Glucose-sensitive albumin-binding derivatives

Abstract

To provide diabetes-related peptide and protein drugs with a glucose-regulated bioactivity, e.g., a weaker glucose-lowering activity of insulin at low blood glucose values.SOLUTION: This invention relates to glucose-sensitive albumin-binding diboron conjugates. More specifically, the invention provides novel diboron compounds, and specifically, diboronate or diboroxol compounds useful as intermediate compounds for synthesis of diboron conjugates.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to glucose-sensitive albumin-binding diboron conjugates. More specifically, the present invention provides novel diboronate or diboroxol compounds useful as intermediate compounds for the synthesis of diboron conjugates. [Background technology]

[0002] Boronic acids are known for their ability to bind glucose and other carbohydrates and polyols via the formation of boronate esters. Although this glucose binding is covalent, the binding equilibrium is rapid and reversible, so binding appears to be a complex formation with a displacement constant (Kd) in the millimolar range.

[0003] Simple boronic acids have a pKa value of approximately 9, but because it is the boronate form that binds most strongly to glucose (see Figure 2), tuning the pKa value of boronic acids using electron-withdrawing groups can provide stronger glucose affinity at physiological pH 7.5. Notably, monoboronates bind glucose with Kd values ​​in the 10-50 mM range, which does not match well with the physiological range of glucose excursions (typically approximately 1-30 mM in diabetic patients).

[0004] As has been extensively studied in the pursuit of optical glucose sensors, the use of diboronic acids can ensure stronger glucose affinity. However, diboronates for use as optical glucose sensors are typically colored and fluorescent (Hansen, Hoeg-Jensen et al., Sensors and Actuators B 161 (2012) 45), properties that are not necessarily desirable for other applications, especially therapeutic ones.

[0005] Diboronate selectivity for glucose over other polyols is a desirable property for in vivo use of the compound. While the majority of diboronate literature has focused on selectivity for glucose over fructose, millimolar blood concentrations of fructose do not occur even after a fructose-rich meal. Meanwhile, blood lactate concentrations are low millimolar at rest but can increase to 10–20 mM during strenuous exercise. Therefore, diboronate compounds with selectivity for glucose over lactate would be advantageous for therapeutic applications (Hansen, Hoeg-Jensen et al., Tetrahedron 67 (2011) 1334). Summary of the Invention [Problem to be solved by the invention]

[0006] Diboronic acids identified for the development of optical glucose sensors typically lack conjugation handles and are therefore less amenable to attachment to protein and peptide-based drugs.

[0007] Many protein and peptide drugs, especially insulin, GLP-1 and amylin, are used to treat diabetes.However, these therapeutic drugs have almost the same biological activity at low blood glucose levels and high blood glucose levels, and the use of these drugs may lead to extremely low blood glucose levels, which is accompanied by the risk of hypoglycemia, a life-threatening condition.

[0008] Although hypoglycemic drugs have been successfully used to treat diabetes, these drugs also have the ability to lower blood glucose levels in situations where patients do not want to change their glucose levels.This may be particularly true when blood glucose is lower than the normal fasting value of about 5 mM glucose.Therefore, it is advantageous to have diabetes-related peptide and protein drugs that have glucose-regulating biological activity, such as the glucose-lowering activity of insulin, which is weaker at low blood glucose levels. [Means for solving the problem]

[0009] The present invention provides certain diboronates and diboroxoles, which bind to glucose with Kd values ​​in the low millimolar range (approximately 0.2-5 mM) and exhibit good selectivity for glucose over lactate. Furthermore, because the diboron compounds of the present invention contain a conjugation handle, e.g., a carboxyl group, they can be conjugated to diabetes-related proteins and peptide-based drugs, for example, via attachment to a (natural or substituted / introduced) lysine residue or the N-terminus of a protein or peptide.

[0010] Furthermore, the diboron compounds of the present invention can bind to human serum albumin (HSA), and thus have a dual effect because this binding is also glucose-sensitive (due to blocking of the receptor binding site on the peptide, the HSA-bound fraction of the diboron peptide is inactive). Albumin binding can generally extend the in vivo half-life of peptide and protein-based drugs. A long-term effect is achieved because the albumin-bound fraction is protected from enzymatic degradation and renal elimination, and only the free fraction is biologically active, thus preventing receptor-mediated clearance of the albumin-bound fraction.

[0011] HSA binding of fatty acid-conjugated protein and peptide drugs is an established method for making peptides / proteins long-acting in vivo. However, it has not been reported that the diboron-conjugated peptides and proteins of the present invention, which do not contain fatty acids, can bind to HSA and that the binding is not sensitive to glucose.

[0012] Accordingly, in its first aspect, the present invention provides novel diboron compounds represented by general formula I, as described herein.

[0013] In another aspect, the present invention provides novel diboron compounds of formula Ia, and more specifically of formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and Ii as described herein.

[0014] In a further aspect, the present invention relates to the use of a diboron compound as an intermediate in the preparation of the diboron conjugates of the present invention.

[0015] In yet another aspect, the present invention provides novel diboron conjugates represented by general formula I', as described herein.

[0016] Other objects of the present invention will become apparent to those skilled in the art from the following detailed description and examples of the invention. [Brief explanation of the drawings]

[0017] The present invention will be further explained by reference to the accompanying drawings, which are described below.

[0018] [Figure 1] FIG. 1 shows a diagram of glucose-sensitive albumin binding. [Figure 2] FIG. 2 shows how glucose is attached to the boronate, shown for the pyranose form. [Figure 3] FIG. 3 shows the 19F-NMR signals from the diboron compound in free form (0.1 mM) and treated with albumin (HSA, 1 mM), or glucose (50 mM), or albumin (1 mM) + glucose (50 mM), thus demonstrating glucose-sensitive albumin binding. [Figure 4] FIG. 4 shows the 19F-NMR signals from the diboron compound of Example 20 with and without albumin and glucose as in FIG. [Figure 5] FIG. 5 shows the 19F-NMR signals from the diboron compound of Example 25 with and without albumin and glucose as in FIG. [Figure 6] FIG. 6 shows the 19F-NMR signals from the diboron compound of Example 26 with and without albumin and glucose as in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0019] Diboron conjugates of the present invention In one aspect, the present invention provides a diboron conjugate represented by the general formula I': R 1 '-X'-R 2 ' In formula I', X' represents a linker of formula Ia'; [ka] During the ceremony, ----, but R 1 ' or R 2 represents a covalent bond to ', D represents the drug substance, W' is a covalent bond, or represents a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); or X' represents a linker of formula Ib'; [ka] During the ceremony, ----, but R 1 ' or R 2 represents a covalent bond to ', R 3 ', -(CH2) m’ (C=O)-W'-D, wherein m' represents an integer ranging from 1 to 4; W' represents a covalent bond or a linker selected from the group consisting of -N-NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); D represents the drug substance, or X' represents a linker of formula Ic'; [ka] This refers to the D- or L-amino acid form, During the ceremony, ----, but R 1 ' or R 2 represents a covalent bond to ', n' represents an integer ranging from 1 to 4; W' is a covalent bond, or represents a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); D represents the drug substance, or X' represents a linker of formula Id'; [ka] which represents the R,R, or S,S, or R,S, or R,S stereoisomers of 3,4-diamino-pyrrolidine, During the ceremony, ----, but R 1 ' or R 2 represents a covalent bond to ', R 4 ' is -(C=O)(CH2) p’ (C=O)-W'-D, wherein W' is a covalent bond or -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CHCH(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue), In the formula, p' represents an integer ranging from 1 to 4, D represents the drug substance, or X' represents a linker of formula Ie'; [ka] During the ceremony, ----, but R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula If'; [ka] During the ceremony, ----, but R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula Ig'; [ka] During the ceremony, ----, but R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula Ih'; [ka] During the ceremony, ----, but R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula Ii'; [ka] During the ceremony, ----, but R 1 ' or R 2 represents a covalent bond to ', W' represents a covalent bond or a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, or -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); D represents the drug substance, R 1 ' and R 2' may be the same or different and each represent a group of formula IIa' or IIb', [ka] During the ceremony, one to four Y' represent H; 0, 1, or 2 Y' represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; one Y' represents the point of attachment to X in formula I' (representing a covalent bond); "X" Formula Ie', If', Ig' or Ih' When R 1 ' or R 2 any Y' in ' represents -(C=O)-W'-D, where W' represents a covalent bond or a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); In the formula, D represents the drug substance.

[0020] The drug substance D to be conjugated according to the present invention may be selected from a number of protein and peptide drugs used in the treatment of diabetes, specifically insulin, GLP-1, and amylin.

[0021] In one embodiment, the diboron conjugate of the present invention may be, inter alia, a compound according to general formula I', where D represents insulin or an insulin analogue.

[0022] In another embodiment, the diboron compound of the present invention is a compound according to general formula I', wherein D represents GLP-1 or a GLP-1 analog.

[0023] In a third embodiment, the diboron compound of the present invention is a compound according to general formula I', where D represents amylin or an amylin analogue.

[0024] The diboron compounds of the present invention may, in particular, be compounds according to general formula I', wherein the diboron compound represented by general formula I' is conjugated to a drug substance D via a lysine (K) residue, which may be a natural or introduced lysine residue, or to the N-terminus of the drug substance.

[0025] In another embodiment, the diboron compound of the present invention may be, in particular, a compound according to general formula I', wherein the diboron compound is conjugated to the drug substance D via a native lysine (K) residue or to the N-terminus of the drug substance.

[0026] In a third embodiment, the diboron compound of the present invention may in particular be a compound according to general formula I', wherein the diboron compound is conjugated to drug substance D via two or more (natural and / or introduced) lysine residues and / or to one or two N-termini of the drug substance.

[0027] Diboron Compounds of the Present Invention In another aspect, the present invention provides diboron compounds, specifically diboronate or diboroxol derivatives, represented by formula I: R 1 -X'-R 2 In formula I, X represents a linker of formula Ia, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to W represents OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or X represents a linker of formula Ib, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to R 3 But -(CH2) m represents (C=O)-W, In the formula, m represents an integer ranging from 1 to 4, W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or X represents a linker of formula Ic, [ka] This refers to the D- or L-amino acid form, During the ceremony, ----, but R 1 or R 2 represents a covalent bond to n represents an integer ranging from 1 to 4; W represents OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or wherein X represents a linker of formula Id, [ka] which represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine, During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 4 is -(C=O)(CH2) m represents (C=O)-W, In the formula, m represents an integer ranging from 1 to 4, W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or X represents a linker of formula Ie, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula If; [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ig, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ih; [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ii; [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, One to four Y's represent H, 0, 1, or 2 Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; one Y represents the point of attachment to X in formula I (representing a covalent bond); X is Formula Ie, If, Ig, or Ih When R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue).

[0028] In one embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ia: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to W represents OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Ia (a covalent bond representing the point of attachment); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; The remaining Y represents H.

[0029] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ia as defined above, wherein: W represents —OH.

[0030] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ia as defined above, wherein: W represents -OH; one of the Y's represents F or CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0031] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ia as defined above, wherein: W represents -OH; one of the Y's represents F; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0032] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ia as defined above, wherein: W represents -OH; R 1 and R 2 are identical and represent a group of formula IIa, one of the Y's represents F; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0033] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ia as defined above, wherein: W represents -OH; R 1 and R 2 are identical and represent a group of formula IIb, one of the Y's represents F; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0034] In another embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ib: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 3 But -(CH2) m represents (C=O)-W, In the formula, m represents an integer ranging from 1 to 4, W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Ib (a covalent bond representing the point of attachment); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0035] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ib as defined above, wherein: m is 1 and W is —OH.

[0036] In a third embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula Ic: [ka] This refers to the D- or L-amino acid form, During the ceremony, ----, but R 1 or R 2 represents a covalent bond to n represents an integer ranging from 1 to 4; W represents OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker X of formula Ic (a covalent bond representing the point of attachment); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0037] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ic, as defined above, wherein: n is an integer ranging from 1 to 3, and W is —OH.

[0038] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ic, as defined above, wherein: n is 1, 2 or 3; W represents -OH; R 1 and R 2 are identical and represent a group of formula IIa or IIb, one of the Y's represents F or CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0039] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ic, as defined above, wherein: n is 1, 2 or 3; W represents -OH; R 1 and R 2 are identical and represent a group of formula IIa, one of the Y's represents F; 2. The diboron compound of claim 1, wherein the remaining Y's represent H. In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ic, as defined above, wherein: n is 1 or 2, W represents -OH; R 1 and R 2 are identical and represent a group of formula IIb, one of the Y's represents F or CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0040] In a fourth embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula Id: [ka] which represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine, During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 4 is -(C=O)(CH2) p represents (C=O)-W, In the formula, p represents an integer ranging from 1 to 4, W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Id (a covalent bond representing the point of attachment); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0041] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Id as defined above, wherein: p is 2 and W is —OH.

[0042] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Id as defined above, wherein: p represents 2; W represents -OH; R 1 and R 2 are identical and represent a group of formula IIb, one of the Y's represents F or CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0043] In a fifth embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula Ie: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker -CO- of formula Ie (representing a covalent bond); R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0044] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Id as defined above, wherein: W is —OH.

[0045] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of formula Ie as defined above, wherein: R 1 and R 2 are identical and represent a group of formula IIa, W represents -OH; one Y represents -COOH or -CONHCH2COOH; one Y represents F or CF3; The remainder of Y represents H.

[0046] In a sixth embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula If: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker -SO- of formula If (representing a covalent bond); R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0047] In a seventh embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula Ig: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker -(SO2)- of formula Ig (a covalent bond representing the point of attachment); R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0048] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ig as defined above, wherein: R 1 and R 2are identical and represent a group of formula IIa, R 1 or R 2 any one Y represents -(C=O)-W, wherein W represents -NHCHCOOH; one Y represents F, CF3, or SF5; 2. The diboron compound of claim 1, wherein the remainder of Y represents H.

[0049] In an eighth embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula Ih: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker -(CF2)- of formula Ih; R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0050] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of formula Ih as defined above, wherein: R 1 and R 2 are identical and represent a group of formula IIa, R 1 or R 2 any one Y represents -(C=O)-W, wherein W represents -NHCHCOOH; one Y represents CF3, 2. The diboron compound of claim 1, wherein the remainder of Y represents H.

[0051] In a ninth embodiment, the diboron compound of the present invention is represented by formula I, wherein X represents a linker of formula Ii: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to W is -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CHCHCOOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker X of formula Ii (a covalent bond representing the point of attachment); 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

[0052] In a further embodiment, the diboron compounds of the present invention are represented by Formula I, wherein X represents a linker of Formula Ii as defined above, wherein: W is —OH.

[0053] In a further embodiment, the diboron compound of the present invention is represented by Formula I, wherein X is represented by Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, as defined above, wherein R 1 and R 2 may be the same or different and each represents a group of formula IIa, [ka] During the ceremony, One to four Y's represent H, 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; one Y represents the point of attachment to X in formula I (representing a covalent bond); X is Formula Ie, If, Ig, or Ih When R 1 or R 2 Any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue).

[0054] In a further embodiment, the diboron compound of the present invention is represented by Formula I, wherein X is represented by Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, as defined above, wherein R 1 and R 2 may be the same or different and each represents a group of formula IIb, [ka] During the ceremony, One to four Y's represent H, 0, 1, or 2 of Y represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3; one Y represents the point of attachment to X in formula I (representing a covalent bond); X is Formula Ie, If, Ig, or Ih When R 1 or R 2 wherein any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue).

[0055] In a further embodiment, the diboron compound of the present invention is 3,5-bis((4-borono-2-fluorobenzamido)methyl)benzoic acid, 3,5-bis((4-borono-3-fluorobenzamido)methyl)benzoic acid, N,N'-bis(4-borono-3-fluorobenzamido)-N-ethyl-glycinamide, (S)-2,4-bis(4-borono-3-fluorobenzamido)butanoic acid, N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid, N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine, N 2 ,N 6 -bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine, 3-borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid, 3-borono-5-(3-borono-5-fluorobenzoyl)benzoic acid, 3-borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid, N 6 -(4-borono-2-fluorobenzoyl)-N 2 -(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]-oxaborole-5-carbonyl)-L-lysine, (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycine, (3-borono-5-(3-borono-5-(trifluoromethyl)benzoyl)benzoyl)glycine, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)glycine, 4-((3S,4S)-3,4-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine, (3-(6-borono-2-(ethoxycarbonyl)-8-fluoro-1,1-dioxide-4H-benzo[b][1,4]thiazin-4-yl)-5-fluorophenyl)boronic acid, (3-borono-5-(3-borono-5-fluorophenyl)sulfonyl)benzoyl)glycine, N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid, 4-((3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-((3-borono-5-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)benzoyl)glycine, 4-[(3R,4R)-3,4-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]-amino]pyrrolidin-1-yl]-4-oxobutanoic acid, 2-((bis(3-borono-5-(trifluoromethyl)phenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid, N-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, N-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 3-(2,3-bis(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanamido)propanoic acid, 2-((bis(3-borono-5-(difluoromethyl)phenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid, 2-((bis(3-borono-5-chlorophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid, and 2-((bis(3-boronophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid.

[0056] Medical Use Viewed from another aspect, the present invention provides novel diboron conjugates for use as pharmaceuticals, particularly as pharmaceuticals for the treatment of metabolic disorders or conditions.

[0057] The binding constants of the diboron compounds of the present invention for glucose have been found to be in the low millimolar range (with Kd in the range of 0.2-5 mM) and therefore match the physiological range of glucose excursions (1-30 mM), specifically the glucose range in which protection against hypoglycemia is desirable (1-5 mM).

[0058] Because blood lactate levels are less variable than, or can be as high as, glucose levels, diboroxole compounds were found to offer the best selectivity for glucose over lactate (see Table 1), although diboronate compounds also have potential.

[0059] Pharmaceutical Composition Viewed from another aspect, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a diboron conjugate of the present invention. In one embodiment, the present invention provides a pharmaceutical composition comprising a diboron conjugate of the present invention and one or more excipients.

[0060] intermediate compound Viewed from another aspect, the present invention provides novel diboron compounds for use as intermediate compounds in the preparation of the novel diboron conjugates of the present invention.

[0061] Thus, in one embodiment, the present invention relates to the use of diboron compounds, specifically diboronate or diboroxol compounds represented by Formula I, as starting materials for the preparation of the diboron conjugates of the present invention.

[0062] Preparation method The diboron compounds of the present invention may be prepared by conventional methods for chemical synthesis, for example, as described in the Examples.

[0063] The diboron compounds of the present invention may then be used as starting materials for the preparation of the diboron conjugates of the present invention.

[0064] Treatment method Viewed from another aspect, the present invention provides a method for treating, preventing, or alleviating a metabolic disease or disorder or symptom in a living animal body, the method comprising the step of administering to such living animal body in need thereof a therapeutically effective amount of a diboron conjugate of the present invention.

[0065] Specific Embodiments The present invention is further illustrated by the following non-limiting embodiments: 1. A diboron conjugate represented by general formula I': [ka] In formula I', X, R 1 , and R 2 is as defined herein.

[0066] 2. A diboron compound represented by formula I, [ka] In formula I, X represents a linker of formula Ia, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to W represents -OH or -NHCH2COOH, or X represents a linker of formula Ib, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to R 3 But -(CH2) m represents COOH, In the formula, m represents an integer ranging from 1 to 4, or X represents a linker of formula Ic, [ka] This refers to the D- or L-amino acid form, During the ceremony, ----, but R 1 Or R 2represents a covalent bond to n represents an integer ranging from 1 to 4; W represents -OH or -NHCH2COOH, or wherein X represents a linker of formula Id, [ka] which represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine, During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to R 4 is -(C=O)(CH2) m (COOH), In the formula, m represents an integer ranging from 1 to 4, or X represents a linker of formula Ie, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula If; [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ig, [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ih; [ka] During the ceremony, ----, but R 1 Or R 2 represents a covalent bond to Formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih Inside, R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, One to four Y's represent H, 0, 1 or 2 of Y represent F, CF3 and / or SF5; one Y represents the point of attachment to X in formula I (representing a covalent bond); In formulas Ie, If, Ig, and Ih , a diboron compound wherein Y represents -COOH or CONHCH2COOH.

[0067] 3. The diboron compound according to embodiment 2, represented by formula I, wherein the linker is of formula Ia: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to W represents -OH or -NHCH2COOH; R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Ia (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0068] 4. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula Ib: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 3 But -(CH2) m represents COOH, In the formula, m represents an integer ranging from 1 to 4, R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Ib (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0069] 5. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula Ic: [ka] This refers to the D- or L-amino acid form, During the ceremony, ----, but R 1 or R 2 represents a covalent bond to n represents an integer ranging from 1 to 4; W represents -OH or -NHCH2COOH; R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker X of formula Ic (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0070] 6. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula Id: [ka] which represents the R,R, or S,S, or R,S, or R,S stereoisomers of 3,4-diamino-pyrrolidine, During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 4 is -(C=O)(CH2) m (COOH), In the formula, m represents an integer ranging from 1 to 4, R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Id (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0071] 7. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula Ie: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker -CO- of formula Ie (representing a covalent bond); one Y represents -COOH or -CONHCH2COOH; 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remainder of Y represents H.

[0072] 8. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula If: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker -SO- of formula If (representing a covalent bond); one Y represents -COOH or -CONHCH2COOH; 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0073] 9. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula Ig: [ka] During the ceremony, ----, but R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker -(SO2)- of formula Ig (a covalent bond representing the point of attachment); one Y represents -COOH or -CONHCH2COOH; 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0074] 10. The diboron compound according to embodiment 2, represented by formula I, wherein X represents a linker of formula Ih: [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker -(CF2)-X of formula Ih (a covalent bond representing the point of attachment); one Y represents -COOH or -CONHCH2COOH; 0, 1 or 2 of Y represent F, CF3 and / or SF5; The diboron compound of embodiment 2, wherein the remaining Y represents H.

[0075] 11. 3,5-bis((4-borono-2-fluorobenzamido)methyl)benzoic acid, 3,5-bis((4-borono-3-fluorobenzamido)methyl)benzoic acid, N,N'-bis(4-borono-3-fluorobenzamido)-N-ethyl-glycinamide, (S)-2,4-bis(4-borono-3-fluorobenzamido)butanoic acid, N-(7-fluoro-1-hydroxy-1,3-dihydro Benzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid, N-(5-fluoro-1- Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine, N 2 ,N 6-bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine, 3-borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid], 3-borono-5-(3-borono-5-fluorobenzoyl)benzoic acid, 3-borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid, N 6 -(4-borono-2-fluorobenzoyl)-N 2 -(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine, (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo-[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycine, 3-Borono-5-(3-borono-5-(trifluoromethyl)benzoyl)glycine), (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)glycine, 4-((3S,4S)-3,4-bis(7-fluoro-1-hydroxy-1,3-hydrobenzo-[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine, (3-(6-borono-2-(ethoxycarbonyl)-8-fluoro-1,1-dioxide-4H-benzo[b][1,4]thiazin-4-yl)-5-fluorophenyl)boronic acid, (3-borono-5-((3-borono-5-fluorophenyl)sulfonyl)benzoyl)-glycine N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid, 4-((3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-((3-borono-5-(pentafluoro-λ 6 4-[(3R,4R)-3,4-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]-amino]pyrrolidin-1-yl]-4-oxobutanoic acid,

[0076] 12. The diboron conjugate of embodiment 1 for use as a medicament.

[0077] 13. A diboron compound according to any one of embodiments 2 to 11 for use as an intermediate compound for the preparation of a diboron conjugate according to embodiment 1.

[0078] 14. A method for treating, preventing, or alleviating a metabolic disease or disorder or symptom in a living animal body, comprising administering a therapeutically effective amount of the diboron conjugate of embodiment 1 to such living animal body in need thereof.

[0079] The present invention is further illustrated by the following non-limiting embodiments.

[0080] 15. Diboron conjugates represented by general formula I', R 1 '-X'-R 2 ' In formula I', X' represents a linker of formula Ia'; [ka] During the ceremony, ----But R 1 ’ Or R 2 ’ represents a covalent bond to D represents the drug substance, W' is a covalent bond, or represents a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); or X' represents a linker of formula Ib'; [ka] During the ceremony, ----But R 1 ' or R 2 represents a covalent bond to R 3', -(CH2) m’ (C=O)-W'-D, wherein m' represents an integer ranging from 1 to 4; W' represents a covalent bond or a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); D represents the drug substance, or X' represents a linker of formula Ic'; [ka] This refers to the D- or L-amino acid form, During the ceremony, ----But R 1 ' or R 2 represents a covalent bond to n' represents an integer ranging from 1 to 4; W' is a covalent bond, or represents a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); D represents the drug substance, or X' represents a linker of formula Id'; [ka] which represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine, During the ceremony, ----But R 1 ' or R 2 represents a covalent bond to R 4 ' is -(C=O)(CH2) p’ (C=O)-W'-D, wherein W' is a covalent bond, or -N-NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue), In the formula, p' represents an integer ranging from 1 to 4, and D represents the drug substance, or X' represents a linker of formula Ie'; [ka] During the ceremony, ----But R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula If'; [ka] During the ceremony, ----But R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula Ig'; [ka] During the ceremony, ----But R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula Ih'; [ka] During the ceremony, ----But R 1 ' or R 2 ' represents a covalent bond to ', or X' represents a linker of formula Ii'; [ka] During the ceremony, ----But R 1 ' or R 2 represents a covalent bond to W' represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 ' and R 2 ' may be the same or different and each represent a group of formula IIa' or IIb', [ka] During the ceremony, one to four Y' represent H; 0, 1, or 2 Y' represent F, Cl, CF2, CF3, and / or SF5; one Y' represents the point of attachment to X in formula I' (representing a covalent bond); X' is Formula Ie', If', Ig' or Ih' When R 1 ' or R 2 any Y in ' represents -(C=O)-W'-D, where W' represents a covalent bond or a linker selected from the group consisting of -NHCH2(C=O)-, -NHCH2CH2(C=O)-, -NHCH2CH2CH2(C=O)-, and -NHCH(COOH)CH2CH2(C=O)- (the latter representing an L-gamma-Glu or D-gamma-Glu residue); A diboron conjugate wherein D represents the drug substance.

[0081] 16. A diboron compound represented by formula I, [ka] In formula I, X represents a linker of formula Ia, [ka] During the ceremony, ----But R 1 Or R 2 represents a covalent bond to W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or X represents a linker of formula Ib, [ka] During the ceremony, ----But R 1 Or R 2 represents a covalent bond to R 3 But -(CH2) m represents (C=O)-W, In the formula, m represents an integer ranging from 1 to 4, W represents OH, NHCH2COOH, NHCH2CH2COOH, NHCH2CH2CH2COOH, or NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or X represents a linker of formula Ic, [ka] This refers to the D- or L-amino acid form, During the ceremony, ----But R 1 or R 2 represents a covalent bond to n represents an integer ranging from 1 to 4; W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or wherein X represents a linker of formula Id, [ka] which represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine, During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 4 is -(C=O)(CH2) p represents (C=O)-W, In the formula, p represents an integer ranging from 1 to 4, W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), or X represents a linker of formula Ie, [ka] During the ceremony, ----But R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula If; [ka] During the ceremony, ----But R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ig, [ka] During the ceremony, ----But R 1 Or R 2 represents a covalent bond to, or X represents a linker of formula Ih; [ka] During the ceremony, ----But R 1 Or R 2represents a covalent bond to, or X represents a linker of formula Ii; [ka] During the ceremony, ----But R 1 Or R 2 represents a covalent bond to W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, One to four Y's represent H, 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; one Y represents the point of attachment to X in formula I (representing a covalent bond); X is Formula Ie, If, Ig, or Ih When R 1 or R 2 Diboron compounds in which any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue).

[0082] 17. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ia: [ka] During the ceremony, ----But R 1 or R 2represents a covalent bond to W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Ia (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0083] 18. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ib: [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 3 But -(CH2) m represents (C=O)-W, In the formula, m represents an integer ranging from 1 to 4, W represents OH, NHCH2COOH, NHCH2CH2COOH, NHCH2CH2CH2COOH, or NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue), R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Ib (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0084] 19. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ic: [ka] This refers to the D- or L-amino acid form, During the ceremony, ----But R 1 or R 2 represents a covalent bond to n represents an integer ranging from 1 to 4; W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker X of formula Ic (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0085] 20. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Id: [ka] which represents the R,R, or S,S, or R,S, or R,S stereoisomers of 3,4-diamino-pyrrolidine, During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 4 is -(C=O)(CH2) p represents (C=O)-W, In the formula, p represents an integer ranging from 1 to 4, W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker X of formula Id (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0086] 21. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ie: [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker -CO- of formula Ie (representing a covalent bond); R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remainder of Y represents H.

[0087] 22. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula If; [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents the point of attachment to the linker -SO- of formula If (representing a covalent bond); R 1 or R 2any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0088] 23. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ig: [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker -(SO2)- of formula Ig (a covalent bond representing the point of attachment); R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0089] 24. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ih: [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker -(CF2)- of formula Ih; R 1 or R 2 any one Y represents -(C=O)-W, where W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0090] 25. The diboron compound according to embodiment 16, represented by formula I, wherein X represents a linker of formula Ii: [ka] During the ceremony, ----But R 1 or R 2 represents a covalent bond to W represents -OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2CH2CH2COOH, or -NHCH(COOH)CH2CH2COOH (the latter representing an L-gamma-Glu or D-gamma-Glu residue); R 1 and R 2 may be the same or different and each represent a group of formula IIa or IIb, [ka] During the ceremony, one Y represents a point of attachment to the linker X of formula Ii (a covalent bond representing the point of attachment); 0, 1 or 2 of Y represent F, Cl, CF2, CF3 and / or SF5; The diboron compound of embodiment 16, wherein the remaining Y represents H.

[0091] 26. 3,5-bis((4-borono-2-fluorobenzamido)methyl)benzoic acid, 3,5-bis((4-borono-3-fluorobenzamido)methyl)benzoic acid, N,N'-bis(4-borono-3-fluorobenzamido)-N-ethyl-glycinamide, (S)-2,4-bis(4-borono-3-fluorobenzamido)butanoic acid, N-(7-fluoro-1-hydroxy-1,3-dihydro Benzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid, N-(5-fluoro-1- Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine, N 2 ,N 6 -bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine, 3-borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid, 3-borono-5-(3-borono-5-fluorobenzoyl)benzoic acid, 3-borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid, N 6 -(4-borono-2-fluorobenzoyl)-N 2-(6-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine, (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo-[c][1,2]oxaborole-6-carboxamido)propanoic acid, (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid, (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6 -carboxamido)propanoic acid, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)-glycine, (3-borono-5-(3-borono-5-(trifluoromethyl)benzoyl)benzoyl)glycine, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)glycine, 4-((3S,4S)-3,4-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-Borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine, (3-(6-borono-2-(ethoxycarbonyl)-8-fluoro-1,1-dioxide-4H-benzo[b][1,4]thiazin-4-yl)-5-fluorophenyl)boronic acid, (3-borono-5-((3-borono-5-fluorophenyl)sulfonyl)benzoyl)glycine, N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl) (3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-(pentafluoro-lambda)-4-yl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid, 4-( ... 6 -sulfanyl)phenyl)sulfonyl)benzoyl)glycine, 2-((bis(3-borono-5-(trifluoromethyl)phenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid, N-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-(difluoromethyl)-1-hydroxy-1,3-dihydromethyl[c][1,2]oxaborole-6-carboxamido)ethyl)-glycine, N-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, A diboron compound selected from the group consisting of 3-(2,3-bis(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanamido)propanoic acid, 2-((bis(3-borono-5-(difluoromethyl)phenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid; 2-((bis(3-borono-5-chlorophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid, and 2-((bis(3-boronophenyl)(oxo)-λ6-sulfanylidene)-amino)acetic acid.

[0092] 27. A diboron conjugate according to any one of embodiments 15 to 26 for use as a medicament.

[0093] 28. A diboron compound according to any one of embodiments 15 to 26, for use as an intermediate compound for the preparation of a diboron conjugate according to embodiment 15.

[0094] 29. A method for treating, preventing, or alleviating a metabolic disease or disorder or symptom in a living animal body, comprising administering to such living animal body in need thereof a therapeutically effective amount of a diboron conjugate of any one of embodiments 15-26. [Example]

[0095] The present invention is further described with reference to the following examples, which are not intended to in any way limit the scope of the invention as claimed.

[0096] Abbreviations used herein AA Acetic Acid AIBN 2,2'-azobis(2-methylpropionitrile) ARS Alizarin Red Sodium DAST (Diethylamino)sulfur trifluoride DCC N,N'-dicycliohexylcarbodiimide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide ELSD Electrospray Detection F-NMR Fluorine-19 Nuclear Magnetic Resonance Spectroscopy FA formic acid HATU 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate HSA Human serum albumin LCMS Liquid Chromatography Mass Spectrometry NBS N-Bromosuccinimide (1-Bromopyrrolidine-2,5-dione) NIS N-Iodosuccinimide (1-iodobromopyrrolidine-2,5-dione) NMR nuclear magnetic resonance spectroscopy HOSu, NOHSu N-hydroxysuccinimide PCC Pyridinium Chlorochromate XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0097] Preparation of the Diboron Compounds of the Invention Example 1 3,5-Bis((4-borono-2-fluorobenzamido)methyl)benzoic acid [ka] 3,5-bis((4-borono-2-fluorobenzamido)methyl)benzoic acid was synthesized according to the reaction schemes shown in Chemical Reaction 1 and Chemical Reaction 2 and according to the procedures described below. [ka]

[0098] 3,5-Dimethylbenzoic acid (4, 27.6 g, 18.4 mmol) was suspended in methanol (80 mL) and treated with concentrated sulfuric acid (8 mL). The mixture was refluxed for 2 days. After neutralization with sodium carbonate (50 g), the mixture was dissolved in water (250 mL) and extracted with diethyl ether (2 × 300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give methyl 3,5-dimethylbenzoate 5 as a pale yellow oil.

[0099] Yield: 29.3g (97%).

[0100] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.67(s,2 H);7.19(s,1 H);3.91(s,3 H);2.37(s,6 H).

[0101] A mixture of the above methyl 3,5-dimethylbenzoate (5, 29.3 g, 178 mmol), N-bromosuccinimide (NBS, 111 g, 623 mmol), and one spatula of azobisisobutyronitrile in methyl formate (450 mL) was heated to reflux for 20 h while irradiating with visible light. The solvent was evaporated, and the residue was dissolved in dichloromethane (200 mL). The precipitated succinimide was filtered, and the filtrate was washed with a saturated aqueous solution of sodium sulfate (2 × 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: hexane / ethyl acetate 15:1). The product was crystallized from an ethyl acetate / cyclohexane mixture to give methyl 3,5-bis(bromomethyl)benzoate 6 as a white solid.

[0102] Yield: 25.6g (45%).

[0103] R F (SiO2, hexane / ethyl acetate 9:1): 0.50.

[0104] 1H NMR spectrum (300 MHz, CDCl3, δ H ):8.02-7.95(m,2 H);7.62(s,1 H);4.51(s,4 H);3.94(s,3 H).

[0105] A suspension of the above bromide 6 (25.3 g, 78.6 mmol) and sodium diformylamide (20.9 g, 220 mmol) in dry acetonitrile (350 mL) was refluxed for 4 h. The white solid was removed by filtration, and the solvent was evaporated. Recrystallization from an ethyl acetate / cyclohexane mixture gave methyl 3,5-bis((N-formylformamido)methyl)benzoate 7 as a white powder.

[0106] Yield: 21.0g (88%).

[0107] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):9.08(s,4 H);7.72(s,2 H);7.44(s,1 H);4.70(s,4 H);3.84(s,3 H).

[0108] The benzoate salt (7, 20.9 g, 68.5 mmol) was dissolved in a mixture of 1,4-dioxane (220 mL) and concentrated hydrochloric acid (280 mL) and heated to reflux for 2 h. After cooling to room temperature, a stream of air was passed through the solution. The product began to precipitate. After 1 h, the solvent was evaporated and the product was recrystallized from a methanol / diethyl ether mixture to give 3,5-bis(aminomethyl)benzoic acid dihydrochloride 8 as a white powder.

[0109] Yield: 17.1g (98%).

[0110] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.26(bs,1 H);8.65(bs,6 H);8.10(s,2 H);7.88(s,1 H);4.08(s,4 H). [ka]

[0111] A mixture of 4-borono-2-fluorobenzoic acid (1, 1.14 g, 6.20 mmol), pinacol (0.74 g, 6.20 mmol), and molecular sieves (2.60 g) in dry toluene (40 mL) was stirred at room temperature overnight. The suspension was filtered, and the solid residue was suspended in dichloromethane (50 mL). Subsequently, hydroxysuccinimide (HOSu, 1.43 g, 12.4 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl, 2.38 g, 12.4 mmol) were added. The resulting mixture was stirred at room temperature overnight. The suspension was filtered, and the filtrate was partitioned between ethyl acetate (80 mL) and 0.1 M aqueous hydrochloric acid (50 mL). The organic layer was washed with 0.1 M aqueous hydrochloric acid (2 × 75 mL) and brine (1 × 75 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give 2,5-dioxopyrrolidin-1-yl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2) as a white powder.

[0112] Yield: 1.36g (62%).

[0113] 1 H NMR spectrum (400 MHz, CDCl3, δ H ):8.07-8.03(m,1 H);7.69-7.65(m,1 H);7.65-7.60(m,1 H);2.92(bs,4 H);1.37(s,12 H).

[0114] 3,5-Bis(aminomethyl)benzoic acid dihydrochloride (3, 152 mg, 0.60 mmol) was dissolved in water (2 mL). Subsequently, N,N-diisopropylethylamine (0.04 mL, 0.24 mmol), N,N-dimethylformamide (4 mL), and 2,5-dioxopyrrolidin-1-yl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2, 0.44 g, 1.20 mmol) were added. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The liquid residue was dissolved in aqueous trifluoroacetic acid (50%, 10 mL) and stirred overnight at 90 °C. The precipitate was collected by filtration and washed with acetonitrile to give the title compound (4) as a white powder.

[0115] Yield: 105 mg (35%).

[0116] 1 H NMR spectrum (400 MHz, DMSO-d6, δ H ):12.94(bs,1 H);9.03-8.88(m,2 H);8.36(s,4 H);7.83(s,2 H);7.67-7.53(m,7 H);4.51(d,J=5.9 Hz,4 H).

[0117] LC-MS purity: 99% (ELSD).

[0118] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 2.21 min.

[0119] LC-MS m / z: 513.4 (M+H) + .

[0120] Example 2 3,5-bis((4-borono-3-fluorobenzamido)methyl)benzoic acid [ka] 3,5-bis((4-borono-3-fluorobenzamido)methyl)benzoic acid was prepared from 4-borono-3-fluorobenzoic acid in the same manner as the compound of Example 1.

[0121] Example 3 N,N'- Bis(4-borono-3-fluorobenzamido)-N-ethyl-glycinamide [ka] N,N'-bis(4-borono-3-fluorobenzamido)-N-ethyl-glycinamide was prepared from 4-borono-3-fluorobenzoic acid in the same manner as the compound of Example 5.

[0122] Example 4 (S)-2,4-bis(4-borono-3-fluorobenzamido)butanoic acid [ka] (S)-2,4-bis(4-borono-3-fluorobenzamido)butanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 3 and according to the procedure described below. [ka]

[0123] L-2,4-Diaminobutyric acid dihydrochloride (0.20 g, 1.69 mmol) was dissolved in water (3.6 mL). Subsequently, N,N-diisopropylethylamine (1.18 mL, 6.76 mmol), N,N-dimethylformamide (7.2 mL), and 2,5-dioxopyrrolidin-1-yl 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1, 1.23 g, 3.38 mmol) were added. The mixture was stirred overnight at room temperature and then acidified with 1 M aqueous hydrochloric acid. The solvent was coevaporated three times with toluene. The residue was dissolved in a dichloromethane / toluene mixture (1:1, 100 mL). The residue was dissolved in ethyl acetate (60 mL) and washed with water (3 × 40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in dichloromethane (3 mL) and the product began to precipitate. Cyclohexane was added (35 mL). The precipitate was collected by filtration, washed with cyclohexane, and dried under vacuum to give 2,4-bis(4-(1,3,2-dioxaborolan-2-yl)-3-fluorobenzamido)butanoic acid (2) as a clear oil.

[0124] Yield: 960 mg (92%).

[0125] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.90-7.75(m,2 H);7.65-7.40(m,5 H);7.11-7.02(m,1 H);4.91-4.79(m,1 H);3.58-3.50(s,2 H);2.10-1.70(m,4 H);1.36(s,24 H).

[0126] LC-MS purity: 100% (ELSD).

[0127] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA): 2.82 min, 3.56 min, 4.53 min.

[0128] LC-MS m / z: 615.6 (M+H)+ , 533.5 (M+H-pinacol) + , 451.4 (M + H-2 × pinacol) + .

[0129] The above acid (2, 200 mg, 0.32 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.75 mL). Sodium metaperiodate (0.35 g, 1.63 mmol) was added, and the resulting mixture was vigorously stirred at ambient temperature (24 °C) for 2 h. The resulting suspension was evaporated in vacuo. The residue was purified by preparative LC / MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) to give the title compound (3) as a white solid.

[0130] Yield: 50.0 mg (26%).

[0131] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):8.73(d,J=7.5 Hz,1 H);8.58(t,J=5.5 Hz,1 H);8.35(d,J=7.9 Hz,4 H);7.70-7.50(m,6 H);4.49-4.42(m,1 H);3.54-3.43(m,2 H);2.19-1.95(m,2 H).

[0132] LC-MS purity: 100% (ELSD).

[0133] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.80 min.

[0134] LC-MS m / z: 450.4 (M+H) + .

[0135] Example 5 N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction schemes shown in Chemical Reaction 4 and Chemical Reaction 5 and in accordance with the procedures described below. [ka]

[0136] Ethane-1,2-diamine (2, 44.0 mL, 659 mmol) was dissolved in anhydrous dichloromethane (300 mL), and tert-butyl 2-bromoacetate (1, 11.0 mL, 81.7 mmol) in anhydrous dichloromethane (20 mL) was added using a syringe pump (3 mL / h) under an argon atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 10 h. The resulting mixture was extracted with water (200 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in cold diethyl ether (150 mL) and precipitated with a 3 M solution of hydrogen chloride in diethyl ether to give tert-butyl (2-aminoethyl)glycinate hydrochloride (3) as a white solid.

[0137] Yield: 10.8g (63%).

[0138] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):3.31(s,2 H);2.83-2.75(m,2 H);2.73-2.64(m,2 H);1.47(s,9 H). [ka]

[0139] 7-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (2, 0.30 g, 1.53 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU, 0.58 g, 1.53 mmol) and N,N-diisopropylethylamine (1.06 mL, 6.12 mmol) were added. After 5 min, tert-butyl (2-aminoethyl)glycinate hydrochloride (1, 0.16 g, 0.77 mmol) was added to the reaction mixture at room temperature, and the reaction was stirred for 16 h. The volatiles were then evaporated under reduced pressure, and the ester 3 was used in the next step without further purification.

[0140] LC-MS purity: 40% (ELSD).

[0141] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.48 min.

[0142] LC-MS m / z: 531.7 (M+H) + .

[0143] tert-Butyl N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycinate (3, <0.77 mmol) was dissolved in a 5.2 M solution of hydrogen chloride in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. The volatiles were then evaporated under reduced pressure, and the residue was purified by preparative HPLC (Column X-Bridge, C18, 15 μm, 50 × 250 mm, acetonitrile / water 3:97 to 30:70 + 0.05% AA) and lyophilized to give N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine 4 as a white solid.

[0144] Yield: 81 mg (22%).

[0145] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):9.41-9.33(m,2 H);8.42-8.18(m,1 H);7.81-7.64(m,1 H);7.43-7.11(m,3 H);5.07-4.97(m,4 H);4.22(s,1 H);3.98(s,1 H);3.68(t,J=6.5 Hz,1H);3.60-3.40(m,3H).

[0146] LC-MS purity: 96% (ELSD).

[0147] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.98 min.

[0148] LC-MS m / z: 475.5(M+H)+.

[0149] Example 6 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid [ka] 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 6 and according to the procedure described below. [ka]

[0150] Butyllithium (2.35 M in hexane, 53.0 ml, 125 mmol) was added dropwise over 20 minutes to a nitrogen-purged solution of 2,2,6,6-tetramethylpiperidine (17.7 g, 125 mmol) in anhydrous tetrahydrofuran (100 mL), maintaining the internal temperature below −35° C. A solution of 2-fluoro-4-methylbenzonitrile (1, 15.0 g, 111 mmol) in dry tetrahydrofuran (50 mL) was added dropwise to the above mixture at a rate that maintained the internal temperature below −70° C. The mixture was then warmed to −50° C. for 45 minutes. A solution of iodine (31.0 g, 122 mmol) in tetrahydrofuran (50 mL) was added dropwise to the reaction mixture, maintaining the internal temperature below −60° C. The mixture was stirred at ambient temperature for 12 hours and then quenched by pouring into a stirred solution of sodium thiosulfate (10 g) in water (500 mL). The mixture was stirred for 1 hour. The mixture was treated with ethyl acetate (300 mL), and the aqueous phase was separated and re-extracted (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and evaporated. The residue was loaded onto silica by coevaporation, and column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / diethyl ether 10:1) gave the crude product, which was crystallized from methanol to give 2-fluoro-3-iodo-4-methylbenzonitrile (2) as a white crystalline solid.

[0151] Yield: 18.49g (64%).

[0152] R F (SiO2, cyclohexane / diethyl ether 9:1): 0.35

[0153] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 7.48 (dd, J = 7.9 and 6.5 Hz, 1 H); 7.17-7.12 (m, 1 H), 2.56 (s, 3 H).

[0154] A slurry of 2-fluoro-3-iodo-4-methylbenzonitrile (2, 18.5 g, 70.7 mmol) in 75% sulfuric acid (29 mL) was stirred for 2 hours at 150° C. After cooling, the mixture was poured onto ice / water (275 g) and the precipitated solid was filtered, washed with water, and dried to give 2-fluoro-3-iodo-4-methylbenzoic acid (3) as a cream solid.

[0155] Yield: 19.18g (97%).

[0156] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.30(s,1 H);7.75(t,J=7.8 Hz,1 H);7.27(d,J=8.0 Hz,1 H);2.47(s,3 H).

[0157] Acetyl chloride (4.90 mL, 68.7 mmol) was added dropwise to a stirred suspension of 2-fluoro-3-iodo-4-methylbenzoic acid (3, 19.1 g, 68.3 mmol) in dry methanol (75 mL) at 0° C. The mixture was refluxed for 9 hours. The volatiles were removed by evaporation under reduced pressure, and the residue was treated with ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The mixture was filtered through a cotton plug (200 mL ethyl acetate wash). The phases were separated, and the organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from isopropanol / water (1:1, 30 mL) to give methyl 2-fluoro-3-iodo-4-methylbenzoate (4) as off-white needles.

[0158] Yield: 18.36g (91%).

[0159] R F (SiO2, cyclohexane / diethyl ether 9:1): 0.50

[0160] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.80(t,J=7.7 Hz,1 H);7.10(d,J=8.0 Hz,1 H);3.93(s,3 H);2.52(s,3 H).

[0161] A solution of 2-fluoro-3-iodo-4-methylbenzoate (4, 18.5 g, 62.9 mmol), bis(pinacolato)diboron (5, 24.0 g, 94.4 mmol), anhydrous potassium acetate (18.5 g, 189 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (1.02 g, 1.25 mmol) in anhydrous dimethyl sulfoxide (250 mL) was stirred at 110 °C for 20 hours under an argon atmosphere. The reaction mixture was then cooled to ambient temperature, diluted with water (2000 mL), and extracted with ethyl acetate (4 × 500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / dichloromethane 9:1) to give methyl 2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6). Yield: 13.0g (70%).

[0162] R F (SiO2, cyclohexane / dichloromethane 9:1): 0.30

[0163] 1 H NMR spectrum (300 MHz, CDCl3, δ H):7.84(t,J=8.0 Hz,1 H);7.00(d,J=8.1 Hz,1 H);3.90(s,3 H);2.47(s,3 H);1.39(s,12 H).

[0164] A solution of methyl 2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6, 11.7 g, 39.8 mmol), 1-bromopyrrolidine-2,5-dione (NBS, 9.20 g, 51.7 mmol), and 2,2'-azobis(2-methylpropionitrile) (AIBN, 0.33 g, 1.99 mmol) in benzotrifluoride (170 mL) was stirred at 85 °C for 16 h. The reaction mixture was cooled to ambient temperature, and a 12% aqueous solution of potassium hydroxide (80 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The aqueous layer was separated, and another portion of a 12% aqueous solution of potassium hydroxide (50 mL) was added to the organic layer, and the reaction mixture was stirred at room temperature for an additional 30 min. The combined aqueous layers were then acidified with 1 M aqueous hydrochloric acid to a pH of less than 1 and allowed to stir at ambient temperature for 20 h. The precipitate was filtered to give 7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7) as a beige solid.

[0165] Yield: 5.34g (68%).

[0166] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):9.39(s,1 H);7.97(t,J=7.3 Hz,1 H);7.32(d,J=7.9 Hz,1 H);5.04(s,2 H).

[0167] LC-MS purity: 100% (ELSD).

[0168] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 3.95 min.

[0169] LC-MS m / z: 373.4 (M+H)+ .

[0170] 1-Hydroxy-2,5-pyrrolidinedione (HOSu, 1.17 g, 10.2 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine hydrochloride (EDC·HCl, 1.95 g, 10.2 mmol) were added to a solution of 7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7, 2.00 g, 10.2 mmol) in a mixture of tetrahydrofuran / N,N-dimethylformamide (5:1, 50 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. The volatiles were then evaporated, and the residue was dissolved in ethyl acetate (200 mL) and extracted with 1 M aqueous hydrochloric acid (2 × 80 mL) and brine (1 × 50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from hot 2-propanol (50 mL) to give 2,5-dioxopyrrolidin-1-yl 7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8) as a pale yellow solid.

[0171] Yield: 1.30 mg (44%).

[0172] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ): 9.56 (s, 1 H); 8.15 (dd, J = 7.9 and 6.6 Hz, 1 H); 7.50 (d, J = 8.1 Hz, 1 H); 5.12 (s, 2 H); 2.84 (s, 4 H).

[0173] LC-MS purity: 100% (ELSD).

[0174] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95–100:0 + 0.1% FA): 3.20 min.

[0175] LC-MS m / z: 294.4 (M+H) + .

[0176] A solution of 2,5-dioxopyrrolidin-1-yl 7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8, 200 mg, 0.68 mmol), 3,5-bis(aminomethyl)benzoic acid dihydrochloride (9, 86.0 mg, 0.34 mmol), and N,N-diisopropylethylamine (0.36 mL) in a mixture of N,N-dimethylformamide / water (4:1, 10 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was then evaporated, and the residue was precipitated with 20% aqueous acetonitrile (15 mL). The resulting suspension was diluted with an additional portion of water (20 mL) and centrifuged. The solid was then collected, purified by preparative LC / MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA), and lyophilized to give 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid (10) as a white solid.

[0177] Yield: 71.0 mg (39%).

[0178] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):9.38(s,2 H);8.99-8.87(m,2 H);7.83(s,2 H);7.76(t,J=7.3 Hz,2 H);7.55(s,1 H);7.30(d,J=7.9 Hz,2 H);5.03(s,4 H);4.52(d,J=5.7 Hz,4 H).

[0179] LC-MS purity: 100% (ELSD).

[0180] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.16 min.

[0181] LC-MS m / z: 537.7 (M+H)+ .

[0182] Example 7 N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 7 and in accordance with the procedures described below. [ka]

[0183] A solution of 5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (1, 140 mg, 0.71 mmol), 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU, 265 mg, 0.70 mmol), and N,N-diisopropylethylamine (0.31 mL, 1.79 mmol) in dichloromethane (5 mL) was allowed to stir at ambient temperature. After 5 minutes, tert-butyl(2-aminoethyl)glycinate hydrochloride (2, 0.09 g, 0.36 mmol) was added to the reaction mixture at room temperature, and the reaction was stirred for 18 hours. The volatiles were then evaporated under reduced pressure, and concentrated hydrochloric acid (2 mL) was added. The reaction mixture was allowed to stir at ambient temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was then added to adjust the pH to neutral. The aqueous layer was extracted with acetonitrile (3 × 10 mL) and ethyl acetate (2 × 10 mL). The organic solution was then evaporated under reduced pressure. The crude product 3 was purified by preparative LC / MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). The isolated compound 3 was then purified by preparative HPLC (Column X-Select, C18, 15 μm, 30 × 150 mm, acetonitrile / water 3:97 to 30:70 + 0.05% AA) and lyophilized to give N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine (3) as a white solid.

[0184] Yield: 10 mg (6%).

[0185] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):9.39-9.23(m,2 H);8.55-8.22(m,1 H);8.05-7.93(m,1 H);7.67-7.63(m,1 H);7.36-7.21(m,2 H);5.00-4.97(m,4 H);4.20(s,1 H);3.88(s,1 H);3.70-3.65(m,2 H);3.57-3.53(m,2 H).

[0186] LC-MS purity: 100% (ELSD).

[0187] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.98 min.

[0188] LC-MS m / z: 475.5(M+H)+.

[0189] Example 8 N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction schemes shown in Chemical Reaction 8 and Chemical Reaction 9 and in accordance with the procedures described below. [ka]

[0190] A vigorously stirred solution of 3-fluoro-4-methylbenzoic acid (1, 61.7 g, 400 mmol) in sulfuric acid (96%, 400 mL) was cooled with an external ice-water bath, and N-bromosuccinimide (72.0 g, 405 mmol) was added in three portions over 20 minutes. The mixture was stirred at room temperature for 4 hours, then another portion of N-bromosuccinimide (72.0 g, 405 mmol) was added in one portion, and the whole mixture was stirred at room temperature overnight. The resulting suspension was diluted with ice water (3.00 L) and stirred for 10 minutes. The solid was filtered, washed with water (200 mL), triturated with water (3 × 600 mL), and sucked out as much as possible. The wet solid was suspended in water (400 mL), stirred at room temperature, and sodium hydroxide solution (50.0 g, 1.25 mol in 200 mL of water) was added. The resulting solution was heated to 40 °C overnight. Filtration of the slightly cloudy solution gave a clear, yellowish filtrate, to which potassium bisulfate solution (180 g, 1.32 mol in 400 mL of water) was added. The white precipitate was extracted with a 4:1 mixture of dichloromethane / tetrahydrofuran (2 × 500 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness to give a white solid residue. Thionyl chloride (30.0 mL, 413 mmol) was added to a stirred, cooled (−78 °C) suspension of this residue in anhydrous methanol (500 mL). The reaction mixture was allowed to warm to room temperature and then heated to 60 °C overnight. The solution was cooled to room temperature and kept at 4 °C overnight. The crystalline material was filtered, washed with methanol (2 × 50 mL), tert-butyl methyl ether (2 × 50 mL), and filtered under vacuum to give methyl 2,3-dibromo-5-fluoro-4-methylbenzoate (2) as colorless crystals.

[0191] Yield: 78.2g (60%).

[0192] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.37(d,J=9.0 Hz,1 H);3.94(s,3 H);2.46(d,J=2.3 Hz,3 H).

[0193] LC-MS purity: 98% (UV).

[0194] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 40:60 to 100:0 + 0.1% FA): 4.55 min.

[0195] LC-MS m / z: 327.2 (M+H) + .

[0196] A suspension of finely powdered copper (44.0 g, 692 mmol) and methyl 2,3-dibromo-5-fluoro-4-methylbenzoate (2, 75.2 g, 231 mmol) in propionic acid (100 mL) was stirred and heated to 85-90 °C for 6 h, cooled to room temperature, and diluted with a mixture of cyclohexane / toluene (3:1, 800 mL). The reaction mixture was washed with water (3 × 200 mL), 10% aqueous potassium bisulfate (2 × 200 mL), and brine (2 × 300 mL). The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness to give a yellowish oil, which was purified by silicagel 60 (0.040-0.060 mm, eluent: cyclohexane / toluene 3:1) to give methyl 3-bromo-5-fluoro-4-methylbenzoate (3) as colorless crystals.

[0197] Yield: 52.5g (92%).

[0198] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.51(s,1 H);7.37(d,J=9.0 Hz,1 H);3.86(s,3 H);2.37(d,J=2.4 Hz,3 H).

[0199] LC-MS purity: 99% (UV).

[0200] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 40:60 to 100:0 + 0.1% FA): 3.72 min.

[0201] LC-MS m / z: 347.3 (M+H) + .

[0202] Methyl 3-bromo-5-fluoro-4-methylbenzoate (3, 51.9 g, 210 mmol) was dissolved in anhydrous 1,4-dioxane (400 mL), anhydrous potassium acetate (65.3 g, 666 mmol) and bis(pinacolato)diboron (4, 75.1 g, 296 mmol) were added at room temperature, and the mixture was degassed. 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.88 g, 2.57 mmol) was added, and the mixture was heated to 75 °C for 40 h under an argon atmosphere. The mixture was concentrated under reduced pressure, dissolved in toluene (1.1 L), and extracted with water (2 × 200 mL). The organic solution was dried using anhydrous sodium sulfate, evaporated under reduced pressure, and then purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: toluene / ethyl acetate 9:1) to give methyl 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5) as a white solid.

[0203] Yield: 50.0g (81%).

[0204] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.20(s,1 H);7.70(d,J=10.0 Hz,1 H);3.85(s,3 H);2.50(s,3 H);1.36(s,12 H).

[0205] LC-MS purity: 100% (ELSD).

[0206] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 40:60 to 100:0 + 0.1% FA): 6.12 min.

[0207] LC-MS m / z: 295.4 (M+H) + .

[0208] Azobisisobutyronitrile (AIBN, 0.86 g, 5.20 mmol) and N-bromosuccinimide (NBS, 25.4 g, 143 mmol) were added to a solution of methyl 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5, 40.0 g, 136 mmol) in 1,2-dichloroethane (200 mL). The mixture was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane (500 mL), and extracted with water (2 × 500 mL). The organic solution was dried over anhydrous magnesium sulfate and evaporated to dryness to give methyl 4-(bromomethyl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6) as yellowish crystals. The product was used in the next step without further purification.

[0209] Yield: 35.5g (70%).

[0210] LC-MS purity: 96% (ELSD).

[0211] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 40:60 to 100:0 + 0.1% FA): 6.53 min.

[0212] LC-MS m / z: 373.4 (M+H) + .

[0213] Methyl 4-(bromomethyl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6, 7.46 g, 20.0 mmol) was stirred with 2.5 M aqueous sodium hydroxide (40.0 mL, 100 mmol) at room temperature overnight. 6 M aqueous hydrochloric acid (20.0 mL, 120 mmol) was added, and the mixture was stirred for 30 minutes and kept at 4 °C overnight. The white precipitate was collected by filtration, washed with water (2 × 100 mL), and air-dried to give 4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7) as a white solid, which was used in the next step without further purification.

[0214] Yield: 3.76g (96%).

[0215] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.8(s,1 H);9.57(s,1 H);8.20(s,1 H);7.72(d,J=7.1 Hz,1 H);5.14(s,2 H).

[0216] LC-MS purity: 95% (ELSD).

[0217] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.22 min.

[0218] LC-MS m / z: 197.4 (M+H) + . [ka]

[0219] 4-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (1, 0.30 g, 1.53 mmol) was dissolved in acetonitrile (5 mL). 2,3,4,5,6-Pentafluorophenol (0.28 g, 1.53 mmol) and N,N-dicyclohexylcarbodiimide (0.32 g, 1.53 mmol) were added at room temperature. After stirring for 16 hours, the precipitate was filtered, and the filtrate was evaporated under reduced pressure to give perfluorophenyl 4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (2) as a white solid.

[0220] Yield: 0.41 g (74%).

[0221] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):9.72(s,1 H);8.46(s,1 H);8.05(d,J=8.1 Hz,1 H);5.23(s,2 H).

[0222] (2-Aminoethyl)glycine (3, 0.06 g, 0.50 mmol) was dissolved in N,N-dimethylformamide (3 mL), and triethylamine (0.42 mL, 3.00 mmol) and perfluorophenyl 4-fluoro-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (2, 0.40 g, 1.00 mmol) were added at room temperature. After stirring at room temperature for 16 h, all volatiles were then evaporated under reduced pressure, and the residue was precipitated from ethyl acetate (40 mL), purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA), and lyophilized to give N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine (4) as a white solid.

[0223] Yield: 47.0 mg (20%).

[0224] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.83(bs,1 H);9.63-9.41(m,2 H);8.78-8.52(m,1 H);8.13-7.92(m,1 H);7.79-7.45(m,2 H);7.22-6.99(m,1 H);5.19-5.01(m,4 H);4.20(s,1 H);4.00(s,1 H);3.71-3.36(m,4 H).

[0225] LC-MS purity: 100% (ELSD).

[0226] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.19 min.

[0227] LC-MS m / z: 475.3 (M+H) + .

[0228] Example 9: N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine [ka] N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 10 and in accordance with the procedures described below. [ka]

[0229] 6-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxylic acid (2, 0.25 g, 1.27 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU, 0.49 g, 1.27 mmol) and N,N-diisopropylethylamine (0.89 mL, 5.10 mmol) were added. After 5 min, tert-butyl (2-aminoethyl)glycinate hydrochloride (1, 0.13 g, 0.64 mmol) was added to the reaction mixture at room temperature, and the reaction was stirred for 3 days. The volatiles were then evaporated under reduced pressure, and the ester 3 was used in the next step without further purification.

[0230] LC-MS purity: 66% (ELSD).

[0231] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.55 min.

[0232] LC-MS m / z: 531.5 (M+H) + .

[0233] tert-Butyl N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycinate (3, <0.64 mmol) was dissolved in a 3.5 M solution of hydrogen chloride in 1,4-dioxane (20 mL), and the mixture was stirred at room temperature for 3 h. The volatiles were then evaporated under reduced pressure, and the residue was purified by preparative HPLC (Column X-Select, C18, 15 μm, 30 × 150 mm, acetonitrile / water 3:97 to 30:70 + 0.05% AA) and lyophilized to give N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine 4 as a white solid.

[0234] Yield: 0.04g (14%).

[0235] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):9.53-9.40(m,2 H);8.55-8.23(m,1 H);7.67-7.40(m,3 H);7.36-7.22(m,1 H);5.04-4.94(m,3 H);4.76(bs,1 H);4.22(s,1 H);3.97(s,1 H);3.73-3.64(m,2 H);3.58-3.52(m,2 H).

[0236] LC-MS purity: 100% (ELSD).

[0237] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.97 min.

[0238] LC-MS m / z: 475.4 (M+H) + .

[0239] Example 10 N 2 ,N 6 -Bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine [ka] N 2 ,N 6 -Bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine was synthesized according to the reaction scheme shown in Chemical Reaction 11 and in accordance with the procedure described below. [ka]

[0240] L-Lysine hydrochloride (1, 68.0 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (6 mL) and water (3 mL). N,N-Diisopropylethylamine (0.39 mL, 2.25 mmol) and 2,5-dioxopyrrolidin-1-yl 6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxylate (2, 0.22 g, 0.75 mmol) were added at room temperature. After stirring for 3 h, the volatiles were evaporated under reduced pressure, and the residue was purified by preparative HPLC (Column X-Bridge, C18, 15 μm, 30 × 150 mm, acetonitrile / water 3:97 to 30:70 + 0.05% AA) and lyophilized to give N,N-dimethylformamide (6 mL) as a white solid. 2 ,N 6 -bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine (3) was obtained.

[0241] Yield: 89.0 mg (47%).

[0242] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.65(bs,1 H);9.41(d,J=5.9 Hz,2 H);8.60(d,J=1.5 Hz,1 H);8.39(t,J=5.3 Hz,1 H);7.62-7.53(m,2 H);7.53-7.43(m,2 H);4.97(d,J=5.5 Hz,4 H);4.41-4.29(m,1 H);3.30-3.20(m,2 H);1.88-1.68(m,2 H);1.60-1.37(m,4 H).

[0243] LC-MS purity: 97% (ELSD).

[0244] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.08 min.

[0245] LC-MS m / z: 503.5(M+H)+.

[0246] Example 11 3-Borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid [ka] 3-Borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 12 and following the procedure described below. [ka]

[0247] 3-Bromo-4-fluorobenzaldehyde (1, 4.06 g, 20.0 mmol) and periodic acid (5.02 g, 22.0 mmol) were suspended in acetonitrile (100 mL), and pyridinium chlorochromate (PCC, 86.0 mg, 0.40 mmol) was added with stirring. The resulting viscous suspension was stirred for 2 hours and then concentrated to half its volume. Water (300 mL) was added with stirring, resulting in the precipitation of a white solid, which was collected by filtration, washed with water (2 × 50 mL), and air-dried to give 3-bromo-4-fluorobenzoic acid (2).

[0248] Yield: 3.85g (88%).

[0249] 3-Bromo-4-fluorobenzoic acid (2, 2.19 g, 10.0 mmol) was dissolved in sulfuric acid (25 mL), and N-iodosuccinimide (NIS, 2.47 g, 3.00 mmol) was added in portions with stirring. The reaction mixture was then stirred for 1 hour and then poured into ice-cold water (150 mL) to precipitate the product, which was washed with water (2 × 20 mL) and air-dried. The crude acid was recrystallized from toluene to give the title compound, 3-bromo-4-fluoro-5-iodobenzoic acid (3), as an off-white solid.

[0250] Yield: 2.46g (81%).

[0251] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):9.60(bs,1 H);8.30(s,1 H);8.13(s,1 H).

[0252] 3-Bromo-4-fluoro-5-iodobenzoic acid (3, 1.72 g, 5.00 mmol) was dissolved in dry tetrahydrofuran (15 mL) and cooled to 0 °C in an ice bath. Neat borane-dimethyl sulfide (1.00 mL, 10.0 mmol) was added (gas evolution), and the resulting mixture was stirred for 16 h (overnight). The reaction mixture was carefully quenched with methanol (2 mL), evaporated to dryness, and the residue was co-distilled with methanol (2 × 10 mL). The resulting solid was triturated with n-hexane and filtered to give (3-bromo-4-fluoro-5-iodophenyl)methanol (4) as a white solid.

[0253] Yield: 1.48g (90%).

[0254] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.74-7.66(m,1 H);7.58-7.50(m,1 H);4.64(s,2 H);1.87(bs,1 H).

[0255] (3-Bromo-4-fluoro-5-iodophenyl)methanol (4, 825 mg, 2.50 mmol), anhydrous potassium carbonate (690 mg, 5.00 mmol), copper iodide (95.0 mg, 0.50 mmol), and 3-bromo-4-fluorobenzenethiol (5, 776 mg, 3.75 mmol) were suspended in dry 1,2-dimethoxyethane (10 mL), and the resulting suspension was stirred at 80 °C for 48 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20 mL), filtered through Celite (washed with ethyl acetate), and evaporated. The residue was purified by flash chromatography (Silicagel 60, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 3:1) to give 6 as a colorless oil. This was dissolved in methanol (10 mL) and water (5 mL), and potassium peroxymonosulfate (2.30 g, 3.75 mmol) was added in portions. After stirring for 16 h, the reaction mixture was taken up in ethyl acetate (50 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by flash chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 3:1-1:1) to give (3-bromo-5-((3-bromo-4-fluorophenyl)sulfonyl)-4-fluorophenyl)methanol (7) as a colorless solid.

[0256] Yield: 663 mg (60%).

[0257] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.26-8.19 (m, 1 H); 8.05-7.97 (m, 2 H); 7.89-7.83 (m, 1 H); 7.36-7.26 (m, 1 H, overlap with CHCl3); 4.79 (s, 2 H); 2.18 (bs, 1 H).

[0258] LC-MS purity: 100% (ELSD).

[0259] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 2.14 min. LC-MS m / z: 443.2 (M+H) + .

[0260] (3-Bromo-5-((3-bromo-4-fluorophenyl)sulfonyl)-4-fluorophenyl)methanol (7, 621 mg, 1.405 mmol) and periodic acid (707 mg, 3.1 mmol) were suspended in acetonitrile (10 mL), and pyridinium chlorochromate (PCC, 15 mg, 0.07 mmol) was added with stirring. The resulting viscous suspension was stirred for 16 h, then the mixture was taken up in ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give pure 3-bromo-5-((3-bromo-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid (8) as a colorless solid.

[0261] Yield: 620 mg (97%).

[0262] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.52-8.46(m,1 H);8.33-8.26(m,1 H);8.07-8.00(m,1 H),7.86-7.79(m,1 H),7.22-7.13(s,1 H);4.24(bs,1 H).

[0263] LC-MS purity: 100% (ELSD).

[0264] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 2.66 min.

[0265] LC-MS m / z: 457.8 (M+H) + .

[0266] A 25 mL reaction vessel was charged with potassium acetate (392 mg, 4.00 mmol), and the salt was dried under vacuum at 110° C. for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with 3-bromo-5-((3-bromo-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid (8, 364 mg, 0.80 mmol), palladium acetate (9.0 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 38.0 mg, 0.08 mmol), and bis(pinacolato)diboron (447 mg, 1.76 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous tetrahydrofuran (4 mL) was added via syringe. The vessel was sealed with a rubber septum and immersed in a heating bath preheated to 60 °C. After stirring at 400 rpm for 20 h (overnight), the reaction mixture was diluted with dichloromethane (15 mL) and quickly filtered through a short plug of Celite (3.00 g) with additional dichloromethane (3 × 5 mL). The filtrate was concentrated under reduced pressure to give crude 4-fluoro-3-((4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (9) as a beige foam. A portion of this material was purified by preparative LC-MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) (pinacol ester hydrolysis occurred spontaneously). Fractions were pooled and lyophilized to give 3-borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid (10) as a white solid.

[0267] Yield: 34 mg (11%).

[0268] 1 H NMR spectrum (300 MHz, acetone-d / DO, 10:1, δ H):8.70-8.64(m,1 H);8.59-8.53(m,1 H);8.35-8.28(m,1 H),8.14-8.05(m,1 H),7.38-7.28(s,1 H).

[0269] LC-MS purity: 100% (ELSD).

[0270] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 3.28 min.

[0271] LC-MS m / z: 387.4 (M+H) + .

[0272] Example 12 3-Borono-5-(3-borono-5-fluorobenzoyl)benzoic acid [ka]

[0273] 3-Borono-5-(3-borono-5-fluorobenzoyl)benzoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 13 and according to the procedure described below. [ka]

[0274] 3-Bromo-5-iodobenzoic acid (1, 6.52 g, 20.0 mmol) was suspended in methanol (40 mL) and methanesulfonic acid (0.4 mL) was added. The resulting mixture was stirred at 60°C (oil bath) for 16 hours. The resulting clear solution was cooled to -20°C in a freezer for 16 hours, and the resulting solid was collected by filtration, washed with chilled (-20°C) methanol, and dried under vacuum to give methyl 3-bromo-5-iodobenzoate (2) as an off-white solid.

[0275] Yield: 4.70g (69%).

[0276] 1H NMR spectrum (300 MHz, CDCl3, δ H ):8.30(s,1 H);8.14(s,1 H);8.04(s,1 H);3.93(s,1 H).

[0277] 1,3-Dibromo-5-fluorobenzene (3, 0.63 mL, 5.00 mmol) was dissolved in dry diethyl ether (15 mL) and cooled to -78 °C. 2.35 M n-butyllithium in hexanes (2.20 mL, 2.35 M in hexanes, 5.25 mmol) was added dropwise with stirring. After 15 min, dry N,N-dimethylformamide (0.77 mL, 10.0 mmol) was added, and the resulting mixture was stirred for 15 min and then warmed to ambient temperature. After 1 h, the reaction mixture was quenched with 1 M aqueous hydrochloric acid (15 mL). The layers were separated, and the organic layer was washed with brine (15 mL), dried over anhydrous magnesium sulfate, and evaporated to give 3-bromo-5-fluorobenzaldehyde (4) as a yellowish oil, which solidified upon storage in the freezer.

[0278] Yield: 1.02g (100%).

[0279] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):9.92(s,1 H);7.80(bs,1 H);7.50(bs,2 H).

[0280] Methyl 3-bromo-5-iodobenzoate (2, 341 mg, 1.00 mmol) was dissolved in dry tetrahydrofuran (4 mL) under a nitrogen atmosphere and cooled to -40 °C. 1.3 M isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (0.80 mL, 1.05 mmol) was added dropwise slowly. After 30 minutes, 3-bromo-5-fluorobenzaldehyde (4, 243 mg, 1.20 mmol) was added using dry tetrahydrofuran (0.5 mL). The resulting mixture was allowed to warm to room temperature overnight (16 hours). The reaction was quenched by the addition of 0.5 M aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (1 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash column chromatography (Silicagel 60, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 10:1–6:1) to give methyl 3-bromo-5-((3-bromo-5-fluorophenyl)(hydroxy)methyl)benzoate) (5) as a colorless oil. This was dissolved in dry dichloromethane (5 mL), and pyridinium chlorochromate (PCC, 200 mg, 0.93 mmol) was added. The reaction mixture was then stirred overnight (16 h) and then quenched with 2-propanol (0.3 mL). After stirring at room temperature for 1 h, the reaction mixture was filtered through a silica gel plug (5 g) covered with Celite S and washed with dichloromethane (2 × 10 mL). The solvent was removed under vacuum, and the residue was purified by flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / dichloromethane 6:1-2:1) to give methyl 3-bromo-5-(3-bromo-5-fluorobenzoyl)benzoate (6) as a colorless solid.

[0281] Yield: 208 mg (50%).

[0282] 1 H NMR spectrum (300 MHz, CDCl3, δ H):8.43(s,1 H);8.30(s,1 H);8.11(s,1 H);7.71(s,1 H);7.53(d,J=7.6 Hz,1 H);7.41(d,J=8.3 Hz,1 H);3.97(s,3 H).

[0283] LC-MS purity: 100% (ELSD).

[0284] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 2.84 min.

[0285] LC-MS m / z: No molecular oil or fragments could be detected.

[0286] A 25 mL reaction vessel was charged with potassium acetate (188 mg, 1.92 mmol), and the salt was dried under vacuum at 110° C. for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with methyl 3-bromo-5-(3-bromo-5-fluorobenzoyl)benzoate (6, 200 mg, 0.48 mmol), palladium acetate (5.40 mg, 0.24 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 23.0 mg, 0.48 mmol), and bis(pinacolato)diboron (270 mg, 1.06 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous tetrahydrofuran (3 mL) was added via syringe. The vessel was sealed with a rubber septum and immersed in a heating bath preheated to 60 °C. After stirring at 400 rpm for 16 h (overnight), the reaction mixture was cooled to ambient temperature, diluted with cyclohexane (24 mL), and filtered through a short plug (5 g) of Celite S-covered silica with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure to give methyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7) as a yellowish waxy solid.

[0287] Yield: 245mg (100%).

[0288] 1 H NMR スペクトル (300 MHz, CDCl3, δ H ):8.69(s,1 H);8.48(s,1 H);8.38(s,1 H);7.97(s,1 H);7.72(d,J=8.5 Hz,1 H);7.54(d,J=9.0 Hz,1 H);3.95(s,3 H);1.36(s,12 H);1.35(s,12 H).

[0289] LC-MS purity: 100% (ELSD).

[0290] LC-MS Rt (Kinetex C18, 4.6mm × 50mm, Atomy / Water 70:30~100:0+0.1%FA): 3.79 points.

[0291] LC-MS m / z: 511.6(M+H)+.

[0292] Methyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7, 245 mg, 0.48 mmol) was dissolved in acetonitrile (3 mL) and water (0.6 mL). Periodic acid (438 mg, 1.92 mmol) was added, and the resulting mixture was vigorously stirred at ambient temperature for 1 hour. The reaction mixture was taken up in ethyl acetate (20 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in methanol (3 mL) and water (0.3 mL), and potassium hydroxide (270 mg, 4.80 mmol) was added in one portion. The reaction mixture was stirred for 48 hours, diluted with 1 M aqueous potassium hydroxide (5 mL) and water (10 mL), and washed with dichloromethane (2 × 7 mL). The aqueous phase was acidified by the addition of concentrated hydrochloric acid (3 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was dissolved in a minimum amount of wet (well-shaken with water) 2-methyltetrahydrofuran, and the solution was added dropwise with stirring to ice-cold n-hexane (5 mL), resulting in precipitation of the product. The solid was collected by filtration and washed with cyclohexane (2 × 5 mL) to give the title compound 3-borono-5-(3-borono-5-fluorobenzoyl)benzoic acid (8) as an off-white solid.

[0293] Yield: 133.0 mg (83%).

[0294] 1 H NMR spectrum (300 MHz, acetone-d / DO; 10:1, δ H ):8.75(s,1 H);8.47-8.40(m,2 H);8.05(s,1 H);7.85-7.78(m,1 H);7.60-7.53(m,1 H).

[0295] LC-MS purity: 100% (ELSD).

[0296] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 2.52 min.

[0297] LC-MS m / z: 333.4 (M+H) + .

[0298] Example 13 3-Borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid [ka] 3-Borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid was synthesized according to the reaction schemes shown in Chemical Reaction 14 and Chemical Reaction 15 and according to the procedures described below. [ka]

[0299] 1,5-Dibromo-2,4-difluorobenzene (1, 1.36 g, 5.00 mmol) was dissolved in dry diethyl ether (15 mL) and cooled to -78 °C. 2.35 M n-butyllithium in hexanes (2.20 mL, 5.25 mmol) was added dropwise with stirring. After 15 min, dry N,N-dimethylformamide (0.77 mL, 10.0 mmol) was added, and the resulting mixture was stirred for 15 min and then warmed to ambient temperature. After 1 h, the reaction mixture was quenched with 1.0 M aqueous hydrochloric acid (15 mL). The layers were separated, and the organic layer was washed with brine (15 mL), dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 20:1) to give 5-bromo-2,4-difluorobenzaldehyde (2) as a colorless oil that solidified upon storage in a freezer.

[0300] Yield: 780 mg (70%).

[0301] 1H NMR spectrum (300 MHz, CDCl3, δ H ): 10.26 (s, 1 H); 8.14 (dd, J = 9.6 and 8.0 Hz, 1 H); 7.05 (d, J = 8.0 Hz, 1 H).

[0302] Methyl 3-bromo-5-iodobenzoate (3, 681 mg, 2.00 mmol) was dissolved in dry tetrahydrofuran (4 mL) under a nitrogen atmosphere and cooled to -40 °C. 1.3 M isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.7 mL, 2.20 mmol) was slowly added dropwise. After 30 minutes, 5-bromo-2,4-difluorobenzaldehyde (2, 530 mg, 2.40 mmol) was added using dry tetrahydrofuran (0.5 mL). The resulting mixture was allowed to warm to room temperature overnight (16 hours). The reaction was quenched by the addition of 0.5 M aqueous hydrochloric acid (15 mL) and extracted with ethyl acetate (1 × 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash column chromatography (Silicagel 60, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 8:1) to give methyl 3-bromo-5-((5-bromo-2,4-difluorophenyl)(hydroxy)methyl)benzoate (4) as a colorless oil. This was dissolved in dry dichloromethane (7 mL), and pyridinium chlorochromate (PCC, 491 mg, 2.28 mmol) was added. The reaction mixture was then stirred overnight (16 h) and then quenched with 2-propanol (0.6 mL). After stirring at room temperature for 1 h, the reaction mixture was filtered through a silica gel plug (10 g) covered with Celite S and washed with dichloromethane (2 × 20 mL). The solvent was removed under vacuum, and the residue was purified by flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / dichloromethane 6:1-2:1) to give methyl 3-bromo-5-(5-bromo-2,4-difluorobenzoyl)benzoate (5) as a colorless solid.

[0303] Yield: 606 mg (70%).

[0304] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.41 (s, 1 H); 8.29 (d, J = 1.6 Hz, 1 H); 8.12 (d, J = 1.2 Hz, 1 H); 7.87 (t, J = 7.3 Hz, 1 H); 7.04 (dd, J = 9.3 and 8.1 Hz, 1 H); 3.96 (s, 3 H).

[0305] LC-MS purity: 100% (ELSD).

[0306] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 2.76 min.

[0307] LC-MS m / z: 435.3 (M+H) + .

[0308] A 25 mL reaction vessel was charged with potassium acetate (524 mg, 5.35 mmol), and the salt was dried under vacuum at 110° C. for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with methyl 3-bromo-5-(5-bromo-2,4-difluorobenzoyl)benzoate (5, 581 mg, 1.34 mmol), palladium acetate (9.00 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 38.0 mg, 0.08 mmol), and bis(pinacolato)diboron (748 mg, 2.94 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous tetrahydrofuran (6 mL) was added via syringe. The vessel was sealed with a rubber septum and immersed in a heating bath preheated to 60 °C. After stirring at 400 rpm for 16 h (overnight), the reaction mixture was cooled to ambient temperature, diluted with cyclohexane (18 mL), and filtered through a short plug (5.0 g) of Celite S-covered silica with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure to give methyl 3-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6) as a yellowish waxy solid. This was dissolved in acetonitrile (8 mL) and water (2 mL). Periodic acid (1.22 g, 5.35 mmol) was added, and the resulting mixture was vigorously stirred at ambient temperature for 2 hours. The reaction mixture was taken up in ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was dissolved in a minimum amount of wet ethyl acetate (shaken thoroughly with water), and the solution was added dropwise to ice-cold n-hexane (5 mL) with stirring, resulting in precipitation of the product. The solid was collected by filtration and washed with cold n-hexane (2 × 5 mL) to give the title (5-(3-borono-5-(methoxycarbonyl)benzoyl)-2,4-difluorophenyl)boronic acid (7) as an off-white solid.

[0309] Yield: 443.0 mg (90%).

[0310] 1 H NMR spectrum (300 MHz, acetone-d / DO 10:1, δ H ): 8.82-8.68 (m, 1 H); 8.46 (dd, J = 16.8 and 1.4 Hz, 2 H); 8.01 (dd, J = 8.7 and 7.0 Hz, 1 H); 7.12 (dd, J = 10.4 and 9.5 Hz, 1 H); 3.91 (s, 3 H).

[0311] LC-MS purity: 100% (ELSD).

[0312] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 3.99 min.

[0313] LC-MS m / z: 365.3 (M+H) + . [ka]

[0314] (5-(3-Borono-5-(methoxycarbonyl)benzoyl)-2,4-difluorophenyl)boronic acid (1, 200 mg, 548 μmol) was dissolved in methanol (2 mL) and water (0.7 mL). Lithium hydroxide monohydrate (116 mg, 2.76 mmol) was added, and the resulting mixture was vigorously stirred at ambient temperature for 6 hours. The reaction mixture was taken up in ethyl acetate (15 mL), washed with 1 M aqueous hydrochloric acid (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was dissolved in a minimum amount of wet ethyl acetate (shaken thoroughly with water), and the solution was added dropwise with stirring to ice-cold n-hexane (5 mL), resulting in precipitation of the product. The solid was collected by filtration and washed with cold n-hexane (2 × 5 mL) to give the title compound (3-borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid (2) as a colorless solid.

[0315] Yield: 140 mg (73%).

[0316] 1 H NMR spectrum (300 MHz, acetone-d / DO 10:1, δ H ): 8.77 (s, 1 H); 8.46 (dd, J = 10.7 and 1.1 Hz, 2 H); 8.00 (dd, J = 8.7 and 7.0 Hz, 1 H); 7.11 (dd, J = 10.4 and 9.5 Hz, 1 H).

[0317] LC-MS purity: 100% (ELSD).

[0318] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.13 min.

[0319] LC-MS m / z: 351.3 (M+H) + .

[0320] Example 14 N 6 -(4-borono-2-fluorobenzoyl)-N 2 -(6-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine [ka] N 6 -(4-borono-2-fluorobenzoyl)-N 2 -(6-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine was synthesized according to chemical reaction 16 and the procedure described below. [ka]

[0321] N α-(tert-Butoxycarbonyl)-L-lysine (1, 75.0 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (3 mL) and water (1 mL). N,N-Diisopropylethylamine (0.27 mL, 1.53 mmol) and 2,5-dioxopyrrolidin-1-yl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2, 0.20 g, 0.71 mmol) were added at room temperature. After stirring for 3 hours, the volatiles were evaporated under reduced pressure. Compound 3 was dissolved in anhydrous 1,4-dioxane (2 mL) and dissolved in 5.2 M hydrogen chloride solution in 1,4-dioxane (5 mL), and the reaction mixture was then stirred at room temperature. After stirring for 1 h, the volatiles were evaporated under reduced pressure to give compound 4, which was redissolved in N,N-dimethylformamide (3 mL) and water (1 mL). N,N-Diisopropylethylamine (0.32 mL, 1.80 mmol) and 2,5-dioxopyrrolidin-1-yl 6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxylate (5, 89.0 mg, 0.31 mmol) were added at room temperature. After stirring for 2 h, the volatiles were evaporated under reduced pressure, and the residue was purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) and lyophilized to give N as a white solid. 6 -(4-borono-2-fluorobenzoyl)-N 2 -(6-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine (6) was obtained.

[0322] Yield: 88.0 mg (62%).

[0323] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):9.43(bs,1 H);8.70(bs,1 H);8.47(d,J=6.4 Hz,1 H);8.35-8.21(m,1 H);7.68-7.42(m,5 H);4.99(s,2 H);4.39-4.24(m,1 H);3.28-3.18(m,2 H);1.93-1.66(m,2 H);1.62-1.33(m,4 H).

[0324] LC-MS purity: 100% (ELSD).

[0325] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.48 min.

[0326] LC-MS m / z: 491.5 (M+H)+.

[0327] Example 15 (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid [ka] (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 17 and in accordance with the procedure described below. [ka]

[0328] (S)-2,3-Diaminopropanoic acid hydrochloride (1, 50.0 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (2 mL) and water (1 mL). N,N-Diisopropylethylamine (0.37 mL, 2.13 mmol) and 2,5-dioxopyrrolidin-1-yl 7-fluoro-1-hydroxy-1,3-dihydrobenz[c][1,2]oxaborole-6-carboxylate (2, 0.20 g, 0.71 mmol) were added at room temperature. After stirring for 2 hours, the volatiles were evaporated under reduced pressure, and the residue was washed with 1 M aqueous hydrochloric acid (3 mL). The precipitate was collected, purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA), and lyophilized to give (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid (3) as a white solid.

[0329] Yield: 55.0 mg (34%).

[0330] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.90(bs,1 H);9.38(d,J=8.8 Hz,2 H);8.57-8.38(m,2 H);7.88-7.69(m,2 H);7.31(t,J=7.4 Hz,2 H);5.03(d,J=4.2 Hz,4 H);4.72-4.59(m,1 H);3.82-3.65(m,2 H).

[0331] LC-MS purity: 100% (ELSD).

[0332] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 4.22 min.

[0333] LC-MS m / z: 461.5(M+H)+.

[0334] Example 16 (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid [ka] (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid was synthesized according to the reaction schemes shown in Chemical Reaction 18 and Chemical Reaction 19 and in accordance with the procedures described below. [ka]

[0335] 1-Bromopyrrolidine-2,5-dione (NBS, 105 g, 584 mmol) was added to a solution of 2-fluoro-4-methylbenzoic acid (1, 90.0 g, 584 mol) in concentrated sulfuric acid (1.1 L), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then poured into ice water (5 L). The resulting precipitate was filtered, washed with water (1.5 L), dissolved in ethyl acetate (1.2 L), dried over anhydrous sodium sulfate, filtered, and evaporated to give 5-bromo-2-fluoro-4-methylbenzoic acid (2) as a white solid.

[0336] Yield: 133.5g (98%).

[0337] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.20(d,J=6.9 Hz,1 H);7.11(d,J=11.4 Hz,1 H);2.47(s,3 H).

[0338] Concentrated sulfuric acid (10 mL) was added to a solution of 5-bromo-2-fluoro-4-methylbenzoic acid (2, 133 g, 570 mmol) in methanol (1 L), and the reaction mixture was stirred under reflux for 4 hours and at ambient temperature for 16 hours. The reaction mixture was then evaporated under reduced pressure, dissolved in diethyl ether (800 mL), and extracted with water (2 × 600 mL) and a mixture of saturated potassium carbonate solution (300 mL) and brine (300 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 5-bromo-2-fluoro-4-methylbenzoate (3) as a white solid.

[0339] Yield: 125g (89%).

[0340] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.10(d,J=6.6 Hz,1 H);7.06(d,J=11.1 Hz,1 H);3.92(s,3 H);2.43(s,3 H).

[0341] A suspension of 1-bromopyrrolidine-2,5-dione (NBS, 131 g, 735 mmol) and 5-bromo-2-fluoro-4-methylbenzoate (3, 120 g, 490 mmol) in water (1 L) was stirred at 70 °C under a 100 W bulb for 2 days. If the reaction rate was slow, an additional 0.5 equivalents of NBS was added. The solution at 70 °C should remain clear to prevent absorption of radiation. The reaction mixture was extracted with diethyl ether (2 × 1 L). The organic layer was washed with brine (1 L). To reduce the bromine, sodium metabisulfite pentahydrate was added to a separatory funnel until the solution changed color. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by flash chromatography (Silicagel, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 15:1–9:1) to give a mixture of methyl 5-bromo-2-fluoro-4-(bromomethyl)benzoate (4) and the product of radical dibromination. The mixture was diluted with dry tetrahydrofuran (600 mL), and N,N-diisopropylethylamine (26.0 mL, 200 mmol) and diethyl phosphite (35.0 mL, 200 mmol) were added to the solution at 0 °C. The reaction mixture was then stirred at ambient temperature for 18 h. The solvent was evaporated, and the crude product was dissolved in ethyl acetate and washed with water (1 L), 1 M hydrochloric acid (300 mL), brine (500 mL), and 1 M aqueous potassium bicarbonate solution (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1) to give methyl 5-bromo-2-fluoro-4-(bromomethyl)benzoate (4).

[0342] Yield 96g (60%)

[0343] R F (SiO2, cyclohexane / ethyl acetate 9:1):0.50.

[0344] 1 H NMR spectrum (300 MHz, CDCl3, δH ):8.16(d,J=6.6 Hz,1 H);7.31(d,J=10.2 Hz,1 H);4.54(s,2 H);3.95(s,3 H).

[0345] A solution of methyl 5-bromo-2-fluoro-4-(bromomethyl)benzoate (4, 96.0 g, 290 mmol) and potassium acetate (59.0 g, 601 mmol) in acetonitrile (1 L) was stirred at 75 °C overnight. The suspension was filtered through cotton wool and evaporated. The crude product was dissolved in dichloromethane and filtered again. Purification by column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1-1:1) gave methyl 5-bromo-2-fluoro-4-(acetylmethyl)benzoate (5).

[0346] Yield: 70g (80%)

[0347] R F (SiO2, cyclohexane / ethyl acetate 9:1): 0.30.

[0348] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.15(d,J=6.3 Hz,1 H);7.24(d,J=11.1 Hz,1 H);5.18(s,2 H);3.95(s,3 H);2.21(s,3 H).

[0349] A solution of methyl 5-bromo-2-fluoro-4-(acetylmethyl)benzoate (5, 70.0 g, 230 mmol), bis(pinacolato)diboron (6, 64.3 g, 253 mmol), potassium acetate (67.6 g, 690 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.00 g, 4.00 mmol) in dry 1,4-dioxane (600 mL) was stirred at 80° C. under an argon atmosphere for 24 hours. The reaction mixture was then cooled to ambient temperature, filtered, and evaporated. The crude product was filtered through silica gel (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1-4:1) to give methyl 2-fluoro-4-(acetylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7).

[0350] Yield: 76.2g (94%).

[0351] R F (SiO2, cyclohexane / ethyl acetate 9:1): 0.30.

[0352] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.42(d,J=8.4 Hz,1 H);7.19(d,J=12 Hz,1 H);5.42(s,2 H);3.94(s,3 H);2.16(s,3 H);1.35(s,12 H).

[0353] A solution of methyl 2-fluoro-4-(acetylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7, 76.2 g, 216 mmol) and sodium hydroxide (43.0 g, 1.08 mol) in water (700 mL) was stirred at ambient temperature for 3 hours. A solution of hydrochloric acid (35%, 120 mL) in water (200 mL) was then added to lower the pH to 1. The reaction mixture was placed in a refrigerator for 16 hours. The precipitate was filtered and lyophilized to give 5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (8) as a white solid.

[0354] Yield: 40.7g (96%).

[0355] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.17(bs,1 H);9.38(bs,1 H);8.29(d,J=7.7 Hz,1 H);7.36(d,J=11.2 Hz,1 H);5.02(s,2 H).

[0356] LC-MS purity: 98% (ELSD).

[0357] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 4.18 min.

[0358] LC-MS m / z: 197.3 (M+H) + . [ka]

[0359] A solution of 2,3,4,5,6-pentafluorophenol (939 mg, 5.10 mmol), 5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (1, 1.00 g, 5.10 mmol), and N,N'-dicyclohexylcarbodiimide (DCC, 1.05 g, 5.10 mmol) in acetonitrile (30 mL) was stirred overnight at ambient temperature. The reaction mixture was filtered, washed with acetonitrile, and evaporated. The crude product 2 (618 mg, 1.71 mmol) was reacted with 2,3-diaminopropionic acid hydrochloride (120 mg, 854 μmol) in N,N-dimethylformamide (12 mL) and water (6 mL) at ambient temperature overnight. The crude product 3 was purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA) and lyophilized to give (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid (3) as a white solid.

[0360] Yield: 54.0 mg (14%).

[0361] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.88(bs,1 H);9.37(d,J=5.9 Hz,2 H);8.55(dd,J=7.3 and 3.4 Hz,1 H);8.50-8.38(m,1 H);8.09(d,J=7.5 Hz,1 H);8.02(d,J=7.5 Hz,1 H);7.36(dd,J=10.8 Hz and 8.3 Hz,2 H);5.01(d,J=4.2 Hz,4 H);4.70-4.59(m,1 H);3.84-3.65(m,2 H).

[0362] LC-MS purity: 100% (ELSD).

[0363] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 4.43 min.

[0364] LC-MS m / z: 461.4 (M+H) + .

[0365] Example 17 (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid [ka] (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 20 and according to the procedure described below. [ka]

[0366] (S)-2,3-Diaminopropanoic acid hydrochloride (1, 72.0 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (6 mL) and water (2 mL). N,N-Diisopropylethylamine (0.54 mL, 3.07 mmol) and 2,5-dioxopyrrolidin-1-yl 4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (2, 0.30 g, 1.02 mmol) were added at room temperature. After stirring for 2 h, the volatiles were evaporated under reduced pressure, and the residue was purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) and lyophilized to give (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid (3) as a white solid.

[0367] Yield: 95.0 mg (40%).

[0368] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):9.55(d,J=6.2 Hz,2 H);8.85(d,J=7.5 Hz,1 H);8.78(t,J=5.5 Hz,1 H);8.07(d,J=16.7 Hz,2 H);7.79-7.62(m,2 H);5.13(d,J=6.1 Hz,4 H);4.75-4.60(m,1 H);3.90-3.64(m,2 H).

[0369] LC-MS purity: 97% (ELSD).

[0370] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95–100:0 + 0.1% FA): 3.30 min.

[0371] LC-MS m / z: 461.4 (M+H) + .

[0372] Example 18 (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycine [ka] (3-Borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycine was synthesized according to the reaction schemes shown in Chemical Reaction 21 and Chemical Reaction 22 and in accordance with the procedures described below. [ka]

[0373] 1,3-Dibromo-5-(trifluoromethyl)benzene (1, 3.03 g, 10.00 mmol) was dissolved in dry diethyl ether (25 mL) and cooled to −78° C. n-Butyllithium (4.24 mL, 2.35 M in hexanes, 10.0 mmol) was added dropwise with stirring. After 15 minutes, dry N,N-dimethylformamide (1.44 mL, 20.0 mmol) was added in one portion, and the resulting mixture was allowed to warm to ambient temperature over 1 hour. The reaction was then quenched by the addition of 1 M aqueous hydrochloric acid (30 mL), and the reaction mixture was taken up in diethyl ether (30 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 20:1) to give 3-bromo-5-(trifluoromethyl)benzaldehyde (2) as a colorless oil.

[0374] Yield: 1366 mg (54%).

[0375] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):10.02(s,1 H);8.20(bs,1 H);8.07(bs,1 H);8.02(bs,1 H).

[0376] Methyl 3-bromo-5-iodobenzoate (3, 1.36 g, 4.00 mmol) was dissolved in dry tetrahydrofuran (12 mL) and cooled to 30 °C. Isopropylmagnesium chloride-lithium chloride complex (3.11 mL, 1.3 M solution in tetrahydrofuran, 4.20 mmol) was added dropwise with stirring. After 30 min, 3-bromo-5-(trifluoromethyl)benzaldehyde (2, 1.21 g, 4.80 mmol) was added using 3 mL of tetrahydrofuran. The resulting mixture was warmed to ambient temperature and quenched after 1 h by the addition of 1 M aqueous hydrochloric acid (15 mL). The reaction mixture was taken up in diethyl ether (50 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product (4) was dissolved in dry dichloromethane (20 mL), and pyridinium chlorochromate (1.29 g, 6.00 mmol) was added with stirring. After stirring for 17 h, the reaction mixture was filtered through a plug of silica (15 g) covered with Celite, and the bed was washed with dichloromethane (3 × 20 mL). The yellowish solution was concentrated in vacuo, and the residue was purified by flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane / dichloromethane 6:1 to 1:1) to give methyl 3-bromo-5-(3-bromo-5-(trifluoromethyl)benzoyl)benzoate (5) as a colorless solid.

[0377] Yield: 1620 mg (87%).

[0378] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.45(t,J=1.4 Hz,1 H);8.29(m,1 H);8.12(t,J=1.6 Hz,1 H);8.08(bs,1 H);8.04(bs,1 H);7.95(bs,1 H);3.97(s,3 H). [ka]

[0379] A 25 mL reaction vessel was charged with methyl 3-bromo-5-(3-bromo-5-(trifluoromethyl)benzoyl)benzoate (1, 1071 mg, 2.30 mmol) and Deoxo-Fluor (3.00 mL). The vessel was sealed, purged with nitrogen, and heated to 90°C (oil bath) for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with dichloromethane (50 mL). The resulting solution was slowly added to saturated aqueous potassium bicarbonate (100 mL), and the biphasic mixture was stirred for 1 hour to decompose excess fluorinating reagent. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 30:1-15:1) to give methyl 3-bromo-5-((3-bromo-5)-(trifluoromethyl)phenyl)difluoromethyl)benzoate (2) as a yellow oil.

[0380] Yield: 1096 mg (97%).

[0381] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.30(s,1 H);8.08(s,1 H);7.88(s,1H);7.83(s,1 H);7.81(s,1 H);7.71(s,1 H);3.96(s,3 H).

[0382] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-62.87(s,3 H);-90.00(s,2 H).

[0383] 3-Bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)difluoromethyl)benzoate (2, 1096 mg, 2.25 mmol) was dissolved in tetrahydrofuran (8 mL), methanol (4 mL), and water (2 mL). Lithium hydroxide monohydrate (377 mg, 9.00 mmol) was added, and the resulting mixture was stirred for 16 hours. It was then taken up in ethyl acetate (40 mL), washed with 1 M aqueous hydrochloric acid (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give crude 3-bromo-5-((3-(bromo-5-(trifluoromethyl)phenyl)difluoromethyl)benzoic acid (3)) as a white solid. This was dissolved in anhydrous acetonitrile (10 mL), and carbonyldiimidazole (CDI, 437 mg, 2.69 mmol) was added. After 30 minutes, glycine tert-butyl ester hydrochloride (564 mg , 3.37 mmol) was added, and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo, the residue was taken up in ethyl acetate (40 mL), and the organic layer was washed with 1 M aqueous hydrochloric acid (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and evaporated. The resulting gum was triturated with n-hexane (12 mL) to induce crystallization, and the resulting solid was collected by filtration, washed with n-hexane (2 × 6 mL), and dried in vacuo to give tert-butyl (3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycinate (4) as a colorless solid.

[0384] Yield: 1220 mg (92%).

[0385] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.03(s,1 H);7.88(s,1 H);7.86(s,1 H);7.79(s,1 H);7.75(s,1 H);6.86(m,1 H);6.86(s,1 H);4.12(d,J=4.9 Hz,2 H);1.50(s,9 H).

[0386] 19F NMR spectrum (282 MHz, CDCl3, δ F ):-62.85(s,3 H);-89.85(s,2 H).

[0387] LC-MS purity: 100% (ELSD).

[0388] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 2.70 min.

[0389] LC-MS m / z: 532.2 (M+H) + .

[0390] A 100 mL reaction vessel was charged with potassium acetate (735 mg, 7.50 mmol), and the salt was dried under vacuum at 110 °C for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with tert-butyl (3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycinate (4, 880 mg, 1.50 mmol), palladium acetate (4.6 mg, 60.0 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 57 mg, 120 μmol), and bis(pinacolato)diboron (838 mg, 3.30 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice). Anhydrous tetrahydrofuran (8.0 mL) was added via syringe, and the vessel was sealed with a plastic stopper and immersed in a heating bath preheated to 60 °C. After stirring at 400 rpm for 4 h, the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (15 mL), and filtered through a short plug (10 g) of silica covered with Celite S using dichloromethane (3 × 20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (3-(difluoro(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycinate (5) as an orange foam.

[0391] This was dissolved in dry dichloromethane (4.0 mL), trifluoroacetic acid (4.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure, and the residue was co-distilled with toluene (3 × 10 mL). The residue was dissolved in acetonitrile (9.0 mL) and water (3.0 mL), periodic acid (1368 mg, 6.00 mmol) was added, and the reaction mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (40 mL) and washed with water (2 × 30 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellowish foam. The foam was dissolved in wet ethyl acetate (5 mL), and n-hexane (15 mL) was added. The mixture was left stirring overnight, and the precipitated product was collected by filtration, washed with n-hexane (2 × 6 mL), and dissolved in acetonitrile (15 mL). The solution was lyophilized to give the title (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycine) (6) as a colorless solid.

[0392] Yield: 558 mg (81%).

[0393] 1 H NMR spectrum (300 MHz, acetone-d / DO 10:1, δ H ): 8.48 (s, 1 H); 8.38 (m, 1 H, exchanged with DO); 8.29 (s, 1 H); 8.25 (s, 1 H); 8.20 (approximately s, 2 H); 7.94 (s, 1 H); 4.16-4.09 (m, 2 H).

[0394] 19 F NMR spectrum (282 MHz, acetone-d / DO 10:1, δ F ):-63.07(s,3 H);-89.89(s,2 H).

[0395] LC-MS purity: 100% (ELSD).

[0396] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.92 min.

[0397] LC-MS m / z: 462.4 (M+H) + .

[0398] Example 19 (3-borono-5-(3-borono-5-(trifluoromethyl)benzoyl)benzoyl)glycine [ka] (3-Borono-5-(3-borono-5-(trifluoromethyl)benzoyl)benzoyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 23 and according to the procedure described below. [ka]

[0399] 1,3-Dibromo-5-(trifluoromethyl)benzene (1, 3.03 g, 10.00 mmol) was dissolved in dry diethyl ether (25 mL) and cooled to −78° C. n-Butyllithium (4.24 mL, 2.35 M in hexanes, 10.0 mmol) was added dropwise with stirring. After 15 minutes, dry N,N-dimethylformamide (1.44 mL, 20.0 mmol) was added in one portion, and the resulting mixture was allowed to warm to ambient temperature over 1 hour. The reaction was then quenched by the addition of 1 M aqueous hydrochloric acid (30 mL), and the reaction mixture was taken up in diethyl ether (30 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 20:1) to give 3-bromo-5-(trifluoromethyl)benzaldehyde (2) as a colorless oil.

[0400] Yield: 1366 mg (54%).

[0401] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):10.02(s,1 H);8.20(bs,1 H);8.07(bs,1 H);8.02(bs,1 H).

[0402] Methyl 3-bromo-5-iodobenzoate (3, 1.36 g, 4.00 mmol) was dissolved in dry tetrahydrofuran (12 mL) and cooled to 30 °C. Isopropylmagnesium chloride-lithium chloride complex (3.11 mL, 1.3 M solution in tetrahydrofuran, 4.20 mmol) was added dropwise with stirring. After 30 min, 3-bromo-5-(trifluoromethyl)benzaldehyde (2, 1.21 g, 4.80 mmol) was added using 3 mL of tetrahydrofuran. The resulting mixture was warmed to ambient temperature and quenched after 1 h by the addition of 1 M aqueous hydrochloric acid (15 mL). The reaction mixture was taken up in diethyl ether (50 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product (4) was dissolved in dry dichloromethane (20 mL), and pyridinium chlorochromate (1.29 g, 6.00 mmol) was added with stirring. After stirring for 17 h, the reaction mixture was filtered through a plug of silica (15 g) covered with Celite, and the bed was washed with dichloromethane (3 × 20 mL). The yellowish solution was concentrated in vacuo, and the residue was purified by flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane / dichloromethane 6:1 to 1:1) to give methyl 3-bromo-5-(3-bromo-5-(trifluoromethyl)benzoyl)benzoate (5) as a colorless solid.

[0403] Yield: 1620 mg (87%).

[0404] 1 H NMR spectrum (300 MHz, CDCl3, δ H):8.45(t,J=1.4 Hz,1 H);8.29(m,1 H);8.12(t,J=1.6 Hz,1 H);8.08(bs,1 H);8.04(bs,1 H);7.95(bs,1 H);3.97(s,3 H).

[0405] Methyl 3-bromo-5-(3-bromo-5-(trifluoromethyl)benzoyl)benzoate (5, 466 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (2 mL), and water (1 mL). Lithium hydroxide monohydrate (210 mg, 5.00 mmol) was added, and the resulting mixture was stirred for 16 hours. It was then taken up in ethyl acetate (30 mL), washed with 1 M aqueous hydrochloric acid (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting solid (6) was added to a solution of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 399 mg, 1.05 mmol) in dry N,N-dimethylformamide (5 mL), followed by triethylamine (0.70 mL, 5.00 mmol). After 10 min, glycine tert-butyl ester hydrochloride (250 mg, 1.50 mmol) was added, and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with 1 M aqueous hydrochloric acid (15 mL), and the precipitated gummy solid was collected by filtration and dried in air. The resulting solid was triturated with n-hexane (5 mL), collected by filtration, and dried under vacuum to give tert-butyl 2-(3-bromo-5-(3-bromo-5-(trifluoromethyl)benzoyl)benzamido)acetate (7) as a colorless solid.

[0406] Yield: 311 mg (55%).

[0407] 1 H NMR spectrum (300 MHz, CDCl3, δ H):8.23(t,J=1.7 Hz,1 H);8.09(t,J=1.5 Hz,1 H);8.07(bs,1 H);8.06-8.01(m,2 H);7.96(bs,1 H);6.67(t,J=3.8 Hz,1 H);4.15(d,J=4.8 Hz,2 H);1.52(s,9 H).

[0408] LC-MS purity: 100% (ELSD).

[0409] LC-MS Rt (Kinetex C18, 4.6mm × 50mm, Atomitor / water 70:30~100:0+0.1%FA): 2.18 points.

[0410] LC-MS m / z: 566.3(M+H)+.

[0411] A 20 mL reaction vessel was charged with potassium acetate (202 mg, 2.06 mmol), and the salt was dried under vacuum at 110 °C for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with tert-butyl 2-(3-bromo-5-(3-bromo-5-(trifluoromethyl)benzoyl)benzamido)acetate (7, 290 mg, 513 μmol), palladium acetate (4.6 mg, 10 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 19.5 mg, 51 μmol), and bis(pinacolato)diboron (287 mg, 1.13 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice). Anhydrous tetrahydrofuran (4 mL) was added via syringe, and the vessel was sealed with a plastic stopper and immersed in a heating bath preheated to 60 °C. After stirring at 400 rpm for 4 h, the reaction mixture was cooled to ambient temperature, diluted with dichloromethane (15 mL), and filtered through a short plug (15 g) of silica covered with Celite S using dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoyl)benzoyl)glycinate (8) as a yellow, waxy foam.

[0412] Yield: 340 mg (quantitative).

[0413] LC-MS purity: 100% (ELSD).

[0414] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 5.57 min, 3.97 min.

[0415] LC-MS m / z: 604.5 (M+H-tBu) + ,522.5(M-pinacol-tBu+H) +

[0416] tert-Butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoyl)benzoyl)glycinate (8, 340 mg, 513 μmol) was mixed with trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. Volatiles were evaporated under reduced pressure. The residue and periodic acid (600 mg, 2.63 mmol) were dissolved in an acetonitrile / water mixture (4:1, 2.5 mL), and the reaction mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL) and brine (5 mL). The organic phase was concentrated under reduced pressure to give a yellow solid, which was purified by preparative LC / MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). Pure fractions were collected and lyophilized to give the title product (9) as a white solid.

[0417] Yield: 101 mg (49%).

[0418] 1 H NMR spectrum (300 MHz, acetone-d / DO 10:1, δ H ):8.66(s,1 H);8.48(s,1 H);8.40(m,3 H);8.15(s,1 H);4.16 (m,2 H).

[0419] 19 F NMR spectrum (282 MHz, acetone-d / DO 10:1, δ F ):63.13(s).

[0420] LC-MS purity: 100% (ELSD).

[0421] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.34 min.

[0422] LC-MS m / z: 440.3 (M+H) + .

[0423] Example 20 (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)glycine [ka] (3-Borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 24 and the procedure described below. [ka]

[0424] 1,3-Dibromo-5-(trifluoromethyl)benzene (1, 5.74 g, 18.0 mmol) was added to a mixture of copper(II) sulfate pentahydrate (225 mg, 1.80 mmol) and potassium hydroxide (5.03 g, 180 mmol) in mixed dimethyl sulfoxide / water (10:1, 38 mL). The reaction flask was flushed with nitrogen, and finally 1,2-ethanediol (2.68 mL, 60.0 mmol) was added through a septum. The reaction mixture was heated to 110 °C overnight. The mixture was then acidified to pH = 2 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the filtration solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane) to give 3-bromo-5-(trifluoromethyl)benzenethiol (2) as a yellow oil.

[0425] Yield: 2.27g (51%).

[0426] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.61(s,1 H);7.56(s,1 H);7.46(s,1 H);3.66(s,1 H).

[0427] 3-Bromo-5-iodobenzoic acid (40.0 g, 122 mmol) was dissolved in methanol, methanesulfonic acid (3 mL) was added, and the reaction mixture was heated to 60° C. overnight. The reaction was then cooled to 0° C. with stirring and then kept in a freezer overnight. Methyl 3-bromo-5-iodobenzoate (3) was obtained as a white solid by filtration.

[0428] Yield: 34.5g (83%).

[0429] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.31(t,J=1.34 Hz,1 H);8.15(t,J=1.50 Hz,1 H);8.05(t,J=1.59 Hz,1 H);3.95(s,3 H).

[0430] 3-Bromo-5-(trifluoromethyl)benzenethiol (2, 2.27 g, 8.80 mmol), methyl 3-bromo-5-iodobenzoate (3, 1.85 g, 5.50 mmol), potassium carbonate (1.51 g, 10.9 mmol), and copper(I) iodide (207 mg, 1.09 mmol) were dissolved in dry dimethoxyethane (22 mL). The reaction flask was heated to 80 °C for 48 h. After this time, the mixture was diluted with ethyl acetate, filtered through Celite S, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 1:0-20:1) to give methyl 3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)thio)benzoate (4) as a yellow oil.

[0431] Yield: 1.93g (75%).

[0432] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.82(m,1 H);7.68(m,3 H);7.52(m,1 H);2.54(s,3 H).

[0433] Methyl 3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)thio)benzoate (4, 1.93 g, 4.10 mmol) and potassium peroxymonosulfate (3.80 g, 6.30 mmol) were suspended in methanol (22 mL) and water (11 mL) was added. The reaction was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate (20 mL) and washed with water (30 mL) followed by brine (30 mL). The organic phase was evaporated under reduced pressure, and the residue was chromatographed by column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1-3:1) to give methyl 3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)thio)benzoate (5) as a white solid.

[0434] Yield: 1.30 g (63%).

[0435] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.53(m,1 H);8.43(m,1 H);8.27(m,2 H);8.16(m,1 H);8.01(m,1 H);4.00(s,3 H).

[0436] Methyl 3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)sulfonyl)benzoate (5, 1.30 g, 2.60 mmol) and lithium hydroxide monohydrate (330 mg, 7.80 mmol) were dissolved in a mixture of methanol / water / tetrahydrofuran (4:2:5, 23 mL), and the reaction mixture was stirred at room temperature overnight. After this time, the mixture was acidified to pH = 2 using 1 M aqueous hydrochloric acid and extracted with ethyl acetate. After evaporation of all volatiles, 3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)sulfonyl)benzoic acid (6) was obtained as a white solid.

[0437] Yield: 1.18g (93%).

[0438] 1H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.91(bs,1 H);8.68(s,2 H);8.50(s,1 H);8.45(s,1 H);8.41(s,1 H);8.32(s,1 H).

[0439] 3-Bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)benzoic acid (6, 1.18 g, 2.40 mmol) was mixed with 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU, 1.01 g, 2.64 mmol) in dry N,N'-dimethylformamide (30 mL) for 30 min, then triethylamine (1.22 g, 12.0 mmol) was added, and glycine tert-butyl ester hydrochloride (810 mg, 4.80 mmol) was added. After the reaction was completed, water was added, and the reaction mixture was extracted with ethyl acetate (25 mL). After all volatiles were evaporated under reduced pressure, the residue was purified by column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 3:1) to give tert-butyl (3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycinate (7) as a white solid.

[0440] Yield: 1.00g (69%).

[0441] LC-MS purity: 100% (ELSD).

[0442] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 4.30 min.

[0443] LC-MS m / z: 602.3 (M+H) + .

[0444] A 50 mL reaction flask was charged with potassium acetate (815 mg, 8.30 mmol), and the salt was dried under vacuum at 110° C. for 1 hour. After cooling to room temperature, the reaction flask was backfilled with nitrogen and charged with tert-butyl (3-bromo-5-((3-bromo-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycinate (7, 1.00 g, 1.66 mmol), palladium acetate (19.0 mg, 82.0 μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 79 mg, 165 μmol), and bis(pinacolato)diboron (930 mg, 3.60 mmol). The reaction flask was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous tetrahydrofuran (8 mL) was added via syringe. The flask was sealed with a plastic stopper and heated to 60 °C. The reaction mixture was stirred overnight, then cooled to ambient temperature, diluted with dichloromethane (30 mL), and filtered through a short plug of silica gel covered with Celite S, rinsing with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycinate (8) as a brown, waxy foam.

[0445] Yield: 1.16 g (quantitative).

[0446] LC-MS purity: 100% (ELSD).

[0447] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 5.40 min, 3.97 min, 2.62 min.

[0448] LC-MS m / z: 640.5 (M+H-tBu) + ,558.4(M-pinacol-tBu+H) + ,476.3(M-2 pinacol-tBu+H)+ .

[0449] Tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycinate (8, 1.16 g, 1.66 mmol) was mixed with trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour, after which all volatiles were evaporated under reduced pressure. (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycine (9) was obtained as a brown waxy foam.

[0450] Yield: 1.06 g (quantitative).

[0451] LC-MS purity: 100% (ELSD).

[0452] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 4.31 min, 2.89 min, 1.12.

[0453] LC-MS m / z: 640.5 (M+H) + , 558.4 (M-pinacol + H) + , 476.3 (M-2 pinacol + H) + .

[0454] (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycine (9, 1.16 g, 1.16 mmol) and periodic acid (430 mg, 4.64 mmol) were dissolved in acetonitrile / water (4:1 mixture, 5 mL), and the reaction mixture was stirred for 2 h. The mixture was then diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was concentrated under reduced pressure to give a residue as a yellow solid, which was removed and purified by preparative LC / MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). All solvents were lyophilized to give (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)benzoyl)glycine (10) as a white solid.

[0455] Yield: 110 mg (14%).

[0456] 1 H NMR spectrum (300 MHz, acetone-d / DO 10:1, δ H ):8.69(s,1 H);8.59(m,3 H);8.36(s,1 H);8.33(s,1 H);4.13(m,2 H).

[0457] 19 F NMR spectrum (282 MHz, acetone-d / DO 10:1, δ F ):63.16(s).

[0458] LC-MS purity: 100% (ELSD).

[0459] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.34 min.

[0460] LC-MS m / z: 476.3 (M+H)+ .

[0461] Example 21 4-((3S,4S)-3,4-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid [ka] 4-((3S,4S)-3,4-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid was synthesized according to the reaction schemes shown in Chemical Reaction 25 and Chemical Reaction 26 and in accordance with the procedures described below. [ka]

[0462] 2,5-Dioxopyrrolidin-1-yl 4-((3S,4S)-3,4-bis((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-oxobutanoate (1, 1.50 g, 3.01 mmol) was dissolved in a tetrahydrofuran / water mixture (1:1, 10 mL) and allowed to stand for 7 days. The mixture was diluted with ethyl acetate (50 mL) and washed with water (2 × 50 mL) and brine (1 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 4-((3S,4S)-3,4-bis((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-oxobutanoic acid (2) as a white solid.

[0463] Yield: 1.15g (95%).

[0464] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):5.58-5.45(m,1 H);5.41-5.30(m,1 H);4.12-3.80(m,4 H);3.35-3.17(m,2 H);2.76-2.39(m,4 H);1.45(s,18 H).

[0465] LC-MS purity: 100% (ELSD).

[0466] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 2.97 min.

[0467] LC-MS m / z: 401.4 (M+H) + .

[0468] The acid (2, 1.14 g, 2.83 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) was added. After 30 minutes, the solvent was evaporated. The residue was suspended in diethyl ether (10 mL), decanted, and dried under vacuum to give 4-((3S,4S)-3,4-diaminopyrrolidin-1-yl)-4-oxobutanoic acid dihydrochloride (3) as a pale brown powder.

[0469] Yield: 0.78g (100%).

[0470] 1 H NMR spectrum (300 MHz, DO, δ H ):4.33-4.17(m,3 H);4.10-3.99(m,1 H);3.92-3.83(m,1 H);3.78-3.68(m,1 H);2.67(s,4 H). [ka]

[0471] 4-((3S,4S)-3,4-Diaminopyrrolidin-1-yl)-4-oxobutanoic acid dihydrochloride (1, 0.16 g, 0.59 mmol) was dissolved in water (3 mL). Then, N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (0.51 mL, 2.95 mmol), and 2,5-dioxopyrrolidin-1-yl 7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (2, 0.34 g, 1.17 mmol) were added. The resulting mixture was stirred at room temperature overnight. The mixture was acidified with 1 M aqueous hydrochloric acid, and the solvent was evaporated. The residue was dissolved in ethyl acetate (40 mL) and washed with water (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by preparative LC / MS (SunFire Prep C18, 5 μm, 19×100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) to give the title compound (3) as a white solid.

[0472] Yield: 16.0 mg (5%).

[0473] Total yield: 16.0 mg (5%).

[0474] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):9.39(s,2 H);8.73-8.63(m,2 H);7.75-7.65(m,2 H);7.34-7.27(m,2 H);5.03(s,4 H);4.63-4.48(m,2 H);3.99-3.88(m,1 H);3.82-3.72(m,1 H);3.47-3.22(m,2 H);2.47-2.39(m,4 H).

[0475] LC-MS purity: 100% (ELSD).

[0476] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.05 min.

[0477] LC-MS m / z: 557.0 (M+H) + .

[0478] Example 22 (3-borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine [ka] (3-Borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 27 and according to the procedure described below. [ka]

[0479] 3-(3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1,546 mg, 1.10 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 439 mg, 1.16 mmol) were dissolved in dry DMF (5 mL) and triethylamine (0.76 mL, 5.50 mmol) was added. After 10 minutes, glycine tert-butyl ester hydrochloride (277 mg, 1.65 mmol) was added, and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was taken up in ethyl acetate (25 mL), washed with 0.5 M aqueous hydrochloric acid (2 × 15 mL), 5% aqueous lithium chloride (2 × 15 mL), 5% aqueous potassium bicarbonate (1 × 15 mL), and brine (15 mL), dried over anhydrous sodium sulfate, and evaporated to give compound 2 as a yellowish powder. The solid was dissolved in acetonitrile (6 mL) and water (1.5 mL), and periodic acid (912 mg, 4.00 mmol) was added. After 1 h, the reaction mixture was taken up in ethyl acetate (25 mL), washed with water (2 × 15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, and evaporated to give a yellowish foam, which was dissolved in trifluoroacetic acid (5 mL) and stirred for 1 h. The volatiles were removed in vacuo, and the residue was coevaporated with ethyl acetate (3 × 15 mL) to give a beige solid, which was triturated with diethyl ether (5 mL) and cyclohexane (5 mL). The resulting solid was collected by filtration, washed with cyclohexane (2 x 5 mL), and dried under vacuum to give the title 3-borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine (3) as a colorless solid.

[0480] Yield: 394 mg (92%).

[0481] 1 H NMR spectrum (300 MHz, acetone-d / DO, δ H):8.60(d,J=0.6 Hz,1 H);8.35(dd,J=8.2,1.5 Hz,2 H);8.04(s,1 H);7.80(ddd,J=9.2,2.7,0.8 Hz,1 H);7.62-7.49(m,1 H);4.12(s,2 H).

[0482] LC-MS purity: 100% (ELSD).

[0483] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 05:95 to 100:0 + 0.1% FA): 3.11 min.

[0484] LC-MS m / z: 390.4 (M+H) + .

[0485] Example 24 (3-borono-5-((3-borono-5-fluorophenyl)sulfonyl)benzoyl)glycine [ka] (3-Borono-5-((3-borono-5-fluorophenyl)sulfonyl)benzoyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 29 and according to the procedure described below. [ka]

[0486] A mixture of 3-bromo-5-fluorobenzenethiol (1, 1.55 g, 7.49 mmol), methyl 3-bromo-5-iodobenzoate (2, 2.81 g, 8.24 mmol), copper(I) iodide (143 mg, 749 μmol), potassium carbonate (2.07 g, 15.0 mmol), and dry 1,2-dimethoxyethane (30.0 mL) was heated at 80° C. under argon over the weekend. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), filtered through Celite, and evaporated to dryness. The residue was redissolved in ethyl acetate (100 mL), washed with 0.5 M aqueous hydrochloric acid (50 mL), 0.5 M aqueous sodium hydroxide (2×50 mL), and 0.5 M aqueous hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 97:3) to give methyl 3-bromo-5-((3-bromo-5-fluorophenyl)thio)benzoate (3) contaminated with methyl 3-bromo-5-iodobenzoate (2) as a pale yellow oil.

[0487] Yield: 2.54g (40%).

[0488] Content: 50% ( 1 H NMR).

[0489] R F (SiO2, n-hexane / ethyl acetate 9:1): 0.50.

[0490] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.13 (m, 1 H); 7.99 (t, J = 1.6 Hz, 1 H); 7.70 (t, J = 1.7 Hz, 1 H); 7.24 (td, J = 1.6 and 0.6 Hz, 1 H); 7.16 (ddd, J = 8.0, 2.3 and 1.7 Hz, 1 H); 6.93 (ddd, J = 8.5, 2.4 and 1.6 Hz, 1 H); 3.94 (s, 3 H).

[0491] 19F NMR spectrum (282 MHz, CDCl3, δ F ):-108.98(s).

[0492] LC-MS purity: 73% (UV 254nm).

[0493] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 3.47 min.

[0494] LC-MS m / z: 421.3 (M+H)+.

[0495] Potassium peroxymonosulfate (2.75 g, 4.48 mmol) was added to a solution of the above methyl 3-bromo-5-((3-bromo-5-fluorophenyl)thio)benzoate (3, 50%, 2.53 g, 2.99 mmol) in N,N-dimethylformamide (30 mL) and water (5 mL), and the reaction mixture was stirred at room temperature overnight. Another portion of Oxone® (2.75 g, 4.48 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and then 15% aqueous potassium bicarbonate solution (60 mL) and 15% aqueous sodium sulfate solution (60 mL) were added to the residue, followed by ethyl acetate (300 mL). The phases were separated, and the organic phase was washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 95:5-9:1) to give methyl 3-bromo-5-((3-bromo-5-fluorophenyl)sulfonyl)benzoate (4) as a white solid.

[0496] Yield: 1.23g (91%).

[0497] R F (SiO2, n-hexane / ethyl acetate 9:1): 0.20.

[0498] 1H NMR spectrum (300 MHz, CDCl3, δ H ): 8.49 (m, 1 H); 8.40 (dd, J = 2.0 and 1.5 Hz, 1 H); 8.24 (t, J = 1.8 Hz, 1 H); 7.90 (td, J = 1.6 and 0.6 Hz, 1 H); 7.62 (ddd, J = 7.3, 2.3 and 1.6 Hz, 1 H); 7.50 (ddd, J = 7.7, 2.4 and 1.7 Hz, 1 H); 3.98 (s, 3 H).

[0499] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-105.73(s).

[0500] LC-MS purity: 100% (ELSD, UV 254nm).

[0501] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 4.14 min.

[0502] LC-MS m / z: 453.2 (M+H)+.

[0503] A solution of sodium hydroxide (535 mg, 13.4 mmol) in water (10 mL) was added to a solution of methyl 3-bromo-5-((3-bromo-5-fluorophenyl)sulfonyl)benzoate (4, 1.21 g, 2.68 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL), and the resulting solution was stirred at room temperature over the weekend. The mixture was concentrated in vacuo, acidified with 1 M aqueous hydrochloric acid (25 mL), and extracted with ethyl acetate (50 mL, 2 × 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in anhydrous N,N-dimethylformamide (20 mL), followed by the addition of 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU, 1.12 g, 2.95 mmol) and N,N-diisopropylethylamine (1.84 mL, 10.7 mmol). The mixture was stirred at room temperature for 5 minutes, then tert-butyl glycinate hydrochloride (483 mg, 3.22 mmol) was added, and stirring was continued for 2 hours. The reaction mixture was partitioned between 0.5 M aqueous hydrochloric acid (100 mL) and ethyl acetate (400 mL). The phases were separated, and the organic phase was washed with 0.5 M aqueous hydrochloric acid (100 mL), water (100 mL), 5% aqueous sodium carbonate solution (100 mL), and brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 9:1) to give tert-butyl (3-bromo-5-((3-bromo-5-fluorophenyl)sulfonyl)benzoyl)glycinate (5) as a colorless foam.

[0504] Yield: 900 mg (61%).

[0505] R F (SiO2, n-hexane / ethyl acetate 3:2): 0.55.

[0506] 1 H NMR spectrum (300 MHz, CDCl3, δ H):8.26(t,J=1.6 Hz,1 H);8.20-8.16(m,2 H);7.89(td,J=1.5 and 0.7 Hz,1 H);7.63-7.58(m,1 H);7.52-7.47(m,1 H);6.75(bs,1 H);4.14(d,J=5.0 Hz,2H);1.52(s,9H).

[0507] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-105.69(s).

[0508] LC-MS purity: 100% (ELSD, UV 254nm).

[0509] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 3.27 min.

[0510] LC-MS m / z: 552.2 (M+H)+.

[0511] A 50 mL reaction flask was charged with potassium acetate (533 mg, 5.43 mmol), and the salt was dried under vacuum at 110° C. for 1 hour. After cooling to room temperature, the reaction flask was backfilled with argon and charged with tert-butyl (3-bromo-5-((3-bromo-5-fluorophenyl)sulfonyl)benzoyl)glycinate (5, 599 mg, 1.09 mmol), palladium acetate (12.2 mg, 54.0 μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 51.8 mg, 109 μmol), and bis(pinacolato)diboron (607 mg, 2.39 mmol). The reaction flask was then evacuated and backfilled with argon (this procedure was repeated twice), anhydrous tetrahydrofuran (7 mL) was added via syringe, and the flask was immersed in an oil bath preheated to 60 °C. The reaction mixture was stirred at 60 °C for 20 h, then cooled to ambient temperature, diluted with dichloromethane (7 mL), and filtered through a short plug of silica gel covered with Celite S, rinsing with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure to give crude tert-butyl (3-((3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycinate (6) as a yellow foam.

[0512] Yield: 772 mg (crude product).

[0513] R F (SiO2, n-hexane / ethyl acetate 3:2): 0.15.

[0514] 1 H NMR spectrum (300 MHz, CDCl3, δ H): 8.53-8.47 (m, 2 H); 8.35 (dd, J = 1.7 and 1.0 Hz, 1 H); 8.17 (dd, J = 1.7 and 0.8 Hz, 1 H); 7.76-7.71 (m, 1 H); 7.70-7.64 (m, 1 H); 6.75 (t, J = 4.9 Hz, 1 H); 4.15 (d, J = 5.0 Hz, 2 H); 1.51 (s, 9 H); 1.36 (s, 12 H); 1.34 (s, 12 H).

[0515] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-110.47(s).

[0516] LC-MS purity: 96% (ELSD).

[0517] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 4.69 min.

[0518] LC-MS m / z: 646.7(M+H)+.

[0519] A mixture of the above crude tert-butyl (3-((3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycinate (6, 772 mg, <1.09 mmol) and trifluoroacetic acid (8.00 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness in vacuo, and the residue was evaporated from dichloromethane (5 × 10 mL) to give crude (3-((3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycine (7) as a yellow foam.

[0520] Yield: 791 mg (crude product).

[0521] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.54-8.48(m,2 H);8.43(m,1 H);8.16(dd,J=1.7 and 0.8 Hz,1 H);7.76-7.71(m,1 H);7.70-7.65(m,1 H);7.39(t,J=5.3 Hz,1 H);4.34(d,J=5.3 Hz,2H);1.36(s,12H);1.34(s,12H).

[0522] LC-MS purity: 85% (ELSD).

[0523] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 3.16 min.

[0524] LC-MS m / z: 590.5(M+H)+.

[0525] A solution of the above crude (3-((3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycine (7, 791 mg, <1.09 mmol) in acetonitrile (6.5 mL) was diluted with water (1.3 mL), followed by the addition of periodic acid (991 mg, 4.35 mmol). The resulting mixture was stirred for 1 h, then partitioned between ethyl acetate (80 mL) and water (20 mL). The phases were separated, and the organic phase was washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was dissolved in a minimum amount of wet ethyl acetate (3 mL), and the resulting solution was slowly added to stirred n-hexane (50 mL) cooled to 0 °C. The precipitated solid was decanted and dried to give 472 mg of crude product (8). A portion of the solid (8, 172 mg) was purified by preparative LC / MS (Synergi Polar-RP 80, 4 μm, 150 × 21.2 mm, acetonitrile / water 0:100 to 100:0 + 0.1% FA). The pure fractions were combined and lyophilized to give the title compound (8) as a white powder.

[0526] Yield: 100 mg (59%).

[0527] R F (SiO2, acetonitrile / water / formic acid 89:10:1):0.25.

[0528] 1 H NMR spectrum (300 MHz, DMSO-d + DCl, δ H ): 8.55 (dd, J = 1.7 and 1.2 Hz, 1 H); 8.50 (dd, J = 1.8 and 1.1 Hz, 1 H); 8.47 (t, J = 1.8 Hz, 1 H); 8.23 ​​(dd, J = 1.7 and 0.7 Hz, 1 H); 7.90-7.85 (m, 1 H); 7.85-7.79 (m, 1 H); 3.93 (s, 2 H).

[0529] 19F NMR spectrum (282 MHz, DMSO-d6 + DCl, δ F ):-110.92(s).

[0530] LC-MS purity: 100% (ELSD, UV 254nm).

[0531] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.12 min.

[0532] LC-MS m / z: 426.4 (M+H)+.

[0533] Example 25 N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 30 and in accordance with the procedures described below. [ka]

[0534] 1-Bromopyrrolidine-2,5-dione (NBS, 34.9 g, 196 mmol) was added to a solution of 3-trifluoromethyl-4-methylbenzoic acid (1, 40.0 g, 196 mmol) in concentrated sulfuric acid (400 mL), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was then poured into ice water (2 L). The resulting precipitate was filtered, washed with water (500 mL), dissolved in ethyl acetate (400 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give 3-bromo-4-methyl-5-trifluoromethylbenzoic acid (2) as a white solid.

[0535] Yield: 55.4g (100%).

[0536] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.71(bs,1 H);8.35(d,J=0.4 Hz,1 H);8.15(d,J=0.9 Hz,1 H);2.56(s,3 H).

[0537] Concentrated sulfuric acid (24 mL) was added to a solution of 3-bromo-4-methyl-5-trifluoromethylbenzoic acid (2, 35.0 g, 124 mmol) in methanol (500 mL), and the reaction mixture was stirred under reflux for 4 hours and at ambient temperature for 16 hours. The reaction mixture was then evaporated under reduced pressure, dissolved in diethyl ether (250 mL), and extracted with water (2 × 100 mL) and a mixture of saturated potassium carbonate solution (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-4-methyl-5-trifluoromethylbenzoate (3) as a white solid.

[0538] Yield: 36g (98%)

[0539] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):8.36(d,J=1.1 Hz,1 H);8.13(d,J=1.1 Hz,1 H);3.90(s,3 H);2.55(d,J=1.3 Hz,3 H).

[0540] A suspension of 1-bromopyrrolidine-2,5-dione (NBS, 32.3 g, 181 mmol) and methyl 3-bromo-4-methyl-5-trifluoromethylbenzoate (3, 35.9 g, 121 mmol) in water (300 mL) was stirred at 80° C. under a 100 W bulb for 6 hours. The reaction mixture was extracted with diethyl ether (2×200 mL). The organic layer was washed with brine (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-4-bromomethyl-5-trifluoromethylbenzoate (4) as a yellow solid.

[0541] Yield: 45.5g (100%).

[0542] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.47(d,J=1.5 Hz,1 H);8.31(d,J=1.3 Hz,1 H);4.75(s,2 H);3.98(s,3 H).

[0543] A solution of 3-bromo-4-bromomethyl-5-trifluoromethylbenzoate (4, 45.5 g, 121 mmol) and potassium acetate (23.7 g, 142 mmol) in acetonitrile (0.5 L) was stirred at 75 °C overnight. The suspension was filtered through cotton wool and evaporated. The crude product was dissolved in dichloromethane and filtered again. Evaporation gave methyl 3-bromo-4-(acetoxymethyl)-5-(trifluoromethyl)benzoate (5) as a white solid.

[0544] Yield: 41.6g (97%).

[0545] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.49(d,J=1.3 Hz,1 H);8.34(d,J=1.3 Hz,1 H);5.37(s,2 H);3.99(s,3 H);2.11(s,3 H).

[0546] A solution of methyl 3-bromo-4-acetylmethyl-5-trifluoromethylbenzoate (5, 40.5 g, 114 mmol), bis(pinacolato)diboron (31.9 g, 126 mmol), potassium acetate (33.6 g, 343 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.50 g, 3.42 mmol) in dry tetrahydrofuran (500 mL) was stirred at 75°C under an argon atmosphere for 12 days. The reaction mixture was then cooled to ambient temperature, filtered, and evaporated. The crude product was filtered through silica gel (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 8:1) to give methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (6).

[0547] Yield: 35.3g (77%).

[0548] R F (SiO2, cyclohexane / ethyl acetate 8:1): 0.40.

[0549] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.65(s,1 H);8.43(s,1 H);5.48(s,2 H);3.97(s,3 H);2.05(s,3 H);1.36(s,12 H).

[0550] A solution of methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (6, 34.0 g, 84.6 mmol) and sodium hydroxide (17.0 g, 425 mmol) in water (300 mL) was stirred at ambient temperature for 3 hours. A solution of hydrochloric acid (35%, 37 mL) in water (100 mL) was then added to lower the pH to 1. The reaction mixture was stirred overnight. The precipitate was filtered and dried to give 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7) as a white solid.

[0551] Yield: 17.0g (82%).

[0552] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.47(bs,1 H);9.66(s,1 H);8.62(s,1 H);8.24(s,1 H);5.22(s,2 H).

[0553] A solution of 2,3,4,5,6-pentafluorophenol (497 mg, 2.70 mmol), 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7, 665 mg, 2.70 mmol), and N,N'-dicyclohexylcarbodiimide (DCC, 556 mg, 2.70 mmol) in acetonitrile (15 mL) was stirred overnight at ambient temperature. The reaction mixture was filtered, washed with acetonitrile, and evaporated to give perfluorophenyl 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8) as a white solid.

[0554] Yield: 1.00g (91%).

[0555] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):9.79(s,1 H);8.86(s,1 H);8.46(s,1 H);5.30(s,2 H).

[0556] A solution of perfluorophenyl 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8, 850 mg, 2.06 mmol), (2-aminoethyl)glycine (9, 122 mg, 1.03 mmol), and triethylamine (1.15 mL, 8.27 mmol) in N,N-dimethylformamide (25 mL) was stirred at ambient temperature for 5 days. The reaction mixture was then evaporated, and the crude product 10 was filtered through a short pad of silica gel (eluent: dichloromethane / methanol 10:1 to 4:1), purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA), and lyophilized to give N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine (10) as a white solid.

[0557] Yield: 70.0 mg (12%).

[0558] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.91(bs,1 H);9.91-9.40(m,2 H);9.02-8.65(m,1 H);8.67-7.41(m,4 H);5.28-5.03(m,4 H);4.37-3.90(m,2 H);3.79-3.42(m,4 H).

[0559] LC-MS purity: 100% (ELSD).

[0560] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.63 min.

[0561] LC-MS m / z: 575.5(M+H)+.

[0562] Example 26 (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid [ka] (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 31 and in accordance with the procedure described below. [ka]

[0563] 1-Hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (1, 3.50 g, 14.2 mmol), N-hydroxysuccinimide (1.64 g, 14.2 mmol), and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (2.72 g, 14.2 mmol) were stirred in tetrahydrofuran (70 mL) and N,N-dimethylformamide (10 mL) at ambient temperature for 4 hours. The reaction mixture was evaporated and extracted with ethyl acetate (3 x 100 mL) and 1 M aqueous hydrochloric acid (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give 2,5-dioxopyrrolidin-1-yl 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (2) as a white solid.

[0564] Yield: 4.87g (100%).

[0565] LC-MS purity: 100% (ELSD).

[0566] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 2.32 min.

[0567] LC-MS m / z: 344.3 (M+H) + .

[0568] A solution of 2,5-dioxopyrrolidin-1-yl 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (2, 515 mg, 1.50 mmol), (S)-2,3-diaminopropanoic acid hydrochloride (3, 98.0 mg, 0.70 mmol), and N,N-diisopropylethylamine (0.75 mL, 4.20 mmol) in N,N-dimethylformamide (15 mL) and water (4 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated, purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA), and lyophilized to give (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid (4) as a white solid.

[0569] Yield: 153 mg (39%).

[0570] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.90(bs,1 H);9.62(d,J=4.2 Hz,2 H);9.10(d,J=8.1 Hz,1 H);8.99(t,J=5.2 Hz,1 H);8.50(d,J=15.0 Hz,2 H);8.25(d,J=21.1 Hz,2 H);5.21(d,J=5.5 Hz,4 H);4.84-4.63(m,1 H);3.99-3.81(m,1 H);3.79-3.59(m,1 H).

[0571] LC-MS purity: 100% (ELSD).

[0572] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95–100:0 + 0.1% FA): 3.70 min.

[0573] LC-MS m / z: 561.5 (M+H)+.

[0574] Example 27 4-((3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid [ka] 4-((3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 32 and in accordance with the procedures described below. [ka]

[0575] 2,5-Dioxopyrrolidin-1-yl 4-((3S,4S)-3,4-bis((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-oxobutanoate (1, 6.57 g, 13.2 mmol) was dissolved in a tetrahydrofuran / water mixture (1:1, 100 mL) and allowed to stand for 5 days. The mixture was diluted with ethyl acetate (100 mL) and washed with 1 M aqueous hydrochloric acid (1 × 100 mL), water (2 × 100 mL), and brine (1 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 4-((3S,4S)-3,4-bis((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-oxobutanoic acid (2) as a white solid.

[0576] Yield: 4.60g (95%).

[0577] 1H NMR spectrum (300 MHz, CDCl3, δ H ):5.54-5.43(m,1 H);5.37-5.24(m,1 H);4.11-3.80(m,4 H);3.33-3.17(m,2 H);2.74-2.42(m,4 H);1.45(s,18 H).

[0578] The acid (2, 4.59 g, 11.4 mmol) was dissolved in dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (100 mL) was added. After 30 minutes, the solvent was evaporated. The residue was suspended in ethyl acetate (100 mL), and the insoluble material was filtered, washed with ethyl acetate, and dried under vacuum to give 4-((3S,4S)-3,4-diaminopyrrolidin-1-yl)-4-oxobutanoic acid dihydrochloride (3) as a white powder.

[0579] Yield: 3.33g (100%).

[0580] 1 H NMR spectrum (300 MHz, DO, δ H ):4.32-4.17(m,3 H);4.09-3.99(m,1 H);3.91-3.84(m,1 H);3.77-3.68(m,1 H);2.67(s,4 H).

[0581] A solution of 4-((3S,4S)-3,4-diaminopyrrolidin-1-yl)-4-oxobutanoic acid dihydrochloride (3, 137 mg, 0.50 mmol), 2,5-dioxopyrrolidin-1-yl 1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (4, 343 mg, 1.00 mmol), and N,N-diisopropylethylamine (0.54 mL, 3.00 mmol) in N,N-dimethylformamide (12 mL) and water (3 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated, purified by preparative HPLC (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA), and lyophilized to give 4-((3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid (5) as a white solid.

[0582] Yield: 103 mg (31%).

[0583] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ) 12.12 (bs, 1 H); 9.63 (s, 2 H); 9.01 (dd, J = 10.2 and 7.2 Hz, 2 H); 8.48 (s, 2 H); 8.23 ​​(s, 2 H); 5.20 (s, 4 H); 4.82-4.55 (m, 2 H); 4.01 (dd, J = 10.4 and 6.3 Hz, 1 H); 3.86 (dd, J = 12.3 and 7.0 Hz, 1 H); 3.50 (dd, J = 10.7 and 7.4 Hz, 2 H); 2.49-2.37 (m, 4 H).

[0584] LC-MS purity: 100% (ELSD).

[0585] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.66 min.

[0586] LC-MS m / z: 658.7 (M+H) + .

[0587] Example 28 (3-borono-5-((3-borono-5-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)benzoyl)glycine [ka] (3-borono-5-((3-borono-5-(pentafluoro-λ 6 (-sulfanyl)phenyl)sulfonyl)-benzoyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 33 and following the procedure described below. [ka]

[0588] N-Bromosuccinimide (25.2 g, 142 mmol) was dissolved in pentafluoro(3-nitrophenyl) λ 6 To a mixture of 1, 23.3 g, 93.5 mmol), trifluoroacetic acid (75 mL), and 98% sulfuric acid (25 mL) was added in 10 equal portions at 40 °C for 8 h. The reaction mixture was stirred overnight at 40 °C. The mixture was then partitioned between ethyl acetate (0.5 L) and ice-cold water (1 L). The organic layer was washed with 10% aqueous potassium carbonate solution (1 L), 10% aqueous sodium sulfate solution (1 L), and brine (1 L) and then dried over anhydrous magnesium sulfate. The solvent was removed under vacuum, and the residue was purified twice by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 100:0-90:10) to give (3-bromo-5-nitrophenyl)pentafluoro-λ as a yellowish crystalline solid. 6 -sulfane (2) was obtained.

[0589] Yield: 10.9g (36%).

[0590] 1 H NMR spectrum (300 MHz, CDCl3, δH ):8.62-8.51(m,2 H);8.24(t,J=1.7 Hz,1 H).

[0591] (3-Bromo-5-nitrophenyl)pentafluoro-λ in methanol / water (2:1, 36 mL) 6 A thoroughly degassed mixture of 2-sulfane (5.88 g, 17.9 mmol), iron (5.01 g, 89.6 mmol), and ammonium chloride (9.59 g, 179 mmol) was heated to 90 °C under an argon atmosphere for 1.5 h. Insoluble material was removed by filtration, and volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (400 mL), washed with brine (2 × 500 mL), and then dried over anhydrous magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 10:0-9:1) to give 3-bromo-5-(pentafluoro-λ) as a yellowish crystalline solid. 6 -sulfanyl)aniline (3) was obtained.

[0592] Yield: 4.86g (91%).

[0593] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.25(t,J=1.7 Hz,1 H);7.02-6.89(m,2 H);3.95(bs,2 H).

[0594] A solution of sodium nitrite (915 mg, 13.2 mmol) in water (10 mL) was added to 3-bromo-5-(pentafluoro-λ) 6The resulting solution was added dropwise to a mixture of 3.76 g (12.6 mmol) of 2-sulfanylaniline (3) and 3.5 mL of 35% hydrochloric acid at 0° C. The mixture was stirred at 0° C. for an additional 30 minutes. This solution was then added to a solution of potassium O-ethyldithiocarbonate (5.05 g, 31.5 mmol) in water (50 mL) at 50° C., which was heated and stirred for an additional 60 minutes. The mixture was cooled to room temperature and extracted with ethyl acetate (300 mL). The organic phase was washed with 10% aqueous sodium hydroxide solution (500 mL), brine (500 mL), 0.5 M aqueous hydrochloric acid solution (500 mL), and brine (500 mL), and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol (50 mL), and a solution of potassium hydroxide (7.08 g, 126 mmol) in water (50 mL) was added. The resulting mixture was heated to 80°C for 12 hours. Volatiles were removed under reduced pressure. The residue was diluted with water (350 mL) and washed with diethyl ether (500 mL). The aqueous phase was acidified to pH 1 with 35% hydrochloric acid and then extracted with ethyl acetate (500 mL). The organic phase was washed with brine (2 x 500 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane) to give 3-bromo-5-(pentafluoro-λ)-2-(2-bromo-2-methyl-2-propanol) as a colorless crystalline solid contaminated with an unidentified, inseparable impurity. 6 -sulfanyl)benzenethiol (4) was obtained.

[0595] Yield: 1.64g (<41%).

[0596] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.70-7.65(m,1 H);7.62-7.35(m,2 H);3.69(s,1 H).

[0597] 3-Bromo-5-pentafluorofluoro-λ 6A mixture of (4, 1.62 g, 5.14 mmol), methyl 3-bromo-5-iodobenzoate (5, 1.75 g, 5.14 mmol), copper(I) iodide (98.0 mg, 0.51 mol), potassium carbonate (1.42 g, 10.3 mmol), and dry 1,2-dimethoxyethane (20 mL) was heated at 80 °C for 48 h under argon. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), filtered through Celite, and evaporated to dryness. The residue was dissolved in ethyl acetate (250 mL), washed with 1 M aqueous hydrochloric acid (250 mL) and brine (250 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 100:0-98:2) to give 3-bromo-5-((pentafluoro-λ)-3-bromo-5-iodobenzoate) contaminated with methyl 3-bromo-5-iodobenzoate (5) as a pale yellow oil. 6 Methyl-sulfanyl)phenyl)thio)benzoate (6) was obtained.

[0598] Yield: 1.46g.

[0599] Content: Approximately 60% ( 1 H NMR).

[0600] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.16(t,J=1.7 Hz,1 H);8.01(t,J=1.7 Hz,1 H);7.79(t,J=1.7 Hz,1 H);7.72(t,J=1.7 Hz,1 H);7.63(t,J=1.7 Hz,1 H);7.51(s,1 H);3.94(s,3 H).

[0601] Potassium peroxymonosulfate (2.52 g, 4.10 mmol) was dissolved in 3-bromo-5-(pentafluoro-λ)-2-(2-bromo-2-methyl-2-propanol)-2-one in N,N-dimethylformamide (30 mL) and water (5 mL). 6A solution of methyl 3-bromo-5-((3-sulfanyl)phenyl)thio)benzoate (6, 1.45 g, <2.74 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Another portion of potassium peroxymonosulfate (2.52 g, 4.10 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, after which 15% aqueous potassium bicarbonate (60 mL) and 15% aqueous sodium sulfate (60 mL) were added to the residue, followed by ethyl acetate (300 mL). The phases were separated, and the organic phase was washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 100:0-95:5) to give 3-bromo-5-((3-bromo-5-(pentafluoro-λ))benzoate as a white solid. 6 Methyl-sulfanyl)phenyl)sulfonyl)benzoate (7) was obtained.

[0602] Yield: 421 mg (3 to 6%).

[0603] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.54-8.48(m,1 H);8.45-8.40(m,1 H);8.28(t,J=1.7 Hz,1 H);8.26(t,J=1.7Hz,1 H);8.21(t,J=1.8 Hz,1 H);8.12(t,J= 1.8 Hz,1 H);3.99(s,3 H).

[0604] LC-MS purity: 100% (ELSD).

[0605] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 2.25 min.

[0606] LC-MS m / z: mass not observed.

[0607] A solution of sodium hydroxide (169 mg, 4.22 mmol) in water (10 mL) was dissolved in 3-bromo-5-(pentafluoro-λ)-2-(2-bromo-4-methyl-2-propanol) in tetrahydrofuran / methanol (2:1, 30 mL) 6 To a solution of methyl 3-bromo-5-((3-bromo-5-pentafluoro-λ)phenyl)sulfonyl)benzoate (7, 472 mg, 10.9 mmol) was added. The mixture was stirred at room temperature for 20 hours. The volatiles were removed under reduced pressure. The residue was acidified with 1 M aqueous hydrochloric acid (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic phases were washed with brine (250 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed under vacuum to give 3-bromo-5-((3-bromo-5-(pentafluoro-λ)phenyl)sulfonyl)benzoate as a yellowish solid. 6 -sulfanyl)phenyl)sulfonyl)benzoic acid (8) was obtained, which was used in the next step without further purification.

[0608] Yield: 448 mg (97%).

[0609] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.57(t,J=1.6 Hz,1 H);8.50-8.46(m,1 H);8.33-8.28(m,2 H);8.23(t,J=1.8 Hz,1 H);8.13(t,J=1.8 Hz,1 H).

[0610] LC-MS purity: 100% (ELSD).

[0611] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 4.82 min.

[0612] LC-MS m / z: mass not observed.

[0613] 3-Bromo-5-((3-bromo-5-(pentafluoro-λ))-2-methyl-2-propanol in anhydrous N,N-dimethylformamide (20 mL) 6A mixture of (-sulfanyl)phenyl)sulfonyl)benzoic acid (8, 448 mg, 0.82 mmol), tert-butyl glycinate hydrochloride (166 mg, 0.99 mmol), N,N-diisopropylethylamine (0.57 mL, 3.29 mmol), and 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (V) (HATU, 344 mg, 0.91 mmol) was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate (150 mL) and 0.5 M aqueous hydrochloric acid (150 mL). The organic phase was washed with brine (150 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 95:5-9:1) to give tert-butyl(3-bromo-5-(pentafluoro-λ)) as a colorless foam. 6 -sulfanyl)phenyl)sulfonyl)benzoyl)glycinate (9) was obtained.

[0614] Yield: 462 mg (85%).

[0615] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.28(s,2 H);8.24-8.16(m,3 H);8.12(t,J=1.7 Hz,1 H);6.70(t,J=4.6 Hz,1 H);4.14(d,J=5.0 Hz,2 H);1.52(s,9 H).

[0616] LC-MS purity: 100% (ELSD), 100% (UV, 254nm).

[0617] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 3.27 min.

[0618] LC-MS m / z: 604.2 (M-tBu) +.

[0619] tert-Butyl (3-bromo-5-(pentafluoro-λ)) in anhydrous tetrahydrofuran (25 mL) 6 A mixture of 3-(3-(pentafluoro-2-sulfanyl)phenyl)sulfonyl)benzoyl)glycinate (9, 444 mg, 0.67 mmol), palladium acetate (8.00 mg, 34.0 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 32.0 mg, 67.0 μmol), bis(pinacolato)diboron (376 mg, 1.48 mmol), and potassium acetate (330 mg, 3.36 mmol) was heated at 60 °C under an argon atmosphere for 23 h. The mixture was cooled to room temperature, diluted with dichloromethane (200 mL), and passed through a short plug of silica (Silicagel 60, 0.040-0.060 mm, eluent: dichloromethane). The solvent was removed under reduced pressure to give crude tert-butyl (3-(pentafluoro-2-sulfanyl)phenyl)sulfonyl)benzoylglycinate as a brownish foam. 6 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)glycinate (10). This was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) was added. The resulting solution was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was dissolved in aqueous acetonitrile (3:1, 50 mL) and periodic acid (617 mg, 2.70 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The organic phase was washed with brine (250 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed under vacuum, and the residue was purified twice by preparative LC / MS (SunFire Prep C18, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). The product-containing fractions were lyophilized to give (3-borono-5-(pentafluoro-λ)-2-(4-methyl-2-propanol)-2-one as a white solid. 6-sulfanyl)phenyl)sulfonyl)benzoyl)glycine (11) was obtained.

[0620] Yield: 142 mg (40%).

[0621] 1 H NMR spectrum (300 MHz, DMSO-d + 1 drop of 20% DCl in D2O, δ H ):8.67(s,1 H);8.62-8.52(m,3 H);8.52-8.47(m,1 H);8.41-8.34(m,1 H);3.94(s,2 H).

[0622] LC-MS purity: 100% (ELSD), 100% (UV, 254nm).

[0623] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.44 min.

[0624] LC-MS m / z: 534.3 (M+H) + .

[0625] Example 29 4-[(3R,4R)-3,4-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]pyrrolidin-1-yl]-4-oxobutanoic acid [ka] 4-[(3R,4R)-3,4-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]pyrrolidin-1-yl]-4-oxobutanoic acid was prepared from 4-((3R,4R)-3,4-bis((tert-butoxycarbonyl)amino)-pyrrolidin-1-yl)-4-oxobutanoic acid in a similar manner to the compound of Example 27.

[0626] Example 30 2-((bis(3-borono-5-(trifluoromethyl)phenyl)(oxo)- λ 6-Sulfanylidene)amino)acetic acid [ka] 2-((bis(3-borono-5-(trifluoromethyl)phenyl)(oxo)-λ-sulfanylidene)amino)acetic acid was synthesized according to the reaction scheme shown in Chemical Reaction 34 and according to the procedure described below. [ka]

[0627] A mixture of 1-iodo-3-(trifluoromethyl)-benzene (1, 5.44 g, 20.0 mmol), 3-(trifluoromethyl)-benzenethiol (2, 4.28 g, 24.0 mmol), copper(I) iodide (380 mg, 2.00 mmol), potassium carbonate (6.63 g, 48.0 mmol), and dry 1,2-dimethoxyethane (40 mL) was heated at 80° C. under argon for 2 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), filtered over Celite, and evaporated to dryness. The residue was redissolved in ethyl acetate (300 mL), washed with water (100 mL), 5% aqueous sodium carbonate (2×100 mL), and 1 M aqueous hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue (contaminated with unwanted diaryl disulfides) was dissolved in acetic acid (80 mL). Zinc powder (7.00 g) was added, and the mixture was heated at 60 °C for 3 h. It was then cooled to room temperature, diluted with toluene (80 mL), filtered through Celite, and evaporated to dryness. The residue was partitioned between toluene (300 mL) and water (150 mL). The phases were separated, and the organic phase was washed with 1 M aqueous sodium hydroxide solution (2 × 200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was subjected to flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane) to give bis(3-(trifluoromethyl)phenyl)sulfane (3) as a colorless liquid. Yield: 4.01g (62%).

[0628] R F(SiO2, cyclohexane / ethyl acetate 95:5): 0.50.

[0629] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.65-7.61(m,2 H);7.58-7.42(m,6 H).

[0630] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-62.90(s).

[0631] LC-MS purity: 93% (UV 254nm).

[0632] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 2.96 min.

[0633] LC-MS m / z: 323.4 (M+H) + .

[0634] (Diacetoxyiodo)benzene (9.82 g, 30.5 mmol) was added to a mixture of bis(3-(trifluoromethyl)phenyl)sulfane (3, 3.93 g, 12.2 mmol) and ammonium carbamate (1.90 g, 24.4 mmol) in methanol (24.4 mL). The resulting pale yellow solution was stirred at room temperature for 3 hours, and then it was evaporated to dryness under vacuum. A solution of potassium bicarbonate (20 g) and sodium thiosulfate (20 g) in water (200 mL) was added to the residue, followed by ethyl acetate (200 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 × 100 mL). The organic fractions were combined, dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 99:1-70:30) to give iminobis(3-(trifluoromethyl)phenyl-λ) as a pale yellow oil. 6 -sulfanone (4) was obtained.

[0635] Yield: 3.50g (81%).

[0636] R F (SiO2, n-hexane / ethyl acetate 1:1): 0.50.

[0637] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.37-8.34(m,2 H);8.29-8.24(m,2 H);7.88-7.81(m,2 H);7.73-7.65(m,2 H);3.28(bs,1 H).

[0638] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-62.78(s).

[0639] LC-MS purity: 100% (ELSD, UV 254nm).

[0640] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 3.53 min.

[0641] LC-MS m / z: 354.4 (M+H) + .

[0642] Sodium hydride (60% dispersion in mineral oil, 310 mg, 7.75 mmol) was dissolved in iminobis(3-(trifluoromethyl)phenyl)-λ in dry N,N-dimethylformamide (20 mL). 6 To a solution of 4-sulfanone (4, 2.49 g, 7.05 mmol) was added and the mixture was stirred at room temperature for 1 hour. tert-Butyl bromoacetate (2.36 mL, 10.6 mmol) was added and the mixture was stirred for 60 minutes. oThe mixture was heated to 10°C and stirred at this temperature for 2.5 h. The mixture was cooled to room temperature and partitioned between 10% aqueous sodium hydrogen sulfate (300 mL) and ethyl acetate (600 mL). The separated organic layer was washed with water (3 × 200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was purified by flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane / ethyl acetate 99:1–70:30) to give tert-butyl 2-((oxobis(3-(trifluoromethyl)phenyl)-λ)-2-methyl-2-oxo-2-oxo-1 ... 6 -sulfanylidene)amino)acetate (5) was obtained.

[0643] Yield: 2.94g (89%).

[0644] R F (SiO2, n-hexane / ethyl acetate 1:1): 0.55.

[0645] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.34(s,2 H);8.28(d,J=7.9 Hz,2 H);7.83(d,J=7.9 Hz,2 H);7.67(t,J=7.9,2 H);3.77(s,2 H);1.48(s,9 H).

[0646] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-62.77(s).

[0647] LC-MS purity: 100% (ELSD, UV 254nm).

[0648] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 4.62 min.

[0649] LC-MS m / z: 468.4 (M+H) + .

[0650] tert-Butyl 2-((oxobis(3-(trifluoromethyl)phenyl)-λ 6 (-sulfanylidene)amino)acetate (5, 501 mg, 1.07 mmol), bis(pinacolato)diboron (680 mg, 2.68 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (21.0 mg, 0.03 mmol), and 4,4-di-tert-butyl-2,2-dipyridyl (20.0 mg, 0.08 mmol) were dissolved in degassed tetrahydrofuran (3 mL) under argon. The resulting mixture was warmed to 60 °C and heated at this temperature for 6 h. The mixture was evaporated to dryness and the residue was purified by quick flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: dichloromethane) to give tert-butyl 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ as an off-white foam. 6 -sulfanylidene)amino)acetate (6).

[0651] Yield: 748 mg (97%).

[0652] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):

[0653] 8.59(s,2 H);8.42(s,2 H);8.21(s,2 H);3.76(s,2 H);1.51(s,9 H);1.36(s,12 H);1.35(s,12 H).

[0654] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-62.59(s).

[0655] LC-MS purity: 100% (ELSD).

[0656] LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile / water 85:15 to 100:0 + 0.1% FA): 1.32 min (M-pinacol), 1.65 (M-pinacol), 5.11 min (M).

[0657] LC-MS m / z: 556.6 (M-2 x pinacol + H) + , 638.8 (M-pinacol + H) + , 721.0(M+H) + .

[0658] Trifluoroacetic acid (6 mL) was dissolved in dichloromethane (2 mL) to prepare a solution of tert-butyl 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ 6 To a solution of 2-(oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ was added a solution of 2-(oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ, 2 ..., 2,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ, 2,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ, 2,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ, 2,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ, 2,4,5, 6 -sulfanylidene)amino)acetic acid (7) was obtained.

[0659] Yield: 678 mg (100%).

[0660] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.54(s,2 H);8.33(s,2 H);8.27(s,2 H);3.85(s,2 H);1.37(s,12 H);1.37(s,12 H).

[0661] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-62.68(s).

[0662] LC-MS purity: 100% (ELSD).

[0663] LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile / water 85:15 to 100:0 + 0.1% FA): 0.67 min (M-pinacol), 0.84 (M-pinacol), 2.04 min (M).

[0664] LC-MS m / z: 550.5 (M-2 x pinacol + H) + , 582.7 (M-pinacol + H) + , 664.8(M+H) + .

[0665] 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ in acetonitrile (6 mL) 6 A solution of (7, 568 mg, 856 μmol)-sulfanylideneamino)acetic acid (7, 568 mg, 856 μmol) was diluted with water (2.4 mL), followed by the addition of periodic acid (780 mg, 3.42 mmol). The resulting mixture was stirred for 1 hour, then partitioned between ethyl acetate (120 mL) and water (30 mL). The phases were separated, and the organic phase was washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was dissolved in 0.5 M aqueous sodium hydroxide solution (30 mL) and washed with dichloromethane (3 × 40 mL). The aqueous layer was acidified with 1 M aqueous hydrochloric acid solution (30 mL) and extracted with ethyl acetate (2 × 60 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo until the product began to precipitate (approximately 10 mL volume). The suspension was diluted with n-hexane (50 mL) and placed in a freezer for 30 minutes. The precipitate was collected by filtration, washed with n-hexane (3×5 mL), dried under vacuum, and dissolved in 50% aqueous acetonitrile (60 mL). The resulting solution was lyophilized to give the title compound (8) as a white powder.

[0666] Yield: 338 mg (79%).

[0667] 1H NMR spectrum (300 MHz, DMSO-d + DCl, δ H ):8.60(s,2 H);8.35(s,4 H);3.70(s,2 H).

[0668] 19 F NMR spectrum (282 MHz, DMSO-d6 + DCl, δ F ):-61.24(s).

[0669] LC-MS purity: 100% (ELSD, UV 254nm).

[0670] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.89 min.

[0671] LC-MS m / z: 500.5(M+H)+.

[0672] Example 31 N-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 35 and in accordance with the procedures described below. [ka]

[0673] N-iodosuccinimide (NIS, 61.5 g, 274 mmol) was added to a solution of 3-bromo-4-methylbenzoic acid (1, 56.0 g, 260 mmol) in concentrated sulfuric acid (1 L), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was then poured into ice water (2 L). The resulting mixture was poured into an ice bath (2 L), and the precipitate was filtered, washed with water, and dried under vacuum to give 3-bromo-5-iodo-4-methylbenzoic acid (2) as an off-white solid. Yield: 87.8g (99%). 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):8.30(d, J=1.7 Hz,1 H);8.06(d,J=1.7 Hz,1 H);2.64(s,3 H).

[0674] Concentrated sulfuric acid (25 mL) was added to a solution of 3-bromo-5-iodo-4-methylbenzoic acid (2, 30.0 g, 88.0 mmol) in methanol (1 L), and the reaction mixture was stirred under reflux overnight. The reaction mixture was then evaporated under reduced pressure, dissolved in diethyl ether (500 mL), and washed with water (2 × 200 mL) and a saturated solution of potassium carbonate (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-5-iodo-4-methylbenzoate (3) as a white solid.

[0675] Yield: 26.1g (84%).

[0676] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):8.32(d,J=1.7 Hz,1 H);8.09(d,J=1.3 Hz,1 H);3.86(s,3 H);2.65(s,3 H).

[0677] To a solution of methyl 3-bromo-5-iodo-4-methylbenzoate (3, 9.00 g, 25.4 mmol) in dry tetrahydrofuran (250 mL) was added dropwise a 1.3 M solution of isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (21.6 mL, 28.0 mmol) at −30° C. under an inert atmosphere and stirred for 20 minutes. N,N-dimethylformamide (3.60 mL, 38.1 mmol) was then added at −30° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was then evaporated under reduced pressure, dissolved in ethyl acetate (200 mL), and washed with water (2×100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-5-formyl-4-methylbenzoate (4) as a white solid. Yield: 6.24g (96%).

[0678] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):10.27(s,1 H);8.53-8.34(m,2 H);3.97(s,3 H);2.82(s,3 H).

[0679] A solution of 3-bromo-5-formyl-4-methylbenzoate (4, 6.23 g, 24.3 mmol) and (diethylamino)sulfur trifluoride (DAST, 6.40 mL, 48.5 mmol) in dichloromethane (150 mL) was stirred at ambient temperature for 16 hours. The reaction was quenched by the addition of water (75 mL) and extracted with dichloromethane (2 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-5-(difluoromethyl)-4-methylbenzoate (5) as a white solid.

[0680] Yield: 6.53g (96%).

[0681] 1 H NMR spectrum (300 MHz, CDCl3, δ H):8.35(d,J=1.1 Hz,1 H);8.14(d,J=0.9 Hz,1 H);6.78(t,J=54.8 Hz,1 H);3.93(s,3 H);2.55(t,J=1.4 Hz,3 H).

[0682] A solution of 1-bromopyrrolidine-2,5-dione (NBS, 4.57 g, 25.7 mmol), methyl 3-bromo-5-(difluoromethyl)-4-methylbenzoate (5, 6.53 g, 23.4 mmol), and 2,2-azobis(2-methylpropionitrile) (AIBN, 192 mg, 1.17 mmol) in PhCF3 (200 mL) was stirred at 85°C overnight. The reaction mixture was evaporated and then extracted with diethyl ether (2 × 200 mL). The organic layer was washed with brine (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product 6 was stirred with potassium acetate (4.59 g, 46.8 mmol) in acetonitrile (200 mL) at 75°C overnight. The suspension was filtered through filter paper and evaporated. The crude product was dissolved in dichloromethane and filtered again. The filtrate was evaporated and purified by column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 7:1) to give methyl 4-(acetoxymethyl)-3-bromo-5-(difluoromethyl)benzoate (7) as a white solid.

[0683] Yield: 4.24g (54%).

[0684] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.40(s,1 H);8.26(s,1 H);7.02(t,J=54.7 Hz,1 H);5.38(s,2 H);3.97(s,3 H);2.11(s,3 H).

[0685] A solution of methyl 4-(acetoxymethyl)-3-bromo-5-(difluoromethyl)benzoate (7, 4.24 g, 12.6 mmol), bis(pinacolato)diboron (3.52 g, 13.9 mmol), potassium acetate (3.70 g, 37.8 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (513 mg, 0.63 mmol) in dry tetrahydrofuran (100 mL) was stirred at 75° C. under an argon atmosphere for 10 days. The reaction mixture was then cooled to ambient temperature, filtered, and evaporated. The crude product was filtered through a silica gel column (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1) to give methyl 4-(acetoxymethyl)-3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (8). Yield: 2.82g (53%).

[0686] R F (SiO2, cyclohexane / ethyl acetate 9:1): 0.40.

[0687] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.57(s,1 H);8.38(s,1 H);7.04(t,J=55.1 Hz,1 H);5.54(s,2 H);3.97(s,3 H);2.06(s,3 H);1.39(s,12 H).

[0688] A solution of methyl 4-(acetoxymethyl)-3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (8, 2.82 g, 7.34 mmol) and sodium hydroxide (1.47 g, 36.7 mmol) in water (50 mL) was stirred at ambient temperature for 3 hours. A solution of concentrated hydrochloric acid (4 mL) in water (10 mL) was then added to lower the pH to 1. The reaction mixture was left in the refrigerator overnight. The precipitate was filtered and dried to give 4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (9) as a white solid.

[0689] Yield: 1.32g (79%).

[0690] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.25(bs,1 H);9.54(s,1 H);8.51(s,1 H);8.20(s,1 H);7.22(t,J=55.1 Hz,1 H);5.19(s,2 H).

[0691] A solution of 2,3,4,5,6-pentafluorophenol (242 mg, 1.32 mmol), 4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (9, 300 mg, 1.32 mmol), and N,N'-dicyclohexylcarbodiimide (DCC, 272 mg, 1.32 mmol) in acetonitrile (20 mL) was stirred overnight at ambient temperature. The reaction mixture was filtered, evaporated, dissolved in acetonitrile, refiltered, and evaporated to give perfluorophenyl 4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (10) as a white solid.

[0692] Yield: 520 mg (100%).

[0693] LC-MS purity: 100% (ELSD).

[0694] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 4.65 min.

[0695] LC-MS m / z: 395.5(M+H)+.

[0696] A solution of perfluorophenyl 4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (10, 520 mg, 1.32 mmol), (2-aminoethyl)glycine (11, 78.0 mg, 0.66 mmol), and triethylamine (1.84 mL, 6.60 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 3 days. The reaction mixture was then evaporated, and the crude product 12 was purified by preparative HPLC (SunFire Prep C18 OBD, 5 m, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) and lyophilized to give N-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine (12) as a white solid.

[0697] Yield: 110 mg (31%).

[0698] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.89(bs,1 H);9.63-9.35(m,2 H);8.92-6.70(m,7 H);5.25-5.08(m,4 H);4.28-3.94(m,2 H);3.74-3.35(m,4 H).

[0699] LC-MS purity: 100% (ELSD).

[0700] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95–100:0 + 0.1% FA): 3.30 min.

[0701] LC-MS m / z: 539.4 (M+H) + .

[0702] Example 32 N-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 36 and in accordance with the procedures described below. [ka]

[0703] Concentrated sulfuric acid (4.00 mL, 73.3 mmol) was added to a solution of 3-chloro-4-methylbenzoic acid (1, 25.0 g, 147 mmol) in methanol (200 mL), and the reaction mixture was stirred at 60° C. for 2 days. The solution was cooled to room temperature, sodium bicarbonate (6.80 g, 80.0 mmol) was added, and the mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (300 mL) and water (250 mL). The organic layer was separated, washed with 0.5 M aqueous sodium hydroxide solution (2×250 mL), 0.5 M aqueous hydrochloric acid solution (200 mL), and brine (150 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to give methyl 3-chloro-4-methylbenzoate (2) as an orange oil.

[0704] Yield: 27.0g (98%).

[0705] RF(SiO2, dichloromethane / methanol 95:5): 0.80.

[0706] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.00 (d, J = 1.65 Hz, 1 H); 7.80 (dd, J = 7.9 and 1.5 Hz, 1 H); 7.28 (d, J = 8.1 Hz, 1 H); 3.90 (s, 3 H); 2.42 (s, 3 H).

[0707] Methyl 3-chloro-4-methylbenzoate (2, 26.0 g, 141 mmol) was dissolved in sulfuric acid (150 mL), followed by the addition of N-iodosuccinimide (38.0 g, 169 mmol). The resulting mixture was stirred at room temperature overnight and then poured onto ice. When the ice had completely melted, the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with 5% aqueous sodium thiosulfate (3 × 100 mL) and water (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was recrystallized from hot heptane (150 mL) to give methyl 3-chloro-5-iodo-4-methylbenzoate (3) as a white powder. Yield: 32.0g (73%).

[0708] RF(SiO2, dichloromethane / methanol 95:5): 0.80.

[0709] 1 H NMR spectrum (300 MHz, DMSO-d6, δ Η ):8.38(dd,J=1.3 Hz,1 H);8.00(dd,J=1.3 Hz,1 H);3.87(s,3 H);2.54(s,3 H).

[0710] A stirred mixture of methyl 3-chloro-4-methylbenzoate (3, 30.0 g, 96.6 mmol), 1-bromopyrrolidine-2,5-dione (NBS, 18.9 g, 106 mmol), and water (400 mL) in a wide beaker was placed under a reptile D3 basking lamp (100 W, UVA, UVB, IR) and heated to 90-100 °C until the mixture went from a suspension to an oily consistency. Another portion of 1-bromopyrrolidine-2,5-dione (0.00 g, 11.3 mmol) was added after 6 h, and the mixture was stirred for an additional 5 h. The mixture was cooled to room temperature and subsequently extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with 5% aqueous sodium thiosulfate solution (3 × 100 mL), water (1 × 100 mL), brine (1 × 100 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to give crude methyl 4-(bromomethyl)-3-chloro-5-iodobenzoate (4) as a yellow solid.

[0711] Yield: 29.5g (78%).

[0712] R F (SiO2, cyclohexane / ethyl acetate 8:2): 0.70.

[0713] 1 H NMR spectrum (300 MHz, DMSO-d6, δ Η ):8.80(s,1 H);8.41(s,1 H);4.81(s,2 H);3.94(s,3 H).

[0714] A mixture of the above crude methyl 4-(bromomethyl)-3-chloro-5-iodobenzoate (4, 28.0 g, 71.9 mmol) and potassium acetate (21.2 g, 216 mmol) in acetonitrile (600 mL) was heated at 80° C. for 7 hours. The mixture was cooled to room temperature, and the solid was removed by filtration and washed with ethyl acetate (3×50 mL). The filtrate was evaporated to dryness, and the residue was partitioned between ethyl acetate (500 mL) and water (200 mL). The organic layer was separated, washed with water (200 mL) and brine (2×200 mL), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography (Silicagel, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 97:3) followed by recrystallization from hot cyclohexane to give pure methyl 4-(acetoxymethyl)-3-chloro-5-iodobenzoate (5) as a white solid.

[0715] Yield: 19.3g (62%).

[0716] R F (SiO2, cyclohexane / ethyl acetate 4:1): 0.60.

[0717] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.42(d,J=3.3 Hz,1 H);8.04(d,J=3.6 Hz,1 H);5.40(s,2 H);3.94(s,3 H);2.12(s,3 H).

[0718] LC-MS purity: 100% (UV 254nm).

[0719] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 2.62 min.

[0720] LC-MS m / z: 369.5 (M+H)+.

[0721] [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.48 g, 3.39 mmol) was added to a degassed solution of methyl 4-(acetoxymethyl)-3-chloro-5-iodobenzoate (5, 25.0 g, 63.8 mmol), bis(pinacolato)diboron (19.0 g, 74.6 mmol), and potassium acetate (20.0 g, 204 mmol) in dry 1,4-dioxane (300 mL) under argon. The mixture was warmed to 80°C and stirred at this temperature for 3 days. The mixture was cooled to room temperature, then diluted with dichloromethane (200 mL) and passed through a short column of silica gel covered with Celite, followed by elution with dichloromethane. The product-containing fractions were combined and evaporated to dryness. The residue was purified by flash column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1-7:3) to give methyl 4-(acetoxymethyl)-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6) as a yellow oil.

[0722] Yield: 25.0g (100%).

[0723] R F (SiO2, cyclohexane / ethyl acetate 8:2):0.4.

[0724] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.34 (d, J = 1.65 Hz, 1 H); 8.12 (d, J = 8.2 and 2.0 Hz, 1 H); 5.52 (s, 2 H); 3.93 (s, 3 H); 2.05 (s, 3 H); 1.34 (s, 12 H).

[0725] LC-MS purity: 100% (ELSD), 88% (UV 254nm).

[0726] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 3.54 min.

[0727] LC-MS m / z: 369.6 (M+H)+.

[0728] Methyl 4-(acetoxymethyl)-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6, 25.0 g, <63.8 mmol) was added to a solution of sodium hydroxide (12.8 g, 319 mmol) in water (300 mL), and the resulting mixture was stirred at room temperature for 5 hours. The mixture was filtered and acidified with 35% hydrochloric acid (39.6 mL, 444 mmol). The resulting white suspension was stirred for an additional hour. The precipitate was filtered, washed with water (5 × 50 mL), dissolved in 80% aqueous acetonitrile (500 mL), filtered, and the solution mixture was lyophilized to give 4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7) as a white powder.

[0729] Yield: 9.00g (63%).

[0730] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):13.30(s,1 H);9.60(s,1 H);8.32(d,J= 1.1 Hz,1 H);8.00(d,J=1.1 Hz,1 H);5.06(s,2 H).

[0731] LC-MS purity: 99% (ELSD).

[0732] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.90 min.

[0733] LC-MS m / z: 213.3 (M+H) + .

[0734] N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (3.40 g, 17.9 mmol) was added to a suspension of 4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7, 3.80 g, 17.9 mmol) and pentafluorophenol (3.30 g, 17.9 mmol) in a solution of acetonitrile / dichloromethane (1:1, 150 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. The residue was partitioned between ethyl acetate (200 mL) and 10% aqueous potassium hydrogen sulfate solution (200 mL). The organic layer was separated, washed with water (2 × 100 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was dissolved in dichloromethane and placed in the refrigerator overnight. The solid was filtered and washed with ethyl acetate (2 × 20 mL). The filtrates were combined and evaporated to dryness. Cyclohexane (100 mL) was added to the residue, and the mixture was stirred at room temperature for 15 min. The mixture was decanted, and the precipitate was dried under vacuum to give perfluorophenyl 4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8) as an off-white solid.

[0735] Yield: 4.80g (71%).

[0736] LC-MS purity: 98% (ELSD).

[0737] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 4.48 min.

[0738] LC-MS m / z: 379.4 (M+H) + .

[0739] N,N-Diisopropylethylamine (2.35 mL, 13.5 mmol) was added to a mixture of perfluorophenyl 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (9, 1.40 g, 3.72 mmol) and L-2,3-diaminopropionic acid hydrochloride (9, N-2-aminoethylglycine, 200 mg, 1.70 mmol) in a solution of N,N-dimethylformamide / water (4:1, 20 mL), and the resulting solution was stirred at room temperature overnight. The mixture was evaporated to dryness under vacuum, and the residue was partitioned between 1 M aqueous hydrochloric acid (40 mL) and ethyl acetate (50 mL). The phases were separated, and the organic phase was extracted with ethyl acetate (2 × 25 mL). All organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was evaporated three times with toluene. Dichloromethane (50 mL) was added, and the resulting suspension was stirred at room temperature for 2 h. The solid was decanted and everything was repeated once more. The precipitate was triturated with a mixture of dichloromethane / methanol / formic acid (1000:20:3), and the solid was collected by filtration, washed with cyclohexane (2×5 mL), and air-dried to give the title compound (10) as a white powder.

[0740] Yield: 180 mg (21%).

[0741] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.87(bs,1 H);9.67-9.37(m,1 H);8.87-7.09(m,5 H);5.15-4.86(m,4 H);4.34-3.92(m,2 H);3.60-3.24(m,4 H).

[0742] LC-MS purity: 100% (ELSD).

[0743] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.58 min.

[0744] LC-MS m / z: 507.3 (M+H) + .

[0745] Example 33 (S)-3-(2,3-bis(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanamido)propanoic acid [ka] (S)-3-(2,3-bis(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanamide)propanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 37 and in accordance with the procedure described below. [ka]

[0746] 2-Chlorotrityl chloride resin, 100-200 mesh, 1.5 mmol / g (3.30 g, 4.95 mmol) was allowed to swell in dry dichloromethane (300 mL) for 30 min. 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (1, Fmoc-beta-Ala-OH, 0.50 g, 1.60 mmol) in dry dichloromethane (100 mL) and N,N-diisopropylethylamine (2.00 mL, 15.5 mmol) was added. The mixture was shaken overnight. The resin was then filtered and treated with a solution of N,N-diisopropylethylamine / methanol / dichloromethane mixture (1:2:8, 2 x 5 min, 2 x 50 mL). The resin was washed with dichloromethane (3 x 100 mL), 2-propanol (3 x 100 mL), and N,N-dimethylformamide (3 x 100 mL). The Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 100 mL). The resin was washed with N,N-dimethylformamide (3 × 100 mL), 2-propanol (3 × 100 mL), and dichloromethane (3 × 100 mL). A solution of (S)-2,3-bis((((8a9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (2, Fmoc-Dap(Fmoc)-OH, 1.00 g, 1.82 mmol) and N,N-diisopropylethylamine (3.00 mL, 4.04 mmol) in dichloromethane (100 mL) was added. The solution was added to the resin, and the mixture was shaken for 5 hours. The resin was filtered and washed with dichloromethane (3 x 100 mL), 2-propanol (3 x 100 mL), and dichloromethane (3 x 100 mL). The Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 100 mL). The resin was washed with dichloromethane (3 x 100 mL), 2-propanol (3 x 100 mL), and dichloromethane (3 x 100 mL).A solution of pentafluorophenyl 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (3, 1.40 g, 3.72 mmol, Example 8 above) and N,N-diisopropylethylamine (6.00 mL, 60.0 mmol) in N,N-dimethylformamide (50 mL) was added to the resin, and the mixture was shaken for 5 h. The resin was washed with dichloromethane (3 × 100 mL), 2-propanol (3 × 100 mL), N,N-dimethylformamide (3 × 100 mL), and dichloromethane (5 × 100 mL).

[0747] The product was cleaved from the resin by treatment with 1,1,1,3,3,3-hexafluoroisopropanol in dichloromethane (3:1, 100 mL). The resin was filtered and washed with dichloromethane (3 × 100 mL). The solutions were mixed and the solvent was evaporated to dryness to give a crude mixture that was subjected to purification by preparative LC / MS (SunFire Prep C18 OBD, 5 m, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). Pure fractions were combined and lyophilized to give the title compound (4) as a white powder.

[0748] Yield: 103 mg (11%).

[0749] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.16(bs,1 H);9.54(d,J=6.24 Hz,2 H);8.74-8.63(m,2 H);8.19(d,J=1.1 Hz,1 H);8.15-8.08(m,2 H);8.02(d,J=1.28 Hz,1 H);7.09(d,J=1.1 Hz,1 H);5.03(d,J=7.34 Hz,4 H);4.71-4.61(m,1 H);3.59(t,J=5.59 Hz,2 H);

[0750] 3.30-3.23(m,2 H);2.37(t,J=7.15 Hz,2 H).

[0751] LC-MS purity: 100% (ELSD, UV 254nm).

[0752] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.63 min.

[0753] LC-MS m / z: 563.0 (M+H) + .

[0754] Example 34 2-((bis(3-borono-5-(difluoromethyl)phenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid [ka] 2-((bis(3-borono-5-(difluoromethyl)phenyl)(oxo)-λ-sulfanylidene)amino)acetic acid was synthesized according to the reaction scheme shown in Chemical Reaction 38 and according to the procedure described below. [ka]

[0755] A mixture of 3-iodobenzaldehyde (1, 4.00 g, 17.2 mmol) in Deoxo-Fluor (12 mL) was stirred overnight at room temperature. It was then diluted with dichloromethane (150 mL), followed by the dropwise addition of 10% aqueous potassium carbonate (200 mL) at 0°C. The phases were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane) to give 1-(difluoromethyl)-3-iodobenzene (2) as a colorless oil.

[0756] Yield: 3.22g (74%).

[0757] R F (SiO2, cyclohexane): 0.50.

[0758] 1H NMR spectrum (300 MHz, CDCl3, δ H ):7.89-7.85(m,1 H);7.85-7.79(m,1 H);7.52-7.46(m,1 H);7.24-7.17(m,1 H);6.59(t,J=56.2 Hz,1 H).

[0759] Iodide (2, 1.48 g, 5.81 mmol) was dissolved in dry tetrahydrofuran (20 mL) under a nitrogen atmosphere and cooled to -30°C. A 1.3 M solution of isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (4.69 mL, 6.10 mmol) was added dropwise. The resulting solution was stirred at -30°C for 1.5 h. A solution of bis(phenylsulfonyl)sulfide (0.82 g, 2.61 mmol) in degassed tetrahydrofuran (10 mL) was then added. The mixture was allowed to warm to room temperature (approximately 2 h). The reaction was quenched by the addition of 20% aqueous ammonium chloride solution (30 mL) and extracted with diethyl ether (50 mL). The organic layer was washed with water (3 × 50 mL) and brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane) to give bis(3-(difluoromethyl)phenyl)sulfane (3) as a colorless oil, which crystallized in the refrigerator.

[0760] Yield: 568 mg (76%).

[0761] R F (SiO2, cyclohexane): 0.20.

[0762] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.52-7.48(m,2 H);7.48-7.37(m,6 H);6.61(t,J=56.3 Hz,2 H).

[0763] 19 F NMR spectrum (282 MHz, CDCl3, δF ):-111.21(s);-111.40(s).

[0764] (Diacetoxyiodo)benzene (966 mg, 3.00 mmol) was added to a mixture of sulfide (3, 343 mg, 1.20 mmol) and ammonium carbamate (187 mg, 2.40 mmol) in methanol (5.5 mL). The resulting pale yellow solution was stirred at room temperature for 3 hours, and then it was evaporated to dryness under vacuum. A solution of potassium bicarbonate (2 g) and sodium thiosulfate (2 g) in water (20 mL) was added to the residue, followed by ethyl acetate (70 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 70 mL). The organic fractions were combined, dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was purified by flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane / ethyl acetate 2:1) to give bis(3-(difluoromethyl)phenyl)(imino)-λ as a white solid. 6 -sulfanone (4) was obtained.

[0765] Yield: 553 mg (89%).

[0766] R F (SiO2, n-hexane / ethyl acetate 1:1): 0.45.

[0767] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.24-8.12(m,4 H);7.75-7.68(m,2 H);7.68-7.58(m,2 H);6.70(t,J=56.0 Hz,2 H);3.20(bs,1 H).

[0768] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-111.74(s);-111.94(s).

[0769] LC-MS purity: 100% (ELSD).

[0770] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 2.70 min.

[0771] LC-MS m / z: 317.3 (M+H) + .

[0772] A 60% dispersion of sodium hydride in mineral oil (0.08 g, 1.88 mmol) was added to a solution of the above compound (4, 543 mg, 1.71 mmol) in dry N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 1 h. tert-Butyl bromoacetate (0.38 mL, 2.57 mmol) was added, and the mixture was heated to 60 °C and stirred at this temperature for 2.5 h. The mixture was cooled to room temperature and partitioned between 10% aqueous sodium hydrogen sulfate (30 mL) and ethyl acetate (60 mL). The separated organic layer was washed with water (3 × 30 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was purified by flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane / ethyl acetate 4:1) to give tert-butyl 2-((bis(3-(difluoromethyl)phenyl)(oxo)-λ) as a colorless oil. 6 -sulfanylidene)amino)amino)acetate (5) was obtained.

[0773] Yield: 708 mg (96%).

[0774] R F (SiO2, n-hexane / ethyl acetate 1:1): 0.65.

[0775] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):

[0776] 8.23-8.16(m,4 H);7.75-7.70(m,2 H);7.67-7.58(m,2 H);6.69(t,J=56.0 Hz,2 H);3.76(s,2 H);1.47(s,9 H).

[0777] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-111.56(s);-111.76(s).

[0778] The compound prepared above (5, 700 mg, 1.62 mmol), bis(pinacolato)diboron (1.03 g, 4.05 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (33.0 mg, 0.05 mmol), and 4,4-di-tert-butyl-2,2-dipyridyl (dtbpy, 30.0 mg, 0.11 mmol) were dissolved in degassed tetrahydrofuran (16 mL) under nitrogen. The resulting mixture was warmed to 50 °C and heated at this temperature overnight. The mixture was evaporated to dryness and the residue was purified by quick flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: dichloromethane) to give a beige foam and tert-butyl 2-((bis(3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(oxo)-λ 6 -sulfanylidene)amino)acetate (6).

[0779] Yield: 945 mg (85%).

[0780] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.53(s,2 H);8.30(s,2 H);8.11(s,4 H);6.69(t,J=56.0 Hz,2 H);3.75(s,2 H);1.51(s,9 H);1.35(s,12 H);1.35(s,12 H).

[0781] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-111.26(s);-111.49(s).

[0782] Trifluoroacetic acid (20 mL) was added to a solution of the above compound (6, 935 mg, 1.04 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness in vacuo, and the residue was evaporated from dichloromethane (5 × 10 mL) to give 2-((bis(3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(oxo)-λ as a beige foam. 6 -sulfanylidene)amino)acetic acid (7) was obtained.

[0783] Yield: 858 mg (100%).

[0784] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.49(s,2 H);8.22(s,2 H);8.18(s,2 H);6.72(t,J=55.8 Hz,2 H);3.88(s,2 H);1.37(s,12 H);1.37(s,12 H).

[0785] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-111.84(s);-112.03(s).

[0786] A solution of the acid (7, 858 mg, 1.37 mmol) in acetonitrile (16 mL) was diluted with water (4 mL), followed by the addition of periodic acid (1.25 g, 5.48 mmol). The resulting mixture was stirred for 1 hour, then partitioned between ethyl acetate (120 mL) and water (30 mL). The phases were separated, and the organic phase was washed with water (1 × 60 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was dissolved in 0.5 M sodium hydroxide solution (50 mL) and washed with dichloromethane (2 × 80 mL). The aqueous layer was acidified with 1 M aqueous hydrochloric acid (80 mL) and extracted with ethyl acetate (3 × 120 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and evaporated. A portion of the residual material (0.20 g) was purified by preparative LC / MS (SunFire Prep C18 OBD, 5 m, 19×100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) to give the title compound (8) as a white powder.

[0787] Yield: 170 mg (85%).

[0788] 1 H NMR spectrum (300 MHz, DMSO-d + DCl, δ H ):8.48(s,2 H);8.19(s,4 H);7.14(t,J=55.6 Hz,2 H);3.65(s,2 H).

[0789] 19 F NMR spectrum (282 MHz, DMSO-d6 + DCl, δ F ):-110.64(s);-110.84(s).

[0790] LC-MS purity: 100% (ELSD).

[0791] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.27 min.

[0792] LC-MS m / z: 462.9 (M+H) + .

[0793] Example 35 2-((bis(3-borono-5-chlorophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid [ka] 2-((bis(3-borono-5-chlorophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid was synthesized according to the reaction scheme shown in Chemical Reaction 39 and following the procedure described below. [ka]

[0794] A well-stirred suspension of 3-chloroiodobenzene (1, 10.2 g, 42.6 mmol), sodium sulfide nonahydrate (7.16 g, 29.8 mmol), potassium carbonate (5.89 g, 42.6 mmol), and copper(I) iodide (811 mg, 4.26 mmol) in dry N,N-dimethylformamide (85 mL) was heated to 120 °C (oil bath) for 72 h. After cooling to ambient temperature, the reaction mixture was diluted with diethyl ether (150 mL), filtered through a pad of Celite, and the pad was washed with additional diethyl ether (3 × 100 mL). The filtrate was transferred to a separatory funnel and washed with water (200 mL) and 1 M aqueous sodium hydroxide solution (2 × 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane) to give bis(3-chlorophenyl)sulfane (2) as a colorless oil.

[0795] Yield: 4.66g (86%). 1 H NMR spectrum (300 MHz, DMSO-d 6,δH ) :7.45-7.38(m,6 H);7.35-7.29(m,2 H).

[0796] LC-MS purity: 97% (UV 254).

[0797] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 3.25 min.

[0798] LC-MS m / z: 254.1 (M+H) + .

[0799] To a well-stirred solution of bis(3-chlorophenyl)sulfane (2, 4.00 g, 15.7 mmol) in methanol (37 mL) was added ammonium carbamate (2.84 g, 31.4 mmol) and bis(acetoxy)iodobenzene (14.7 g, 39.3 mmol). After 2 h, the reaction mixture was evaporated under vacuum, and the residue was dissolved in ethyl acetate (40 mL) and washed with 10% aqueous sodium thiosulfate (40 mL), 10% aqueous potassium bicarbonate (40 mL), and brine (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash column chromatography (Silicagel 60, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 3:1) to obtain bis(3-chlorophenyl)(imino)-λ as a yellowish oil. 6 -sulfanone (3) was obtained.

[0800] Yield: 4.13g (94%).

[0801] 1 H NMR spectrum (300 MHz, CDCl 3,δH ):8.03(t,J=1.8 Hz,2 H);7.95-7.88(m,2 H);7.55-7.49(m,2 H);7.44(t,J=7.9 Hz,2 H);3.15(bs,1 H).

[0802] LC-MS purity: 100% (ELSD, UV 242).

[0803] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 40:60 to 100:0 + 0.1% FA): 2.65 min.

[0804] LC-MS m / z: 286.2(M+H)+.

[0805] Bis(3-chlorophenyl)(imino)-λ in anhydrous N,N-dimethylformamide (45 mL) 6 To an ice-cooled, well-stirred solution of 2-((bis(3-chlorophenyl)(oxo)-λ)sulfanone (3, 4.13 g, 16.2 mmol) under nitrogen was added sodium hydride (712 mg, 17.8 mmol). After 5 min, tert-butyl bromoacetate (4.74 mL, 24.3 mmol) was added. The reaction mixture was allowed to reach ambient temperature and stirred for 1 h. The reaction mixture was then taken up in ethyl acetate (160 mL) and washed with 10% aqueous ammonium chloride solution (160 mL), water (2 x 160 mL), and brine (160 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 20:1-3:1) to give tert-butyl 2-((bis(3-chlorophenyl)(oxo)-λ)sulfanone as a yellowish oil. 6 -sulfanylidene)amino)acetate (4) was obtained.

[0806] Yield: 4.73g (76%).

[0807] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.04 (t, J = 1.8 Hz, 2 H); 7.94 (dt, J = 7.7, 1.4 Hz and 2 H); 7.55-7.49 (m, 2 H); 7.44 (t, J = 7.9 Hz, 2 H); 3.76 (s, 2 H); 1.48 (s, 9 H).

[0808] LC-MS purity: 100% (ELSD, UV 242).

[0809] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 40:60 to 100:0 + 0.1% FA): 4.29 min.

[0810] LC-MS m / z: 400.3 (M+H) + .

[0811] tert-Butyl 2-((bis(3-chlorophenyl)(oxo)-λ 6 (4,400 mg, 1.00 mmol), bis(pinacolato)diboron (635 mg, 2.50 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (26.5 mg, 0.04 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy, 26.5 mg, 0.04 mmol) were dissolved in dry, degassed tetrahydrofuran (4 mL) under nitrogen. The reaction mixture was stirred at 60 °C (oil bath) for 16 h. The reaction mixture was then evaporated to dryness, and the residue was dissolved in dichloromethane (10 mL) and filtered through a plug of silica gel (7.00 g) covered with Celite using dichloromethane (4 × 15 mL). The filtrate was evaporated to give crude tert-butyl 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-λ as a yellowish foam. 6 -sulfanylidene)amino)acetate (5) was obtained.

[0812] This was dissolved in acetonitrile (6 mL) and water (2 mL), and periodic acid (1596 mg, 7.00 mmol) was added. The resulting mixture was stirred for 1 hour, and then it was partitioned between ethyl acetate (30 mL) and water (30 mL). The phases were separated, and the organic layer was washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a yellowish waxy solid.

[0813] The solid was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness under vacuum, and the residue was co-distilled with ethyl acetate (5 × 10 mL) and acetonitrile (5 × 5 mL). A portion of the residue was dissolved in an acetonitrile / water mixture (3:1, 4 mL) and purified by preparative LC / MS (SunFire Prep C18 OBD, 5 μm, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) to give 2-((bis(3-borono-5-chlorophenyl)(oxo)-λ) as a colorless solid. 6 -sulfanylidene)amino)acetic acid (6) was obtained.

[0814] Yield: 125 mg (29%).

[0815] 1 H NMR spectrum (300 MHz, acetone-d + D2O, δ H ): 8.39 (bs, 2 H); 8.10 (bs, 2 H); 7.99 (bs, 2 H); 3.77 (s, 2 H, overlapping with water signal).

[0816] LC-MS purity: 100% (ELSD).

[0817] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 2.70 min.

[0818] LC-MS m / z: 432.2 (M+H) + .

[0819] Example 36 2-((bis(3-boronophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid [ka] 2-((bis(3-boronophenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid was synthesized according to the reaction scheme shown in Chemical Reaction 40 and according to the procedure described below. [ka]

[0820] A 25 mL reaction vessel was charged with potassium acetate (1.14 g, 11.6 mmol), and the salt was dried under vacuum at 110 C for 1 h. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with tert-butyl 2-((bis(3-chlorophenyl)(oxo)-λ-sulfanylidene)amino)acetate (1, 925 mg, 2.32 mmol), palladium acetate (20.8 mg, 93.0 mol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos, 88.2 mg, 0.19 mmol), and bis(pinacolato)diboron (1.18 g, 4.64 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous tetrahydrofuran (10 mL) was added via syringe. The vessel was sealed with a plastic stopper and immersed in a heating bath preheated to 60°C. After stirring at 400 rpm for 16 h, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (40 mL), and filtered through a short plug (25 g) of silica covered with Celite S with ethyl acetate (3 × 40 mL). The filtrate was concentrated under reduced pressure to give crude product 2 as a yellowish oil. This was triturated with acetonitrile (10 mL), and the precipitate (XPhos oxide) was filtered. The filtrate was evaporated under vacuum and co-distilled with cyclohexane (3 × 20 mL) to give a yellowish foam, which was triturated to give tert-butyl 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-λ as a yellow oil. 6 -sulfanylidene)amino)acetate (2).

[0821] Yield: 1.30 g (96%).

[0822] 1 H NMR spectrum (300 MHz, CDCl3, δ H):8.45(s,2 H);8.15(s,2 H);7.94(d,J = 7.3 Hz,2 H);7.48(t,J = 7.7 Hz,2 H);3.75(s,2 H);1.49(s,9 H);1.34(s,24 H).

[0823] LC-MS purity: 100% (ELSD, UV 270nm).

[0824] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 70:30 to 100:0 + 0.1% FA): 2.8 min.

[0825] LC-MS m / z: 584.6(M+H)+.

[0826] Trifluoroacetic acid (12 mL) was dissolved in dichloromethane (4 mL) to give tert-butyl 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-λ 6 To a solution of 2-(oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-λ-sulfanylidene)amino)acetate (2, 1.30 g, 2.20 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness in vacuo, and the residue was evaporated from dichloromethane (5 × 10 mL) to give 2-(oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-λ-sulfanylidene)amino)acetate (2, 1.30 g, 2.20 mmol), as an off-white foam. 6 (-sulfanylidene)amino)acetic acid was obtained.

[0827] 2-((oxobis(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-λ) in acetonitrile (12 mL) 6A solution of 2-((bis(3-boronophenyl)(oxo)-λ)-bis(3-boronophenyl)-2-methyl-2-methyl-1-propanol (1.00 g, 1.90 mmol) was diluted with water (4 mL), followed by the addition of periodic acid (1.73 g, 7.60 mmol). The resulting mixture was stirred for 1 h, then diluted with ethyl acetate (100 mL) and washed with 5% brine (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. A portion of the residue was dissolved in an acetonitrile / water mixture (3:1, 4 mL) and purified by preparative LC / MS (SunFire Prep C18 OBD, 5 m, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). The resulting solution was lyophilized to give 2-((bis(3-boronophenyl)(oxo)-λ)-bis(3-boronophenyl)-2-methyl-1-methyl-1-propanol (1.00 g, 1.90 mmol). 6 -sulfanylidene)amino)acetic acid (3) was obtained.

[0828] Yield: 700 mg (80%).

[0829] 1 H NMR spectrum (300 MHz, acetone-d + D2O, δ H ):8.50(s, 2 H);8.05(t,J=7.8 Hz,4 H);7.55(t,J=7.7 Hz,4 H);3.72(s,2 H).

[0830] LC-MS purity: 100% (ELSD, UV 260nm).

[0831] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.19 min.

[0832] Example 37 N-(1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 41 and in accordance with the procedures described below. [ka]

[0833] 4-Methyl-2-(trifluoromethyl)benzoic acid (1, 25.0 g, 123 mmol) was dissolved in sulfuric acid (183 mL), followed by the addition of N-iodosuccinimide (33.1 g, 147 mmol). The resulting mixture was stirred at room temperature overnight and then poured onto ice. When the ice had completely melted, the mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with 5% aqueous sodium thiosulfate solution (2 × 250 mL) and water (1 × 250 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 5-iodo-4-methyl-2-(trifluoromethyl)benzoic acid (2) as a beige powder. Yield: 37.7 g (93%).

[0834] 1 H NMR spectrum (300 MHz, DMSO-d6, δ Η ):13.68(bs,1 H);8.22(s,1 H);7.76(s,1 H);2.47(s,3 H).

[0835] A mixture of 5-iodo-4-methyl-2-(trifluoromethyl)benzoic acid (2, 22.2 g, 67.2 mmol), triethyl orthoformate (14.7 mL, 134 mmol), and methanesulfonic acid (2.8 mL) in methanol (135 mL) was refluxed at 80 °C overnight under a nitrogen atmosphere. The solvent was evaporated. The residue was dissolved in 5% aqueous sodium carbonate (200 mL) and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with water (1 × 300 mL) and brine (1 × 200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by quick flash column chromatography (Silicagel 60, 0.040–0.063 mm, eluent: cyclohexane / ethyl acetate 9:1) to give methyl 5-iodo-4-methyl-2-(trifluoromethyl)benzoate (3) as white crystals. Yield: 35.9g (91%).

[0836] R F (cyclohexane / ethyl acetate 9:1): 0.50.

[0837] 1 H NMR spectrum (300 MHz, CDCl3, δ Η ):8.26(s,1 H);7.57(s,1 H);3.93(s,3 H);2.53(s,3 H).

[0838] A mixture of methyl 5-iodo-4-methyl-2-(trifluoromethyl)benzoate (3, 35.9 g, 104 mmol), N-bromosuccinimide (20.4 g, 114 mmol), and 2,2-azobis(2-methylpropionitrile) (AIBN, 5.12 g, 31.2 mmol) in benzotrifluoride (95 mL) was added to 85 mL of HCl. oThe mixture was stirred at 75°C overnight. Although complete conversion was not achieved, the reaction proceeded. Dichloromethane (150 mL) was added, and the mixture was washed with water (3 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in acetonitrile (440 mL), and potassium acetate (10.2 g, 104 mmol) was added. The mixture was stirred at 75°C overnight. The insoluble material was filtered, and the filtrate was evaporated. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / dichloromethane 4:1 to 1:1.5) to give methyl 4-(acetoxymethyl)-5-iodo-2-(trifluoromethyl)benzoate (4) as a white powder. Yield: 17.5 g (42%).

[0839] R F (cyclohexane / ethyl acetate 9:1): 0.35.

[0840] 1 H NMR spectrum (300 MHz, CDCl3, δ Η ):8.28(s,1 H);7.70(s,1 H);5.16(s,2 H);3.95(s,3 H);2.20(s,3 H).

[0841] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-59.96(s).

[0842] A mixture of methyl 4-(acetoxymethyl)-5-iodo-2-(trifluoromethyl)benzoate (4, 17.5 g, 43.5 mmol), bis(pinacolato)diboron (14.3 g, 56.5 mmol), and dry potassium acetate (21.3 g, 217 mmol) in dry N,N-dimethyl sulfoxide (110 mL) was degassed, and then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (1.59 g, 2.17 mmol) was added. The reaction mixture was stirred overnight at 95 °C under a nitrogen atmosphere. After cooling, diethyl ether (500 mL) was added, and the precipitate was filtered through a Celite pad. The filtrate was washed with 5% aqueous sodium chloride solution (3 × 500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 4-(acetoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzoate (5) as a black oil, which was used in the next step without further purification.

[0843] Yield: 22.5g.

[0844] 1 H NMR spectrum (300 MHz, CDCl3, δ Η ):8.22(s,1 H);7.74(s,1 H);5.44(s,2 H);3.94(s,3 H);2.14(s,3 H);1.36(s,12 H).

[0845] 19 F NMR spectrum (282 MHz, CDCl3, δ F ):-60.07(s).

[0846] Methyl 4-(acetoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzoate (5, 17.5 g, 43.5 mmol) was suspended in a solution of sodium hydroxide (8.70 g, 217 mmol) in water (150 mL). The mixture was stirred at room temperature for 6 hours, and then extracted with diethyl ether (2 × 200 mL). The aqueous phase was acidified with concentrated hydrochloric acid (18.9 mL), and the resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with water, and dried to give 1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (6) as a gray powder.

[0847] Yield: 7.62g (71%).

[0848] 1 H NMR spectrum (300 MHz, DMSO-d6, δ Η ):13.50(bs,1 H);9.57(s,1 H);8.16(s,1 H);7.92(s,1 H);5.11(s,2 H).

[0849] 19 F NMR spectrum (282 MHz, DMSO-d6, δ F ):-57.91(s).

[0850] LC-MS purity: 100% (ELSD).

[0851] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 2.77 min.

[0852] LC-MS m / z: 245.9 (M−H) - .

[0853] 1-Hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (6, 6.71 g, 27.3 mmol) was dissolved in a tetrahydrofuran / dichloromethane mixture (1:1, 50 mL), followed by the addition of 2,3,4,5,6-pentafluorophenol (5.03 g, 27.3 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (5.23 g, 27.3 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in ethyl acetate (150 mL) and washed with water (3 × 100 mL) and brine (1 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in diethyl ether (10 mL), and n-hexane (200 mL) was added. The precipitate was filtered, and the filtrate was evaporated. The same procedure was repeated twice with the precipitate. All filtrates were combined and evaporated to dryness to give perfluorophenyl 1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (7) as a yellow, solid oil.

[0854] Yield: 9.76g (87%).

[0855] 1 H NMR spectrum (300 MHz, DMSO-d6, δ Η ):9.74(s,1 H);8.53(s,1 H);8.16(s,1 H);5.18(s,2 H).

[0856] Perfluorophenyl 1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (7, 9.51 g, 23.1 mmol) was dissolved in N,N-dimethylformamide (30 mL). Then, N,N-diisopropylethylamine (10.1 mL, 57.7 mmol) and a solution of (2-aminoethyl)glycine hydrochloride (8, 1.78 g, 11.5 mmol) in water (30 mL) were added. The resulting mixture was stirred overnight at room temperature. The solvent was then evaporated. The residue was dissolved in ethyl acetate (200 mL) and washed with 1 M aqueous hydrochloric acid (1 × 200 mL), water (2 × 200 mL), and brine (1 × 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was treated with cyclohexane. The precipitate was filtered, washed with cyclohexane, and purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: dichloromethane / methanol / formic acid 10:1:0.05). The product-containing fractions were combined and evaporated. The residue was treated with cyclohexane. The precipitate was filtered, washed with cyclohexane, dissolved in acetonitrile (50 mL), and lyophilized to give the title compound (9) as a beige powder.

[0857] Yield: 3.63g (55%).

[0858] 1 H NMR spectrum (300 MHz, AcOD-d4, 80 C, δ Η ):8.04-7.66(m,4 H);5.28-5.04(m,4 H);4.63-4.34(m,1 H);4.22-3.78(m,3 H);3.72-3.49(m,2 H).

[0859] LC-MS purity: 100% (ELSD).

[0860] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 4.15 min.

[0861] LC-MS m / z: 574.0 (M+H)+.

[0862] Example 38 2-((bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(oxo)- λ6-sulfanylidene)amino)acetic acid [ka] 2-((bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(oxo)-λ-sulfanylidene)amino)acetic acid was synthesized according to the reaction schemes shown in Chemical Reaction 42 and Chemical Reaction 43 and in accordance with the procedures described below. [ka]

[0863] A solution of 3-bromo-4-methyl-5-trifluoromethylbenzoic acid (1, 26.6 g, 94.0 mmol), triethylamine (16.0 mL, 113 mmol), and diphenylphosphoryl azide (24.0 mL, 113 mmol) in a mixture of N,N-dimethylformamide and tert-butanol (1:5, 0.5 L) was stirred at 110° C. for 5 hours. The reaction mixture was then evaporated, and the crude product was dissolved in ethyl acetate (0.5 L) and washed with 10% aqueous citric acid (300 mL), 10% aqueous sodium bicarbonate (300 mL), and brine (300 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1) to give tert-butyl (3-bromo-4-methyl-5-(trifluoromethyl)phenyl)carbamate (2) as a white solid.

[0864] Yield: 13.5g (41%).

[0865] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):7.91(s,1 H);7.55(d,J=2.4 Hz,1 H);6.49(bs,1 H);2.47(d,J=1.5 Hz,3 H);1.54(s,9 H).

[0866] tert-Butyl (3-bromo-4-methyl-5-(trifluoromethyl)phenyl)carbamate (2, 10.0 g, 28.2 mmol) was dissolved in 2-propanol (60 mL) and concentrated aqueous hydrochloric acid (15 mL) was added. After 48 h, the reaction mixture was evaporated, taken up in diethyl ether (100 mL), and washed with 1 M aqueous sodium hydroxide solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give crude 3-bromo-4-methyl-5-(trifluoromethyl)aniline (3) as a yellowish oil, which was carried on to the next step without purification.

[0867] 3-Bromo-4-methyl-5-(trifluoromethyl)aniline (3) was dissolved in ice-cold acetonitrile (110 mL) and 4-toluenesulfonic acid monohydrate (16.1 g, 84.6 mmol) was added. Ice-cold water (45 mL) was added to the mixture to improve stirring. A solution of sodium nitrite (3.90 g, 56.4 mmol) and potassium iodide (11.7 g, 70.5 mmol) in water (30 mL) was then added dropwise to the acetonitrile solution (cooled in an ice bath). After the addition was complete and gas evolution had ceased, the reaction mixture was allowed to reach ambient temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, taken up in diethyl ether (100 mL), and washed with 10% aqueous potassium carbonate solution (100 mL) and 10% aqueous sodium thiosulfate solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product, which was subjected to flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: pure cyclohexane) to give 1-bromo-5-iodo-2-methyl-3-(trifluoromethyl)benzene (4) as a yellow oil.

[0868] Yield: 7.06 g (69%).

[0869] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.09(s,1 H);7.89(s,1 H);2.49(s,3 H).

[0870] A mixture of 1-bromo-5-iodo-2-methyl-3-(trifluoromethyl)benzene (4, 6.65 g, 18.2 mmol), N-bromosuccinimide (4.22 g, 23.7 mmol), and AIBN (299 mg, 1.82 mmol) was suspended in benzotrifluoride (27 mL) and heated to 85 °C (oil bath) for 24 h. Additional AIBN (299 mg, 1.82 mmol) was added, and the reaction mixture was heated with stirring for an additional 24 h. After cooling to ambient temperature, the reaction mixture was taken up in diethyl ether (100 mL) and washed with 10% aqueous potassium bicarbonate solution (100 mL), water (100 mL), 10% aqueous sodium thiosulfate solution (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude benzyl bromide. This was dissolved in dry acetonitrile (27 mL) and potassium acetate (3.60 g, 36.0 mmol) was added. The resulting suspension was heated to 80 °C (oil bath) for 24 h. After cooling to ambient temperature, the reaction mixture was taken up in diethyl ether (100 mL) and filtered through a short plug of silica gel (50 g) covered with Celite. The filtrate was evaporated in vacuo, and the residue was subjected to flash column chromatography (Silicagel 60, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 10:1) to give 2-bromo-4-iodo-6-(trifluoromethyl)benzyl acetate (5) as a colorless solid.

[0871] Yield: 6.60g (85%).

[0872] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.20(s,1 H);8.00(s,1 H);5.27(s,2 H);2.09(s,3 H).

[0873] 2-Bromo-4-iodo-6-(trifluoromethyl)benzyl acetate (5, 5.16 g, 12.2 mmol) was dissolved in dry methanol (36 mL) and potassium carbonate (5.00 g, 36.2 mmol) was added. After 90 min, the reaction mixture was taken up in diethyl ether (100 mL) and filtered through a short plug of silica gel (50 g) covered with Celite. The filtrate was evaporated in vacuo to give pure 2-bromo-4-iodo-6-(trifluoromethyl)phenyl)methanol (6) as a colorless solid. Yield: 4.64 g (quantitative). 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.18(s,1 H);7.98(s,1 H);4.87(d,J=6.9 Hz,2 H),2.08(t,J=6.9 Hz,1 H).

[0874] 2-Bromo-4-iodo-6-(trifluoromethyl)phenyl)methanol (6, 4.64 g, 12.2 mmol) was dissolved in dry-ice-cooled dichloromethane (36 mL) and N,N-diisopropylethylamine (DIPEA, 4.20 mL, 24.4 mmol) was added, followed by ethoxymethyl chloride (1.45 mL, 15.6 mmol). The reaction mixture was allowed to reach ambient temperature and stirred for 48 hours, after which it was quenched with methanol (5 mL). After 2 hours, the reaction mixture was evaporated in vacuo, and the residue was taken up in diethyl ether (100 mL) and washed with 10% aqueous potassium bisulfate solution (100 mL), water (100 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 20:1) to give 1-bromo-2-((ethoxymethoxy)methyl)-5-iodo-3-(trifluoromethyl)benzene (7) as a colorless solid. Yield: 4.57 g (85%).

[0875] 1H NMR spectrum (300 MHz, CDCl3, δ H ):8.20(s,1 H);7.98(s,1 H);4.83(s,2 H);4.75(s,2 H);3.71(q,J=7.1 Hz,2 H);1.27(t,J=7.1 Hz,3 H).

[0876] 1-Bromo-2-((ethoxymethoxy)methyl)-5-iodo-3-(trifluoromethyl)benzene (7, 3.32 g, 7.57 mmol) was dissolved in dry tetrahydrofuran (23 mL) under an inert atmosphere and cooled to 30°C (methanol / dry ice bath). A 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (6.10 mL, 7.93 mmol) was added dropwise with stirring. After 30 minutes, a solution of bis(phenylsulfonyl)sulfide (1.07 mg, 3.41 mmol) in dry tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was then allowed to slowly reach ambient temperature (the cooling bath was allowed to expire) before being quenched with 10% aqueous ammonium chloride solution (15 mL). The reaction mixture was taken up in diethyl ether (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 30:1) to give bis(3-bromo-4-((ethoxymethoxy)methyl)-5-(trifluoromethyl)phenyl)sulfane (8) as a colorless solid. Yield: 1.96 g (87%). 1 H NMR spectrum (300 MHz, CDCl3, δ H ):7.76(s,2 H);7.65(s,2 H);4.84(s,4 H);4.79(s,4 H);3.71(q,J=7.1 Hz,4 H);1.26(t,J=7.1 Hz,6 H). [ka]

[0877] To a well-stirred solution of (3-bromo-4-((ethoxymethoxy)methyl)-5-(trifluoromethyl)phenyl)sulfane 1 (997 mg, 1.52 mmol, compound) in a mixture of tetrahydrofuran (3 mL) and methanol (6 mL) was added ammonium carbamate (238 mg, 3.04 mmol) and bis(acetoxy)iodobenzene (1.22 g, 3.80 mmol). After 3 h, additional ammonium carbamate (119 mg, 1.52 mmol) and bis(acetoxy)iodobenzene (611 mg, 1.90 mmol) were added to the reaction mixture. After an additional 6 h, additional ammonium carbamate (119 mg, 1.52 mmol) and bis(acetoxy)iodobenzene (611 mg, 1.90 mmol) were added to the reaction mixture and stirred for an additional 10 h. The reaction mixture was then evaporated, and the crude product was dissolved in ethyl acetate (40 mL) and washed with 10% aqueous sodium thiosulfate solution (40 mL), 10% aqueous potassium bicarbonate solution (40 mL), and brine (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was recrystallized from hexane to give bis(3-bromo-4-((ethoxymethoxy)methyl)-5-(trifluoromethyl)phenyl)(imino)-λ. 6 -sulfanone 2 was obtained.

[0878] Yield: 800 mg (77%).

[0879] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.45(s,2 H);8.27(s,2 H);4.81(about s, 8 H);3.67(q,J=7.0 Hz,4 H);3.33(bs,1 H);1.23(t,J=7.0 Hz,6 H).

[0880] LC-MS purity: 100% (ELSD, UV 242).

[0881] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 85:15 to 100:0 + 0.1% FA): 1.56 min.

[0882] LC-MS m / z: 688.3(M+H)+.

[0883] Bis(3-bromo-4-((ethoxymethoxy)methyl)-5-(trifluoromethyl)phenyl)(imino)-λ in anhydrous N,N-dimethylformamide 6 To an ice-cooled, well-stirred solution of 2-(2, 756 mg, 1.10 mmol) of 2-sulfanone was added under nitrogen (58.0 mg, 1.43 mmol). After 5 min, tert-butyl bromoacetate (321 mg, 1.65 mmol) was added. The reaction mixture was allowed to reach ambient temperature and stirred for 1 h. The reaction mixture was then taken up in ethyl acetate (40 mL) and washed with 10% aqueous ammonium chloride solution (40 mL), water (2 × 40 mL), and brine (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 10:1) to give tert-butyl 2-((bis(3-bromo-4-((ethoxymethoxy)methyl)-5-(trifluoromethyl)phenyl)(oxo)-λ) as a colorless oil. 6 (-sulfanylidene)amino)-acetate (3) was obtained. Yield: 847 mg (96%).

[0884] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.47(s,2 H);8.28(s,2 H);4.81(about s,8 H);3.77(s,2 H);3.67(q,J=7.0 Hz,4 H);1.49(s,9 H);1.23(t,J=7.0 Hz,6 H).

[0885] LC-MS purity: 100% (ELSD, UV 242).

[0886] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 85:15 to 100:0 + 0.1% FA): 3.04 min.

[0887] LC-MS m / z: 802.5(M+H)+.

[0888] A 50 mL reaction vessel was charged with potassium acetate (490 mg, 5.00 mmol), and the salt was dried under vacuum at 110 °C for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and tert-butyl 2-((bis(3-bromo-4-((ethoxymethoxy)methyl)-5-(trifluoromethyl)phenyl)(oxo)-λ 6 A mixture of 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II), bis(pinacolato)diboron (635 mg, 2.50 mmol), and bis(sulfanylidene)amino)-acetate (3, 801 mg, 1.00 mmol), dichloromethane (41.0 mg, 50.0 mol), and bis(pinacolato)diboron (635 mg, 2.50 mmol) was added to the reaction vessel. The vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous 1,4-dioxane (5 mL) was added via syringe. The vessel was sealed with a plastic stopper and immersed in a heating bath preheated to 80 °C. After stirring at 400 rpm for 16 h (overnight), the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (30 mL), and filtered through a short plug (10 g) of silica covered with Celite S using ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 2-((bis(4-((ethoxymethoxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)(oxo)-λ as a brownish waxy foam. 6This gave 4-sulfanylidene-amino)acetate (4). This was dissolved in acetonitrile (6 mL) and water (1 mL), and periodic acid (912 mg, 4.00 mmol) was added. After 2 hours, the reaction mixture was taken up in ethyl acetate (30 mL) and washed with water (2 x 30 mL) and brine (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product as an orange wax. This was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and concentrated hydrochloric acid solution (1 mL) was added. After 2 hours, the reaction mixture was taken up, heated to 50°C, and stirred for 5 hours. This was then taken up in ethyl acetate (30 mL) and washed with water (30 mL) and brine (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product as a beige solid. This was dissolved in a minimum amount of diethyl ether, and hexane (3 volumes) was added. The precipitated product was collected by filtration, washed with cold hexane (2 × 5 mL), and air-dried to give 2-((bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo-[c][1,2]oxaborol-6-yl)(oxo)-λ) as an off-white solid. 6 -sulfanylidene)amino)acetic acid (5) was obtained.

[0889] Yield: 405 mg (78%).

[0890] 1 H NMR spectrum (300 MHz, acetone-d / DO, δ H ): 8.68(s,2 H); 8.47(s,2 H); 5.21(s,4 H); 3.83(s,2 H) partially overlapping with water signal.

[0891] LC-MS purity: 100% (ELSD)

[0892] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 3.84 min.

[0893] LC-MS m / z: 524.3 (M+H) + .

[0894] Example 39 (3-borono-5-((3-boronophenyl)sulfonyl)benzoyl)glycine [ka] (3-Borono-5-((3-boronophenyl)sulfonyl)benzoyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 44 and according to the procedure described below. [ka]

[0895] 3-Bromo-5-iodobenzoic acid (1, 32.7 g, 100 mmol) was suspended in methanol (150 mL) and methanesulfonic acid (3 mL) was added. The resulting mixture was stirred at 60°C (oil bath) for 20 hours. The resulting clear solution was cooled to -20°C in a freezer for 20 hours, and the resulting solid was collected by filtration, washed with chilled (-20°C) methanol, and dried under vacuum to give methyl 3-bromo-5-iodobenzoate (2) as an off-white solid. Yield: 26.0g (76%).

[0896] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.30(s,1 H);8.14(s,1 H);8.04(s,1 H);3.93(s,1 H).

[0897] Methyl 3-bromo-5-iodobenzoate (2, 2.62 g, 10.0 mmol), anhydrous potassium carbonate (3.45 g, 25.0 mmol), copper iodide (381 mg, 2.00 mmol), and 3-bromobenzenethiol (3, 1.78 mL, 15.0 mmol) were suspended in dry 1,2-dimethoxyethane (25 mL), and the resulting suspension was stirred at 80 °C for 48 h. After cooling to ambient temperature, the reaction mixture was diluted with cyclohexane (80 mL), filtered through a pad of silica gel (40 g) covered with Celite (washed with ethyl acetate / cyclohexane 1:10, 3 × 30 mL), and evaporated in vacuo. The residue was dissolved in acetic acid (30 mL), and 30% aqueous hydrogen peroxide (4.00 mL, 39.2 mmol) was added in several portions (exothermic). After stirring at 80° C. for 16 hours, the reaction mixture was evaporated in vacuo, taken up in ethyl acetate (100 mL), and washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the methyl ester 5 as a yellow oil. This was dissolved in tetrahydrofuran (30 mL) and water (15 mL), and lithium hydroxide monohydrate (840 mg, 20.0 mmol) was added. After stirring for 48 hours, the reaction mixture was evaporated in vacuo, taken up in ethyl acetate (100 mL), and washed with 1 M aqueous hydrochloric acid (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the crude product as a brownish solid. This was purified by recrystallization from toluene to give pure 3-bromo-5-((3-bromophenyl)sulfonyl)benzoic acid (6) as a beige solid. Yield: 1.67 g (40%).

[0898] 1 H NMR spectrum (300 MHz, acetone-d6, δ H ):8.53(s,1 H);8.45(s,1 H);8.38(s,1 H);8.27(s,1 H);8.12(d,J=8.0 Hz,1 H);7.92(d,J=7.9 Hz,1 H);7.64(t,J=8.0 Hz,1 H).

[0899] LC-MS purity: 100% (ELSD, UV 242nm).

[0900] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 3.63 min.

[0901] LC-MS m / z: 421.2 (M+H) + .

[0902] A solution of 3-bromo-5-((3-bromophenyl)sulfonyl)benzoic acid (6, 924 mg, 2.20 mmol) and carbonyldiimidazole (CDI, 428 mg, 2.64 mmol) in anhydrous acetonitrile (8.0 mL) was stirred for 16 h. Glycine tert-butyl ester hydrochloride (480 mg, 2.86 mmol) was then added, followed by triethylamine (1 mL). After stirring for 16 h, the reaction mixture was evaporated in vacuo, taken up in ethyl acetate (30 mL), and washed with 1 M aqueous potassium bisulfate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the crude product as a yellowish solid, which was subjected to flash column chromatography (Silicagel 60, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 5:1-4:1) to give tert-butyl (3-bromo-5-((3-bromophenyl)sulfonyl)benzoyl)glycinate (7) as a white foam.

[0903] Yield: 1.08g (92%).

[0904] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.26(s,1 H);8.18(s,1 H);8.15(s,1 H);8.09(s,1 H);7.89(d,J=7.9 Hz,1 H);7.79-7.69(m,1 H);7.43(t,J=7.9 Hz,1 H);6.76(bs,1 H);4.13(d,J=5.0 Hz,2 H);1.51(s,9 H).

[0905] LC-MS purity: 100% (ELSD, UV 242nm).

[0906] LC-MS Rt (Kinetex C18, 4.6mm × 50mm, Atolu / water 35:65~100:0+0.1%FA): 4.13 points.

[0907] LC-MS m / z: 534.3 (M+H) + .

[0908] A 25 mL reaction vessel was charged with potassium acetate (490 mg, 5.00 mmol), and the salt was dried under vacuum at 110° C. for 1 hour. After cooling to room temperature, the reaction vessel was backfilled with nitrogen and charged with methyl tert-butyl(3-bromo-5-((3-bromophenyl)sulfonyl)benzoyl)glycinate (7, 533 mg, 1.00 mmol), palladium acetate (8.90 mg, 0.04 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos, 39.0 mg, 0.08 mmol), and bis(pinacolato)diboron (610 mg, 2.40 mmol). The reaction vessel was then evacuated and backfilled with nitrogen (this procedure was repeated twice), and anhydrous tetrahydrofuran (5 mL) was added via syringe. The vessel was sealed with a rubber septum and immersed in a heating bath preheated to 60 °C. After stirring at 400 rpm for 16 h (overnight), the reaction mixture was cooled to ambient temperature, diluted with cyclohexane (24 mL), and filtered through a short plug (7 g) of Celite S-covered silica with dichloromethane (3 × 15 mL). The filtrate was concentrated under reduced pressure to give the intermediate tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)benzoyl)glycinate (8) as a brownish waxy solid. This was dissolved in a mixture of 1,2-dichloroethane (2.5 mL) and trifluoroacetic acid (2.5 mL). After 2 hours, the reaction mixture was evaporated under vacuum, and the residue was co-distilled with ethyl acetate (3 × 10 mL). The resulting foam was dissolved in acetonitrile (6 mL) and water (2 mL), and periodic acid (1.37 g, 6.00 mmol) was added. The resulting mixture was vigorously stirred at ambient temperature for 2 hours. The reaction mixture was taken up in ethyl acetate (30 mL) and washed with water (2 × 20 mL) and brine (20 mL). The organic layer was extracted with 1 M aqueous sodium hydroxide solution (20 mL) and water (10 mL), and the aqueous extracts were combined and washed with dichloromethane (2 × 10 mL). The aqueous phase was acidified by the addition of concentrated hydrochloric acid (3 mL) and extracted with ethyl acetate (2 × 20 mL).The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was dissolved in a minimum amount of wet (well-shaken with water) ethyl acetate, and the solution was added dropwise to ice-cold n-hexane (5 mL) with stirring, resulting in precipitation of the product. The solid was collected by filtration and washed with hexane (2 × 5 mL) to give the title (3-borono-5-((3-boronophenyl)sulfonyl)benzoyl)glycine (9) as a colorless solid. Yield: 221.0 mg (54%).

[0909] 1 H NMR spectrum (300 MHz, acetone-d / DO; 10:1, δ H ):8.64-8.50(m,3 H);8.46(s,1 H);8.15-7.99(m,2 H);7.59(t,J=7.7 Hz,1 H);4.22-4.04(m,2 H).

[0910] LC-MS purity: 100% (ELSD, UV 242nm).

[0911] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 20:80 to 100:0 + 0.1% FA): 2.45 min.

[0912] LC-MS m / z: 408.4 (M+H) + .

[0913] Example 40 (S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propane acid [ka] (S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid was synthesized according to the reaction scheme shown in Chemical Reaction 45 and according to the procedure described below. [ka]

[0914] Concentrated sulfuric acid (96%, 1.00 mL, 18.0 mmol) was added to a solution of 3-bromo-4-methylbenzoic acid (1, 25.0 g, 116 mmol) in methanol (500 mL), and the reaction mixture was stirred at 60 °C for 43 h. The solution was cooled to room temperature, sodium bicarbonate (4.39 g, 53.3 mmol) was added, and the mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (600 mL) and water (250 mL). The organic layer was separated, washed with 0.5 M aqueous sodium hydroxide solution (2 × 250 mL), 5% aqueous sodium carbonate solution (2 × 200 mL), 0.5 M aqueous hydrochloric acid solution (200 mL), water (200 mL), and brine (150 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to give methyl 3-bromo-4-methylbenzoate (2) as an orange oil. Yield: 25.16 g (94%). R F (SiO2, cyclohexane / ethyl acetate 9:1): 0.45.

[0915] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.21 (d, J = 1.7 Hz, 1 H); 7.87 (dd, J = 7.9 and 1.7 Hz, 1 H); 7.30 (d, J = 7.9 Hz, 1 H); 3.92 (s, 3 H); 2.46 (s, 3 H).

[0916] A stirred mixture of 3-bromo-4-methylbenzoate (2, 24.8 g, 108 mmol), 1-bromo-pyrrolidine-2,5-dione (NBS, 21.2 g, 119 mmol), and water (360 mL) in a wide beaker was placed under a reptile D3 basking lamp (100 W, UVA, UVB, IR) and heated to 70-80 °C. Another portion of 1-bromopyrrolidine-2,5-dione (NBS, 3.86 g, 21.7 mmol) was added after 4 h, and the mixture was stirred for an additional 1 h. The mixture was cooled to room temperature and subsequently extracted with ethyl acetate (2 × 250 mL). The combined organic layers were washed with water (4 × 200 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to give crude methyl 3-bromo-4-(bromomethyl)benzoate (3) as a yellow oil. Yield: 34.06g (74%).

[0917] R F (SiO2, cyclohexane / ethyl acetate 9:1): 0.30.

[0918] 1 H NMR purity: 72% by weight.

[0919] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.25 (d, J = 1.7 Hz, 1 H); 7.96 (dd, J = 8.1 and 1.7 Hz, 1 H); 7.54 (d, J = 8.1 Hz, 1 H); 4.61 (s, 2 H); 3.94 (s, 3 H).

[0920] A mixture of the above crude methyl 3-bromo-4-(bromomethyl)benzoate (3, 72%, 34.1 g, 80.1 mmol) and potassium acetate (23.6 g, 240 mmol) in acetonitrile (800 mL) was heated at 75 °C for 5 h. The mixture was cooled to room temperature, and the solid was removed by filtration and washed with ethyl acetate (3 × 50 mL). The filtrate was evaporated to dryness, and the residue was partitioned between ethyl acetate (700 mL) and water (200 mL). The organic layer was separated, washed with water (200 mL) and brine (2 × 200 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The residue was purified by flash column chromatography (Silicagel, 0.063–0.200 mm, eluent: cyclohexane / ethyl acetate 97:3) to give pure methyl 4-(acetoxymethyl)-3-bromobenzoate (4) as a white solid. Yield: 19.39g (84%).

[0921] R F (SiO2, n-hexane / ethyl acetate 4:1): 0.25.

[0922] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.24 (d, J = 1.5 Hz, 1 H); 7.99 (dd, J = 8.0 and 1.6 Hz, 1 H); 7.48 (d, J = 8.1 Hz, 1 H); 5.23 (s, 2 H); 3.94 (s, 3 H); 2.18 (s, 3 H).

[0923] LC-MS purity: 100% (UV 254nm).

[0924] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 2.41 min.

[0925] LC-MS m / z: 287.2; 289.2 (M+H) + .

[0926] [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.32 g, 3.18 mmol) was added to a degassed solution of methyl 4-(acetoxymethyl)-3-bromobenzoate (4, 18.2 g, 63.5 mmol), bis(pinacolato)diboron (17.7 g, 69.9 mmol), and potassium acetate (18.7 g, 191 mmol) in dry 1,4-dioxane (165 mL) under argon. The mixture was warmed to 80 °C and stirred at this temperature for 16 h. The mixture was cooled to room temperature, then diluted with dichloromethane (165 mL) and passed through a short column of silica gel covered with Celite, followed by elution with dichloromethane. The product-containing fractions were combined and evaporated to dryness. The residue was purified by flash column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1-7:3) to give methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5) as a yellow solid. Yield: 21.80 g (>100%).

[0927] R F (SiO2, cyclohexane / ethyl acetate 9:1):0.15.

[0928] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.49 (d, J = 1.8 Hz, 1 H); 8.10 (dd, J = 8.1 and 2.0 Hz, 1 H); 7.46 (d, J = 8.1 Hz, 1 H); 5.43 (s, 2 H); 3.93 (s, 3 H); 2.12 (s, 3 H), 1.36 (s, 12 H).

[0929] LC-MS purity: 100% (ELSD), 88% (UV 254nm).

[0930] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 50:50 to 100:0 + 0.1% FA): 3.26 min.

[0931] LC-MS m / z: 335.5 (M+H)+.

[0932] Methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5, 21.8 g, <63.5 mmol) was added to a solution of sodium hydroxide (12.7 g, 318 mmol) in water (200 mL), and the resulting mixture was stirred at room temperature for 5 hours. The mixture was filtered, washed with diethyl ether (200 mL), and acidified with 35% hydrochloric acid (39.6 mL, 444 mmol). The resulting white suspension was placed in the refrigerator over the weekend. The precipitate was filtered, washed with water (3 × 50 mL), and suspended in 20% aqueous acetonitrile (100 mL). The mixture was lyophilized to give 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (6) as a white powder. Yield: 10.63 g (94%).

[0933] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ): 12.90 (s, 1 H); 9.35 (s, 1 H); 8.37 (s, 1 H); 8.04 (dd, J = 8.0 and 1.6 Hz, 1 H); 7.52 (d, J = 7.9 Hz, 1 H); 5.05 (s, 2 H).

[0934] LC-MS purity: 100% (ELSD).

[0935] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.90 min.

[0936] LC-MS m / z: 179.2 (M+H) + .

[0937] N,N'-Dicyclohexylcarbodiimide (DCC, 2.50 g, 12.1 mmol) was added to a suspension of 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (6, 2.16 g, 12.1 mmol) and pentafluorophenol (PfpOH, 2.23 g, 12.1 mmol) in acetonitrile (150 mL), and the mixture was stirred at room temperature overnight. The solid was filtered and washed with ethyl acetate (5 × 20 mL). The filtrate was mixed and evaporated to dryness. Cyclohexane (100 mL) was added to the residue, and the mixture was stirred at room temperature for 15 minutes. The mixture was decanted, and the precipitate was dried under vacuum to give perfluorophenyl 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (7) as an off-white solid. Yield: 2.67 g (64%).

[0938] 1 H NMR spectrum (300 MHz, CDCl3, δ H ): 8.62 (s, 1 H); 8.32 (dd, J = 8.1 and 1.7 Hz, 1 H); 7.55 (d, J = 8.3 Hz, 1 H); 5.22 (s, 2 H).

[0939] LC-MS purity: 98% (ELSD).

[0940] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 35:65 to 100:0 + 0.1% FA): 4.08 min.

[0941] LC-MS m / z: 345.3 (M+H) + .

[0942] Triethylamine (1.65 mL, 11.8 mmol) was added to a mixture of perfluorophenyl 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (7, 713 mg, 2.07 mmol) and L-2,3-diaminopropionic acid hydrochloride (8, L-Dap-OHHCl, 139 mg, 0.99 mmol) in N,N-dimethylformamide (10.0 mL), and the resulting solution was stirred at room temperature over the weekend. The mixture was evaporated to dryness in vacuo, and the residue was partitioned between 1 M aqueous hydrochloric acid (25 mL) and ethyl acetate (50 mL). The phases were separated, and the organic phase was extracted with ethyl acetate (2 × 25 mL). All organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to a volume of approximately 3 mL. Cyclohexane (100 mL) was added, and the resulting suspension was stirred at room temperature overnight. The precipitate was collected by filtration and dried under vacuum. The precipitate (crude, 9, 288 mg) was dissolved in 50% aqueous acetonitrile (4.8 mL) and subjected to purification by preparative LC / MS (SunFire Prep C18 OBD, 5 m, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA). Pure fractions were combined and lyophilized to give the title compound (9) as a white powder. Yield: 116 mg (28%).

[0943] 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):12.73(bs,1 H);9.33(s,1 H);9.30(s,1 H);8.76(d,J=7.5 Hz,1 H);8.70(t,J=5.9 Hz,1 H);8.25(d,J=0.7 Hz,1 H);8.20(d,J=0.9 Hz,1 H);7.96(dd,J=8.1 and 1.7 Hz,1 H);7.90(dd,J=7.9 and 1.7 Hz,1 H);7.52(d,J=8.8 Hz,1 H);7.48(d,J=8.3 Hz,1 H);5.05(s,2 H);5.03(s,2 H);4.71-4.62(m,1 H);3.81-3.73(m,2 H).

[0944] LC-MS purity: 100% (ELSD, UV 254nm).

[0945] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.56 min.

[0946] LC-MS m / z: 425.4 (M+H) + .

[0947] Example 41 N-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine [ka] N-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 46 and in accordance with the procedures described below. [ka]

[0948] A mixture of methyl 3-(benzoylthio)-5-bromo-4-methylbenzoate (1, 2.90 g, 7.95 mmol) and potassium carbonate (2.19 g, 15.9 mmol) was dissolved in dry methanol (100 mL) with heating and then stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was evaporated and coevaporated with toluene. Methyl iodide (70 mL) was then added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and then coevaporated several times with dichloromethane. The crude product was extracted with ethyl acetate (100 mL), 1 M aqueous hydrochloric acid (50 mL), water (50 mL), and brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography (Silicagel, 0.063-0.200 mm, eluent: cyclohexane / ethyl acetate 9:1) to give methyl 3-bromo-4-methyl-5-(methylthio)benzoate (2) as a white solid.

[0949] Yield: 1.83g (84%).

[0950] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.01(d,J=1.3 Hz,1 H);7.75(s,1 H);3.93(s,3 H);2.53(s,3 H);2.50(s,3 H).

[0951] Hydrogen peroxide (5 mL) was added to a solution of methyl 3-bromo-4-methyl-5-(methylthio)benzoate (2, 1.83 g, 6.65 mmol) in acetic acid (70 mL), and the reaction mixture was stirred at 70° C. for 2 hours. The solvent was then evaporated to give methyl 3-bromo-4-methyl-5-(methylsulfonyl)benzoate (3) as an off-white solid. Yield: 2.05 g (100%). 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):8.46(d,J=1.7 Hz,1 H);8.40(d,J=1.8 Hz,1 H);3.91(s,3 H);3.34(s,3 H);2.79(s,3 H).

[0952] A solution of 1-bromopyrrolidine-2,5-dione (NBS, 1.31 g, 7.35 mmol), 3-bromo-4-methyl-5-(methylsulfonyl)benzoate (3, 2.05 g, 6.65 mmol), and 2,2-azobis(2-methyl-propionitrile) (AIBN, 55.0 mg, 0.33 mmol) in PhCF3 (20 mL) was stirred at 85°C overnight. The reaction mixture was evaporated and then extracted with diethyl ether (2 x 50 mL). The organic layer was washed with brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-4-(bromomethyl)-5-(methylsulfonyl)benzoate (4) as a yellowish solid. Yield: 2.43 g (94%). 1 H NMR spectrum (300 MHz, DMSO-d6, δ H ):8.47(d,J=1.1 Hz,2 H);5.14(bs,2 H);3.92(s,3 H);3.44(s,3 H). Methyl 3-bromo-4-(bromomethyl)-5-(methylsulfonyl)benzoate (4, 2.70 g, 7.00 mmol) was stirred with potassium acetate (1.37 g, 14.0 mmol) in acetonitrile (70 mL) at 75°C overnight. The suspension was filtered through a Celite pad and evaporated under vacuum. The crude product was dissolved in dichloromethane and filtered again. The filtrate was evaporated and purified by column chromatography (Silicagel 60, 0.040-0.063 mm, eluent: cyclohexane / ethyl acetate 7:1) to give methyl 4-(acetoxymethyl)-3-bromo-5-(methylsulfonyl)benzoate (5) as a white solid. Yield: 4.24 g (54%).

[0953] 1 H NMR spectrum (300 MHz, CDCl3, δ H ):8.74(s,1 H);8.55(s,1 H);5.76(s,2 H);3.99(s,3 H);3.21(s,3 H);2.11(s,3 H).

[0954] LC-MS purity: 100% (ELSD).

[0955] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 30:70 to 100:0 + 0.1% FA): 2.46 min.

[0956] LC-MS m / z: 366.9 (M+H) + .

[0957] A mixture of methyl 4-(acetoxymethyl)-3-bromo-5-((trifluoromethyl)sulfonyl)benzoate (5, 1.97 g, 5.38 mmol), bis(pinacolato)diboron (1.64 g, 6.46 mmol), and dry potassium acetate (1.58 g, 16.1 mmol) and [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium-dichloromethane complex (220 mg, 269 mol) was suspended in dry, degassed 1,4-dioxane (20 mL). The reaction mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The crude reaction mixture was then taken up in ethyl acetate (60 mL) and filtered through a short pad of silica gel and a short pad of silica (20 g) covered with Celite (using ethyl acetate, 3 × 60 mL). The filtrate was evaporated in vacuo to give crude methyl 4-(acetoxymethyl)-3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6) as a yellowish solid.

[0958] This was dissolved in tetrahydrofuran (15 mL) and water (15 mL), and lithium hydroxide monohydrate (1.13 g, 26.9 mmol) was added. The mixture was stirred at room temperature for 2 hours, then diluted with water (60 mL), and transferred to a separatory funnel, where it was extracted with dichloromethane (2 × 40 mL) and diethyl ether (40 mL). The aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered, washed thoroughly with water, and dried to give 1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7) as an off-white solid. Yield: 1.20 g (87%). 1 H NMR spectrum (300 MHz, acetone-d / DO, δ Η ):8.67(s,1 H);8.54(s,1 H);5.40(s,2 H);3.23(s,3 H).

[0959] LC-MS purity: 100% (ELSD, UV 240nm).

[0960] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 10:90 to 100:0 + 0.1% FA): 2.10 min.

[0961] LC-MS m / z: 255.2 (M−H) - .

[0962] 1-Hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (7, 1.02 g, 4.00 mmol), 2,3,4,5,6-pentafluorophenol (1030 mg, 5.60 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.07 g, 5.60 mmol) were suspended in dichloromethane (20 mL) and acetonitrile (10 mL). The mixture was stirred at room temperature overnight. The solvent was then evaporated. The residue was dissolved in ethyl acetate (70 mL) and washed with water (2 × 40 mL) and brine (1 × 40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was dissolved in hot ethyl acetate (10 mL), and cyclohexane (30 mL) was slowly added. After cooling to ambient temperature, a solid precipitated. After 2 h, it was collected by filtration, washed with cyclohexane, and air-dried to give perfluorophenyl 1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8) as an off-white solid.

[0963] Yield: 1.65 mg (98%).

[0964] 1 H NMR spectrum (300 MHz, acetone-d / DO, δ Η ):8.88(s,1 H);8.73(s,1 H);5.49(s,2 H);3.30(s,3 H). 19 F NMR spectrum (282 MHz, acetone-d / DO, δ F ):-154.63(d,J=17.0 Hz);-159.62(t,J=21.3 Hz);164.43(t,J=19.1 Hz).

[0965] LC-MS purity: 100% (ELSD, UV 240nm).

[0966] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 10:90 to 100:0 + 0.1% FA): 3.44 min. LC-MS m / z: 421.0 (M−H) - .

[0967] Perfluorophenyl 1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (8, 422 mg, 1.00 mmol) and (2-aminoethyl)glycine (9, 59.0 mg, 0.50 mmol) were dissolved in a 2:1 N,N-dimethylformamide / water mixture (3 mL). Triethylamine (500 L) was then added, and the resulting mixture was stirred at room temperature overnight. It was then acidified with 1 M aqueous potassium bisulfate solution (15 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was coevaporated with toluene (3 × 10 mL) and triturated with diethyl ether (3 mL). The precipitate was filtered, washed with diethyl ether (2 × 2 mL), and air-dried. The resulting powder was purified by preparative LC / MS (SunFire Prep C18 OBD, 5 m, 19 × 100 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA) and lyophilized to give the title N-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine (10) as a colorless solid. Yield: 99.0 mg (32%).

[0968] 1 H NMR spectrum (300 MHz, AcOD-d4, δ Η ):8.74-8.46(m,1 H);8.35(about d,1 H);8.06(about d,1 H);7.96(bs,1 H);5.49-5.32(m,4 H);4.39(about d,2 H);4.03-3.61(m,4 H);3.21-3.03(m,6 H).

[0969] LC-MS purity: 100% (ELSD, UV 254nm).

[0970] LC-MS Rt (Kinetex C18, 4.6 mm × 50 mm, acetonitrile / water 5:95 to 100:0 + 0.1% FA): 3.14 min.

[0971] LC-MS m / z: 595.0 (M+H) + .

[0972] Example 42 N-(1-hydroxy-4-((trifluoromethyl)sulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-((trifluoromethyl)sulfonyl)-1,3-dihydrobenzo-[c][1,2]oxaborole-6-carboxamido)ethyl)glycine [ka] N-(1-hydroxy-4-((trifluoromethyl)sulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-((trifluoromethyl)sulfonyl)-1,3-dihydrobenzo-[c][1,2]oxaborole-6-carboxamido)ethyl)glycine was synthesized according to the reaction scheme shown in Chemical Reaction 47 and in accordance with the procedures described below. [ka]

[0973] N-iodosuccinimide (NIS, 61.5 g, 274 mmol) was added to a solution of 3-bromo-4-methylbenzoic acid (1, 56.0 g, 260 mmol) in concentrated sulfuric acid (1 L), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was then poured into ice water (2 L). The resulting mixture was poured into an ice bath (2 L), and the precipitate was filtered, washed with water, and dried under vacuum to give 3-bromo-5-iodo-4-methylbenzoic acid (2) as an off-white solid. Yield: 87.8 g (99%). 1 H NMR spectrum (300 MHz, DMSO-d6, δ H):8.30(d, J=1.7 Hz,1 H);8.06(d,J=1.7 Hz,1 H);2.64(s,3 H).

[0974] Concentrated sulfuric acid (35 mL) was added to a solution of 3-bromo-5-iodo-4-methylbenzoic acid (2, 55.4 g, 162 mmol) in methanol (1.5 L), and the reaction mixture was stirred at reflux overnight. The reaction mixture was then evaporated under reduced pressure, dissolved in diethyl ether (1 L), and washed with water (2 × 500 mL) and saturated aqueous potassium carbonate (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 3-bromo-5-...

Claims

1. Formula I: 【Chemistry 1】 A diboron compound represented by the formula: ・In formula I, X represents a linker of formula Ia, 【Chemistry 2】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, or X represents a linker of formula Ib, 【Chemistry 3】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to R ３ But -(CH ２ ) ｍ (C═O)—W, In the formula, m represents an integer ranging from 1 to 4; W is OH, NHCH ２ COOH, NHCH ２ CH ２ COOH, NHCH ２ CH ２ CH ２ COOH, or NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, or X represents a linker of formula Ic, 【Chemistry 4】 The linker represents a D- or L-amino acid form, During the ceremony, --- is R １ Or R ２ represents a covalent bond to n represents an integer ranging from 1 to 4; W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, or in which X represents a linker of formula Id, 【Chemistry 5】 said linker represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine; During the ceremony, --- is R １ Or R ２ represents a covalent bond to R ４ -(C=O)(CH ２ ) ｐ (C═O)—W, In the formula, p represents an integer ranging from 1 to 4; W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, or X represents a linker of formula Ie, 【Chemistry 6】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to, or X represents a linker of formula If, 【Chemistry 7】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to, or X represents a linker of formula Ig, 【Chemistry 8】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to, or X represents a linker of formula Ih, 【Chemistry 9】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to, or X represents a linker of formula Ii, 【Chemistry 10】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 11】 During the ceremony, one to four Y's represent H; Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents one Y represents a point of attachment to X in formula I (a covalent bond representing the same); When X is of formula Ie, If, Ig, or Ih, R １ Or R ２ In any one of the above, one Y represents -(C=O)-W, where W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ Diboron compounds, which represent COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue.

2. 2. The diboron compound of claim 1 , represented by formula I, wherein X represents a linker of formula Ia: 【Chemistry 12】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 13】 During the ceremony, one Y represents a point of attachment to the linker X of formula Ia (a covalent bond representing the same); Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

3. 2. The diboron compound of claim 1 , represented by formula I, wherein X represents a linker of formula Ib: 【Chemistry 14】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to R ３ But -(CH ２ ) ｍ (C═O)—W, In the formula, m represents an integer ranging from 1 to 4; W is OH, NHCH ２ COOH, NHCH ２ CH ２ COOH, NHCH ２ CH ２ CH ２ COOH, or NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 15】 During the ceremony, one Y represents a point of attachment to the linker X of formula Ib (a covalent bond representing Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

4. 2. The diboron compound of claim 1 represented by formula I, wherein X represents a linker of formula Ic: 【Chemistry 16】 The linker represents a D- or L-amino acid form, During the ceremony, --- is R １ Or R ２ represents a covalent bond to n represents an integer ranging from 1 to 4; W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 17】 During the ceremony, one Y represents a point of attachment to the linker X of formula Ic (a covalent bond representing the same); Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

5. 2. The diboron compound of claim 1 , represented by formula I, wherein X represents a linker of formula Id: 【Chemistry 18】 said linker represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine; During the ceremony, --- is R １ Or R ２ represents a covalent bond to R ４ -(C=O)(CH ２ ) ｐ (C═O)—W, In the formula, p represents an integer ranging from 1 to 4; W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 19】 During the ceremony, one Y represents a point of attachment to the linker X of formula Id (a covalent bond representing Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

6. 2. The diboron compound of claim 1 , represented by formula I, wherein X represents a linker of formula Ie: 【Chemistry 20】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 21】 During the ceremony, one Y represents the point of attachment to the linker -CO- of formula Ie (a covalent bond representing R １ Or R ２ In any one of the above, one Y represents -(C=O)-W, where W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1 , wherein the remainder of Y represents H.

7. 2. The diboron compound of claim 1 , represented by formula I, wherein X represents a linker of formula If: 【Chemical 22】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 23】 During the ceremony, one Y represents a point of attachment to the linker -SO- of formula If (a covalent bond representing R １ Or R ２ In any one of the above, one Y represents -(C=O)-W, where W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

8. 2. The diboron compound of claim 1 represented by formula I, wherein X represents a linker of formula Ig: 【Chemistry 24】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemistry 25】 During the ceremony, One Y is a linker -(SO ２ )- represents the point of attachment to (a covalent bond representing) R １ Or R ２ In any one of the above, one Y represents -(C=O)-W, where W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

9. 2. The diboron compound of claim 1 represented by formula I, wherein X represents a linker of formula Ih: 【Chemistry 26】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, 【Chemical 27】 During the ceremony, One Y is a linker -(CF ２ )- represents the point of attachment to (a covalent bond representing) R １ Or R ２ In any one of the above, one Y represents -(C=O)-W, where W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

10. 2. The diboron compound of claim 1 represented by formula I, wherein: X represents a linker of formula Ii, 【Chemistry 28】 During the ceremony, --- is R １ Or R ２ represents a covalent bond to W is -OH, -NHCH ２ COOH, -NHCH ２ CH ２ COOH, -NHCH ２ CH ２ CH ２ COOH, or -NHCH(COOH)CH ２ CH ２ COOH, said group representing an L-gamma-Glu or D-gamma-Glu residue, R １ and R ２ may be the same or different and each represents a group of formula IIa or IIb, ​ During the ceremony, one Y represents a point of attachment to the linker X of formula Ii (a covalent bond representing the same); Y is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two of Y are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents 2. The diboron compound of claim 1, wherein the remaining Y's represent H.

11. 3,5-bis((4-borono-2-fluorobenzamido)methyl)benzoic acid, 3,5-bis((4-borono-3-fluorobenzamido)methyl)benzoic acid, N,N'-bis(4-borono-3-fluorobenzamido)-N-ethyl-glycinamide, (S)-2,4-bis(4-borono-3-fluorobenzamido)butanoic acid, N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 3,5-bis((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)methyl)benzoic acid, N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, N-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-N-(2-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamido)ethyl)glycine, N ２ , N ６ -bis(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonyl)-L-lysine, 3-borono-5-((3-borono-4-fluorophenyl)sulfonyl)-4-fluorobenzoic acid, 3-borono-5-(3-borono-5-fluorobenzoyl)benzoic acid, 3-borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid, N ６ -(4-borono-2-fluorobenzoyl)-N ２ -(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]-oxaborole-5-carbonyl)-L-lysine, (S)-2,3-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (S)-2,3-bis(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (S)-2,3-bis(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-propanoic acid, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)difluoromethyl)benzoyl)glycine, (3-borono-5-(3-borono-5-(trifluoromethyl)benzoyl)benzoyl)glycine, (3-borono-5-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)glycine, 4-((3S,4S)-3,4-bis(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-(3-borono-5-fluorobenzoyl)benzoyl)glycine, (3-(6-borono-2-(ethoxycarbonyl)-8-fluoro-1,1-dioxide-4H-benzo[b][1,4]thiazin-4-yl)-5-fluorophenyl)boronic acid, (3-borono-5-((3-borono-5-fluorophenyl)sulfonyl)benzoyl)glycine, N-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, (S)-2,3-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid, 4-((3S,4S)-3,4-bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)pyrrolidin-1-yl)-4-oxobutanoic acid, (3-borono-5-((3-borono-5-(pentafluoro-λ ６ -sulfanyl)phenyl)sulfonyl)benzoyl)glycine, 2-((bis(3-borono-5-(trifluoromethyl)phenyl)(oxo)-lambda6-sulfanylidene)amino)acetic acid, N-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, N-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 3-(2,3-bis(4-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanamide)propanoic acid, 2-((bis(3-borono-5-(difluoromethyl)phenyl)(oxo)-lambda6-sulfanylidene)amino)acetic acid, 2-((bis(3-borono-5-chlorophenyl)(oxo)-lambda6-sulfanylidene)amino)acetic acid, 2-((bis(3-boronophenyl)(oxo)-lambda6-sulfanylidene)amino)acetic acid, N-(1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-5-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, 2-((bis(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(oxo)-lambda 6-sulfanylidene)amino)acetic acid, (3-borono-5-((3-boronophenyl)sulfonyl)benzoyl)glycine, (S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)propanoic acid, N-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-(methylsulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-ethyl)glycine, N-(1-hydroxy-4-((trifluoromethyl)sulfonyl)-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-N-(2-(1-hydroxy-4-((trifluoromethyl)sulfonyl)-1,3-dihydrobenzo-[c][1,2]oxaborole-6-carboxamido)ethyl)glycine, 4-borono-2-((3-borono-5-(trifluoromethyl)phenyl)sulfonyl)-6-(trifluoromethyl)benzoic acid, and 2. The diboron compound of claim 1, selected from the group consisting of 2-((bis(3-borono-5-(trifluoromethoxy)phenyl)(oxo)-λ6-sulfanylidene)amino)acetic acid.

12. A diboron conjugate, wherein the diboron compound according to any one of claims 1 to 11 is conjugated to a drug substance via an optional linker.

13. 13. The diboron conjugate of claim 12, wherein the diboron compound is conjugated to the drug substance via an optional linker by derivatization of a carboxylic acid moiety of the diboron compound.

14. General formula I': R １ ’-X’-R ２ ’ A diboron conjugate represented by: ・In formula I', X′ represents a linker of formula Ia′, 【Chemistry 30】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to D represents the drug substance; W' is a covalent bond or -NHCH ２ (C=O)-, -NHCH ２ CH ２ (C=O)-, -NHCH ２ CH ２ CH ２ (C=O)-, and -NHCH(COOH)CH ２ CH ２ (C=O)-, said group representing an L-gamma-Glu or D-gamma-Glu residue; or X′ represents a linker of formula Ib′, 【Chemistry 31】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to R ３ ', -(CH ２ ) ｍ’ (C═O)-W′-D, m' represents an integer ranging from 1 to 4; W' is a covalent bond or -NHCH ２ (C=O)-, -NHCH ２ CH ２ (C=O)-, -NHCH ２ CH ２ CH ２ (C=O)-, and -NHCH(COOH)CH ２ CH ２ (C═O)—, said group representing an L-gamma-Glu or D-gamma-Glu residue; D represents a drug substance, or X′ represents a linker of formula Ic′, 【Chemistry 32】 The linker represents a D- or L-amino acid form, During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to n' represents an integer ranging from 1 to 4; W' is a covalent bond or -NHCH ２ (C=O)-, -NHCH ２ CH ２ (C=O)-, -NHCH ２ CH ２ CH ２ (C=O)-, and -NHCH(COOH)CH ２ CH ２ (C═O)—, said group representing an L-gamma-Glu or D-gamma-Glu residue; D represents a drug substance, or X' represents a linker of formula Id', 【Chemical 33】 said linker represents the R,R or S,S or R,S or R,S stereoisomer of 3,4-diamino-pyrrolidine; During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to R ４ ' is -(C=O)(CH ２ ) ｐ’ (C═O)-W′-D, W' is a covalent bond or -NHCH ２ (C=O)-, -NHCH ２ CH ２ (C=O)-, -NHCH ２ CH ２ CH ２ (C=O)-, and -NHCH(COOH)CH ２ CH ２ (C═O)—, said group representing an L-gamma-Glu or D-gamma-Glu residue; In the formula, p' represents an integer ranging from 1 to 4; D represents a drug substance, or X′ represents a linker of formula Ie′, 【Chemical 34】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to ', or X′ represents a linker of formula If′, 【Chemistry 35】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to ', or X′ represents a linker of formula Ig′, 【Chemical 36】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to ', or X′ represents a linker of formula Ih′, 【Chemical 37】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to ', or X′ represents a linker of formula Ii′, 【Chemical Formula 38】 During the ceremony, --- is R １ ' or R ２ ' represents a covalent bond to W' is a covalent bond or -NHCH ２ (C=O)-, -NHCH ２ CH ２ (C=O)-, -NHCH ２ CH ２ CH ２ (C=O)-, and -NHCH(COOH)CH ２ CH ２ (C═O)—, said group representing an L-gamma-Glu or D-gamma-Glu residue; R １ ' and R ２ ' may be the same or different and each represents a group of formula IIa' or IIb', 【Chemical Formula 39】 During the ceremony, one to four Y' represent H; Y' is F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ or one or two Y' are F, Cl, CF ２ , C.F. ３ , S.F. ５ , O.C.F. ３ , S.O. ２ CH ３ and / or SO ２ CF ３ represents one Y' represents the point of attachment to X' of formula I' (a covalent bond representing the same); When X′ is of formula Ie′, If′, Ig′, or Ih′, R １ ' or R ２ One Y in any one of the formulas 1 to 4 represents -(C=O)-W'-D, where W' is a covalent bond or -NHCH ２ (C=O)-, -NHCH ２ CH ２ (C=O)-, -NHCH ２ CH ２ CH ２ (C=O)-, and -NHCH(COOH)CH ２ CH ２ (C═O)—, wherein said group represents an L-gamma-Glu or D-gamma-Glu residue, and D represents a drug substance; Diboron conjugates.

15. A diboron compound according to any one of claims 1 to 11 for use as an intermediate compound for the preparation of a diboron conjugate according to any one of claims 12 to 14.

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