). The combined organic phases were dried and evaporated under reduced pressure, and the residue was purified by pre-HPLC (0.1 % TFA in MeCN) to give the desired product (71 mg, yield 18%) as a white solid. ¹ H NMR (400 MHz, DMSO-cfe): d 11.47 (s, 1 H), 9.23 (s, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 1 H), 5.02 (s, 2H), 3.22-3.17 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H) ppm.

HPLC purity: 96.0% at 210 nm and 98.3% at 254 nm. MS (M+H) ⁺ : m/z = 287.9.

57. Isopropyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate

[0277] The title compound was prepared by reacting propane-2-thiol with 7-chloro-6- isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (89 mg, yield 22%). ¹ H NMR (400 MHz, DMSO-cfe): d 1 1.39 (s, 1 H), 9.24 (s, 1 H), 7.47 (d, J = 7.9

Hz, 1 H), 7.40 (d, J = 7.9 Hz, 1 H), 5.02 (s, 2H), 3.94-3.87 (m, 1 H), 1.35 (d, J = 5.7 Hz, 6H) ppm. HPLC purity: 97.9% at 210 nm and 99.1 % at 254 nm. MS (M+H) ⁺ : m/z =

301.9.

58. Propyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamodithioate

[0278] The title compound was prepared by reacting propane-1-thiol with 7-chloro-6- isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a yellow solid (62 mg, yield 15%). ¹ H NMR (400 MHz, DMSO-cfe): d 1 1.47 (s, 1 H), 9.25 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 5.02 (s, 2H), 3.19 (t, J = 6.9 Hz, 2H), 1.67-1.62 (m, 2H), 0.95 (t, J = 7.1 Hz, 3H) ppm. HPLC purity: 98.5% at 210 nm and 99.5% at 254 nm. MS (M+H) ⁺ : m/z = 301.9. 59. Benzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate

[0279] The title compound was prepared by reacting phenyl ethanethiol with 7- chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a light yellow solid (48 g, yield 10%). ¹ H NMR (400 MHz, DMSO-cfe): d 1 1.58 (s, 1 H), 9.24 (s, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.44-7.25 (m, 6H), 5.01 (s, 2H), 4.53 (s, 2H) ppm. HPLC purity: 96.7% at 210 nm and 99.5% at 254 nm. MS (M+H) ⁺ : m/z = 349.9.

60. Cyclohexyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamodithioate

[0280] The title compound was prepared by reacting cyclohexanethiol with 7-chloro- 6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (100 mg, yield 22%). ¹ H NMR (400 MHz, DMSO-cfe): d 1 1.38 (s, 1 H), 9.23 (s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 5.02 (s, 2H), 3.90-3.70 (m, 1 H), 2.10-1.90 (m, 2H), 1.80-1.20 (m, 8H) ppm. HPLC purity: 97.3% at 210 nm and 99.8% at 254 nm. MS (M+H) ⁺ : m/z = 342.0.

61. 4-Fluorobenzyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamodithioate

[0281] The title compound was prepared by reacting (4-fluorophenyl)methanethiol with 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (79 mg, yield 16%). ¹ H NMR (400 MHz, DMSO-cfe): d 1 1.60 (s, 1 H), 9.26 (s, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.50-7.40 (m, 2H), 7.20-7.10 (m, 2H), 5.01 (s, 2H), 4.53 (s, 2H) ppm. HPLC purity: 95.6% at 210 nm and 98.0% at 254 nm. MS (M+H) ⁺ : m/z = 368.0.

62. 4-Chlorobenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate

[0282] The title compound was prepared by reacting (4-chlorophenyl)methanethiol with 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (121 mg, yield 23%). ¹ H NMR (400 MHz, DMSO-cfe): d 11.62 (br. s, 1 H), 9.25 (s, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.50-7.30 (m, 5H), 5.01 (s, 2H), 4.54 (s, 2H) ppm. HPLC purity: 97.9% at 210 nm and 99.5% at 254 nm. MS (M-H)-: m/z = 382.0.

63. tert-Butyl (2-(((7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioyl)thio)ethyl)carbamate

[0283] The title compound was prepared by reacting tert-butyl (2- mercaptoethyl)carbamate with 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)- ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (70 mg). ¹ H NMR (400 MHz, DMSO-cfe): d 11.53 (br. s, 1 H), 9.24 (s, 1 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.40 (d, J = 7.2 Hz, 1 H), 5.02 (s, 2H), 3.40-3.20 (m, 4H), 1.40 (s, 9H) ppm. HPLC purity: 96.6% at 210 nm and 98.4% at 254 nm. MS

(M-H)-: m/z = 400.9.

64. 2-Aminoethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate hydrogen chloride

[0284] The Boc-group of tert-butyl (2-(((7-chloro-1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioyl)thio)ethyl)carbamate (40 mg) was removed using HCI in dioxane to give the title compound (35 mg). ). ¹ H NMR (400 MHz, DMSO-de): d 1 1.74 (br. s, 1 H), 9.28 (br. s, 1 H), 7.95 (br. s, 3H), 7.50 (d, J = 7.2 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 1 H), 5.02 (s, 2H), 3.45 (br. s, 2H), 3.10 (br. s, 2H) ppm. HPLC purity: 98.8% at 210 nm and 99.7% at 254 nm. MS (M+H) ⁺ : m/z = 302.9.

65. tert-Butyl 4-(((7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioyl)thio)cyclohexane-1-carboxylate

[0285] The title compound was prepared by reacting tert-butyl 4-mercaptopiperidine- 1-carboxylate with 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (113 mg). ¹ H NMR (400 MHz, DMSO-cfe): d 1 1.49 (br. s, 1 H), 9.29 (br. s, 1 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 5.02 (s, 2H), 4.00-3.90 (m,

1 H), 3.90-3.70 (m, 2H), 3.10-2.90 (m, 2H), 2.10-2.00 (m, 2H), 1.60-1.40 (m, 2H), 1.39 (s, 9H) ppm. HPLC purity: 96.5% at 210 nm and 97.9% at 254 nm. MS (M-H)-: m/z = 441.1.

66. Piperidin-4-yl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate hydrogen chloride

[0286] tert-butyl 4-(((7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioyl)thio)piperidine-1-carboxylate (200 mg) was treated with HCI in dioxane to remove the Boc-group giving the desired product (183 mg) after a normal work-up and purification procedure. ¹ H NMR (400 MHz, DMSO-cfe): d 11.61 (br. s, 1 H), 9.28 (br. s, 1 H), 8.79 (br. s, 2H), 7.48 (d, J = 10.4 Hz, 1 H), 7.41 (d, J = 10.4 Hz, 1 H), 5.02 (s, 2H), 4.00-3.90 (m, 1 H), 3.50-3.20 (m, 2H), 3.20-3.00 (m, 2H), 2.40-2.15 (m, 2H), 1.90-1.60 (m, 2H) ppm. HPLC purity: 94.6% at 210 nm and 97.5% at 254 nm. MS (M+H) ⁺ : m/z = 343.0.

67. 2-Hydroxyethyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate

[0287] 2-Mercaptoethan-1-ol (2 g) was reacted with 3,4-dihydro-2H-pyran (1.2 eq) in the presence of the catalytic amount of 4-methylbenzenesulfonic acid in DCM to give 2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1 -thiol (2.2 g). This intermediate (1 g) was used to react with 7-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 mg, 1.33 mmol) by following the procedure described above for the synthesis of its ethyl analog. The subsequent THP-protected compound was hydrolyzed with addition of 6N HCI to generate the final compound as a white solid (163 mg) after a normal work-up and purification procedure. ¹ H NMR (400 MHz, DMSO-cfe): d 11.53 (s, 1 H), 9.24 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 5.40-4.90 (br. s, 1 H),

5.01 (s, 2H), 3.70-3.55 (m, 2H), 3.40-3.25 (m, 2H) ppm. HPLC purity: 99.4% at 210 nm and 99.9% at 254 nm. MS (M+H) ⁺ : m/z = 304.0.

68. 2-Methoxyethyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamodithioate

[0288] The title compound was prepared by reacting 2-methoxyethane-1 -thiol with 7- chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol using the procedure described above for the synthesis of its ethyl analog. It was obtained as a white solid (19 g). ¹ H NMR (400 MHz, DMSO-cfe): d 10.54 (br. s, 1 H), 9.23 (s, 1 H), 8.19 (d, J = 11.2 Hz, 1 H), 7.42 (d, J = 11.2 Hz, 1 H), 4.99 (s, 2H), 3.61 (t, J = 8.4 Hz, 2H), 3.27 (s, 3H),

2.54 (m, 2H) ppm. HPLC purity: 98.0% at 210 nm and 98.8% at 254 nm. MS

(M+MeCN) ⁺ : m/z = 358.0.

69. Methyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamodithioate [0289] A mixture of 1 ,2-dimethyldisulfane, 7-chloro-6- isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (300 g), zinc and AICI3 in MeCN and water in a sealed tube was heated at 100°C overnight. A normal work-up and purification procedure afforded the desired product (57 mg) as a white solid. ¹ H NMR (400 MHz, DMSO-cfe): d 11.52 (br. s, 1 H), 9.24 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 5.01 (s, 2H), 2.56 (s, 3H) ppm. HPLC purity: 98.7% at 210 nm and 98.9% at 254 nm. MS (M+H) ⁺ : m/z = 274.0.

70. 1 -(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3-(2- hydroxyethyl)thiourel

[0290] tert-butyl (2-hydroxyethyl)carbamate was reacted with 7-chloro-6- isothiocyanatobenzo [c][1 ,2]oxaborol-1 (3H)-ol (300 mg) in DMF at 100°C giving an intermediate, which was treated with HCI in dioxane to remove the Boc-group affording the desired final compound (59 mg) as an off-white solid. ¹ H NMR (400 MHz, DMSO-cfe): d 9.26 (s, 1 H), 9.16 (s, 1 H), 7.98 (s, 1 H), 7.74 (d, = 7.2 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2H), 4.82 (m, 1 H), 3.54 (s, 4H) ppm. HPLC purity: 95.4% at 210 nm and 97.6% at 254 nm. MS (M+H) ⁺ : m/z = 287.0.

71. (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioic O-acid

[0291] To a mixture of thiocarbonyl dichloride (75.23 mg, 654.31 pmol, 50.16 pL, 1.2 eq) in DCM (2 mL) was added MeOH (17.47 mg, 545.26 pmol, 22.06 pL, 1 eq) at 0

°C. The mixture was stirred at 0 °C for 10 min, then 5-chloro-1-hydroxy-3H-2, 1- benzoxaborol-6-amine (0.1 g, 545.26 pmol, 1 eq) was added to the mixture and the mixture was stirred at 20 °C for 3 h. The residue was poured into ice-water (w/w =

1/1) (5 mL) and the resulting mixture was adjusted to pH~5. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was purified by pre-HPLC (column: Nano-micro

Kromasil C18 100*30mm 5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-

65%, 10 min) to afford (5-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioic O-acid (0.036 g, 147.19 pmol, 27.00% yield, 99.55% purity) as white solid. ¹ H NMR (DMSO-cfe, 400 MHz) d 9.48 (s, 1 H), 7.77 (s, 1 H), 7.74 (s, 1 H), 4.99 (s, 2H). MS (ESI): mass calcd. For C ₈ H ₇ BCIN0 ₃ S 242.99, m/z found 224.0 [M-H ₂ 0- H]-. Purity by HPLC: 99.55% (220 nm), 100% (254 nm).

72. O-methyl (5-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1 ,2]oxaborol-6-yl) carbamothioate

[0292] To a mixture of 5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.1 g, 545.26 umol, 1 eq) and di(imidazol-1-yl)methanethione (106.89 mg, 599.79 pmol, 1.1 eq) in DCM (3 ml_) was added DMAP (3.33 mg, 27.26 pmol, 0.05 eq) in one portion at 20°C. The mixture was stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure. The crude N-(5-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)-1 H-imidazole-1-carbothioamide was dissolved in MeOH (3 ml_), and NaOMe (147.28 mg, 2.73 mmol, 5 eq) was added to the mixture, the resulting mixture was then stirred at 40°C for 12 h. The mixture was adjusted to pH~5 with 3N HCI. The residue was purified by pre-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 25%- 50%, 10 min) to afford O-methyl (5- ch loro- 1- hydroxy- 1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioate (0.039 g, 149.94 pmol, 27.50% yield, 99% purity) as white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.86 (s, 1 H), 9.36 (s, 1 H), 7.62 (s, 1 H), 7.62 (s, 1 H), 4.99 (s, 2H), 3.94 (s, 3H). MS (ESI): mass calcd.

For C9H9BCINO3S 257.01 , m/z found 256.0 [M-H]\ Purity by HPLC: 99% (220 nm), 99.47% (254 nm).

73. O-ethyl (5-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6-yl) carbamothioate

[0293] To a mixture of N-(5-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)- 1 H- imidazole-1 -carbothioamide (0.15 g, 511.01 pmol, 1 eq) in EtOH (5 ml_) was added NaOEt (173.87 mg, 2.56 mmol, 5 eq) in one portion at 20°C. The mixture was stirred at 40°C for 12 h. The mixture was adjusted to pH~5 by 3N HCI. The residue was purification by pre-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 30%-45%, 10 min) to afford O-ethyl (5- chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioate (0.055 g, 193.52 umol, 37.87% yield, 95.54% purity) as yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 10.80 (s, 1 H), 9.34 (s, 1 H), 7.61 (s, 1 H), 7.59 (s, 1 H), 4.98 (s, 2H), 4.54-4.44 (m, 2H), 1.30-1.21 (m, 3H). MS (ESI): mass calcd. For C ₁₀ H ₁₁ BCINO ₃ S 271.02, m/z found 270.0 [M-H]\ Purity by HPLC: 95.54% (220 nm), 100% (254 nm).

74. O-propyl (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate

[0294] NaH (239.61 mg, 5.99 mmol, 60% purity, 11.72 eq) was added to propan-1-ol (3.19 g, 53.16 mmol, 3.99 ml_, 104.03 eq) at 0°C. The mixture was stirred at 0°C for 20 min. Then N-(5-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-1 H- imidazole-1 carbothioamide (0.15 g, 51 1.01 umol, 1 eq) was added to above mixture and it was stirred at 40°C for 15 h. The mixture was adjusted to pH~4 by 2N HCI. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18

100*30mm 5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 40%-65%, 10 min) to afford O-propyl (5-chloro-1 -hydroxy- 1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate (0.021 g, 73.54 umol, 14.39% yield, 100% purity) as yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 10.80 (s, 1 H), 9.33 (s, 1 H), 7.75 (s, 1 H), 7.61

(s, 1 H), 4.98 (s, 2H), 4.44-4.26 (m, 2H), 1.79-1.51 (m, 2H), 1.04-0.71 (m, 3H) MS (ESI): mass calcd. For C11 H13BCINO3S 285.04, m/z found 286.0 [M+H] ⁺ . Purity by

HPLC: 100% (220 nm), 100% (254 nm).

75. O-benzyl (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate

[0295] 5-chloro-6-isothiocyanatobenzo[c][1,2]oxaborol-1 (3H)-ol To a mixture of thiophosgene (470.21 mg, 4.09 mmol, 313.47 uL, 3 eq) in DCM (3 ml_) was added 5- chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.25 g, 1.36 mmol, 1 eq) and NaOH (163.58 mg, 4.09 mmol, 3 eq) at 0°C under N ₂ . The mixture was stirred at 20°C for 2 h. To the residue was added water (5 ml_) at 0°C and adjusted to pH~5 with aq HCI acid. The aqueous phase was extracted with DCM (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuum to afford 5-chloro-6- isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (0.3 g, crude) as yellow solid.

[0296] A mixture of 5-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (150.00 mg, 665.31 umol, 1 eq) and phenylmethanol (179.86 mg, 1.66 mmol, 172.94 uL, 2.5 eq) in DMF (2 ml_) was stirred at 80°C for 15 h. After cooling to room temperature, the pH was adjusted to ~4 with one drop of 2N HCI. The mixture was then purified by pre-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-65%, 10 min) to afford O-benzyl 2-(5-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)ethanethioate (0.04 g, 115.35 umol, 17.34% yield, 96.20% purity) as yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.99 (s, 1 H), 9.34 (s,

1 H), 7.71 (s, 1 H), 7.62 (s, 1 H), 7.53-7.21 (m, 5H), 5.53 (s, 2H), 4.99 (s, 2H). MS (ESI): mass calcd. For C15H13BCINO3S 333.04, m/z found 331.9 [M-H]\ Purity by HPLC: 96.20% (220 nm), 99.59% (254 nm).

76. O-isopropyl (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl) carbamothioate

40°C, 15 h

[0297] Sodium propan-2-olate To propan-2-ol (1.57 g, 26.13 mmol, 2 mL, 1 eq) was added NaH (522.55 mg, 13.07 mmol, 60% purity, 0.5 eq) at 0°C. The mixture was stirred at 20°C for 30 min to afford isopropoxysodium in propan-2-ol. The solution was used to next step directly.

[0298] To a mixture of N-(5-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl) - 1 H-imidazole-1-carbothioamide (0.15 g, 51 1.01 umol, 1 eq) in isopropanol (5 mL) was added isopropoxysodium (209.71 mg, 2.56 mmol, 5 eq) in one portion at 20°C. The mixture was stirred at 40°C for 15 h. The mixture was adjusted to pH~4 by 2N HCI. The residue was purified by pre-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-50%, 10 min) to afford O-isopropyl (5- chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1, 2] oxaborol-6-yl)carbamothioate (0.037 g, 128.24 umol, 25.10% yield, 98.97% purity) as yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.70 (s, 1 H), 9.36 (s, 1 H), 7.65 (s, 1 H), 7.61 (s, 1 H), 5.46 (t, J = 6.0Hz, 2H), 4.99 (s, 2H), 1.31-1.93 (m, 6H). MS (ESI): mass calcd. For C11 H13BCINO3S 285.04, m/z found 284.0 [M-H]\ Purity by HPLC: 98.97% (220 nm), 100% (254 nm). 77. O-4-fluorobenzyl (5-chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol - 6-yl)carbamothioate

[0299] To a mixture of 5-chloro-6-isothiocyanatobenzo[c][1 ,2]oxaborol-1 (3H)-ol (0.1 g, 443.54 umol, 1 eq) in DMF (2 ml_) was added (4-fluorophenyl)methanol (559.43 mg, 4.44 mmol, 478.14 uL, 10 eq) in one portion at 20°C. The mixture was stirred at 80°C for 15 h, and then cooled to room temperate. It was adjusted to pH~4 with 2N HCI. The residue purified by pre-HPLC (column: Nano-micro Kromasil C18

100*30mm 5um;mobile phase: [water (0.1 %TFA)-MeOH]; B%: 55%-80%, 10 min) to afford O-4-fluorobenzyl (5-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl) carbamothioate (0.042 g, 1 15.28 pmol, 25.99% yield, 96.5% purity) as light yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.37 (s, 1 H), 7.71-7.54 (m, 3H), 7.41-7.06 (m, 3H), 5.51 (s, 2H), 4.98 (s, 2H). MS (ESI): mass calcd. For C15H12BCIFNO3S 351.03, m/z found 349.9 [M-H]\ Purity by HPLC: 96.50% (220 nm), 98.34% (254 nm).

78. 0-(2,2,2-trifluoroethyl) (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0300] Sodium 2,2,2-trifluoroethanolate To 2,2,2-trifluoroethanol (2.78 g, 26.13 mmol, 2 ml_, 1 eq) was added NaH (522.55 mg, 13.07 mmol, 60% purity, 0.5 eq) at 0°C. The mixture was stirred at 20°C for 1 h, and then used to next step directly.

[0301] To a mixture of N-(5-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)- 1 H-imidazole-1-carbothioamide (0.2 g, 681.35 umol, 1 eq) in 2,2,2-trifluoroethanol (2 ml_) was added 2,2,2-trifluoroethoxysodium (415.69 mg, 3.41 mmol, 5 eq) in one portion at 20°C. The mixture was stirred at 40°C for 15 h, then cooled to room temperature. It was adjusted to pH~4 by 2N HCI. The resulting residue was purified by pre-HPLC (column: x-charge150*25mm*5um; mobile phase: [water (0.1 %TFA)- ACN]; B%: 38%-50%, 10 min) to afford 0-(2,2,2-trifluoroethyl) (5-chloro-1- hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl) carbamothioate (0.097 g, 298.00 umol, 43.74% yield, 100% purity) as light yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.41 (s, 1 H), 9.39 (s, 1 H), 7.71-7.57 (m, 2H), 5.23-5.09 (m, 2H), 5.00 (s, 2H). MS

(ESI): mass calcd. For C10H8BCIF3NO3S 325.00, m/z found 324.0 [M-H]\ Purity by HPLC: 100% (220 nm), 100% (254 nm).

79. Methyl N-(1 -hydroxy-3H-2,1-benzoxaborol-6-yl)carbamodithioate

[0302] To a mixture of 1-hydroxy-3H-2, 1-benzoxaborol-6-amine (200 mg, 1.34 mmol, 1 eq) in DMSO (3 ml_) was added CS ₂ (204.46 mg, 2.69 mmol, 162.27 uL, 2 eq) and NaOH (20 M, 100.70 uL, 1.5 eq) in portions at 20°C. The mixture was stirred at 20°C for 12 h and then CH3I (285.87 mg, 2.01 mmol, 125.38 uL, 1.5 eq) was added at 20°C. The mixture was stirred at 20°C for 1 h and then quenched by addition of saturated NH4CI solution (10 ml_), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase:

[water(0.1 %TFA)-ACN];B%: 30%-60%, 10min) to afford methyl N-(1-hydroxy-3H-2,1- benzoxaborol-6-yl)carbamodithioate (15 mg, 62.73 umol, 4.67% yield) as yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.68 (s, 1 H), 9.26 (s, 1 H), 7.80-7.95 (m, 1 H), 7.55-7.65 (m, 1 H), 7.42(d, J = 8.0 Hz, 1 H), 4.99 (s, 2H), 2.57 (s, 3H). MS (ESI): mass calcd. For C ₉ HI ₀ BNO ₂ S ₂ 239.02, m/z found 240.0 [M+H] ⁺ . Purity by HPLC: 98.15% (220 nm), 99.27% (254 nm).

80. 0-(2-hydroxyethyl) (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0303] Sodium 2-((tert-butyldimethylsilyl)oxy)ethanolate To 2-[tert- butyl(dimethyl)silyl]oxyethanol (2 g, 11.34 mmol, 1 eq) was added NaH (226.83 mg, 5.67 mmol, 60% purity, 0.50 eq) at 0°C. The mixture was stirred at 20°C for 1 hr to afford a solution of sodium 2-((tert-butyldimethylsilyl)oxy)ethanolate in 2-[tert- butyl(dimethyl)silyl]oxyethanol, which was used without further purification. [0304] 0-(2-((tert-butyldimethylsilyl)oxy)ethyl) (5-chloro-1 -hydroxy-1 ,3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate To a mixture of N-(5-chloro-1- hydroxy-3H-2,1-benzoxaborol-6-yl)imidazole-1- carbothioamide (0.25 g, 851.68 umol, 1 eq) in 2-[tert-butyl(dimethyl)silyl]oxyethanol (5 ml_) was added sodium 2-((tert- butyldimethylsilyl)oxy)ethanolate (844.48 mg, 4.26 mmol, 5 eq) in one portion at 20°C. The resulting mixture was stirred at 40°C for 15 hr. The reaction mixture was poured into water (5 ml_) and adjusted to pH~5. The aqueous phase was extracted with ethyl acetate (20 ml_ x 3). The combined organic phase was washed with brine (20 ml_), dried over anhydrous Na2S0 ₄ , filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to afford 0-(2- ((tert-butyldimethylsilyl)oxy)ethyl)(5-chloro-1 -hydroxy-1 , 3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioate (0.2 g, crude) as yellow oil.

[0305] To a mixture of 0-(2-((tert-butyldimethylsilyl)oxy)ethyl) (5-chloro- 1 -hydroxy- 1 , 3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamothioate (0.2 g, 141.87 umol, 1 eq) in THF (5 ml_) was added HCI (3 M, 236.44 uL, 5 eq) in one portion at 20°C. The mixture was stirred at 20°C for 2 hr. The residue was poured into water (10 ml_).

The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na ₂ SC>4, filtered and concentrated under vacuum. The residue was purified by pre-HPLC (column: x- charge150*25mm*5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 15%-40%, 10 min) to afford 0-(2-hydroxyethyl) (5-chloro-1 -hydroxy-1 ,3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate (0.025 g, 85.97 umol, 60.60% yield, 98.88% purity) as white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.87 (s, 1 H), 9.35 (s, 1 H), 7.67 (s, 1 H), 7.61 (s, 1 H), 4.99 (s, 2H), 4.42 (m, 2H), 3.72-3.70 (m, 2H). MS (ESI): mass calcd. For CioHnBCIN0 ₄ S 287.02, m/z found 286.0 [M-H]\ HPLC: 98.88% (220 nm), 100% (254 nm).

81. 0-2,4-difluorobenzyl (5-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1, 2] oxaborol-6-yl)carbamothioate

[0306] (2,4-difluorophenyl)methanol To a suspension of LiAIH ₄ (2.40 g, 63.25 mmol, 2 eq) in THF (50 mL) was added 2,4-difluorobenzoic acid (5 g, 31.63 mmol, 1 eq) in THF (50 mL) dropwise at 0°C under N ₂ . The mixture was stirred at 20°C for 2 hr. The reaction was quenched by Na ₂ SO ₄ .10H ₂ O, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum

ethergradient: 50 mL/min) to afford (2,4-difluorophenyl)methanol (3 g, 20.82 mmol, 65.82% yield) as light yellow oil. ¹ H NMR (CDCIs, 400 MHz) d 7.42-7.39 (m, 1 H), 6.89-6.88 (m, 1 H), 6.85-6.79 (m, 1 H), 4.73 (s, 2H)

[0307] To a mixture of (5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-yl) thiocyanate (0.25 g, 1.1 1 mmol, 1 eq) in DMF (5 ml_) was added (2,4-difluorophenyl)methanol (1.60 g, 1 1.09 mmol, 239.07 uL, 10 eq) in one portion at 20°C. The mixture was stirred at 80°C for 15 hr. The mixture was adjusted to pH~6 by 2N HCI. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.1 %TFA)-MeOH]; B%: 60%-75%, 10 min) to afford 0-2,4- difluorobenzyl (5-chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamothioate (0.169 g, 450.65 umol, 40.64% yield, 98.55% purity) as white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.01 (s, 1 H), 9.34 (s, 1 H), 7.80-7.05 (m, 5H), 5.52 (s, 2H), 4.99 (s, 2H). MS (ESI): mass calcd. For C15H11 BCIF2NO3S 369.02, m/z found 368.0 [M-H]\ HPLC: 98.55% (220 nm), 100% (254 nm).

82. O-(l -phenylethyl) (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1, 2] oxaborol-6-yl)carbamothioate ,

[0308] To a mixture of 7-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole

(100.00 g, 443.54 umol, 1 eq) in DMF (2 ml_) was addedl-phenylethanol (270.92 mg, 2.22 mmol, 268.24 uL, 5 eq) in one portion at 20°C. The mixture was stirred at 80°C for 15 hr. The mixture was adjusted to pH~4 by 2N HCI. The residue was purified by pre-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-65%, 10 min) to afford O-(l-phenylethyl) (7-chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 ,2]oxaborol-6-yl) carbamothioate (0.02 g, 54.75 umol, 12.34% yield, 95.16% purity) as a light yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.89 (s, 1 H), 9.19 (s, 1 H), 7.43-7.16 (m, 7H), 6.55-6.33 (m, 1 H), 4.99 (s, 2H), 1.65-1.46 (m, 3H). MS (ESI): mass calcd. For Ci ₆ Hi ₅ BCIN0 ₃ S 347.06, m/z found 346.1 [M-H]\ Purity by HPLC: 95.16% (220 nm), 99.46% (254 nm).

83. O-4-methoxybenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0309] The title compound was prepared using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-de, 400 MHz) d 9.96 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.98 (s, 2H), 4.08 (s, 2H), 3.73 (s, 3H). MS (ESI): mass calcd. For Ci ₆ Hi ₅ BCIN0 ₄ S 363.05, m/z found 362.0 [M-H]\ Purity by HPLC: 99.93% (220 nm), 100% (254 nm).

84. 0-2,4-dichlorobenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0310] The title compound was prepared using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-de, 400 MHz) d 11.07 (s, 1 H), 9.21 (s, 1 H), 7.72- 7.66 (m, 2H), 7.53-7.39 (m, 3H), 5.57 (s, 2H), 5.00 (s, 2H). MS (ESI): mass calcd. For C ₁₅ H ₁₁ BCI ₃ NO ₃ S 400.96, m/z found 399.9 [M-H]\ Purity by HPLC: 97.70% (220 nm),

100% (254 nm)

85. O-3-methoxybenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0311] The title compound was prepared using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1 -hydroxy- 1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-de, 400 MHz) d 10.96 (s, 1 H), 9.21 (s, 1 H), 7.56- 7.23 (m, 3H), 7.21-6.81 (m, 3H), 5.49 (s, 2H), 4.99 (s, 2H), 3.77-3.65 (m, 3H); ¹ H NMR (MeOD, 400 MHz) d 6.92-6.71 (m, 3H), 6.47-6.32 (m, 3H), 5.05 (s, 2H), 4.57 (s, 2H), 2.85 (s, 3H). MS (ESI): mass calcd. For C ₁₆ H ₁₅ BCINO ₄ S 363.05, m/z found 362.0 [M-H]-. Purity by HPLC: 99.75% (220 nm), 100% (254 nm).

86. 0-3,4-dimethoxybenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0312] The title compound was prepared using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.97 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 6.98 (s, 1 H), 6.95-6.87 (m, 2H), 4.98 (s, 2H), 4.08 (s,

2H), 3.72 (s, 6H). MS (ESI): mass calcd. For C17H17BCINO5S 393.06, m/z found 410.0 [M+H2O-H]-. Purity by HPLC: 99.53% (220 nm), 99.81 % (254 nm).

87. 0-3,4-dichlorobenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0313] The title compound was prepared using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.04 (s, 1 H), 9.21 (s, 1 H), 7.77- 7.68 (m, 2H), 7.47-7.25 (m, 3H), 5.53 (s, 2H), 5.00 (s, 2H). MS (ESI): mass calcd. For C15H11BCI3NO3S 400.96, m/z found 399.9 [M-H]\ Purity by HPLC: 97.44% (220 nm), 100% (254 nm).

88. 0-3,5-dimethoxybenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0314] The title compound was prepared using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1 -hydroxy- 1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-d _e , 400 MHz) d 10.97 (s, 1 H), 9.21 (s, 1 H), 7.51- 7.37 (m, 2H), 6.65 (s, 1 H), 6.47-6.37 (m, 2H), 5.46-5.37 (m, 2H), 4.99 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H). MS (ESI): mass calcd. For C17H17BCINO5S 393.06, m/z found 392.0 [M-H]-. Purity by HPLC: 100% (220 nm), 100% (254 nm).

89. 0-4-(methylthio)benzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamothioate

[0315] (4-(methylthio)phenyl)methanol To a mixture of LiAIH4 (1.35 g, 35.67 mmol, 2 eq) in THF (30 ml_) was added 4-methylsulfanylbenzoic acid (3 g, 17.83 mmol, 1 eq) in THF (30 mL) at 0°C under N2. The mixture was stirred at 20°C for 4 hr. The reaction was quenched by adding Na2SO ₄ .1 0H2O slowly, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum

ethergradient: 50 mL/min) to afford (4-(methylthio)phenyl)methanol (2.5 g, 16.21 mmol, 90.89% yield) as a white solid. ¹ H NMR (CDCh, 400 MHz) d 7.36-7.26 (m, 4H), 4.66 (s, 2H), 2.51 (s, 3H)

[0316] 0-4-(methylthio)benzyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1, 2] oxaborol-6-yl)carbamothioate was prepared from (4- (methylthio)phenyl)methanol using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-d _e , 400 MHz) d 10.93 (s, 1 H), 9.20 (s, 1 H), 7.57- 7.20 (m, 6H), 5.49 (s, 2H), 4.99 (s, 2H), 2.46 (s, 3H); ¹ H NMR (MeOD, 400 MHz) d 7.32-7.21 (m, 6H), 5.52 (s, 2H), 5.05 (s, 2H), 2.49 (s, 3H) MS (ESI): mass calcd. For C16H15BCINO3S2 379.03, m/z found 378.0 [M-H]\ Purity by HPLC: 96.14% (220 nm), 98.48% (254 nm).

90. 0-2-bromo-4-(methylthio)benzyl (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate

[0317] 2-bromo-4-(methylthio)benzoic acid To a mixture of 2-bromo-4-fluoro- benzoic acid (2.5 g, 11.42 mmol, 2.75 ml_, 1 eq) in DMF (30 ml_) was added NaSMe (4.00 g, 57.08 mmol, 3.64 ml_, 5 eq) in one portion at 25°C. The mixture was stirred at 25°C for 15 hr, then poured into ice-water (20 ml_) and adjusted to pH~4. White solid precipitated and the mixture was filtered and 2-bromo-4-(methylthio) benzoic acid (2 g, 8.09 mmol, 70.90% yield) was obtained as a white solid. The residue was used to next step directly. ¹ H NMR (CDC , 400 MHz) d 7.95 (d, J = 8.4 Hz, 1 H), 7.50 (s, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 2.53 (s, 3H)

[0318] (2-bromo-4-(methylthio)phenyl)methanol To a mixture of 2-bromo-4- methylsulfanyl-benzoic acid (2 g, 8.09 mmol, 1 eq) in THF (20 ml_) was added

BH3.THF (1 M, 16.19 ml_, 2 eq) slowly at 0°C. The mixture was stirred at 20°C for 15 hr. The mixture was cooled to 0°C. The residue was poured into ice-water (w/w = 1/1) (20 ml_). The aqueous phase was extracted with ethyl acetate (20 ml_ x 3). The combined organic phase was washed with brine (30 ml_), dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0-50%, Ethyl acetate/Petroleum ethergradient: 40 mL/min) to afford (2-bromo-4- (methylthio)phenyl)methanol (1.5 g, 6.43 mmol, 79.50% yield) as yellow oil. ¹ H NMR (CDCI3, 400 MHz) d 7.41 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.20 (dd, J = 8.0, 2.0 Hz, 1 H), 4.71 (s, 2H), 2.49 (s, 3H)

[0319] 0-2-bromo-4-(methylthio)benzyl (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamothioate was prepared from (2-bromo- 4-(methylthio)phenyl)methanol using the same procedure as that for 0-(1- phenylethyl) (7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamothioate. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.03 (s, 1 H), 9.21 (s, 1 H), 7.54- 7.22 (m, 5H), 5.50 (s, 2H), 5.00 (s, 2H), 2.51 (s, 3H). MS (ESI): mass calcd. For Ci ₆ Hi ₄ BBrCIN0 ₃ S ₂ 456.94, m/z found 457.9/455.9 [M-H]\ Purity by HPLC: 98.50% (220 nm), 99.04% (254 nm).

91. 1 -(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3- isopropylthiourea

[0320] To a mixture of 7-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.15 g, 665.31 umol, 1 eq) in DMF (3 ml_) was added propan-2-amine (196.63 mg, 3.33 mmol, 285.80 uL, 5 eq) in one portion at 20°C. The resulting mixture was stirred at 20°C for 12 hr. The reaction mixture was adjusted to pH~5 by 2N HCI and concentrated in vacuum, giving a residue that was purified by pre-HPLC (column: x- charge150*25mm*5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 20%-35%, 10 min) to afford 1-(7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3- isopropylthiourea (0.066 g, 231.54 umol, 34.80% yield, 99.83% purity) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.14 (s, 1 H), 8.94 (s, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.75 (s, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 4.96 (s, 2H), 4.36 (m, 1 H), 1.15 (d, J = 6.4 Hz, 6H). MS (ESI): mass calcd. For C11 H14BCIN2O2S 284.06, m/z found 283.0 [M-H]\ Purity by HPLC: 99.83% (220 nm), 100% (254 nm).

92. 1 -(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3- propylthiourea

[0321] The title compound was prepared by using the same procedure as that for 1- (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3- isopropylthiourea. ¹ H NMR (DMSO-de, 400 MHz) d 9.16 (s, 1 H), 9.09 (s, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.98 (s, 2H), 3.35-3.30 (m, 2H), 1.57-1.52 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H). MS (ESI): mass calcd. For

C11 H14BCIN2O2S 284.06, m/z found 283.0 [M-H]\ Purity by HPLC: 95.89% (220 nm), 98.24% (254 nm).

93. 1 -(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3- cyclohexylthiourea

[0322] The title compound was prepared using the same procedure as that for 1 -(7- chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylthiourea. ¹ H NMR (DMSO-de, 400 MHz) d 9.14 (s, 1 H), 8.97 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.80 (s, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2H), 4.15-3.95 (m, 1 H), 1.93-1.90 (m, 2H), 1.75-1.67 (m, 2H), 1.58-1.55 (m, 1 H), 1.32-1.18 (m, 5H). MS (ESI): mass calcd. For C14H18BCIN2O2S 324.09, m/z found 323.1 [M-H]\ Purity by HPLC: 100% (220 nm), 100% (254 nm).

94. 4-Methoxybenzyl (7-chloro-1 -hydroxy-1, 3-dihydrobenzo[c][1 ,2] oxaborol-

6-yl)carbamodithioate

[0323] To a mixture of 7-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (150.00 g, 665.31 umol, 1 eq) in DMF (3 ml_) was added(4- methoxyphenyl)methanethiol (513.05 mg, 3.33 mmol, 462.21 uL, 5 eq) in one portion at 20°C. The mixture was stirred at 50°C for 30 hr. The mixture was adjusted to pH~4 by 2N HCI, concentrated in vacuum, giving a residue was purified by pre-HPLC (column: x-charge150*25mm*5um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-65%, 10 min) to afford 4-methoxybenzyl (7-chloro-1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamodithioate (0.142 g, 368.98 umol, 55.46% yield, 98.66% purity) as a white solid. ¹ H NMR (DMSO-de, 400 MHz) d 11.54 (s, 1 H), 9.24 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.35-7.30 (m, 2H), 6.89-6.88 (m, 2H), 5.01 (s, 2H), 4.46 (s, 2H), 3.73 (s, 3H). MS (ESI): mass calcd. For C16H15BCINO3S2 379.03, m/z found 380.0 [M+H] ⁺ . Purity by HPLC: 98.66% (220 nm), 99.23% (254 nm).

95. 2,4-dichlorobenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)carbamodithioate

[0324] The title compound was prepared using the same procedure as that for 4- methoxybenzyl (7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6- yl)carbamodithioate. ¹ H NMR (DMSO-de, 400 MHz) d 11.67 (s, 1 H), 9.25 (s, 1 H), 7.65-7.60 (m, 2H), 7.49 (d, J = 8.0 Hz, 1 H), 7.43-7.39 (m, 2H), 5.01 (s, 2H), 4.61 (s, 2H). MS (ESI): mass calcd. For C15H11BCI3NO2S2 416.94, m/z found 419.9/417.9 [M+H] ⁺ . Purity by HPLC: 93.18% (220 nm), 99.32% (254 nm).

96. Isopropyl N-(1 -hydroxy-3H-2,1-benzoxaborol-6-yl)carbamodithioate

[0325] To a mixture of 1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.1 g, 671.35 umol, 1 eq) in DMSO (2 mL) was added CS2 (102.23 mg, 1.34 mmol, 81.14 uL, 2 eq) and benzyl(trimethyl)ammonium hydroxide (421.05 mg, 1.01 mmol, 457.67 uL, 40% purity, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 12 h and then 2- iodopropane (171.18 mg, 1.01 mmol, 100.70 uL, 1.5 eq) was added to the mixture at 25°C. After addition, the mixture was stirred at 25°C for 2 h. The reaction mixture was then quenched by addition sat. aqueous NH ₄ CI solution (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water(0.1 %TFA)-ACN];B%: 30%-45%, 10min).

Compound isopropyl N-(1-hydroxy-3H-2,1-benzoxaborol-6-yl)carbamodithioate (29 mg, 108.54 umol, 16.17% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.57 (s, 1 H), 9.27 (s, 1 H), 7.86 (m, 1 H), 7.56 (m, 1 H), 7.42 (d, J = 7.6

Hz, 1 H), 4.98 (s, 2H), 3.97-3.90 (m, 1 H), 1.36 (d, J = 6.4 Hz, 6H). MS (ESI): mass calcd. For Cn Hi ₄ BN0 ₂ S ₂ 267.06, m/z found 268.0 [M+H] ⁺ . Purity by HPLC: 100.00% (220 nm), 100.00% (254 nm).

97. Isopropyl N-(5-chloro-1 -hydroxy-3H-2,1-benzoxaborol-6-yl)

carbamodithioate

[0326] To a mixture of 5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.15 g, 817.89 umol, 1 eq) in DMSO (3 mL) was added CS ₂ (124.55 mg, 1.64 mmol, 98.85 uL, 2 eq) and benzyl(trimethyl)ammonium;hydroxide (512.96 mg, 1.23 mmol, 557.57 uL, 40% purity, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 12 h. Then 2- iodopropane (208.55 mg, 1.23 mmol, 122.68 uL, 1.5 eq) was added into the reaction mixture at 25°C. The resulting mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by addition saturated aqueous NH ₄ CI (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure, giving a residue that was purified by prep-HPLC (column: Nano-micro Kromasil C18

100*30mm 5um; mobile phase: [water(0.1 %TFA)-ACN];B%: 25%-55%, 10min) to afford isopropyl N-(5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamodithioate (25 mg, 82.89 umol, 10.13% yield) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.44 (s, 1 H), 9.37 (s, 1 H), 7.66 (s, 1 H), 7.65 (s, 1 H), 5.01 (s, 2H), 3.94-3.87 (m, 1 H),

1.35 (d, J = 5.6 Hz, 6H). MS (ESI): mass calcd. For Cn Hi ₃ BCIN0 ₂ S ₂ 301.02, m/z found 302.0 [M+H] ⁺ . Purity by HPLC: 100.00% (220 nm), 100.00% (254 nm).

98. Methyl N-(5-chloro-1-hydroxy-3H-2,1 -benzoxaborol-6-yl)

carbamodithioate

[0327] To a mixture of 5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (150.00 g, 817.88 umol, 1 eq) in DMSO (5 ml_) was added CS ₂ (124.55 mg, 1.64 mmol, 98.85 uL, 2 eq) and benzyl(trimethyl)ammonium hydroxide (512.96 mg, 1.23 mmol, 557.57 uL, 40% purity, 1.5 eq) in portions at 25°C. The mixture was stirred at 25°C for 12 h and then CH3I (174.14 mg, 1.23 mmol, 76.38 uL, 1.5 eq) was added to the mixture at 25°C. The mixture was stirred at 25°C for 2 h and quenched by addition saturated aqueous NH ₄ CI (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase:

[water(0.1 %TFA)-ACN]; B%: 30%-45%,10min). Compound methyl N-(5-chloro-1- hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamodithioate (36 mg, 131.59 umol, 16.09% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.55 (s, 1 H), 9.38 (s, 1 H), 7.68 (s, 1 H), 7.66 (s, 1 H), 5.01 (s, 2H), 2.57 (s, 3H). MS (ESI): mass calcd. For C ₉ H ₉ BCIN0 ₂ S ₂ 272.99, m/z found 274.0 [M+H] ⁺ . Purity by HPLC: 98.45% (220 nm), 100.00% (254 nm).

99. Allyl N-(7-chloro-1 -hydroxy-3H-2,1 -benzoxaborol-6-yl) carbamodithioate

[0328] To a mixture of 7-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (150.00 mg, 817.89 umol, 1 eq) in DMSO (3 mL) was added CS ₂ (124.55 mg, 1.64 mmol, 98.85 uL, 2 eq) and benzyl(trimethyl)ammonium hydroxide (512.96 mg, 1.23 mmol, 557.57 uL, 40% purity, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 12 h, and then 3-bromoprop-1-ene (148.42 mg, 1.23 mmol, 1.5 eq) was added dropwise to the mixture at 25°C. The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by addition HCI (2N, 3 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x-charge150*25mm*5um; mobile phase: [water(0.1 %TFA)- ACN];B%: 25%-55%,10min). Compound allyl N-(7-chloro-1-hydroxy-3H-2, 1- benzoxaborol-6-yl)carbamodithioate (34 mg, 113.48 umol, 13.88% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.55 (s, 1 H), 9.24 (s,

1 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.40 (m, J = 7.6 Hz, 1 H), 5.89-5.87 (m, 1 H), 5.30 (d, J = 16.8 Hz, 1 H), 5.13 (d, J = 10.4 Hz, 1 H), 5.01 (s, 2H), 3.93 (d, J = 5.2 Hz, 2H). MS

(ESI): mass calcd. For C11 H11BCINO2S2 299.00, m/z found 300.0 [M+H] ⁺ . Purity by HPLC: 94.01 % (220 nm), 98.50% (254 nm).

100. Butyl N-(7-chloro-1 -hydroxy-3H-2, 1 -benzoxaborol-6-yl)carbamodithioate

[0329] To a mixture of 7-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (150 mg, 817.89 umol, 1 eq) in DMSO (3 mL) was added CS2 (124.55 mg, 1.64 mmol, 98.85 uL, 2 eq) and benzyl(trimethyl)ammonium hydroxide (512.96 mg, 1.23 mmol, 557.57 uL, 40% purity, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 12 h and then 1- bromobutane (168.10 mg, 1.23 mmol, 132.36 uL, 1.5 eq) was added dropwise to the mixture at 25°C. It was stirred at 25°C for 12 h, then quenched by addition HCI (2N,

3 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x- charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-ACN]; B%: 40%- 50%,10min). Compound butyl N-(7-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6- yl)carbamodithioate (14 mg, 44.35 umol, 5.42% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 11.45 (s, 1 H), 9.22 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 5.01 (s, 2H), 3.21 (t, J = 6.8 Hz, 2H), 1.60-1.58 (m, 2H), 1.38-1.36 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). MS (ESI): mass calcd. For

C12H15BCINO4S2 315.03, m/z found 316.0 [M+H] ⁺ . Purity by HPLC: 72.31 % (220 nm), 93.96% (254 nm).

101. 4-(methylthio)benzyl (7-chloro-1 -hydroxy-1, 3- dihydrobenzo[c][1,2]oxaborol-6-yl)carbamodithioate

[0330] To a mixture of 7-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.2 g, 1.09 mmol, 1 eq) in DMF (3 ml_) was added CS2 (166.06 mg, 2.18 mmol, 131.80 uL, 2 eq) and benzyl(trimethyl)ammonium hydroxide (683.95 mg, 1.64 mmol, 743.42 uL, 40% purity, 1.5 eq) at 25°C. The resulting mixture was stirred at 25°C for 12 h, then 1- (bromomethyl)-4-methylsulfanyl-benzene (355.17 mg, 1.64 mmol, 1.5 eq) was added to the reaction mixture at 25°C. The mixture was stirred at 25°C for 2 h, and then quenched by addition HCI (2N, 2 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x-charge150*25mm*5um; mobile phase: [water(0.1 %TFA)- ACN]; B%: 50%-60%, 10min). Compound 4-(methylthio)benzyl (7-chloro- 1 -hydroxy- 1 , 3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)carbamodithioate (23 mg, 58.12 umol, 5.33% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.57 (s, 1 H), 9.24 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.36-7.25 (m, 2H),

7.20 (d, J = 7.6 Hz, 2H), 5.00 (s, 2H), 4.49 (s, 2H), 2.45 (s, 3H). MS (ESI): mass calcd. For C16H15BCINO2S3 395.00, m/z found 396.0 [M+H] ⁺ . Purity by HPLC: 90.56% (220 nm), 93.66% (254 nm).

102. tert-butyl N-[2-[(5-chloro-1 -hydroxy-3H-2,1 -benzoxaborol -6- yl)carbamothioylsulfanyl]ethyl]carbamate

[0331] To a mixture of 5-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (120 mg, 532.25 umol, 1 eq) and in DMSO (3 ml_) was added tert-butyl N-(2- sulfanylethyl)carbamate (471.74 mg, 2.66 mmol, 5 eq) at 25°C. The mixture was stirred at 40°C for 12 h. The reaction mixture was quenched by addition sat. aq. NH4CI (10 ml_), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ SC>4, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x-charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-ACN]; B%: 35%- 60%,10min). Compound tert-butyl N-[2-[(5-chloro-1-hydroxy-3H-2, 1-benzoxaborol - 6-yl)carbamothioylsulfanyl]ethyl]carbamate (107 mg, 265.69 umol, 49.92% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.57 (s, 1 H), 9.37 (s, 1 H), 7.68 (s, 1 H), 7.66 (s, 1 H), 7.04 (s, 1 H), 5.01 (s, 2H), 3.30-3.14 (m, 4H), 1.37 (s, 9H). MS (ESI): mass calcd. For Ci ₅ H ₂ oBCIN ₂ 0 ₄ S ₂ 402.06, m/z found 346.9 [M+H- 56] ⁺ . Purity by HPLC: 91.48% (220 nm), 95.94% (254 nm).

103. 2-Aminoethyl N-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol -6- yl)carbamodithioate

[0332] To a mixture of tert-butyl N-[2-[(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl) carbamothioylsulfanyl]ethyl]carbamate (0.2 g, 496.62 umol, 1 eq) in EtOAc (3 mL) was added HCI/EtOAc (4 M, 1.24 mL, 10 eq) at 25°C. The mixture was stirred at 25°C for 2 h, and then concentrated under reduced pressure to give 2-aminoethyl N- (5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)carbamodithioat e (155 mg, crude,

HCI) as a yellow solid. ¹ H NMR (DMSO-d _e , 400 MHz) d 11.82 (s, 1 H), 9.46 (s, 1 H), 8.17 (s, 3H), 7.73 (s, 1 H), 7.67 (s, 1 H), 5.01 (s, 2H), 3.48 (m, 2H), 3.08 (m, 2H). MS (ESI): mass calcd. For C10H13BCI2N2O2S2337.99, m/z found 303.0 [M+H] ⁺ . Purity by HPLC: 78.16% (220 nm), 94.09% (254 nm).

104. (3,4-dichlorophenyl)methyl N-(7-chloro-1 -hydroxy-3H-2,1 -benzoxaborol- 6-yl)carbamodithioate

[0333] To a mixture of 7-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (150 mg,

817.89 umol, 1 eq) in DMF (3 ml_) was added CS2 (124.55 mg, 1.64 mmol, 98.85 uL, 2 eq) and benzyl(trimethyl)ammonium;hydroxide (512.96 mg, 1.23 mmol, 557.57 uL, 40% purity, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 12 h and then 4- (bromomethyl)-1 ,2-dichloro-benzene (294.35 mg, 1.23 mmol, 1.5 eq) was added at 25°C. The mixture was stirred at 25°C for 0.5 h then quenched by addition HCI (2N,

2 ml_), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ SC>4, filtered and

concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x-charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-ACN];B%: 60%- 75%,10min, column: x-charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-

ACN];B%: 55%-65%, 10min ). Compound (3,4-dichlorophenyl)methyl N-(7-chloro-1- hydroxy-3H-2, 1-benzoxaborol-6-yl) carbamodithioate (17 mg, 40.62 umol, 4.97% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.65 (s, 1 H), 9.24 (s, 1 H), 7.67 (s, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 2H), 5.01 (s, 2H), 4.56 (s, 2H). MS (ESI): mass calcd. For C15H11BCI3NO2S2

416.94, m/z found 417.8 [M+H] ⁺ . Purity by HPLC: 66.94% (220 nm), 89.57% (254 nm).

105. sec-butyl N-(7-chloro-1 -hydroxy-3H-2,1-benzoxaborol-6-yl)

carbamodithioate

[0334] To a mixture of 7-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.15 g, 665.31 umol, 1 eq) in DMF (3 mL) was added butane-2-thiol (300.01 mg, 3.33 mmol, 361.46 uL, 5 eq) in portions at 25°C. The mixture was stirred at 50°C for 12 h, and then quenched by addition sat. aq. NH ₄ CI (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x-charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-ACN];B%: 40%-60%, 10min). Compound sec-butyl N-(7-chloro-1- hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamodithioate (21 mg, 66.53 umol, 10.00% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.40 (s, 1 H), 9.24 (s, 1 H), 7.47-7.40 (m, 2H), 5.01 (s, 2H), 3.82 (m, 1 H), 1.66-1.65 (m, 2H), 1.33- 1.32 (m, 3H), 0.94-0.93 (m, 3H). MS (ESI): mass calcd. For C12H15BCINO2S2 315.03, m/z found 315.9 [M+H] ⁺ . Purity by HPLC: 77.89% (220 nm), 96.03% (254 nm).

106. Isopropyl N-(5,7-dichloro-1-hydroxy-3H-2,1-benzoxaborol -6- yl)carbamodithioate

[0335] 5,7-dichloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole To a mixture of 5,7-dichloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.5 g, 2.30 mmol, 1 eq) in DCM (10 mL) was added NaOH (275.43 mg, 6.89 mmol, 3 eq) at 20°C under N2. Thiocarbonyl dichloride (659.77 mg, 5.74 mmol, 439.85 uL, 2.5 eq) was then added to the resulting mixture at 20°C under N2. The reaction was stirred at 20°C for 1 h under N ₂ and then filtered. The filtrate was concentrated in vacuo. Compound 5,7- dichloro-1 -hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.5 g, crude) was obtained as yellow gum. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 7.71 (s, 1 H), 4.99 (s, 2H).

[0336] To a solution of 5,7-dichloro-1-hydroxy-6-isothiocyanato-3H-2,1- benzoxaborole (0.15 g, 577.13 umol, 1 eq) in DMF (3 mL) was added propane-2-thiol (52.75 mg, 692.56 umol, 64.64 uL, 1.2 eq) at 20°C. The mixture was stirred at 50°C for 2 h. H2O (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organics were washed with brine (10 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase:

[water (0.1 %TFA)-ACN]; B%: 40%-50%, 10min). Compound isopropyl N-(5,7- dichloro-1-hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamodithioate (30 mg, 87.76 umol, 15.21 % yield, 98.31 % purity) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.38 (s, 1 H), 9.34 (s, 1 H), 7.62 (s, 1 H), 5.01 (s, 2H), 3.93-3.84 (m, 1 H), 1.39 (d, J = 6.8 Hz, 6H). MS (ESI): mass calcd. For C11 H12BCI2NO2S2 334.98, m/z found 334.0 [M-H]-. Purity by HPLC: 98.31 % (220 nm), 100% (254 nm).

107. 2-aminoethyl N-(5,7-dichloro-1-hydroxy-3H-2,1 -benzoxaborol -6- yl)carbamodithioate

[0337] 5,7-dichloro-1 -hydroxy-6-isothiocyanato-3H-2,1-benzoxaborole To a mixture of 5,7-dichloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.5 g, 2.30 mmol, 1 eq) in DCM (5 ml_) was added NaOH (275.41 mg, 6.89 mmol, 3 eq) at 0°C. The mixture was stirred at 0°C for 10 min and then thiocarbonyl dichloride (659.77 mg, 5.74 mmol, 439.85 uL, 2.5 eq) was added to mixture at 0°C. After stirring at 25°C for

50 min, the reaction mixture was quenched by addition H ₂ 0 (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure. Compound 5,7-dichloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.5 g, crude) was obtained as yellow oil. The crude product 5,7-dichloro-1-hydroxy-6- isothiocyanato-3H-2, 1- benzoxaborole (0.5 g, crude) was used into the next step without further purification. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.51 (s, 1 H), 7.70 (s, 1 H), 4.99 (s, 2H).

[0338] To a mixture of 5,7-dichloro-1-hydroxy-6-isothiocyanato-3H-2, 1- benzoxaborole (0.4 g, 1.54 mmol, 1 eq) in DMF (4 mL) was added tert-butyl N-(2- sulfanylethyl)carbamate (1.36 g, 7.70 mmol, 5 eq) in portions at 25°C. The mixture was stirred at 40°C for 12 h and then quenched by addition sat. aq. NH4CI (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: x- charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-ACN];B%: 40%- 55%,10min). Compound tert-butyl N-[2-[(5,7-dichloro-1-hydroxy-3H-2,1 - benzoxaborol -6-yl)carbamothioylsulfanyl]ethyl]carbamate (180 mg, 411.74 umol, 26.75% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.55 (s, 1 H), 9.34 (s, 1 H), 7.63 (s, 1 H), 7.08 (s, 1 H), 5.01 (s, 2H), 3.26-3.09 (m, 4H),

1.39 (s, 9H). MS (ESI): mass calcd. For C15H19BCI2N2O4S2 436.03, m/z found 380.9 [M+H-56] ⁺ . Purity by HPLC: 92.5% (220 nm), 99.12% (254 nm).

108. 2-aminoethyl N-(5,7-dichloro-1-hydroxy-3H-2,1 -benzoxaborol -6- yl)carbamodithioate

[0339] To a mixture of tert-butyl N-[2-[(5,7-dichloro-1-hydroxy-3H-2, 1-benzoxaborol- 6-yl) carbamothioylsulfanyl]ethyl]carbamate (0.15 g, 343.12 umol, 1 eq) in EtOAc (3 ml_) was added HCI/EtOAc (4 M, 857.79 uL, 10 eq) at 25°C. The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure. Compound 2-aminoethyl N-(5,7-dichloro-1-hydroxy-3H-2, 1-benzoxaborol-6- yl)carbamodithioate (1 19 mg, crude, HCI) was obtained as a yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 1 1.79 (s, 1 H), 9.37 (s, 1 H), 8.06 (s, 3H), 7.65 (s, 1 H), 5.01 (s, 2H), 3.48 (t, J = 7.2 Hz, 2H), 3.14-2.96 (m, 2H). MS (ESI): mass calcd. For

C10H12BCI3N2O2S2 371.95, m/z found 336.9 [M+H] ⁺ . Purity by HPLC: 56.5% (220 nm), 99.45% (254 nm).

109. (2-bromo-4-methylsulfanyl-phenyl)methyl N-(7-chloro-1 - hydroxy-3H-2,1- benzoxaborol-6-yl)carbamodithioate

[0340] 2-bromo-1-(chloromethyl)-4-methylsulfanyl-benzene To a mixture of (2- bromo-4-methylsulfanyl-phenyl)methanol (0.2 g, 857.91 umol, 1 eq) in DCM (4 ml_) was added dropwise TEA (173.62 mg, 1.72 mmol, 238.82 uL, 2 eq) and 4- methylbenzenesulfonyl chloride (179.91 mg, 943.70 umol, 1.1 eq) at 0°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was quenched by addition H2O (10 ml_), extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and

concentrated under reduced pressure. Compound 2-bromo-1-(chloromethyl)-4- methylsulfanyl-benzene (0.2 g, crude) was obtained as yellow oil. The crude product 2-bromo-1-(chloromethyl)-4-methylsulfanyl-benzene (0.2 g, crude) was used into the next step without further purification. ¹ H NMR (CDCI ₃ , 400 MHz) d 7.43 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.18 (dd, J = 8.0, 2.0 Hz, 1 H), 4.67 (s, 2H), 2.49 (s, 3H). [0341] S-[(2-bromo-4-methylsulfanyl-phenyl)methyl] ethanethioate To a mixture of 2-bromo-1-(chloromethyl)-4-methylsulfanyl-benzene (0.2 g, 795.00 umol, 1 eq) in DMF (3 ml_) was added potassium ethanethioate (181.59 mg, 1.59 mmol, 2 eq) at 25°C. The mixture was stirred at 40°C for 12 h. The reaction mixture was quenched by addition H2O (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Compound S-[(2-bromo-4- methylsulfanyl-phenyl)methyl] ethanethioate (0.1 g, crude) was obtained as yellow oil. ¹ H NMR (DMSO-de, 400 MHz) d 7.46 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.22 (dd, J = 8.0, 1.6 Hz, 1 H), 4.14 (s, 2H), 2.48 (s, 3H), 2.34 (s, 3H).

[0342] (2-bromo-4-methylsulfanyl-phenyl)methanethiol To a mixture of S-[(2- bromo-4-methylsulfanyl-phenyl)methyl] ethanethioate (0.5 g, 1.72 mmol, 1 eq) in MeOH (5 mL) was added K ₂ CO ₃ (474.58 mg, 3.43 mmol, 2 eq) at 25°C. The mixture was stirred at 25°C for 4 h under N ₂ . The reaction mixture was quenched by addition ice-H ₂ 0 (v:v = 1 : 1 , 20 mL) , the reaction mixture was adjusted pH = 4 by HCI (2N), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Compound (2-bromo-4-methylsulfanyl-phenyl)methanethiol (0.4 g, crude) was obtained as a yellow solid.

[0343] To a mixture of 7-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.15 g, 665.31 umol, 1 eq) in DMF (3 mL) was added (2-bromo-4-methylsulfanyl- phenyl)methanethiol (381.31 mg, 1.53 mmol, 2.3 eq) at 25°C. The mixture was stirred at 50°C for 12 h. The reaction mixture was quenched by addition H ₂ 0 (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase: [water(0.1 %TFA)-ACN]; B%: 55%- 70%,10min). Compound (2-bromo-4-methylsulfanyl -phenyl)methyl N-(7-chloro- 1-hydroxy-3H-2,1 -benzoxaborol-6-yl)carbamodithioate (13 mg, 27.39 umol,

4.12% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.62 (s, 1 H), 9.24 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.24 (d, J =

7.6 Hz, 1 H), 5.00 (s, 2H), 4.57 (s, 2H). ¹ H NMR (MeOD, 400 MHz) d 7.54 (d, J = 8.2 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.44 (s, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.18 (dd, J = 8.2 Hz, 1.6 Hz, 1 H), 5.06 (s, 2H), 4.65 (s, 2H), 2.47 (s, 3H). MS (ESI): mass calcd.

For Ci ₆ Hi ₄ BBrCIN0 ₂ S ₃ 472.92, m/z found 475.8 [M+H] ⁺ . Purity by HPLC: 74.58% (220 nm), 96.06% (254 nm). PART II: Experimental Procedures for Syntheses of 6-(Carbamate-related) - CBOs

6-amino-7-chlorobenzo[c][1 ,2]oxaborol-1 (3H)-ol

H ₂ , Pd/C

EtOAc, 25°C, 2 h

C, 1 .5 h

[0344] To a solution of (2-formylphenyl)boronic acid (10 g, 66.69 mmol, 1 eq) in THF

(100 ml_) was added NaBFU in portions (5.05 g, 133.39 mmol, 2 eq) at 0°C over 5 min. After addition, the mixture was stirred at 25°C for 1 hr. The reaction mixture was quenched by adding aq. HCI (2M) at 0°C until pH to 7, and then diluted with EtOAc (30 ml_) and extracted with EtOAc (30 ml_ x 3). The combined organic layers were washed with brine (30 ml_ x 3), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give benzo[c][1 ,2]oxaborol-1 (3H)-ol (7.7 g, 57.49 mmol, 86.2% yield) as a white solid. ¹ H NMR (CDCI _3, 400 MHz): d 7.78 (d, J = 7.2 Hz, 1 H), 7.53-7.49 (m, 1 H), 7.41-7.36 (m, 2 H), 5.75 (s, 1 H) and 5.15 (s, 2 H) ppm. To a solution of fuming HNO3 (70 ml_) was added benzo[c][1 ,2]oxaborol-1 (3H)-ol (6.7 g, 50.02 mmol, 1 eq) at -30°C over 5 min. After addition, the mixture was stirred at -

30°C for 30 min. The reaction mixture was poured with stirring into water and ice (80 ml_) and stirred at 0°C for 40 min. Solid was precipitated. The solid was filtered and dried under vacuum to afford 1-hydroxy-6-nitro-3H-2, 1-benzoxaborole (6 g, 33.53 mmol, 67.0% yield, 100% purity) as a pale yellow solid. ¹ H NMR (DMSO-d _6, 400 MHz): d 9.59 (s, 1 H), 8.57 (s, 1 H), 8.33 (dd, J = 8.4, 2.0 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 5.1 1 (s, 2 H) ppm. MS (ESI): mass calcd. For C ₇ H ₈ BN0 ₂ 149.06, m/z found 150.1 [M+H] ⁺ . Purity by HPLC: 100% (220 nm) and 100% (254 nm). To a solution of 1-hydroxy-6-nitro-3H-2, 1-benzoxaborole (950 mg, 5.31 mmol, 1 eq) in EtOAc (20 ml_) was added Pd/C (200 mg, 10%) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated to give crude product. The crude product was purified by re-crystallization from 20 ml_ of MTBE to give 6-aminobenzo[c][1 ,2]oxaborol-1 (3H)-ol (0.73 g, 4.90 mmol, 92.3% yield, 100% purity) as a pale yellow solid. ¹ H NMR (DMSO-d _6, 400 MHz): d 8.90 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.87 (s, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 4.97 (s, 2 H), 4.80 (s, 2 H) ppm. MS (ESI): mass calcd. For C ₇ H ₈ BN0 ₂ 149.06, m/z found 150.1 [M+H] ⁺ . Purity by HPLC: 100% (220 nm) and 100% (254 nm). To a solution of 6-aminobenzo[c][1 ,2]oxaborol-1 (3H)-ol (1 g, 6.71 mmol, 1 eq) in DMF (15 ml_) was added NCS (0.95 g, 7.11 mmol, 1.06 eq) at 0°C. The mixture was stirred at 25°C for 1.5 hr. The reaction mixture was quenched by adding ice-water (50 ml_) at 0°C, and then diluted and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by re

crystallization from MTBE (20 mL) to afford crude product (800 mg, brown solid). Part of the crude product (270 mg, brown solid) was further purified by prep-TLC (S1O2, Ethyl acetate/MeOH=10/1) to give 6-amino-7-chlorobenzo[c][1 ,2]oxaborol- 1 (3H)-ol (44.6 mg, 96.3% purity) was obtained as a yellow solid. ¹ H NMR (DMSO-d _6, 400 MHz): d 8.89 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 5.21 (s, 2 H), 4.82 (s, 2 H) ppm. MS (ESI): mass calcd. For C7H7BCINO2 183.03, m/z found 184.2 [M+H] ⁺ . Purity by HPLC: 96.33% (220 nm).

110. Isopropyl N-(1 -hydroxy-3H-2,1-benzoxaborol-6-yl)-N-methyl - carbamodithioate

[0345] tert-Butyl N-(1-hydroxy-3H-2,1 -benzoxaborol-6-yl)carbamate To a solution of 1-hydroxy-3H-2,1-benzoxaborol-6-amine (1.5 g, 10.07 mmol, 1 eq) in t-BuOH (20 ml_) was added B0C2O (3.30 g, 15.11 mmol, 3.47 ml_, 1.5 eq) in one portion at 25°C. The mixture was stirred at 50°C for 16 h. The reaction mixture was concentrated in vacuum. The residue was triturated with petroleum ether (20 ml_) for 30 minutes. Then the mixture was filtered, and the filter cake was washed with petroleum ether (50 ml_). The filter cake was dried in vacuum to give tert-butyl N-(1-hydroxy-3H-2, 1- benzoxaborol-6-yl) carbamate (2.4 g, 9.64 mmol, 95.69% yield) as an off-white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.33 (s, 1 H), 9.13 (s, 1 H), 7.88 (s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.0 Hz, 1 H), 4.91 (s, 2H), 1.48 (s, 9H).

[0346] tert-butyl N-(1-hydroxy-3H-2,1 -benzoxaborol-6-yl)-N-methyl-carbamate To a solution of tert-butyl N-(1-hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamate (2.4 g, 9.64 mmol, 1 eq) in DMF (20 ml_) was added NaH (963.49 mg, 24.09 mmol, 60% purity, 2.5 eq) in portions at 0°C. The mixture was stirred at 0°C for 1 h. Then Mel (1.64 g, 11.56 mmol, 719.84 uL, 1.2 eq) was added to the reaction dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 h. Then the reaction mixture was quenched with H2O (20 ml_) at 0°C and adjusted to pH = 5 with 2N HCI. The mixture was extracted with EtOAc (20 ml_ x 3). The combined organic phase was washed with brine (20 ml_), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ethergradient @ 50 mL/min). Compound tert-butyl N-(1-hydroxy-3H-2, 1-benzoxaborol-6-yl)-N-methyl - carbamate (2.4 g, 9.12 mmol, 94.67% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 9.19 (s, 1 H), 7.58 (s, 1 H), 7.39-7.34 (m, 2H), 4.97 (s, 2H), 3.18 (s, 3H), 1.39 (s, 9H).

[0347] 1-hydroxy-N-methyl-3H-2,1-benzoxaborol-6-amine To a solution of tert- butyl N-(1-hydroxy-3H-2, 1-benzoxaborol-6-yl)-N-methyl-carbamate (1.2 g, 4.56 mmol, 1 eq) in EtOAc (5 ml_) was added HCI/EtOAc (4 M, 11.40 ml_, 10 eq) in one portion at 25°C. The mixture was stirred at 25°C for 1 h. The reaction mixture was filtered. The filter cake was dissolved in H ₂ 0 (15 ml_), adjusted to pH = 7 with aq. NaHC03. The mixture was extracted with EtOAc (20 ml_ x 3). The combined organics were washed with brine (20 ml_), dried over Na ₂ S04, filtered and

concentrated in vacuo. Compound 1-hydroxy-N-methyl-3H-2,1-benzoxaborol-6- amine (0.5 g, 3.07 mmol, 67.26% yield) was obtained as a white solid. ¹ H NMR (DMSO-de, 400 MHz) d 8.92 (s, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 2.0 Hz,

1 H), 6.70 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 5.57 (q, J = 4.8 Hz, 1 H), 4.84 (s, 2H), 2.68 (d,

J = 5.2 Hz, 3H).

[0348] To a solution of 1-hydroxy-N-methyl-3H-2, 1-benzoxaborol-6-amine (0.3 g,

1.84 mmol, 1 eq) in EtOH (5 ml_) was added K2CO3 (279.84 mg, 2.02 mmol, 1.1 eq) and CS2 (280.30 mg, 3.68 mmol, 222.46 uL, 2 eq) at 25°C under N2. The mixture was stirred at 25°C for 16 h. Then 2-iodopropane (312.90 mg, 1.84 mmol, 184.06 uL, 1 eq) was added to the reaction mixture at 25°C. The reaction mixture was stirred at 25°C for 2 h. Water (10 ml_) was added and the reaction mixture was adjusted to pH = 5 with 2N HCI. Then the mixture was extracted with EtOAc (10 mL x 3). The combined organics were washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-65%, 10min). Compound isopropyl N-(1-hydroxy-3H-2,1 -benzoxaborol-6-yl)-N-methyl- carbamodithioate (0.168 g, 597.44 umol, 32.46% yield, 100% purity) was obtained as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.33 (s, 1 H), 7.58 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 5.05 (s, 2H), 3.84-3.75 (m, 3H), 3.67 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H). MS (ESI): mass calcd. For CI ₂ HI ₆ BN0 ₂ S ₂ 281.07, m/z found

280.1 [M-H]-. Purity by HPLC: 100% (220 nm), 100% (254 nm).

111. tert-butyl (1 -hydroxy-7-methyl-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6- yl)carbamate

[0349] POC (27.17 g, 177.22 mmol, 16.47 ml_, 2.2 eq) was added dropwise to DMF (50.05 g, 684.73 mmol, 8.5 eq) at room temperature while stirring. This resulting mixture was slowly added into a solution of 2-methylbenzene-1 ,3-diol (10 g, 80.56 mmol, 1 eq) in DMF (50 ml_) at room temperature. The reaction mixture was then stirred at room temperature for 4 h. The reaction was quenched by adding 300 ml_ of 10% NaOH aqueous solution at 0 °C, then extracted with EtOAc (100 ml_ x 3). The combined organic layers were discarded. The pH of the aqueous phase was adjusted to 3 with 4 M HCI aqueous solution, extracted with EtOAc (100 ml_ x 3).

The combined organic layers were washed with H ₂ 0 (100 ml_ x 2), dried over anhydrous Na ₂ SC>4, and concentrated in vacuo to give a residue that was purified by column chromatography (Si0 ₂ , Petroleum ether/Ethyl acetate=50/1 to 10/1) to give 2,4-dihydroxy-3-methyl-benzaldehyde (6.5 g, 42.72 mmol, 53.03% yield) as a yellow solid. ¹ H NMR (CDCI _3, 400 MHz) d 11.60 (s, 1 H), 10.76 (s, 1 H), 9.70 (s, 1 H), 7.42 (d, J = 8.8 Hz, 1 H), 6.55 (d, J = 8.8 Hz, 1 H), 1.98 (s, 3H).

[0350] To a solution of 2,4-dihydroxy-3-methyl-benzaldehyde (5.4 g, 35.49 mmol, 1 eq) and pyridine (2.53 g, 31.94 mmol, 2.58 ml_, 0.9 eq) in DCM (20 ml_) was added Tf ₂ 0 (11.02 g, 39.04 mmol, 6.44 ml_, 1.1 eq) and DMAP (433.60 mg, 3.55 mmol, 0.1 eq). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction was quenched by adding 100 ml_ of H ₂ 0 at 0°C, extracted with DCM (100 ml_ x 3), the combined organic layers were washed with brine (100 ml_ x 1), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to give a residue that was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give (4-formyl-3-hydroxy-2- methyl-phenyl)trifluoromethane sulfonate (7.2 g, 25.33 mmol, 71.38% yield) as yellow oil. ¹ H NMR (CDCI _3, 400 MHz) d 11.62 (s, 1 H), 9.91 (s, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 1 H), 2.28 (s, 3H).

[0351] (4-formyl-3-hydroxy-2-methyl-phenyl) trifluoromethanesulfonate (7.2 g, 25.33 mmol, 1 eq), NH2B0C (7.42 g, 63.33 mmol, 2.5 eq), XPhos (2.42 g, 5.07 mmol, 0.2 eq), Pd2(dba) ₃ (2.32 g, 2.53 mmol, 0.1 eq) and Cs ₂ C0 ₃ (24.76 g, 76.00 mmol, 3 eq) in dioxane (150 ml_) was heated up to 95°C under nitrogen atmosphere. The mixture was kept stirring for 12 h. Then the reaction mixture was filtered, and the filtrate was concentrated in vacuo, giving a residue that was diluted with H2O (100 ml_) and extracted with EtOAc (100 ml_ x 3). The combined organic layers were washed with brine (100 ml_ x 2), dried over anhydrous Na2S0 ₄ , filtered and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 10/1) to give tert-butyl N-(4- formyl-3-hydroxy-2-methyl-phenyl)carbamate (3.8 g, 10.59 mmol, 41.79% yield, 70% purity) as a light yellow solid. ¹ H NMR (CDCI _3, 400 MHz) d 11.61 (s, 1 H), 9.74 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 2.14 (s, 3H), 1.55 (s, 9H).

[0352] To a solution of tert-butyl N-(4-formyl-3-hydroxy-2-methyl-phenyl)carbamate (2.8 g, 7.80 mmol, 1 eq) in DCM (50 ml_) was added DMAP (285.88 mg, 2.34 mmol, 0.3 eq) and TEA (1.58 g, 15.60 mmol, 2.17 ml_, 2 eq) at 0 °C. 1 , 1 , 1-trifluoro-N- phenyl-N-(trifluorom1 , 1 , 1- trifluoro-N-phenyl-N-

(trifluoromethylsulfonyl)methanesulfonamide (2.79 g, 7.80 mmol, 1 eq) was added at 0 °C. The reaction mixture was kept stirring at room temperature for 12 h. The reaction was quenched by adding 100 ml_ of H2O, and then extracted with DCM (100 ml_ x 3). The combined organic layers were washed with brine (200 ml_ x 2), dried over anhydrous Na2S0 ₄ , filtered and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give [3-(tert-butoxycarbonylamino)-6- formyl-2-methyl-phenyl] trifluoromethanesulfonate (1.6 g, 3.34 mmol, 42.81 % yield, 80% purity) as a yellow solid. ¹ H NMR (CDCI _3, 400 MHz) d 10.11 (s, 1 H), 8.29 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 2.30 (s, 3H), 1.55 (s, 9H).

[0353] A mixture of [3-(tert-butoxycarbonylamino)-6-formyl-2-methyl- phenyl]trifluoromethane sulfonate (1.5 g, 3.91 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (1.49 g, 5.87 mmol, 1.5 eq), Pd(dppf)Cl2 (143.16 mg, 195.65 pmol, 0.05 eq), KOAc (576.03 mg, 5.87 mmol, 1.5 eq) in dioxane (50 ml_) was degassed and purged with N ₂ for 3 times, and then the reaction mixture was stirred at 90°C for 12 h under N ₂ atmosphere.

Then the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by column chromatography (Si0 ₂ , Petroleum ether/Ethyl acetate = 1/0 to 8/1) to give tert-butyl N-[4-formyl-2-methyl-3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenyl]carbamate (1.05 g, 2.33 mmol, 59.43% yield, 80% purity) as a yellow solid. ¹ H NMR (CDCh _, 400 MHz) d 9.82 (s, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 1 H), 6.55 (s, 1 H), 2.31 (s, 3H), 1.55 (s, 9H), 1.48 (s, 12H).

[0354] A mixture of tert-butyl N-[4-formyl-2-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) phenyl]carbamate (1.0 g, 2.77 mmol, 1 eq) in THF (5 ml_) and MeOH (0.1 ml_) was added NaBH ₄ (157.09 mg, 4.15 mmol, 1.5 eq) in portions at 0 °C. The resulting mixture was kept stirring at room temperature for 12 h under N ₂ atmosphere. Then the reaction was quenched by adding 10 ml_ of 2N HCI at 0°C. The reaction mixture was diluted with H ₂ 0 (10 ml_) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 ml_ x 2), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert- butyl N-(1-hydroxy-7-methyl-3H-2, 1-benzoxaborol-6-yl)carbamate (700 mg, 2.66 mmol, 96.11 % yield) as a colorless gum. ¹ H NMR (DMSO-d _6, 400 MHz) d 8.94 (s, 1 H), 8.49 (s, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 4.91 (s, 2H), 2.32 (s, 3H), 1.45 (s, 9H). MS (ESI): mass calcd. For CI ₃ HI ₈ BN0 ₄ 263.13, m/z found 208.1

[M+H-56] ⁺ . Purity by HPLC: 100.00% (220 nm), 100.00% (254 nm).

112. tert-butyl N-(5-chloro-1 -hydroxy-7-methyl-3H-2,1-benzoxaborol-6- yl)carbamate

[0355] To a solution of tert-butyl N-(1-hydroxy-7-methyl-3H-2, 1-benzoxaborol-6- yl)carbamate (0.6 g, 2.28 mmol, 1 eq) in DMF (2 mL) was added N-chlorosuccinimide (456.79 mg, 3.42 mmol, 1.5 eq) at 0 °C. Then the reaction mixture was stirred at 45°C for 12 h. The reaction mixture was diluted with H ₂ 0 (5 mL) and extracted with EtOAc (15 mL x 4). The combined organic layers were washed with brine (10 mL x 1), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give crude product (0.45 g) as a yellow solid. The residue (0.2 g, crude) was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase:

[water(10mM NH4HC03)-ACN]; B%: 25%-45%, 12min) to give tert-butyl N-(5-chloro- 1-hydroxy-7-methyl-3H-2, 1-benzoxaborol-6- yl)carbamate (0.018 g, 56.04 pmol, 2.46% yield, 92.63% purity) as a white solid. ¹ H NMR (DMSO-d _6, 400 MHz) d 9.10 (s, 1 H), 8.61 (br s, 1 H), 7.38 (s, 1 H), 4.93 (s, 2H), 2.34 (s, 3H), 1.45 (br s, 9H). MS (ESI): mass calcd. For C ₁₃ H ₁₇ BCINO ₄ 297.09, m/z found 296.1 [M-H]\ Purity by HPLC: 92.63% (220 nm), 100% (254 nm).

113. tert-Butyl (5, 7-dichloro-1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamate

[0356] To a mixture of methyl 4-amino-2-hydroxy-benzoate (200 g, 1.20 mol, 1 eq) in MeCN (500 ml_) was added B0C2O (261.12 g, 1.20 mol, 274.86 ml_, 1 eq). The reaction mixture was stirred at 70°C for 48 h. The reaction mixture was concentrated in vacuo to give a residue that was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate=1 :0 to 5:1) to give methyl 4-(tert- butoxycarbonylamino)-2-hydroxy-benzoate (110 g, 411.56 mmol, 34.40% yield) as a white solid. ¹ H NMR (DMSO-d _e , 400 MHz) d 10.61 (s, 1 H), 9.75 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H), 7.01 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 3.85 (s, 3H), 1.48 (s, 9H).

[0357] To a solution of methyl 4-(tert-butoxycarbonylamino)-2-hydroxy-benzoate (110 g, 411.56 mmol, 1 eq) in 1 ,2-dichloroethane (1000 ml_) was added N- chlorosuccinimide (82.43 g, 617.34 mmol, 1.5 eq). The reaction mixture was stirred at 85°C for 16 h. Then the reaction mixture was concentrated in vacuo, giving a residue that was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate=1 :0 to 10: 1) to give methyl 4-(tert-butoxycarbonylamino)-5-chloro-2-hydroxy- benzoate (53 g, 175.66 mmol, 42.68% yield) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.49 (s, 1 H), 8.63 (s, 1 H), 7.74 (s, 1 H), 7.51 (s, 1 H), 3.86 (s, 3H), 1.48 (S, 9H).

[0358] To a mixture of methyl 4-(tert-butoxycarbonylamino)-5-chloro-2-hydroxy- benzoate (48 g, 159.09 mmol, 1 eq), TEA (32.20 g, 318.17 mmol, 44.29 ml_, 2 eq) and DMAP (1.94 g, 15.91 mmol, 0.1 eq) in DCM (500 ml_) was added Tf ₂ 0 (58.35 g, 206.81 mmol, 34.12 ml_, 1.3 eq) dropwise at 0°C. The mixture was stirred at 0°C for 0.5 h. The mixture was poured into ice-water (300 ml_) and then extracted with DCM (200 ml_ x 3). The combined organics were washed with brine (200 ml_), dried over Na ₂ SC>4, filtered and concentrated in vacuo, giving a residue that was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 150 mL/min) to give methyl 4-(tert-butoxycarbonylamino)-5 -chloro-2-(trifluoromethylsulfonyloxy)benzoate (65 g, 149.84 mmol, 94.19% yield) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.19 (s, 1 H), 8.07-8.06 (m, 2H), 3.87 (s, 3H), 1.49 (s, 9H).

[0359] A mixture of methyl 4-(tert-butoxycarbonylamino)-5-chloro-2- (trifluoromethylsulfonyloxy) benzoate (65 g, 149.84 mmol, 1 eq), Bis(neopentyl glycolato)diboron (BPD) (57.08 g, 224.77 mmol, 1.5 eq), KOAc (36.77 g, 374.61 mmol, 2.5 eq) and Pd(dppf)CI ₂ CH ₂ CI ₂ (6.12 g, 7.49 mmol, 0.05 eq) in dioxane (500 ml_) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80°C for 16 h under N ₂ atmosphere. The reaction mixture was passed through a pad of celite, and the filtrate was concentrated in vacuo, giving a residue that was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 150 mL/min). Compound methyl 4-(tert-butoxycarbonylamino)-5-chloro-2-(4,4,5,5-tetramethyl -1 ,3,2 -dioxaborolan-2-yl)benzoate (35 g, crude) was obtained as a light yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 8.81 (s, 1 H), 7.88 (s, 1 H), 7.80 (s, 1 H), 3.83 (s, 3H), 1.48 (s, 9H), 1.32 (s, 12H).

[0360] To a mixture of methyl 4-(tert-butoxycarbonylamino)-5-chloro-2-(4, 4,5,5- tetramethyl-1 ,3,2 -dioxaborolan-2-yl)benzoate (30 g, 72.87 mmol, 1 eq) in THF (250 mL) and MeOH (25 mL) was added NaBH ₄ (5.51 g, 145.74 mmol, 2 eq) in ice bath. The mixture was then stirred at 20°C for 1 h. The pH of the mixture was adjusted to 2 with HCI (2N). Then the mixture was extracted with EtOAc (100 mL x 3), and the combined organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SC>4, filtered and concentrated in vacuo, giving a residue that was purified by prep-HPLC (column: Xtimate C18 10m 250 mm *50mm; mobile phase: [water (10mM NH ₄ HC0 ₃ )-ACN]; B%: 25%-55%, 30min). Compound tert-butyl N-(5-chloro-1- hydroxy-3H-2,1-benzoxaborol -6-yl)carbamate (9 g, 31.74 mmol, 43.56% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-de, 400 MHz) d 9.31 (s, 1 H), 8.65 (s, 1 H), 7.88 (s, 1 H), 7.53 (S, 1 H), 4.95 (s, 2H), 1.46 (s, 9H).

[0361] To a mixture of tert-butyl N-(5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6- yl)carbamate (0.6 g, 2.12 mmol, 1 eq) in DMF (10 ml_) was added N- chlorosuccinimide (565.19 mg, 4.23 mmol, 2 eq) in one portion at room temperature. The mixture was stirred at 30°C for 8 h, then the reaction was quenched by addition of H2O (10 ml_), extracted with EtOAc (20 ml_ x 3). The combined organic layers were washed with brine (20 ml_ x 3), dried over anhydrous Na ₂ S0 ₄ , filtered to give a filtrate, to which was added DCM (2 ml_), and precipitation was formed, the precipitation was collected by filtration to give tert-butyl N-(5,7-dichloro-1-hydroxy-3H- 2, 1-benzoxaborol-6-yl)carbamate (176 mg, 553.53 pmol, 26.16% yield) as a white solid. ¹ H NMR (DMSO-de, 400 MHz) d 9.27 (s, 1 H), 8.91 (s, 1 H), 7.57 (s, 1 H), 4.97 (s, 2H), 1.57-1.22 (m, 9H). MS (ESI): mass calcd. For C12H14BCI2NO4 317.04, m/z found 262.0 [M+H-56] ⁺ . Purity by HPLC: 97.8% (220 nm), 100.00% (254 nm).

114. tert-butyl N-(5,7-dichloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl) -N- methyl-carbamate

To a mixture of tert-butyl N-(5,7-dichloro-1-hydroxy-3H-2, 1-benzoxaborol-6- yl)carbamate (0.2 g, 629.01 pmol, 1 eq) in DMF (2 ml_) was added NaH (75.47 mg, 1.89 mmol, 60% purity, 3 eq) in portions at 0°C. The mixture was stirred at 0°C for

0.5 h and then Mel (89.28 mg, 629.01 pmol, 39.16 pL, 1 eq) was added at 0°C, and the resulting mixture was stirred at 0°C for 0.5 h. The reaction was quenched by addition of sat. aq. NH ₄ CI (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ S04, filtered and concentrated under reduced pressure, giving a residue that was purified by prep- HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase:

[water(0.1 %TFA)-ACN]; B%: 35%-65%, 10 min) to give tert-butyl N-(5,7- dichloro-1- hydroxy-3H-2, 1-benzoxaborol-6-yl)-N-methyl-carbamate (130 mg, 391.58 pmol, 62.25% yield) as a white solid. ¹ H NMR (DMSO-de, 400 MHz) d 9.36-9.33 (m, 1 H), 7.64 (s, 1 H), 5.05-4.94 (m, 2H), 3.04-3.00 (m, 3H), 1.47-1.26 (m, 9H). MS (ESI): mass calcd. For C13H16BCI2NO4 331.05, m/z found 276.0 [M-56+H] ⁺ . Purity by HPLC: 99.18% (220 nm), 100.00% (254 nm). 115. Methyl N-(5-chloro-1-hydroxy-3H-2,1 -benzoxaborol-6-yl)carbamate

[0362] To a solution of 5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (200 mg, 1.09 mmol, 1 eq) in THF (5 mL) was added pyridine (1.29 g, 16.36 mmol, 1.32 mL, 15 eq) and methyl carbonochloridate (206 mg, 2.18 mmol, 168.93 pL, 2 eq) at 0 °C.

The mixture was stirred at 25°C for 12 h, then the reaction mixture was diluted with H ₂ 0 (10 mL) at 0°C, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SC>4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (S1O2, Petroleum ether:Ethyl acetate=3: 1). Compound methyl N-(5-chloro-1-hydroxy-3H- 2, 1-benzoxaborol-6-yl)carbamate (120 mg, 497.03 pmol, 45.58% yield) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₃ , 400 MHz) d 9.32 (s, 1 H), 9.07 (s, 1 H), 7.85 (s, 1 H), 7.56 (s, 1 H), 4.96 (s, 2H), 3.66 (s, 3H). MS (ESI): mass calcd. For C9H9BCINO4 241.03 m/z found 242.0 [M+H] ⁺ . Purity by HPLC: 100% (220 nm), 100% (254 nm). 116. Methyl N-(5,7-dichloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)carbamate

[0363] To a solution of methyl N-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6- yl)carbamate (80 g, 331.35 pmol, 1 eq) in DMF (2 ml_) was added N- chlorosuccinimide (88 mg, 662.70 pmol, 2 eq) at 20 °C. The resulting mixture was kept stirring at 75°C for 12 h. Then the reaction mixture was poured into ice/water (10 ml_) at 0 °C, and then extracted with EtOAc (5 ml_ x 3). The combined organic layers were washed with brine (10 ml_ x 1), dried over Na2S0 ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: Nano-micro Kromasil C18 100*30mm 5um; mobile phase:

[water(0.1 %TFA)-ACN]; B%: 20%-50%, 10min). Compound methyl N-(5,7-dichloro-1- hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamate (44 mg, 159.49 pmol, 48.13% yield) was obtained as a white solid. ¹ H NMR (DMSO-d ₃ , 400 MHz) d 9.29 (s, 1 H), 9.25 (brs, 1 H), 7.60 (s, 1 H), 4.98 (s, 2H), 3.64 (s, 3H). MS (ESI): mass calcd. For

CgHsBC NC 274.99 m/z found 276.0 [M+H] ⁺ . Purity by HPLC: 100% (220 nm),

100% (254 nm).

117. 1 -(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2] oxaborol-6-yl)-3- propylurea

[0364] To a mixture of 7-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (0.15 g, 817.89 pmol, 1 eq) and 1-isocyanatopropane (69.61 mg, 817.89 pmol, 77.34 pL, 1 eq) in CHCI3 (4 mL) was added TEA (165.52 mg, 1.64 mmol, 227.68 mI_, 2 eq) under N ₂ atmosphere. The mixture was stirred at 25°C for 12 h. The pH of the reaction mixture was adjusted to 4 by HCI (2N), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na ₂ SC>4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (0.04%NH3H20 +10mM NH4HC03)-ACN]; B%: 1 %-30%, 10.5min). 1-(7-chloro-1- hydroxy-3H-2, 1-benzoxaborol-6-yl)-3-propyl-urea (0.033 g, 119.18 pmol, 14.57% yield) was obtained as a white solid. ¹ H NMR (DMSO-d ₆ ,400MHz) d 9.06 (s, 1 H),

8.22 (d, J = 8.4 Hz, 1 H), 7.97 (s, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 6.98 (t, J = 4.8 Hz,

1 H), 4.91 (s, 2H), 3.05 (q, J = 7.2 Hz, 2H), 1.45 (q, J = 7.2Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H). MS (ESI): mass calcd. For Cn Hi ₄ BCIN ₂ 0 ₃ 268.08, m/z found 267.0 [M-H]-.

Purity by HPLC: 99.38% (220 nm), 100% (254 nm).

118. 1 -(7-chloro-1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-6-yl)-3- isopropylurea

[0365] This substance was prepared starting with 7-chloro-1-hydroxy-3H-2, 1- benzoxaborol-6-amine using the same procedure employed for the preparation of 1- (7-chloro-1 -hydroxy-1 , 3-dihydrobenzo[c][1 , 2] oxaborol-6-yl)-3-propylurea. ¹ H NMR (DMSO-de, 400MHz) d 9.08 (s, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.88 (s, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 4.91 (s, 2H), 3.78-3.71 (m, 1 H), 1.10 (d, J = 6.4 Hz, 6 H). MS (ESI): mass calcd. For CnHi ₄ BCIN ₂ 0 ₃ 268.08, m/z found 267.0 [M-H]-. Purity by HPLC: 99.66% (220 nm), 100% (254 nm).

119. Cyclopropylmethyl N-(7-chloro-1 -hydroxy-3H-2,1-benzoxaborol-6-yl) carbamate

[0366] To a solution of 7-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.1 g, 545.26 pmol, 1 eq) and TEA (110.35 mg, 1.09 mmol, 151.79 mI_, 2 eq) in DCM (5 ml_) was added bis(trichloromethyl)carbonate (64.72 mg, 218.10 pmol, 0.4 eq) in portions at 0 °C. The resulting mixture was stirred at 20°C for 16 h. Then

cyclopropylmethanol (47.18 mg, 654.31 pmol, 51.73 mI_, 1.2 eq) was added in one portion at 0 °C. The reaction mixture was stirred for 2 h at room temperature. H ₂ 0 (10 ml_) was added and the reaction mixture was extracted with EtOAc (10 mL x 3), the organic phases were combined and washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo, giving a residue that was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.1 %TFA)- ACN]; B%: 25%-45%, 12min). Cyclopropylmethyl N-(7-chloro-1 -hydroxy-3H-2, 1- benzoxaborol-6-yl)carbamate (0.027 g, 93.30 pmol, 17.1 1 % yield, 97.27% purity) was obtained as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.12 (s, 1 H), 8.99(s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.96 (s, 2H), 3.91 (d, J = 7.2 Hz, 2H), 1.15-1.09 (m, 1 H), 0.54-0.52 (m, 2H), 0.31-0.29 (m, 2H). MS (ESI): mass calcd. For Ci ₂ Hi ₃ BCIN0 ₄ 281.06, m/z found 282.1 [M+H] ⁺ . Purity by HPLC: 97.27% (220 nm), 97.17% (254 nm).

120. tert-Butyl N-(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)carbamate

[0367] To a solution of methyl 4-(tert-butoxycarbonylamino)-3-fluoro-benzoate (500 mg, 1.86 mmol, 1 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (821 mg, 4.41 mmol, 0.9 mL, 2.38 eq) in THF (4 mL) was added LDA (2 M, 2.32 mL, 2.5 eq) dropwise at -70 °C over a period of 5 min under N ₂ atmosphere. After addition, the mixture was stirred at -70°C for 1 h. The reaction mixture was then quenched by addition of sat. aq. NH ₄ CI (10 mL) at 0 °C, and the pH was adjusted to 5, extracted with EtOAc (5 mL x 3), the organic layers were combined and washed with brine (15 mL x 2), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give methyl 4-(tert-butoxycarbonylamino)-3-fluoro -2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) benzoate (750 g, crude) as brown oil. MS (ESI): mass calcd. For C19H27BFNO6 395.19, m/z found 394.2 [M-H]\

[0368] To a solution of methyl 4-(tert-butoxycarbonylamino)-3-fluoro-2-(4, 4,5,5- tetramethyl-1 ,3,2 -dioxaborolan-2-yl)benzoate (750 mg, 1.90 mmol, 1 eq) in THF (20 ml_) and MeOH (2 ml_) was added NaBFU (180 mg, 4.74 mmol, 2.5 eq) in portions at 0 °C. The mixture was stirred for 1 h at room temperature. The reaction mixture was then quenched with water (20 ml_) and the pH was adjusted to 5 with 2N HCI. The mixture was extracted with EtOAc (20 ml_ x 3), and the organic layers were combined and washed with brine (20 ml_), dried over Na2S0 ₄ , filtered and concentrated in vacuo to give a residue that was purified by prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1 %TFA)-ACN]; B%: 25%-55%, 10min) to give tert-butyl N-(7-fluoro-1-hydroxy-3H -2, 1-benzoxaborol-6-yl)carbamate (0.195 g, 730.17 pmol, 38.48% yield, 100% purity) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 9.25 (s, 1 H), 8.86 (s, 1 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.95 (s, 2H), 1.46 (s, 9H). MS (ESI): mass calcd. For C12H15BFNO4 267.11 , m/z found 266.1 [M-H]\ Purity by HPLC: 100% (220 nm), 100% (254 nm).

121. tert-butyl N-(1-hydroxy-3,3-dimethyl-2,1-benzoxaborol-6-yl)-N-methyl - carbamate

[0369] To a mixture of 1-hydroxy-3,3-dimethyl-2, 1-benzoxaborol-6-amine (1 g, 5.65 mmol, 1 eq) in t-BuOH (10 mL) was added B0C2O (1.85 g, 8.47 mmol, 1.95 mL, 1.5 eq) in one portion at 25°C under N ₂ , then the mixture was heated to 80°C and stirred for 13 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by re-crystallization from petroleum ether (10 mL) to give tert-butyl N-(1 -hydroxy-3, 3 -dimethyl-2, 1-benzoxaborol-6-yl)carbamate (0.88 g, 3.18 mmol, 56.21 % yield) as a yellow solid. ¹ H NMR (DMSO-d _e, 400 MHz) d 9.31 (s, 1 H), 8.98 (s, 1 H), 7.77 (s, 1 H), 7.43 (dd, J = 8.4, 1.6 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 1.48 (s, 9H), 1.40 (s, 6H).

[0370] To a mixture of tert-butyl N-(1-hydroxy-3,3-dimethyl-2, 1-benzoxaborol-6- yl)carbamate (780 mg, 2.81 mmol, 1 eq) in THF (8 mL) was added NaH (135 mg, 3.38 mmol, 60% purity, 1.2 eq) in portions at 0°C under N ₂ . The mixture was stirred at 0 °C for 30 min, then Mel (479 mg, 3.38 mmol, 210.27 pL, 1.2 eq) was added to the reaction mixture, the resulting mixture was stirred at room temperature for 3 h. Then the reaction mixture was poured into ice-water (w/w = 1/1) (10 ml_) and stirred for 1 min, the pH was adjusted to 5-6 with HCI (2N), and the aqueous phase was extracted with ethyl acetate (15 mL x 3), the organic phases were combined and washed with brine (20 mL x 2), dried over anhydrous Na2S0 ₄ , filtered and

concentrated in vacuo, giving the crude product, which was purified by Pre- HPLC(column: Nano-micro Kromasil C18 100*30mm 5um;mobile phase:

[water(0.1 %TFA)-ACN];B%: 45%-60%, 10min) to give tert-butyl N-(1-hydroxy-3,3- dimethyl-2, 1-benzoxaborol-6-yl)-N-methyl-carbamate (360 mg, 1.24 mmol, 43.93% yield, 98.89% purity) as a yellow solid. ¹ H NMR (DMSO-d _6, 400 MHz) d 9.03 (s, 1 H), 7.51 (d, J = 1.6 Hz, 1 H), 7.38-7.32 (m, 2H), 3.18 (s, 3H), 1.43 (s, 6H), 1.39 (s, 9H). MS (ESI): mass calcd. For C15H22BNO4 291.16, m/z found 290.1 [M-H]\ Purity by HPLC: 98.89% (220 nm), 100% (254 nm).

122. tert-butyl N-(5-chloro-7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl) carbamate

[0371] To a solution of 4-amino-3-fluoro-benzoic acid (20 g, 128.93 mmol, 1 eq) in

MeOH (240 ml_) was added H2SO4 (58.88 g, 600.33 mmol, 32.00 ml_, 4.66 eq) drop- wise at 0 °C over a period of 5 min under N2, during which the temperature was maintained below 0 °C, the reaction mixture was warmed to 0°C over a period of 5 min and stirred at 80°C for 15 h. The reaction mixture was neutralized by adding sat. aq. Na ₂ C0 ₃ (100 ml_) at 0°C, and extracted with ethyl acetate (100 ml_ x 3), the combined organic phase was washed with brine (100 ml_ x 2), dried over anhydrous

Na2SC>4, filtered and concentrated in vacuo to give methyl 4-amino-3 -fluoro- benzoate (17 g, 100.50 mmol, 77.95% yield) as a gray brown solid. ¹ H NMR (CDCL- d _6, 400 MHz) d 7.68-7.64 (m, 2H), 6.75 (q, J = 1.6 Hz, 1 H), 4.16 (s, 2H), 3.86 (s, 3H).

[0372] To a mixture of methyl 4-amino-3-fluoro-benzoate (5 g, 29.56 mmol, 1 eq) in

DMF (50 ml_) was added N-chlorosuccinimide (5.13 g, 38.43 mmol, 1.3 eq) in one portion at room temperature under N ₂ , the reaction mixture was stirred for 3 h. Then the mixture was poured into ice-water (w/w = 1/1) (130 ml_) and stirred for 2 min, the aqueous phase was extracted with ethyl acetate (50 ml_ x 3), and the combined organic phase was washed with brine (50 ml_ x 2), dried over anhydrous Na ₂ SC>4, filtered and concentrated in vacuo to give methyl 4-amino-3-chloro-5-fluoro-benzoate (6 g, 29.47 mmol, 99.70% yield) as a yellow Solid. ¹ H NMR (CDCI ₃ -d _6, 400 MHz) d 7.75 (s, 1 H), 7.56 (dd, J = 11.2, 1.6 Hz, 1 H), 4.56 (s, 2H), 3.84 (s, 3H).

[0373] To a solution of methyl 4-amino-3-chloro-5-fluoro-benzoate (3 g, 14.73 mmol,

1 eq) in toluene (60 ml_) was added triphosgene (6.4 g, 21.57 mmol, 1.46 eq, the mixture was heated slowly to 105 °C and maintained at that temperature for 3 h (caution: the reaction is exothermic and started at 80°C), then cooled to room temperature and purged with N ₂ to remove the solvent. The obtained residue was refluxed with t-BuOH (60 ml_) at 90 °C for 5 h, the mixture was cooled to room temperature and concentrated in vacuo, giving a residue that was purified by Prep- HPLC (column: Phenomenex luna C18 250mm*100mm*10um;mobile phase:

[water(0.1 %TFA)-ACN];B%: 35%-65%,20min) to give methyl 4-(tert- butoxycarbonylamino)-3-chloro-5-fluoro-benzoate (2.8 g, 9.22 mmol, 62.57% yield) as a brown solid. ¹ H NMR (DMSO-d _6, 400 MHz) d 9.16 (s, 1 H), 7.84 (s, 1 H), 7.73 (dd, J = 9.6, 2.0 Hz, 1 H), 3.86 (s, 3H), 1.42 (s, 9H).

[0374] To a solution of methyl 4-(tert-butoxycarbonylamino)-3-chloro-5-fluoro- benzoate (2.8 g, 9.22 mmol, 1 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (3.95 g, 21.20 mmol, 4.33 ml_, 2.3 eq) in THF (40 ml_) was added LDA (2 M, 1 1.50 ml_, 2.5 eq) drop-wise at -70°C over a period of 5 min under N ₂ , after addition, the mixture was stirred at -70°C for 1 h. Then additional 3 ml_ of LDA (2 M) was added into the reaction mixture at -70°C under N2, and the resulting mixture was stirred at -70°C for 1 h. The reaction was quenched by adding sat. aq.NH4CI (50 mL) at 0°C, and the pH was adjusted to 6 with 2 N HCI, extracted with EtOAc (15 mL x 3), and the combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SC>4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 ₂ , Petroleum ether/Ethyl acetate=20/1 to 2/1) to give Methyl 4-(tert-butoxycarbonylamino)-5-chloro-3-fluoro-2-(4, 4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl) benzoate (2.8 g, 6.52 mmol, 70.68% yield) as a white solid. ¹ H NMR (CDCI ₃ -d _6, 400 MHz) d 7.83 (s, 1 H), 6.16 (s, 1 H), 3.92 (s, 3H), 1.49 (s, 9H), 1.43 (s, 12H).

[0375] To a mixture of methyl 4-(tert-butoxycarbonylamino)-5-chloro-3-fluoro-2- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate (2.8 g, 6.52 mmol, 1 eq) and MeOH (2.38 g, 74.14 mmol, 3.00 mL, 1 1.38 eq) in THF (30 mL) was added NaBH ₄ (740 mg, 19.55 mmol, 3 eq) in portions at 0 °C, the resulting mixture was kept stirring at room temperature for 30 min. The pH was adjusted to 4 with 2N HCI, and stirred for 30 min, 20 mL of water was added at 0 °C, and aqueous phase was extracted with EtOAc (15 mL x 3), the combined organic layers were washed with brine 60 mL (30 mL x 2), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by re-crystallization from methyl tert-butyl ether (MTBE) (10 mL) to give tert-butyl N-(5-chloro-7-fluoro-1-hydroxy-3H-2, 1- benzoxaborol-6-yl)carbamate (1.5 g, 4.91 mmol, 75.38% yield, 98.74% purity) as a white solid. ¹ H NMR (DMSO-d _6, 400 MHz) d 9.41 (s, 1 H), 8.75 (s, 1 H), 7.44 (s, 1 H), 4.98 (s, 2H), 1.42 (s, 9H). MS (ESI): mass calcd. For Ci ₂ Hi ₄ BCIFN0 ₄ 301.07, m/z found 246.1 [M-56+H] ⁺ . Purity by HPLC: 98.74% (220 nm), 75.04% (254 nm).

123. S-benzyl N-(1-hydroxy-3H-2,1 -benzoxaborol-6-yl)carbamothioate

[0376] To a mixture of 1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.2 g, 1.34 mmol, 1 eq) and bis(trichloromethyl) carbonate (227.11 mg, 765.33 pmol, 0.57 eq) in DCM (6 ml_) was added TEA (339.67 mg, 3.36 mmol, 467.22 mI_, 2.5 eq) and

bis(trichloromethyl) carbonate (227.11 mg, 765.33 pmol, 0.57 eq) at 0°C under N ₂ atmosphere. The mixture was stirred at room temperature for 2 h under N ₂ atmosphere. Then benzyl mercaptan (521.98 mg, 4.20 mmol, 492.43 mI_, 3.13 eq) was added at room temperature, the resulting mixture was kept stirring at room temperature for 12 h. The reaction was quenched by addition of H ₂ 0 (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure, giving a residue that was purified by prep-HPLC (column: x- charge150*25mm*5um; mobile phase: [water(0.1 %TFA)-ACN]; B%: 45%-55%, 10min) to give S-benzyl N-(1-hydroxy-3H-2, 1-benzoxaborol-6-yl) carbamothioate (16 mg, 53.48 pmol, 3.98% yield) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d

10.37 (s, 1 H), 9.23 (s, 1 H), 7.94 (s, 1 H), 7.51 (d, J = 6.0 Hz, 1 H), 7.39-7.29 (m, 5H), 7.25 (d, J = 6.8 Hz, 1 H), 4.93 (s, 2H), 4.16 (s, 2H). MS (ESI): mass calcd. For C15H14BNO3S 299.08, m/z found 300.1 [M+H] ⁺ . Purity by HPLC: 100.00% (220 nm), 100.00% (254 nm).

124. Isopropyl (7-fluoro-1 -hydroxy-1 ,3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamodithioate [0377] To a mixture of 7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (0.4 g, 2.40 mmol, 1 eq) and NaOH (287.52 mg, 7.19 mmol, 3 eq) in DCM (10 ml_) was added thiocarbonyl dichloride (688.74 mg, 5.99 mmol, 459.16 mI_, 2.5 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Then 10 mL of H2O was added, and the mixture was extracted with EtOAc (10 mL x 3), the combined organics were washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered and

concentrated in vacuo, giving compound 7-fluoro-1-hydroxy-6-isothiocyanato-3H- 2, 1-benzoxaborole (0.5 g, crude) was obtained as a yellow solid.

[0378] To a solution of 7-fluoro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.5 g, 2.39 mmol, 1 eq) in DMF (5 mL) was added propane-2-thiol (218.64 mg, 2.87 mmol, 267.94 pL, 1.2 eq) in one portion at room temperature. The mixture was stirred at 50°C for 16 h. Then H2O (10 mL) was added, and the reaction mixture was extracted with EtOAc (10 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo, giving a residue that was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30 mm 5 urn; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%-75%, 10 min) to give compound isopropyl N-(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6 - yl)carbamodithioate (0.1 12 g, 392.75 pmol, 16.42% yield, 100% purity) as an off- white solid. ¹ H NMR (DMSO-de, 400 MHz) d 11.31 (s, 1 H), 9.37 (s, 1 H), 7.48 (m, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 5.02 (s, 2H), 3.93-3.86 (m, 1 H), 1.35 (m, 6H). MS (ESI): mass calcd. For C11 H13BFNO2S2 285.05, m/z found 286.1 [M+H] ⁺ . Purity by HPLC:

100% (220 nm), 100% (254 nm).

125. (4-nitrophenyl)N-(1-hydroxy-3H-2,1- benzoxaborol-6-yl)carbamate

[0379] To a mixture of 1-hydroxy-3H-2, 1-benzoxaborol-6-amine (0.1 g, 671.35 pmol, 1 eq) in DMF (2 mL) was added TEA dropwise (136 mg, 1.34 mmol, 186.89 pL, 2 eq) and (4-nitrophenyl) carbonochloridate (163 mg, 805.62 pmol, 1.2 eq) at 0°C, The mixture was stirred at 25°C for 2 h. The solvent was removed in vacuo, giving a residue that was purified by prep- HPLC (column: Luna C18 100*30 5u;mobile phase: [water(0.1 %TFA)-ACN];B%:60%-75%, 10min) to give to give (4- nitrophenyl)N-(1-hydroxy-3H-2, 1- benzoxaborol-6-yl)carbamate (26 mg, yield: 12.3% ) as a yellow solid. ¹ H NMR (DMSO-d6, 400 MHz) d 10.50 (s, 1 H), 9.25 (s, 1 H), 8.32 (d, J = 4.4 Hz, 2H), 7.91 (s, 1 H), 7.59 (d, J = 3.4Hz, 1 H), 7.55 (d, J = 4.4 Hz, 2H), 7.38 (d, J = 4 Hz, 1 H), 4.95 (s, 2H). MS (ESI): mass calcd. For C ₇ H ₄ CIN0 ₄ 314.07, m/z found 315.0 [M+H] ⁺ . Purity by HPLC: 98.44% (220 nm), 99.20% (254 nm).

126. Isopropyl N-(5-chloro-7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl) carbamodithioate

[0380] A mixture of tert-butyl N-(5-chloro-7-fluoro-1-hydroxy-3H-2, 1-benzoxaborol-6- yl) carbamate (200 mg, 663.34 pmol, 1 eq) in HCI/EtOAc (4 M, 6.00 ml_, 36.18 eq) was stirred at 25°C for 30 min. The reaction mixture was concentrated under reduced pressure to give 5-chloro-7-fluoro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (130 mg, 645.51 pmol, 97.31 % yield, 100% purity) as a yellow solid. ¹ H NMR

(DMSO-de _, 400 MHz) d 9.21 (s, 1 H), 7.15 (s, 1 H), 5.19 (s, 2H), 4.85 (s, 2H). MS (ESI): mass calcd. For C ₇ H ₆ BCIFNO 201.02, m/z found 200.1 [M-H]\ Purity by HPLC: 100% (220 nm), 100% (254 nm).

[0381] To a mixture of 5-chloro-7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (200 mg, 993.10 pmol, 1 eq) and NaOH (119.17 mg, 2.98 mmol, 3 eq) in DCM (4 mL) was added thiocarbonyl dichloride (286 mg, 2.48 mmol, 190.31 pL, 2.5 eq) dropwise at 0 °C, then the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of sat. aq. NH ₄ CI (8 mL) at 0 °C, extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with brine (5 mL x 2), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to give 5- chloro-7-fluoro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (160 mg, 657.22 pmol, 66.18% yield) as a yellow solid. ¹ H NMR (CDCI ₃ -d _6, 400 MHz) d 7.24 (s, 1 H), 5.06 (s, 2H).

[0382] To a solution of 5-chloro-7-fluoro-1-hydroxy-6-isothiocyanato-3H-2, 1- benzoxaborole (160 mg, 657.22 pmol, 1 eq) in DMF (2 mL) was added propane-2- thiol (60 mg, 788.66 pmol, 74 pL, 1.2 eq) in one portion at room temperature, the mixture was stirred at 50°C for 16 h. Then the reaction mixture was poured into ice- water (w/w = 1/1) (5 mL), the aqueous phase was extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with brine (5 mL x 2), dried over anhydrous Na2S0 ₄ , filtered and concentrated in vacuo, giving a residue that was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um;mobile phase: [water (0.1 %TFA)-ACN]; B%: 40%-60%, 10min) to give isopropyl N-(5-chloro- 7-fluoro-1-hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamodithioate (80 mg, 210.06 pmol, 31.96% yield, 83.92% purity) as an off-white solid. ¹ H NMR (DMSO-d _6, 400 MHz) d 11.30 (s, 1 H), 9.44 (s, 1 H), 7.53 (s, 1 H), 5.01 (s, 2H), 3.91 (m, 1 H), 1.30 (m, 6H). MS (ESI): mass calcd. For C12H12BCIFNO2S2 319.01 , m/z found 320.0 [M+H] ⁺ . Purity by HPLC: 83.92% (220 nm), 96.44% (254 nm).

127. O-cyclohexyl N-(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl) carbamothioate

[0383] To a solution of 7-fluoro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (200 g, 956.91 pmol, 1 eq) in DMF (3 ml_) was added cyclohexanol (1 15 mg, 1.15 mmol, 1 19.80 mI_, 1.2 eq) in one portion at room temperature. The mixture was stirred at 50°C for 48 h. Any precipitations were removed by filtration, and the filtrate was concentrated in vacuo to give a residue, which was purified by prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1 %TFA)-ACN]; B%: 35%- 60%, 10min) to give O-cyclohexyl N-(7-fluoro-1-hydroxy-3H-2, 1-benzoxaborol-6- yl)carbamothioate (89 mg, 286.61 pmol, 29.95% yield, 99.56% purity) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.75-10.60 (m, 1 H), 9.31 (s, 1 H), 7.51-7.38 (m, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 5.28-5.22 (m, 1 H), 5.00 (s, 2H), 2.07-1.92 (m, 1 H), 1.84-1.70 (m, 2H), 1.54-1.17 (m, 7H). MS (ESI): mass calcd. For C14H17BFNO3S 309.10, m/z found 308.1 [M-H]\ Purity by HPLC: 99.56% (220 nm), 100% (254 nm). 128. 0-(4-chlorophenyl) N-(7-fluoro-1 -hydroxy-3H-2,1 -benzoxaborol-6-yl) carbamothioate

[0384] To a solution of 4-chlorophenol (150 mg, 1.17 mmol, 114.50 pL, 1 eq) in DCM (10 mL) was added aq. NaOH (0.3 M, 3.75 mL, 1.0 eq) dropwise at 0 °C. The mixture was stirred at room temperature for 10 min. Then thiocarbonyl dichloride (201 mg, 1.75 mmol, 134.16 pL, 1.5 eq) was added and the mixture was stirred at room temperature for 1 h. Then H ₂ 0 (10 mL) was added to the reaction mixture and it was extracted with DCM (10 mL x 2). The combined organic phase was dried over Na2S0 ₄ , filtered and concentrated in vacuo to give a residue that was dissolved in DCM (10 mL) and 7-fluoro-1-hydroxy-3H-2, 1-benzoxaborol-6-amine (585 mg, 3.50 mmol, 3 eq) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for 1 h. H2O (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over Na2S0 ₄ , filtered and concentrated in vacuo to give a residue that was purified by prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1 %TFA)-ACN]; B%: 40%-60%, 10min) to give 0-(4-chlorophenyl) N- (7-fluoro-1 -hydroxy-3H-2, 1 -benzoxaborol-6-yl)carbamothioate (258 mg, 758.42 pmol, 65.00% yield, 99.23% purity) as a white solid. ¹ H NMR (DMSO-d6, T=273+80 K, 400 MHz) d 9.35 (s, 1 H), 9.24 (s, 1 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.28 (d,

J = 8.0 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 5.02 (s, 2H). MS

(ESI): mass calcd. For C ₁₄ H ₁₀ BCIFNO ₃ S 337.01 , m/z found 338.0 [M-H]\ Purity by HPLC: 99.23% (220 nm), 100% (254 nm).

129. S-propyl (1 -hydroxy-1, 3-dihydrobenzo[c][1,2]oxaborol-6- yl)carbamothioate

[0385] To a solution of 1-hydroxy-3H-2,1-benzoxaborol-6-amine (100 mg, 671.34 pmol, 1 eq) and S-propyl chloromethanethioate (1 12 mg, 805.61 pmol, 1.2 eq) in MeCN (2 ml_) was added N-Methylmorpholine (NMM) (68 mg, 671.34 pmol, 73.81 mI_, 1 eq) in one portion at room temperature, the mixture was stirred at room temperature for 1 h. The reaction was quenched with 2 N HCI (5 ml_) and extracted with Ethyl acetate (5 ml_ x 2). The combined organic phase was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to give a residue that was purified by trituration using MTBE/Ethyl acetate (5 ml_/ 2 ml_). The white solid obtained from filtration was dried in vacuo to give S-propyl N-(1-hydroxy-3H-2,1- benzoxaborol-6-yl)carbamothioate (30 mg, 119.47 pmol, 17.80% yield) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 10.29 (s, 1 H), 9.19 (s, 1 H), 7.93 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.93 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 1.65-1.56 (m, 2H) 0.96 (t, J = 7.2 Hz, 3H). MS (ESI): mass calcd. For C11H14BN3OS 251.08, m/z found 252.1 [M+H] ⁺ . Purity by HPLC: 100% (220 nm), 99.68% (254 nm).

130. 2-aminoethyl N-(1-hydroxy-3H-2,1 -benzoxaborol-6-yl)carbamodithioate

[0386] To a mixture of 1-hydroxy-3H-2, 1-benzoxaborol-6-amine (2 g, 13.43 mmol, 1 eq) in DCM (20 ml_) was added NaOH (2.15 g, 53.71 mmol, 4 eq) at 0°C. The mixture was stirred at 0°C for 10 min, then thiocarbonyl dichloride (3.86 g, 33.57 mmol, 2.57 ml_, 2.5 eq) was added at 0°C. The resulting mixture was stirred at room temperature for 50 min, then quenched by addition of H ₂ 0 (20 ml_), extracted with EtOAc (20 ml_ x 3). The combined organic layers were washed with brine (20 ml_ x 3), dried over anhydrous Na ₂ SC>4, filtered and concentrated under reduced pressure to give 1-hydroxy-6-isothiocyanato-3H-2,1-benzoxaborole (1.7 g, 8.90 mmol, 66.28% yield) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 7.20-7.01 (m, 3H), 4.61 (s, 2H).

[0387] To a mixture of 1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (450 mg, 2.36 mmol, 1 eq) in DMSO (5 ml_) was added tert-butyl N-(2-sulfanylethyl)carbamate

(2.51 g, 14.14 mmol, 6 eq) in portions at room temperature. The resulting mixture was stirred at 40°C for 12 h, then quenched by addition of aq. NH4CI (10 ml_), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Nanomicro Kromasil C18 100*30mm 5um;mobile phase: [water(0.1 %TFA)-ACN]; B%: 35%-50%,10min) to give tert-butyl N-[2-[(1-hydroxy-3H-2, 1-benzoxaborol-6-yl) carbamothioylsulfanyl]ethyl]carbamate (0.4 g, 1.09 mmol, 46.10% yield) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.70 (s, 1 H), 9.27 (s, 1 H), 7.91 (s, 1 H), 7.60 (s, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.05 (s, 1 H), 4.99 (s, 2H), 3.30 (t, J = 6.8 Hz, 2H),

3.21 (t, J = 5.6 Hz, 2H), 1.37 (s, 9H).

[0388] To a mixture of tert-butyl N-[2-[(1-hydroxy-3H-2, 1-benzoxaborol-6-yl) carbamothioylsulfanyl] ethyl]carbamate (400 mg, 1.09 mmol, 1 eq) in EtOAc (10 mL) was added HCI/EtOAc (4 M, 2.72 mL, 10 eq) in one portion at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give 2-aminoethyl N-(1-hydroxy-3H-2, 1-benzoxaborol- 6-yl)carbamodithioate (148 mg, 296.41 pmol, 27.29% yield, 61.01 % purity, HCI) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 1 1.92 (s, 1 H), 9.30 (s, 1 H), 8.09 (m, 3H), 7.94 (m, 1 H), 7.62 (m, 1 H), 7.44 (s, J = 8.0 Hz, 2H), 4.99 (s, 2H), 3.49 (m, 2H), 3.09 (m, 2H). MS (ESI): mass calcd. For CioHi ₃ BN ₂ 0 ₂ S ₂ 268.05, m/z found 269.0

[M+H] ⁺ . Purity by HPLC: 61.01 % (220 nm), 77.47% (254 nm).

131. 2-(dimethylamino)ethyl N-(5-chloro-1-hydroxy-3H-2,1- benzoxaborol-6- yl)carbamodithioate [0389] To a mixture of 5-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.2 g, 887.08 pmol, 1 eq) in DMSO (3 ml_) was added 2-(dimethylamino)ethanethiol (754 mg, 5.32 mmol, 6 eq, HCI) in one portion at room temperature. The mixture was stirred at 40°C for 24 h. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water(0.05%HCI)-ACN]; B%: 1 %-35%, 12min) to give 2-(dimethylamino)ethyl N-(5-chloro-1-hydroxy-3H-2, 1-benzoxaborol-6-yl)carbamodithioate (224 mg, 591.79 pmol, 33.36% yield, 96.99% purity, HCI) as an off-white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.87 (s, 1 H), 10.77 (s, 1 H), 9.45 (s, 1 H), 7.73 (s, 1 H), 7.67 (s, 1 H), 5.00 (s, 2H), 3.61 (m, 2H), 3.34 (m, 2H), 2.80 (s, 6H). MS (ESI): mass calcd. For

C12H16BCIN2O2S2 330.04, m/z found 331.0 [M+H] ⁺ . Purity by HPLC: 96.99% (220 nm), 97.18% (254 nm).

132. 2-(dimethylamino)ethyl N-(1-hydroxy-3H-2,1-benzoxaborol-6-yl) carbamodithioate

[0390] To a mixture of 1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (0.2 g,

1.05 mmol, 1 eq) in DMSO (3 mL) was added 2-(dimethylamino)ethanethiol (890 mg, 6.28 mmol, 6 eq, HCI) in one portion at 20°C. The mixture was stirred at 40°C for 24 h. The reaction mixture was filtered, then the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water(0.05%HCI)- ACN];B%: 1 %-30%, 12min) to give 2-(dimethylamino)ethyl N-(1-hydroxy-3H-2, 1- benzoxaborol-6-yl)carbamodithioate (48 mg, 124.57 pmol, 5.95% yield, 86.34% purity, HCI) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.95 (s, 1 H), 10.30 (s, 1 H), 9.30 (s, 1 H), 7.93 (m, 1 H), 7.64 (m, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 5.00 (s, 2H), 3.61 (m, 2H), 3.31 (m, 2H), 2.82 (s, 6H). MS (ESI): mass calcd. For C12H17BN2O2S2

296.08, m/z found 297.1 [M+H] ⁺ . Purity by HPLC: 86.34% (220 nm), 94.1 % (254 nm). 133. 2-(diethylamino)ethyl N-(5-chloro-1-hydroxy-3H-2,1- benzoxaborol-6- yl)carbamodithioate

[0391] To a mixture of 5-chloro-1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole

(0.2 g, 887.08 pmol, 1 eq) in DMSO (3 mL) was added 2-(diethylamino)ethanethiol (903 mg, 5.32 mmol, 6 eq, HCI) in one portion at room temperature. The mixture was stirred at 40°C for 24 h. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water(0.05%HCI)-ACN]; B%: 5%-45%, 12min) to give 2-(diethylamino)ethyl N-(5-chloro-1-hydroxy-3H-2, 1-benzoxaborol- 6-yl) carbamodithioate (319 mg, 749.52 pmol, 42.25% yield, 92.85% purity, HCI salt) as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 11.88 (s, 1 H), 10.37 (s, 1 H), 9.43 (s, 1 H), 7.72 (s, 1 H), 7.68 (s, 1 H), 5.02 (s, 2H), 3.60 (m, 2H), 3.27 (m, 2H), 3.18 (m, 4H), 1.25 (t, J = 7.2 Hz, 6H). MS (ESI): mass calcd. For C14H20BCIN2O2S2 394.05, m/z found 359.1 [M+H] ⁺ . Purity by HPLC: 92.85% (220 nm), 98.51 % (254 nm).

134. 2-(diethylamino)ethyl N-(1-hydroxy-3H-2,1-benzoxaborol-6-yl)

carbamodithioate

[0392] To a mixture of 1-hydroxy-6-isothiocyanato-3H-2, 1-benzoxaborole (200 g, 1.05 mmol, 1 eq) in DMSO (3 ml_) was added 2-(diethylamino)ethanethiol (1.07 g, 6.28 mmol, 6 eq, HCI) in one portion at room temperature. The mixture was stirred at

40 °C for 24 h and then filtered, the filtrate was purified by prep-HPLC (column:

Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (0.05%HCI)-ACN];

B%: 1 %-40%,12min) to give 2-(diethylamino)ethyl N-(1-hydroxy-3H-2,1- benzoxaborol-6-yl)carbamodithioate (64 mg, 155.17 pmol, 7.41 % yield, 87.46% purity, HCI salt) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) d 12.01 (s, 1 H),

10.65 (s, 1 H), 7.95 (m, 1 H), 7.64 (m, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 5.00 (s, 2H), 3.62 (m, 2H), 3.26 (m, 2H), 3.18 (q, J = 6.8 Hz, 4H), 1.25 (q, J = 7.6 Hz, 6H). MS (ESI): mass calcd. For C14H21BN2O2S2 324.1 , m/z found 325.1 [M+H] ⁺ . Purity by HPLC: 87.46% (220 nm), 94.69% (254 nm).

PART III: Biological Materials and Methods

Bacterial, Fungal, and oomycetal isolates

[0393] The isolates of Aspergillus flavus NRRL 3518 and Rhizoctonia solani NRRL 66082 were obtained from USDA Agricultural Research Service Culture Collection. The isolate Septoria tritici UM 084 was obtained from ATCC. The collection of Colletothchum sublineolum FSP270 was gifted by Dr. Louis Prom at USDA-ARS Crop Germplasm Research in College Station, TX. The isolates of Botrytis cinerea B16, Botrytis cinerea B17, Candida albicans was obtained from the Plant Pathology and Environmental Microbiology Department at The Pennsylvania State University, University Park, PA. The Alternaria spp. isolate was kindly gifted by Dr. Inga Meadows at The Department of Entomology and Plant Pathology, Mountain

Research Station in North Carolina State University, Waynesville, NC. The collection of Mycosphaerella fijiensis 11 CR-33 was given by Dr. Jean Ristaino at the

Department of Plant Pathology in North Carolina State University, Raleigh, NC. The isolates of Botrytis cinerea B05.10, Fusarium oxysporum f. sp. cubense TR4, and Phytophthora capsid were obtained from the Texas A&M Agrilife Research, College Station, TX.

Bacterial, Fungal, and oomycetal inoculum preparation

[0394] Bacterial cultures were maintained on LB agar or broth and CFUs can be isolated from the cultures after 2-5 days of incubation at room temperature (20-22°C) with 12 hours fluorescent light (Philips, F40LW). Unless specified, most of the fungal and oomyctal organisms were maintained on potato dextrose agar/broth (PDA/PDB), V8 agar/broth (20% - 200 mL V8 juice, 2 g CaCC>3, 800 mL distilled water, 15 g Agar if necessary), or Malt agar (20g malt extract, l OOOmL distilled water, 15g Agar) and spores can be isolated from the cultures after 1-2 weeks of incubation at room temperature (20-22°C) with 12 hours fluorescent light (Philips, F40LW) or 12hours blacklight (Philips, F40T12) photoperiod. The final concentrations of all inocula were 5 x 10 ⁴ CFU/mL.

[0395] Mycosphaerella fijiensis·. Briefly, mycelial cultures of M. fijiensis isolates 11 CR-33 grown on PDA medium were macerated in water, and 1-5 mL of the resulting suspension was pipetted onto plates of V8 medium. Cultures were incubated at 20°C under continuous, cool-white fluorescent and black light. After 5-7 days, sporulation plates were stimulated to produce conidia by adding 2 mL water and scraping the plates with a cell spreader and removing the resulting suspension. After another 5-7 days, conidia were harvested in the same way, adding 2 mL 0.05% Tween 20 solution, scraping the plates to dislodge spores, and removing the spore suspension by pipetting. Spores were diluted in half strength broth medium.

[0396] Rhizoctonia soianr. due to insufficient spore obtained from these fungi, inocula were prepared as mycelium visible fragments. Mycelia were harvested by filtering through one layer of Miracloth. The mycelia were homogenated in half strength of broth medium using household blender for 10 seconds and filtered through one layer Miracloth. The resultant visible fragments were diluted in half strength broth medium.

[0397] Septoria triticf. Isolate UM084 was maintained on YMDA (4g yeast extract, 4g malt extract, 10g dextrose, 15g agar, lOOOmL distilled water). After 1 week of growth, culture is transferred to YSB media (10g sucrose, 10g yeast extract, l OOOmL distilled water) and grown for 4-7 days then filtered through one layer of Miracloth. The resultant organism was diluted in half strength broth medium.

In vitro antibacterial, antifungal, and anti-oomycetal efficacy of boron-based molecules

[0398] Boron-based compounds were stocked in DMSO with the concentration of 5000 pg/mL (stored at -20°C). The stock solutions were further diluted into sterile half strength broth media in the in vitro assay, in which DMSO final concentration is not greater than 1 % (v/v).

[0399] Agar based assays were done at single concentrations of 25 pg/mL in ½ PDA to determine percent inhibition. Half-strength PDA was amending with 25 pg/mL of compound and poured into 100 mm petri dishes (20 ml_ per petri dish). After amended PDA was given adequate time to cool and harden (12 hours), plugs (5mm) from selected pathogen (bacteria, fungi, oomycete) were placed at the center of each petri dish. Similarly, plugs were placed onto the same medium without the compound amendment and used as a negative control. Control plates were monitored for 5-7 days, until radial growth reached the far edge of the petri dish. At this time, the radial growth for each treated plate was measured as well. Percent inhibition was calculated by subtraction the radial growth of the untreated control from the radial growth of compound amended plate then dividing that difference by the radial growth of the untreated control. This final number was multiplied by 100 to give a

percentage.

[0400] The minimal inhibitory concentrations (MICs) for individual compounds were determined by following a modified broth microdilution protocol. The studies were performed in flat bottom, 96-well microtiter plates (Greiner Bio-One).

[0401] The individual MICs were determined in triplicate in a final volume of 0.2 mL/well with antifungal concentrations of 0.2 - 25 pg/mL (8 serial dilutions down from 25 pg/mL [25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 and 0.20 pg/mL]; control studies with 0 pg/mL of compounds were performed in parallel for each plate). Plates sealed with clear polyester film (VWR) were incubated at a temperature of about 22°C. The progress of fungal growth was monitored at 72 hours, bacterial growth monitored at 24hrs, yeast growth monitored at 48hrs. The MICs were determined as the lowest antifungal concentrations that inhibited fungal growth by greater than 95%

(determined as relative absorbance using the Bio-Tek® Synergy™ H1 microplate reader at 600 nm) relative to the corresponding antifungal-free control.

[0402] The MIC results of the antifungal screening are shown below in Table 1 and Table 2. Potent and Broad Spectrum Antifungal Agents

[0403] The compounds of the present disclosure demonstrate potent and broad- spectrum activity against plant pathogens. As examples, two potent representative compounds, Compound 58 and 49, were used to select for resistant mutants in the genetically tractable model fungus, Saccharomyces cerevisiae. Whole genome sequencing identified substitutions at the active sites of two enzymes in the protein prenylation pathway, Cdc43 (beta subunit of geranylgeranyltransferase type I), and Erg20 (farnesyl pyrophosphate synthetase). Allele replacement experiments confirmed that these substitutions were sufficient to confer resistance against these two compounds. Molecular modeling analysis supports Cdc43 as proximal target of this compound class and additionally suggests that the boron group plays an important role interacting with the catalytic metal ions at the active sites of Cdc43. Finally, compounds 58 and 49 showed synergistic interaction with 14-a- demethylase inhibitor, fluconazole, suggesting potential benefit in deployment of the two classes of fungicides in combination. This study reveals a novel mechanism for boron- containing antifungal compounds and demonstrates that carbamate-substituted benzoxaboroles have significant potential as antifungals for crop protection, and possibly could also lead to new therapeutic agents for human fungal infections.

[0404] Dithiol-carbamates, such as compound 58, are generally more potent than thiolo-carbatates, such as compound 49, and carbamates, such as compound 9.

[0405] While not limiting the scope of the invention, methylation at the 6-NH, appears to reduce activity. Moreover, substitution at X ¹ and X appears tolerable, but di substitution, such as, for example, substitution at both X ¹ and X appears to reduce activity, possibly due to steric hindrance. Also, di-substittution at R ⁸ and R ⁹ appears to reduce activity, as well.

In Vivo Antifungal Activity Assays

Cucumber Podosphaera xanthii (Powdery Mildew)

[0406] Cucumis sativus (cv. National Pickling) seeds were sewn into Sungro propagation mix potting soil using three and a half inch square pots. The plants grew for 14 days with day time temperatures of 29° C ± 2° C and night time temperatures of 24° C ± 2° C. The plants were hand watered as needed daily to ensure uniform germination and similar growth.

[0407] For 200 ppm sprays, the spray solution described below was sprayed by hand onto the plants to wetness (three plants) and allowed to dry for 18 hours.

Plants were sprayed 14 days after sewing. [0408] For 50 ppm sprays, the spray solution described below was sprayed by hand onto the plants to wetness (12 plants) and allowed to dry for 18 hours. Plants were sprayed 14 days after sewing.

[0409] Additional treatments included a spray with an identical solution to the one described above without any compound present (negative control) and a technical grade commercial fungicide (positive control).

[0410] Approximately 18 hours after the plants were sprayed, they were moved into controlled environments and inoculated with Podosphaera xanthii at a concentration of 1 x 10 ^® spores per milliliter. The environment provided for the inoculated plants was 26° C ± 2° C for both day and night temperatures. The relative humidity level in the controlled environment was maintained between 60% and 70% for the duration of the study. Fourteen days after the inoculation ratings were taken on the plants. A scale of zero to ten was used for rating with zero being indicative of no infection as seen by the naked eye, and ten being complete coverage of the adaxial leaf surface with Podosphaera xanthii. One-way analysis of variance (ANOVA) was determined and means were separate via Fisher’s least squared difference (LSD) at a=0.05. Values are reported as % inhibition relative to the untreated control.

Cucumber Pseudoperonospora cubensis (Downy Mildew)

[0411] Cucumis sativus (cv. National Pickling) seeds were sewn into Sungro propagation mix potting soil using three and a half inch square pots. The plants grew for 14 days with day time temperatures of 29° C ± 2° C and night time temperatures of 24° C ± 2° C. The plants were hand watered as needed daily to ensure uniform germination and similar growth.

[0412] For 200 ppm sprays, the spray solution described below was sprayed by hand onto the plants to wetness (three plants) and allowed to dry for 18 hours.

Plants were sprayed 14 days after sewing.

[0413] Additional treatments included a spray with an identical solution to the one described above without any compound present (negative control) and a technical grade commercial fungicide (positive control).

[0414] Approximately 18 hours after the plants were sprayed, they were moved into controlled environments and inoculated with Pseudoperonospora cubensis at a concentration of 1 x 10 ^® spores per milliliter. The environment provided for the inoculated plants was 20° C ± 2° C from 7:00 am to 11 :30 am, 25° C ± 2° C from 12:00 pm to 3:30 pm, 20° C ± 2° C from 4:00 pm to 8:30 pm, and 15° C ± 2° C from 9:00 pm to the following calendar day at 6:30 am. The relative humidity level in the controlled environment was maintained at greater than 90% for the duration of the study. Ten days after the inoculation ratings were taken on the plants. A scale of zero to ten was used for rating with zero being indicative of no infection as seen by the naked eye, and ten being complete coverage of the abaxial leaf surface with Pseudoperonospora cubensis. One-way analysis of variance (ANOVA) was determined and means were separate via Fisher’s least squared difference (LSD) at a=0.05. Values are reported as % inhibition relative to the untreated control.

Wheat Stagonospora Nodorum (also classified as Phaeosphaeria nodorum)

[0415] Triticum aestivum ( cv. AvS,l) seeds were sewn into Sungro propagation mix potting soil using three and a half inch square pots. The plants grew for 14 days with day time temperatures of 29° C ± 2° C and night time temperatures of 24° C ± 2° C. The plants were hand watered as needed daily to ensure uniform germination and similar growth.

[0416] For 200 ppm sprays, the spray solution described below was sprayed by hand onto the plants to wetness (three plants) and allowed to dry for 18 hours.

Plants were sprayed 14 days after sewing.

[0417] Additional treatments included a spray with an identical solution to the one described above without any compound present (negative control) and a technical grade commercial fungicide (positive control).

[0418] Approximately 18 hours after the plants were sprayed, they were moved into controlled environments and inoculated with Stagonospora nodorum at a

concentration of 1 x 10 ^® spores per milliliter. The environment provided for the inoculated plants was 26° C ± 2° C for day and 22° C ± 2° C night temperatures. Daytime was from 7:00 am to 7:00 pm while night was from 7:00 pm to 7:00 am the following calendar day. The relative humidity level in the controlled environment was maintained greater than 90% for the duration of the study. Twenty-one days after the inoculation ratings were taken on the plants. A scale of zero to ten was used for rating with zero being indicative of no infection as seen by the naked eye, and ten being complete coverage of the leaf surface with Stagonospora Nodorum

symptomology. One-way analysis of variance (ANOVA) was determined and means were separate via Fisher’s least squared difference (LSD) at a=0.05. Values are reported as % inhibition relative to the untreated control.

Wheat Zymoseptoria tritici (also classified as Septoria tritici)

[0419] Triticum aestivum ( cv. AvS,l) seeds were sewn into Sungro propagation mix potting soil using three and a half inch square pots. The plants grew for 14 days with day time temperatures of 29° C ± 2° C and night time temperatures of 24° C ± 2° C. The plants were hand watered as needed daily to ensure uniform germination and similar growth.

[0420] For 50 ppm sprays, the spray solution described below was sprayed by hand onto the plants to wetness (12 plants) and allowed to dry for 18 hours. Plants were sprayed 14 days after sewing.

[0421] Additional treatments included a spray with an identical solution to the one described above without any compound present (negative control) and a technical grade commercial fungicide (positive control).

[0422] Approximately 18 hours after the plants were sprayed, they were moved into controlled environments and inoculated with Zymoseptoria tritici at a concentration of 1 x 10 ^® spores per milliliter. The environment provided for the inoculated plants was 26° C ± 2° C for day and 22° C ± 2° C night temperatures. Daytime was from 7:00 am to 7:00 pm while night was from 7:00 pm to 7:00 am the following calendar day. The relative humidity level in the controlled environment was maintained greater than 90% for the duration of the study. Twenty-one days after the inoculation ratings were taken on the plants. A scale of zero to ten was used for rating with zero being indicative of no infection as seen by the naked eye, and ten being complete coverage of the leaf surface with Z. tritici symptomology. One-way analysis of variance (ANOVA) was determined and means were separate via Fisher’s least squared difference (LSD) at a=0.05. Values are reported as % inhibition relative to the untreated control.

Tomato Alternaria solani (Early Blight)

[0423] Solarium lycopersicum ( cv. Money Maker) seeds were sewn into Sungro propagation mix potting soil using three and a half inch square pots. The plants grew for 14 days with day time temperatures of 29° C ± 2° C and night time temperatures of 24° C ± 2° C. The plants were hand watered as needed daily to ensure uniform germination and similar growth.

[0424] For 50 ppm sprays, the spray solution described below was sprayed by hand onto the plants to wetness (12 plants) and allowed to dry for 18 hours. Plants were sprayed 14 days after sewing.

[0425] Additional treatments included a spray with an identical solution to the one described above without any compound present (negative control) and a technical grade commercial fungicide (positive control).

[0426] Approximately 18 hours after the plants were sprayed, they were moved into controlled environments and inoculated with Alternaria solani at a concentration of 1 x 10 ^® spores per milliliter. The environment provided for the inoculated plants was 30° C ± 2° C for day and 26° C ± 2° C night temperatures. Daytime was from 7:00 am to 7:00 pm while night was from 7:00 pm to 7:00 am the following calendar day. The relative humidity level in the controlled environment was maintained greater than 90% for the duration of the study. Twenty-one days after the inoculation ratings were taken on the plants. A scale of zero to ten was used for rating with zero being indicative of no infection as seen by the naked eye, and ten being complete coverage of the leaf surface with A. solani symptomology. One-way analysis of variance (ANOVA) was determined and means were separate via Fisher’s least squared difference (LSD) at a=0.05. Values are reported as % inhibition relative to the untreated control.

Compound Spray Preparation

[0427] 200 ppm spray preparation the experimental compounds were dissolved in DMSO at a concentration of 5 mg/mL. Then, 80pL of this compound solution was added to 0.6 mL acetone. To prepare a water surfactant mixture, 1.4 pL of Silwet Stik2 and 1.4 pL Silwet L-77 were added to 1.39 mL of water and mixed to combine. Then, the acetone compound mixture was added to the water surfactant mixture and shaken to combine. The final concentration of the experimental compound was 200 ppm in 2mL.

[0428] 50 ppm spray preparation. 0.375 mg of experimental compound was added to a vial containing 3.75 mL acetone and vortexed to dissolve. If the experimental compound was not readily soluble in acetone, 0.5 mL of NMP was added as a cosolvent. In separate a vial, 0.0075 mL Silwet Stik2 and 0.0075 mL Silwet L-77 were added to 3.735 mL D.l. water and vortexed to combine to create a water mixture. To prepare the final 50 ppm spray solution, the experimental compound and acetone solution was added to the water mixture and vortexed. If NMP was used as a cosolvent, then only 3.235 mL of the water mixture was used.

In vitro nematicidal efficacy of boron-based molecules on C. elegans

[0429] The boron-based molecules were subjected to the high-throughput screening of nematicidal compounds protocol detailed below.

Preparing Buffers

[0430] LB broth: LB growth medium(for1 liter) 10g bio-tryptone,5g yeast extract, 10g NaCI, make up to 1 liter with ddH20, adjust pH to 7.0, autoclave.

[0431] Nematode Growth Medium (NGM) Agar: Mix 23 g of agar, 3 g of NaCI, 2.5 g of bacto peptone, and deionized water to 0.972 L. Autoclave and let cool to 60 °C, then add 25 mL of 1 M potassium phosphate (KP0 ₄ ) buffer (pH 6.0), 1 mL of 1 M magnesium sulfate (MgSCL), 1 ml_ of 1 M calcium chloride (CaC ), and 1 ml_ of 5 mg/ml_ cholesterol (in ethanol).

[0432] Hypochlorite solution: 4 ml 10% NaOCI bleach solution, 10 ml 1 M NaOH, 4 ml ddH20.

[0433] Potassium citrate pH 6.0: Mix 20 g citric acid monohydrate, 293.5 g tri potassium citrate monohydrate, H20 to 1 litre. Sterilize by autoclaving.

[0434] Trace metals solution: 1.86 g disodium EDTA, 0.69 g FeSCU ·7 H ₂ 0, 0.2 g MnCl _2* 4 H2O, 0.29 g ZnSCU ·7 H2O, 0.025 g CuSCU _* 5 H2O, H2O to 1 liter. Sterilize by autoclaving. Store in the dark.

[0435] S Basal: Mix 5 g of NaCI, 1 g of K ₂ HPO ₄ , 6 g of KH ₂ PO ₄ , and de-ionized water to 1 L, then autoclave.

[0436] S Medium: 1 litre S Basal, 10 ml 1 M potassium citrate pH 6, 10 ml trace metals solution, 3 ml 1 M CaCh, 3 ml 1 M MgSCL. Add components using sterile technique; do not autoclave.

[0437] M9 Buffer: 3 g KH ₂ P0 ₄ , 6 g Na ₂ HP0 ₄ , 5 g NaCI, 1 ml 1 M MgS0 ₄ , H ₂ 0 to 1 litre. Sterilize by autoclaving.

[0438] MYOB dry mix (for 370 g): 27.5 g Trizma® HCI (TRIS HCI), 12 g Trizma® base, 230 g bacto tryptone, 100 g NaCI, 0.4 g cholesterol (95%), mix with shaking.

[0439] MYOB medium (for 1 liter): 7.4g MYOB dry mix, 22g agar, make up to1 liter with ddH20, autoclave.

Preparation of Bacterial Food Source (Concentrated E. coli Strain OP50)

[0440] Inoculate 2 ml_ of autoclaved LB broth with a single colony of E. coli (Strain OP50) and incubate for 4-6 hours at 37 °C with shaking at 250 rpm. Use 0.5 mL of this solution to inoculate 0.5 L of LB in a 1 L Erlenmeyer flask (2 flasks). Incubate for 14 hours (overnight) at 37 °C with shaking at 250 rpm. Centrifuge 1 L overnight cultures in 500 mL centrifuge bottles for 5 minutes at 10,000 x g and 4 °C to pellet the bacteria and decant away remaining media. Resuspend pellet in 25 mL of S Basal. Store at 4 °C.

Preparation of NGM Petri Plates

[0441] Mix 3 g NaCI, 17 g agar, and 2.5 g peptone in a 2 liter Erlenmeyer flask. Add 975 ml H ₂ O. Cover mouth of flask with aluminium foil. Autoclave for 50 minutes. Cool flask in 55°C water bath for 15 minutes. Add 1 ml 1 M CaCh, 1 ml 5 mg/ml cholesterol in ethanol, 1 ml 1 M MgSCL and 25 ml 1 M KPO ₄ buffer. Swirl to mix well. Using sterile procedures, dispense the NGM solution into petri plates using a peristaltic pump. Fill plates 2/3 full of agar. Leave plates at room temperature for 2-3 days before use to allow for detection of contaminants, and to allow excess moisture to evaporate. Plates stored in an air-tight container at room temperature are usable for several weeks.

Preparation of C. Elegans Mass Cultures

[0442] Add 250 ml S Medium to a sterilized 1-2 liter flask. Inoculate the S Medium with a concentrated E. coli OP50 pellet made from 2-3 litres of an overnight culture. Wash each of 4 large plates of C. elegans (just cleared of bacteria) with 5 ml S Medium and add to the 250 ml flask. Put the flask on a shaker at 20°C. Use fairly vigorous shaking so that the culture is well oxygenated. Cultures should be monitored by checking a drop of the culture under the microscope. If the food supply is depleted (the solution is no longer visibly cloudy) add more concentrated E. coli OP50 suspended in S Medium. When there are many adult worms in each drop, the culture is ready to be harvested. This is usually on the 4th or 5th day. Put the flask on ice for 15 minutes to allow the worms to settle. Aspirate most of the liquid from the flask. Transfer the remaining liquid to a 50 ml sterile conical centrifuge tube and spin for at least 2 min at 1150 ^c g to pellet the worms. Young larvae may take longer than 2 minutes to pellet. Aspirate the remaining liquid.

Preparation of C. elegans Eggs

[0443] Add 10 mL hypochlorite solution to the egg pellet and vigorously shake the tube. Incubate 1-3 minutes, with occasional shaking, and while monitoring appearance with the dissecting microscope. Visually confirm only eggs are remaining and proceed to the next step. Spin down the tube at 1 ,000 x g for 1.5 min and aspirate off the supernatant. The pellet should be white with no brown coloration. Wash the pellet 3 times with S basal, spinning down (1 ,000 x g for 1.5 minutes) and aspirating away the supernatant each time. Re-suspend the egg pellet in 2-3 mL S basal. These eggs may now be used for an overnight hatch in buffer to collect L1 larva.

Preparation of L1 Larval C. elegans

[0444] Aseptically transfer the axenized eggs to 250 ml M9 Buffer in a 1-2 liter flask and allow to incubate overnight at 20°C using fairly vigorous shaking to obtained starved L1 animals. Collect L1s in a 15 mL tube with a serological pipette. Spin down L1s in a centrifuge (1 ,000 x g for 1.5 minutes), aspirate away the supernatant. Dilute L1s in S medium to 3 L1s per pL.

Twenty four (24)-Well Assay Plate Setup

[0445] Prepare 1 liter of MYOB medium in a 2-liter flask.After autoclaving, allow MYOB medium to cool for 1 hour in a 60 1C water bath. Using a repeater pipette, add 1 ml warm MYOB medium to each well of forty 24-well tissue culture plates. Add the bioactive small molecule of interest to the media after it has cooled to 60 °C.

Allow the assay plates to reach room temperature (2 hour) and then add 5 pl_ of concentrated OP50 to each well. Add 10 pL of L1 suspension to each well. Dry plates in the laminar flow cabinet for 4-8 hours. Cover plate with lid and incubate at 25 °C for 3-7 days.

Scoring C. elegans Cultures for mortality

[0446] Monitor negative control wells until >95% mortality is observed (about 4 days). Count and record the number of alive and dead animals in each well.

Inhibition rate is scored by the formula: inhibition rate % = dead animal in the well with compounds/(alive + live animals in the well with compounds)*100 - dead animal in the negative control well/(alive + live animals in the negative control well)*100. Plant parasitic nematode in vitro screening assay

[0447] To determine the efficacy of the boron-based molecules, the boron-based molecules were subjected to the in vitro screening assay detailed below.

[0448] Plant parasitic nematode culture: The isolate of Heterodera glycines race 3 (soybean cyst nematode) was obtained from Dr. Senyu Chen, University of

Minnesota, Waseca, MN. The Meloidogyne incognita (southern root-knot nematode) was obtained from Dr. Ernest Bernard, University of Tennessee, Knoxville, TN.

[0449] Nematode inoculum preparation: Nematode eggs were setup for hatching in 4mM ZnCI ₂ solution using modified Baermann tray and incubated in

microbiological laboratory incubator at 25 °C. Freshly hatched J2s (second stage juvenile nematode) were collected and disinfected using antibiotic solution (100pp streptomycin, 50ppm chlortetracycline, and 30ppm quinolinol) before use.

[0450] In vitro nematicidal efficacy of boron-based molecules: The screening assays were conducted using 48-well microtiter plates. Stock solutions of the chemicals were prepared in dimethyl sulfoxide (DMSO) and distributed into microplates for dilutions (or the same volume of DMSO solution as negative Control). A calculated volume of 1% agarose gel was distributed and mixed with the chemical solutions in each well to complete the testing system by targeted concentration levels at 1ppm, 5ppm, and 25ppm. Leave all plates in room temperature to solidify. Each treatment was set up for four replicates.

[0451] An aliquot of nematodes containing approximately 20-30 J2s was distributed onto the surface of the agar plate in each testing well. All screening assays were stored at room temperature. Number of dead J2s were quantified at 24 hours and/or 72 hours after the initial setup. [0452] Statistics: J2 mortality (%) was calculated by (#Dead J2s/ #Total J2s)*100, and then standardized by (%Treatment mortality - %average Control mortality). ANOVA was performed to determine whether there was an overall chemical effect on standardized J2 mortality. Then LSD post hoc test for pairwise comparison (a=0.05) was performed if p-value is smaller than 0.05 in the overall ANOVA test.

[0453] While this specification contains many specific implementation details, these should not be construed as limitations on the scope of any invention or on the scope of what may be claimed, but rather as descriptions of features that may be specific to particular implementations of particular inventions. Certain features that are described in this specification in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in any suitable sub combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub combinations.

[0454] Particular implementations of the subject matter have been described. Other implementations, alterations, and permutations of the described implementations are within the scope of the following claims as will be apparent to those skilled in the art. For example, the actions recited in the claims can be performed in a different order and still achieve desirable results.

[0455] Accordingly, the above description of example implementations does not define or constrain this disclosure. Other changes, substitutions, and alterations are also possible without departing from the spirit and scope of this disclosure.

[0456] A number of embodiments of the present disclosure have been

described. While this specification contains many specific implementation details, the specific implementation details should not be construed as limitations on the scope of any disclosures or of what may be claimed, but rather as descriptions of features specific to particular embodiments of the present disclosure.

[0457] Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in combination in multiple embodiments separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub-combination.

[0458] In certain implementations, multitasking and parallel processing may be advantageous. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the claimed disclosure.