Arginase inhibitors and methods of use thereof

Abstract

The invention relates to arginase inhibitors and methods of use thereof. Disclosed are compounds having the formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds or pharmaceutically acceptable salts thereof, and methods of using these compounds or pharmaceutically acceptable salts thereof to treat cancer or respiratory tract inflammatory diseases: (I) wherein R1 is selected from the group consisting of hydrogen,-CH3, and-(C = O) CH (R1a) NH2; r < 1a > is a C1-C4 alkyl group; y is-(CH2) n-or-(C = O)-; n is an integer selected from 1 and 2; r2 is selected from hydrogen,-CH3 and-(C = X) R4, and R3 is hydrogen or-CH3; or R2 and R3 are linked together with the nitrogen to which they are attached to form a 6-membered heterocyclic ring; x is NH or O; r4 is-CH3 or-[CH (R4a)] mNH2; m is an integer selected from 0 or 1; and R4a is hydrogen or a C1-C6 alkyl group. # imgabs0 #

Description

[0001] This application is a divisional application of an invention patent application with an application date of July 22, 2020, application number 202080052330.9, and invention name “Arginase inhibitors and methods of use thereof”. Background Art

[0002] Arginase is a manganese metalloenzyme that catalyzes the conversion of L-arginine to urea and L-ornithine. Two isoforms exist: arginase 1 is a cytosolic enzyme found primarily in hepatocytes, where it plays a key role in removing ammonia through urea synthesis, and arginase 2 is a mitochondrial enzyme highly expressed in the kidneys, where it is involved in the production of ornithine, a precursor of polyamines and proline that are important for cell proliferation and collagen production, respectively.

[0003] Although L-arginine is not an essential amino acid, as it can be provided by protein turnover in healthy adults, under various physiological and pathological conditions (e.g., pregnancy, autoimmune diseases, cancer), the expression and secretion of arginase increases, leading to reduced L-arginine levels. In particular, immune cells are sensitive to reduced L-arginine levels. When faced with a low L-arginine microenvironment, T cells reduce their proliferation rate and reduce the expression of CD3ζ chain, IFNγ and lytic enzymes, resulting in impaired T cell responsiveness. Dendritic cells respond to low L-arginine conditions by reducing their ability to present antigens, and natural killer cells reduce proliferation and expression of lytic enzymes.

[0004] Tumors use multiple immunosuppressive mechanisms to evade the immune system. One of these is to reduce L-arginine by increasing levels of circulating arginase, increasing arginase expression and secretion by tumor cells, and recruiting myeloid-derived suppressor cells that express and secrete arginase. Together, these mechanisms lead to a reduction in L-arginine in the tumor microenvironment and produce an immunosuppressive phenotype. Pharmacological inhibition of arginase activity has been shown to reverse low L-arginine-induced immunosuppression in animal models. Therefore, potent and selective arginase inhibitors are needed to reverse immunosuppression and reactivate patients' anti-cancer immunity as single agents or in combination with therapies that reverse other immunosuppressive mechanisms. Summary of the invention

[0005] In some embodiments, disclosed are compounds having formula (I) or pharmaceutically acceptable salts thereof:

[0006]

[0007] in

[0008] R 1 is selected from hydrogen, -CH3 and -(C=O)CH(R 1a )NH2;

[0009] R 1a is a C1-C4 alkyl group;

[0010] Y is -(CH2) n -or -(C=O)-;

[0011] n is an integer selected from 1 and 2;

[0012] R 2 is selected from hydrogen, -CH3 and -(C=X)R 4 , and R 3 is hydrogen or -CH3; or

[0013] R 2 and R 3 Joined together with the nitrogen to which they are attached to form a nitrogen-containing 6-membered heterocyclic ring;

[0014] X is NH or O;

[0015] R 4 is -CH3 or -[CH(R 4a )] m NH2;

[0016] m is an integer selected from 0 or 1; and

[0017] R 4a It is hydrogen or C1-C4 alkyl.

[0018] In some embodiments, disclosed are compounds having formula (II) or pharmaceutically acceptable salts thereof:

[0019]

[0020] in

[0021] R 11 Selected from hydrogen, -CH3 and Where * indicates (S) stereochemistry;

[0022] Y 1 Yes - (CH2) p -or -(C=O)-;

[0023] p is an integer selected from 1 and 2;

[0024] R 11a is a C1-C4 alkyl group;

[0025] R 12 is selected from hydrogen, -CH3 and -(C=X 1 )R 14 , and R 13 is hydrogen or -CH3; or

[0026] R12 and R 13 Joined together with the nitrogen to which they are attached to form a nitrogen-containing 6-membered heterocyclic ring;

[0027] X 1 is NH or O;

[0028] R 14 is -CH3 or Where * indicates (S) stereochemistry;

[0029] R 14a is C1-C4 alkyl; and

[0030] q is an integer selected from 0 and 1.

[0031] In some embodiments, disclosed are compounds having formula (III) or pharmaceutically acceptable salts thereof:

[0032]

[0033] in

[0034] R 22 is hydrogen or wherein * indicates (S) stereochemistry; and

[0035] R 24a It is a C1-C4 alkyl group.

[0036] In some embodiments, disclosed are compounds having formula (IV) or pharmaceutically acceptable salts thereof:

[0037]

[0038] in

[0039] R 11 yes Where * indicates (S) stereochemistry; and R 11a It is a C1-C4 alkyl group.

[0040] In some embodiments, a compound in Table 1 or a pharmaceutically acceptable salt thereof is disclosed.

[0041] In some embodiments, a pharmaceutical composition is disclosed, comprising a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0042] In some embodiments, methods of treating cancer are disclosed, comprising administering a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, disclosed are compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) or compounds in Table 1 or pharmaceutically acceptable salts thereof for use in treating cancer.

[0044] In some embodiments, disclosed is the use of a compound having (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer.

[0045] In some embodiments, pharmaceutical compositions are disclosed comprising a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0046] In some embodiments, methods of treating respiratory inflammatory diseases are disclosed, comprising administering a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, disclosed are compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) or compounds in Table 1 or pharmaceutically acceptable salts thereof for use in treating respiratory inflammatory diseases.

[0048] In some embodiments, disclosed is the use of a chemical having (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating respiratory inflammatory diseases.

[0049] In some embodiments, pharmaceutical compositions are disclosed, comprising a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof, for use in treating respiratory inflammatory diseases.

[0050] In some embodiments, the aforementioned respiratory inflammatory disease is chronic obstructive pulmonary disease (COPD) or asthma. DETAILED DESCRIPTION

[0051] In some embodiments, disclosed are compounds having formula (I) or pharmaceutically acceptable salts thereof:

[0052]

[0053] in

[0054] R 1 is selected from hydrogen, -CH3 and -(C=O)CH(R 1a )NH2;

[0055] R 1a is a C1-C4 alkyl group;

[0056] Y is -(CH2) n -or -(C=O)-;

[0057] n is an integer selected from 1 and 2;

[0058] R 2 is selected from hydrogen, -CH3 and -(C=X)R 4 , and R 3 is hydrogen or -CH3; or

[0059] R 2 and R 3 Joined together with the nitrogen to which they are attached to form a nitrogen-containing 6-membered heterocyclic ring;

[0060] X is NH or O;

[0061] R 4 is -CH3 or -[CH(R 4a )] m NH2;

[0062] m is an integer selected from 0 or 1; and

[0063] R 4a It is a C1-C4 alkyl group.

[0064] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0065] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 and R 3 Together with the nitrogen to which they are attached, they are connected to form a nitrogen-containing six-membered heterocyclic ring. In some embodiments, the nitrogen-containing six-membered heterocyclic ring is a morpholinyl ring. In some embodiments, the nitrogen-containing six-membered heterocyclic ring is a piperidinyl ring.

[0066] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2is -CH3, and R 3 It's hydrogen.

[0067] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 is -CH3, and R 3 It is -CH3.

[0068] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is NH, R 4 is [CH(R 4a )] m NH2, and m is 0.

[0069] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 is [CH(R 4a )] m NH2, and m is 0.

[0070] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C3 alkyl group (eg, isopropyl).

[0071] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 m,R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )]m NH2, m is 1, and R 4a is a C2 alkyl group (eg, ethyl).

[0072] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C1 alkyl group (eg, methyl).

[0073] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, and R 4 It is -CH3.

[0074] In some embodiments, in compounds having formula (I), R 1 is -CH3, Y is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0075] In some embodiments, in compounds having formula (I), R 1 is -(C=O)CH(R 1a )NH2,R 1a is C3 alkyl (e.g., isopropyl), R is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0076] In some embodiments, in compounds having formula (I), R 1 is -(C=O)CH(R 1a )NH2,R 1a is C1 alkyl (e.g., methyl), R is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0077] In some embodiments, in compounds having formula (I), R1 is hydrogen, Y is -(CH2) n -, n is 2, R 2 is hydrogen, and R 3 It's hydrogen.

[0078] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(C=O), R 2 is hydrogen, and R 3 It's hydrogen.

[0079] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(C=O), R 2 is -CH3, and R 3 It's hydrogen.

[0080] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C4 alkyl group (eg, isobutyl).

[0081] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C4 alkyl group (eg, tert-butyl).

[0082] In some embodiments, in compounds having formula (I), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a It's hydrogen.

[0083] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia):

[0084]

[0085] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0086] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 and R 3 Together with the nitrogen to which they are attached, they are connected to form a nitrogen-containing six-membered heterocyclic ring. In some embodiments, the nitrogen-containing six-membered heterocyclic ring is a morpholinyl ring. In some embodiments, the nitrogen-containing six-membered heterocyclic ring is a piperidinyl ring.

[0087] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 is -CH3, and R 3 It's hydrogen.

[0088] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 is -CH3, and R 3 It is -CH3.

[0089] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is NH, R 4 is [CH(R 4a )] m NH2, and m is 0.

[0090] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 is [CH(R 4a )] m NH2, and m is 0.

[0091] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C3 alkyl group (eg, isopropyl).

[0092] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 m,R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C2 alkyl group (eg, ethyl).

[0093] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C1 alkyl group (eg, methyl).

[0094] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, and R 4 It is -CH3.

[0095] In some embodiments, in compounds having formula (Ia), R 1 is -CH3, Y is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0096] In some embodiments, in compounds having formula (Ia), R 1 is -(C=O)CH(R 1a )NH2,R 1a is C3 alkyl (e.g., isopropyl), R is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0097] In some embodiments, in compounds having formula (Ia), R 1 is -(C=O)CH(R 1a )NH2,R 1a is C1 alkyl (e.g., methyl), R is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0098] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(CH2) n -, n is 2, R 2 is hydrogen, and R 3 It's hydrogen.

[0099] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(C=O), R 2 and R 3 It's hydrogen.

[0100] In some embodiments, in compounds having formula (Ia), R 1 is hydrogen, Y is -(C=O), R 2 is -CH3, and R 3 It's hydrogen.

[0101] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib):

[0102]

[0103] In some embodiments, in compounds having formula (Ib), R 1is hydrogen, Y is -(CH2) n -, n is 1, R 2 is hydrogen, and R 3 It's hydrogen.

[0104] In some embodiments, in compounds having formula (Ib), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C3 alkyl group (eg, isopropyl).

[0105] In some embodiments, in compounds having formula (Ib), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C1 alkyl group (eg, methyl).

[0106] In some embodiments, in compounds having formula (Ib), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a is a C2 alkyl group (eg, ethyl).

[0107] In some embodiments, in compounds having formula (Ib), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4ais a C4 alkyl group (eg, isobutyl or tert-butyl).

[0108] In some embodiments, in compounds having formula (Ib), R 1 is hydrogen, Y is -(CH2) n -, n is 1, R 2 Yes - (C = X) R 4 , R 3 is hydrogen, X is O, R 4 Yes-[CH(R 4a )] m NH2, m is 1, and R 4a It's hydrogen.

[0109] In some embodiments, disclosed are compounds having formula (II) or pharmaceutically acceptable salts thereof:

[0110]

[0111] in

[0112] R 11 Selected from hydrogen, -CH3 and Where * indicates (S) stereochemistry;

[0113] Y 1 Yes - (CH2) p -or-(C=O);

[0114] p is an integer selected from 1 and 2;

[0115] R 11a is a C1-C4 alkyl group;

[0116] R 12 is selected from hydrogen, -CH3 and -(C=X 1 )R 14 , and R 13 is hydrogen or -CH3; or

[0117] R 12 and R 13 are joined together with the nitrogen to which they are attached to form a 6-membered heterocyclic ring;

[0118] X 1 is NH or O;

[0119] R 14 is -CH3 or Where * indicates (S) stereochemistry;

[0120] R 14a is C1-C4 alkyl; and

[0121] q is an integer selected from 0 and 1.

[0122] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 is hydrogen, and R 13 It's hydrogen.

[0123] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, and R 12 and R 13 Together with the nitrogen to which they are attached, they are connected to form a 6-membered nitrogen-containing heterocyclic ring. In some embodiments, the nitrogen-containing 6-membered heterocyclic ring is a morpholinyl ring. In some embodiments, the nitrogen-containing 6-membered heterocyclic ring is a piperidinyl ring.

[0124] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 is -CH3, and R 13 It's hydrogen.

[0125] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 is -CH3, and R 13 It is -CH3.

[0126] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 Yes-(C=X 1 )R 14 , R 13 It is hydrogen, X 1 Yes NH, R 14 yes And q is 0.

[0127] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 Yes-(C=X 1 )R 14 , R13 It is hydrogen, X 1 It's O, R 14 yes And q is 0.

[0128] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 Yes-(C=X 1 )R 14 , R 13 It is hydrogen, X 1 It's O, R 14 yes q is 1, and R 14a is a C3 alkyl group (eg, isopropyl).

[0129] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 Yes-(C=X 1 )R 14 , R 13 It is hydrogen, X 1 It's O, R 14 yes q is 1, and R 14a is a C2 alkyl group (eg, ethyl).

[0130] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 Yes-(C=X 1 )R 14 , R 13 It is hydrogen, X 1 It's O, R 14 yes q is 1, and R 14a is a C1 alkyl group (eg, methyl).

[0131] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 1, R 12 Yes-(C=X 1 )R 14 , R 13 It is hydrogen, X 1is O, and R 14 It is -CH3.

[0132] In some embodiments, in the compound having formula (II), R 11 Yes -CH3, Y 1 Yes - (CH2) p -, p is 1, R 12 is hydrogen, and R 13 It's hydrogen.

[0133] In some embodiments, in the compound having formula (II), R 11 yes R 11a is C3 alkyl (e.g., isopropyl), Y 1 Yes - (CH2) p -, p is 1, R 12 is hydrogen, and R 13 It's hydrogen.

[0134] In some embodiments, in the compound having formula (II), R 11 yes R 11a is C1 alkyl (e.g., methyl), Y 1 Yes - (CH2) p -, p is 1, R 12 is hydrogen, and R 13 It's hydrogen.

[0135] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 Yes - (CH2) p -, p is 2, R 12 is hydrogen, and R 13 It's hydrogen.

[0136] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 is -(C=O), R 12 is hydrogen, and R 13 It's hydrogen.

[0137] In some embodiments, in the compound having formula (II), R 11 It is hydrogen, Y 1 is -(C=O), R 12 is -CH3, and R 13 It's hydrogen.

[0138] In some embodiments, disclosed are compounds having formula (III) or pharmaceutically acceptable salts thereof:

[0139]

[0140] in

[0141] R 22 is hydrogen or wherein * indicates (S) stereochemistry; and

[0142] R 24a It is a C1-C4 alkyl group.

[0143] In some embodiments, in the compound having formula (III), R 22 It's hydrogen.

[0144] In some embodiments, in the compound having formula (III), R 22 yes And R 24a is a C3 alkyl group (eg, isopropyl).

[0145] In some embodiments, in the compound having formula (III), R 22 yes And R 24a is a C1 alkyl group (eg, methyl).

[0146] In some embodiments, in the compound having formula (III), R 22 yes And R 24a is a C2 alkyl group (eg, ethyl).

[0147] In some embodiments, in the compound having formula (III), R 22 yes And R 24a is a C4 alkyl group (eg, isobutyl or tert-butyl).

[0148] In some embodiments, disclosed are compounds having formula (IV) or pharmaceutically acceptable salts thereof:

[0149]

[0150] in

[0151] R 11 yes Where * indicates (S) stereochemistry; and R 11a It is a C1-C4 alkyl group.

[0152] In some embodiments, a compound in Table 1 or a pharmaceutically acceptable salt thereof is disclosed:

[0153] Table 1

[0154]

[0155]

[0156]

[0157]

[0158] The term "C1-C4 alkyl" includes acyclic saturated alkyl moieties having 1 to 4 carbon atoms. Examples of C1-C4 alkyl moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

[0159] The term "nitrogen-containing six-membered heterocycle" includes saturated cycloalkyl moieties having at least one carbon replaced by nitrogen. Examples of nitrogen-containing six-membered heterocycles include piperidine, piperazine, morpholine, thiomorpholine, and hexahydro-1,3,5-triazine.

[0160] The term "pharmaceutically acceptable salt" includes acid addition salts or base addition salts that retain the biological effectiveness and properties of the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and the compounds in Table 1, and which are typically not biologically or otherwise undesirable. In many cases, the compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and the compounds in Table 1 are capable of forming acid and / or base salts due to the presence of basic and / or carboxyl groups or groups similar thereto.

[0161] Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / hydrogen iodide Iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, palmoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, sulfate / hydrogensulfate, tartrate, toluenesulfonate and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, and the like.

[0162] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonia and salts of ammonium and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0163] Pharmaceutically acceptable salts of compounds of formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (e.g., Na + , Ca 2+ Mg 2+ or K +The invention relates to the preparation of the present invention in the form of a hydroxyl group ... Lists of additional suitable salts can be found, for example, in: "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); Berge et al., "J. Pharm. Sci., 1977, 66, 1-19, and in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0164] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms for compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1, or pharmaceutically acceptable salts thereof. Isotopically labeled compounds have structures depicted by the formula given herein, except that one or more atoms are replaced by atoms of the same element but having a different mass number. Examples of isotopes that may be incorporated into compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1, and pharmaceutically acceptable salts thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 35 S. 36 Cl and 125 I. Isotopically labeled compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0165] Compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 or pharmaceutically acceptable salts thereof may have different isomeric forms. The term "optical isomer", "stereoisomer" or "diastereomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 or pharmaceutically acceptable salts thereof. It should be understood that substituents may be attached to chiral centers of carbon atoms and, therefore, the disclosed compounds include enantiomers, diastereomers and racemates. The term "enantiomer" includes pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. Where appropriate, the term is used to refer to a racemic mixture. The term "diastereomer" or "diastereomer" includes stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral center can be specified by R or S. Resolved compounds of unknown absolute configuration can be specified as (+) or (-) according to the direction of rotation of plane polarized light at the wavelength of the sodium D line (right-handed or left-handed). Certain compounds of formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 or pharmaceutically acceptable salts thereof contain one or more asymmetric centers or axes, and thus may produce enantiomers, diastereomers or other stereoisomeric forms, defined as (R)- or (S)- in terms of absolute stereochemistry. The present disclosure is intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques well known in the art such as chiral HPLC.

[0166] Also disclosed herein are intermediates 1 to 56 and salts thereof in the Examples.

[0167] Pharmaceutical composition

[0168] In some embodiments, a pharmaceutical composition is disclosed, comprising a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0169] The term "pharmaceutically acceptable carrier" includes compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, as determined by those skilled in the art, within the scope of sound medical judgment.

[0170] The disclosed compositions can be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders) or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration or as suppositories for rectal administration).

[0171] The amount of active ingredient that is combined with one or more pharmaceutically acceptable carriers to produce a single dosage form will necessarily vary depending on the host being treated and the particular route of administration. For further information on routes of administration and dosage regimens, the reader is referred to Comprehensive Medicinal Chemistry, Vol. 5, Chapter 25.3 (Editorial Chairman Corwin Hansch), Pergamon Press, 1990.

[0172] Therapeutic practicality

[0173] The compounds of the invention are useful as arginase inhibitors in therapy.

[0174] In one aspect, methods for treating cancer in a subject in need thereof are disclosed, comprising administering to the subject an effective amount of a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0175] In one aspect, methods for treating an inflammatory disease of the respiratory tract in a subject in need thereof are disclosed, comprising administering to the subject an effective amount of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0176] In one aspect, disclosed is a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof for use in treating cancer.

[0177] In one aspect, disclosed are compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) or compounds in Table 1 or pharmaceutically acceptable salts thereof for use in treating respiratory inflammatory diseases.

[0178] In one aspect, disclosed is the use of a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt in the manufacture of a medicament for treating cancer.

[0179] In one aspect, disclosed is the use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt in the manufacture of a medicament for treating an inflammatory disease of the respiratory tract.

[0180] In one aspect, pharmaceutical compositions are disclosed comprising a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof for use in treating cancer.

[0181] In one aspect, pharmaceutical compositions are disclosed comprising a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof, for use in treating respiratory inflammatory diseases.

[0182] The term "cancer" includes, for example, renal cell carcinoma, head and neck squamous cell carcinoma, lung cancer (e.g., small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mesothelioma), pancreatic cancer, colorectal cancer, breast cancer, acute myeloid leukemia (AML), prostate cancer, gastric cancer, bladder cancer, melanoma, kidney cancer, and ovarian cancer. In some embodiments, the cancer has metastasized. In some embodiments, the cancer is associated with arginase 1 and / or arginase 2 regulation.

[0183] In some embodiments, cancer is associated with increased plasma arginase 1 levels. In some embodiments, cancer is associated with decreased plasma arginine levels. In some embodiments, cancer is associated with increased plasma arginase 1 levels and decreased plasma arginine levels. In some embodiments, cancers associated with increased plasma arginase 1 levels and / or decreased plasma arginine levels include renal cell carcinoma, head and neck squamous cell carcinoma, lung cancer (e.g., small cell lung cancer (SCLC), non-small cell lung cancer cell lung cancer (NSCLC), mesothelioma), pancreatic cancer, colorectal cancer, and breast cancer.

[0184] In some embodiments, the cancer secretes arginase 2, such as acute myeloid leukemia and prostate cancer.

[0185] In some embodiments, the cancer is associated with arginase 1-positive tumor-infiltrating immune cells, such as lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), gastric cancer, bladder cancer, colorectal cancer, melanoma, head and neck squamous cell carcinoma, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and kidney cancer.

[0186] The term "inflammatory disease of the respiratory tract" refers to an inflammatory condition or disorder affecting the air spaces, the pulmonary vasculature, the lung interstitium, or a combination thereof. They can be isolated to the lungs or involve multiple organs. In one embodiment, the inflammatory disease of the respiratory tract is an inflammatory lung disease. In another embodiment, the inflammatory lung disease is non-infectious. In some embodiments, the inflammatory disease of the respiratory tract is associated with arginase 1 and / or arginase 2 regulation.

[0187] In some embodiments, the inflammatory disease of the respiratory tract is asthma, chronic obstructive pulmonary disease (COPD), chemically induced pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, or a combination thereof. In some embodiments, the inflammatory disease of the respiratory tract is chronic obstructive pulmonary disease (COPD) or asthma.

[0188] In one aspect, methods for inhibiting arginase in a subject in need thereof are disclosed, comprising administering to the subject an effective amount of a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0189] In one aspect, disclosed are compounds having Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 or pharmaceutically acceptable salts thereof for use in inhibiting arginase.

[0190] In one aspect, disclosed is the use of a compound having Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting arginase.

[0191] In one aspect, pharmaceutical compositions are disclosed comprising a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof for use in inhibiting arginase.

[0192] The term "arginase" includes manganese-containing enzymes belonging to the ureahydrolase family that catalyze the fifth and final step in the urea cycle, converting L-arginine to L-ornithine and urea. The term "arginase" includes two isozymes of the enzyme, such as arginase 1, which plays a role in the urea cycle and is primarily located in the cytoplasm of the liver, and arginase 2, which is located in the mitochondria of several tissues of the body and is involved in the regulation of arginine / ornithine concentrations in cells. In some embodiments, compounds of formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1, or pharmaceutically acceptable salts thereof, are selective for arginase 1. In some embodiments, compounds of formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1, or pharmaceutically acceptable salts thereof, are selective for arginase 2. In some embodiments, compounds of Formula (I), (la), (lb), (II), (III), (IV), and compounds in Table 1, or pharmaceutically acceptable salts thereof, inhibit both arginase 1 and arginase 2.

[0193] The term "effective amount" includes an amount of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof that will cause a biological or medical response in a subject, such as: reducing or inhibiting the activity of an enzyme or protein associated with arginase or cancer; improving symptoms of cancer; or slowing or delaying the progression of cancer. In some embodiments, the term "effective amount" includes an amount of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV) or a compound in Table 1 or a pharmaceutically acceptable salt thereof that is effective, when administered to a subject, to at least partially alleviate, inhibit, and / or ameliorate cancer or inhibit arginase in a subject, and / or reduce or inhibit the growth of a tumor or the proliferation of cancerous cells.

[0194] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject suffers from cancer. In some embodiments, the subject is in need of treatment (e.g., the subject will benefit from treatment biologically or medically). In some embodiments, the subject's plasma arginase 1 level increases. In some embodiments, the subject's arginine level decreases. In some embodiments, the patient's plasma arginase 1 level increases and the arginine level decreases. In some embodiments, the subject suffers from a cancer that secretes arginase 2 (e.g., acute myeloid leukemia or prostate cancer). In some embodiments, the subject has arginase 1-positive tumor-infiltrating immune cells.

[0195] The terms "inhibit, inhibition or inhibiting" include a decrease in the baseline activity of a biological activity or process. In some embodiments, compounds of Formula (I), (Ia), (Ib), (II), (III), (IV) and compounds in Table 1 or pharmaceutically acceptable salts thereof inhibit arginase.

[0196] The terms "treat, treating and treatment" include reducing or inhibiting the activity of an enzyme or protein associated with arginase or in a subject; improving one or more symptoms of cancer; or slowing or delaying the progression of cancer in a subject. The terms "treat, treating and treatment" also include reducing or inhibiting the growth of a tumor or the proliferation of cancerous cells in a subject.

[0197] Examples

[0198] Aspects of the present disclosure can be further defined by reference to the following non-limiting examples, which describe in detail the preparation of certain compounds and intermediates of the present disclosure and methods of using the compounds of the present disclosure. It should be clear to those skilled in the art that many modifications can be made to materials and methods without departing from the scope of the present disclosure.

[0199] Unless otherwise stated:

[0200] (i) Unless otherwise stated, all syntheses were carried out at ambient temperature (i.e. in the range of 17°C to 25°C) and under an atmosphere of an inert gas such as nitrogen;

[0201] (ii) evaporation by rotary evaporation or in vacuo using a Genevac device or Biotage v10 evaporator and work-up procedure after removal of residual solids by filtration;

[0202] (iii) Automation Teledyne Isco Rf or Teledyne Isco Use pre-filled RediSep Rf Gold TM Silica columns (20-40 μm, spherical particles), GraceResolv TM column( Purification was performed by flash chromatography on silica) or Silicycle columns (40-63 μm).

[0203] (iv) Preparative chromatography was performed on a Gilson preparative HPLC instrument equipped with UV acquisition; alternatively, preparative chromatography was performed on a Waters automated purification HPLC-MS instrument equipped with MS and UV triggered acquisition;

[0204] (v) Chiral preparative chromatography was performed on a Gilson instrument (233 injector / fraction collector, 333 and 334 pumps, 155 UV detector) with UV acquisition or on a Varian Prep Star instrument (2 SD1 pumps, 325 UV detector, 701 fraction collector) with the pumps running with Gilson 305 injection; alternatively, chiral preparative chromatography was performed on a Waters Prep 100 SFC-MS instrument with MS and UV triggered acquisition or a Thar MultiGram III SFC instrument with UV acquisition.

[0205] (vi) the yield, when any, need not be the maximum achievable;

[0206] (vii) In general, the structure of the final product having Formula I is confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values ​​are measured in the delta scale [proton magnetic resonance spectra are determined using Bruker Avance 500 (500 MHz), Bruker Avance 400 (400 MHz), Bruker Avance 300 (300 MHz) or Bruker DRX (300 MHz) instruments]; measurements are performed at ambient temperature unless otherwise stated; the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublets; dt, doublet of triplet; bs, broad signal.

[0207] (viii) In general, the final product of Formula I is also characterized by mass spectrometry (LCMS or UPLC) after liquid chromatography; UPLC is performed as follows: using a Waters UPLC equipped with a Waters SQ mass spectrometer (column temperature 40°C, UV = 220-300nm or 190-400nm, mass spectrum = ESI with positive / negative switching) at a flow rate of 1 mL / min using a solvent system of 97% A+3% B to 3% A+97% B for 1.50 min (total run time including equilibration back to starting conditions, etc. is 1.70 min), wherein A = 0.1% formic acid or 0.05% trifluoroacetic acid in water (for acid treatment) or 0.1% ammonium hydroxide in water (for base treatment), and B = acetonitrile. For acid analysis, the column used was Waters Acquity HSS T3 (1.8 μm, 2.1 x 50 mm); for base analysis, the column used was Waters Acquity BEH C18 (1.7 μm, 2.1 x 50 mm). Alternatively, UPLC was performed as follows: using a Waters UPLC equipped with a Waters SQ mass spectrometer (column temperature 30°C, UV = 210-400 nm, mass spectrum = ESI with positive / negative switching) at a flow rate of 1 mL / min using a solvent gradient from 2% to 98% B for 1.5 min (total run time with equilibration back to starting conditions was 2 min), where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile (for acid treatment); or A = 0.1% ammonium hydroxide in water, and B = acetonitrile (for base treatment). For acid analysis, the column used was Waters Acquity HSS T3 (1.8 μm, 2.1 x 30 mm), and for base analysis, the column used was Waters Acquity BEH C18 (1.7 μm, 2.1 x 30 mm); LCMS was performed as follows: using a Waters Alliance HT (2795) equipped with a Waters ZQ ESCi mass spectrometer and a Phenomenex Gemini-NX C18 (5 μm, 110A, 2.1 x 50 mm column), at a flow rate of 1.1 mL / min, 95% A to 95% B for 4 min, holding for 0.5 min, wherein A = 0.1% formic acid, and B = 0.1% formic acid in acetonitrile (for acid treatment); or A = 0.1% ammonium hydroxide in water, and B = acetonitrile (for base treatment).In addition, LCMS was performed as follows: Shimadzu UFLC equipped with a Shimadzu LCMS-2020 mass spectrometer and a Waters HSS C18 (1.8 μm, 2.1 x 50 mm) or Shim-pack XR-ODS (2.2 μm, 3.0 x 50 mm) or Phenomenex Gemini-NX C18 (3 μm, 3.0 x 50 mm) column was used at 0.7 mL / min (for Waters HSS C18 column), 1.0 mL / min (for Shim-pack XR-ODS column) or 1.2 mL / min (for Phenomenex Gemini-NX C18) flow rate, 95% A to 95% B for 2.2 min, hold for 0.6 min, where A = 0.1% formic acid or 0.05% trifluoroacetic acid in water (for acid treatment), or 0.1% ammonium hydroxide or 6.5 mM ammonium carbonate in water (for base treatment), and B = acetonitrile. Unless otherwise stated, reported molecular ions correspond to [M+H]+; for molecules with multiple isotopic patterns (Br, Cl, etc.), unless otherwise stated, the reported values ​​are those obtained for the lowest isotopic mass.

[0208] (ix) Ion exchange purification was usually performed using an SCX-2 (Biotage) column.

[0209] (x) intermediate purity is assessed by thin layer chromatography, mass spectrometry, LCMS, UPLC / MS, HPLC (high performance liquid chromatography) and / or NMR analysis;

[0210] (xi) The following abbreviations are used:-

[0211] EtOAc: Ethyl acetate

[0212] Et2O: diethyl ether

[0213] DMSO: dimethyl sulfoxide

[0214] LAH: Lithium Aluminum Hydride

[0215] LiHMDS: Lithium Hexamethyldisilazane

[0216] MeOH: Methanol

[0217] TFA: trifluoroacetic acid

[0218] MeCN: Acetonitrile

[0219] LCMS: Liquid chromatography-mass spectrometry

[0220] rt or RT: room temperature

[0221] aq: aqueous solution

[0222] THF: Tetrahydrofuran

[0223] DCM: dichloromethane

[0224] DMF: dimethylformamide

[0225] HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0226] TBAF: Tetrabutylammonium fluoride

[0227] AcOH: acetic acid

[0228] DIAD: diisopropyl azodicarboxylate

[0229] Boc-Ala-OH: N-(tert-Butyloxycarbonyl)-L-alanine

[0230] Boc-Val-OH: N-(tert-Butyloxycarbonyl)-L-valine

[0231] HEPES: (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)

[0232] Example 1: (2S,3R)-2-amino-3-(aminomethyl)-6-dihydroxyborylhexanoic acid dihydrochloride

[0233]

[0234] Intermediate 1: (S)-4-(Allyloxy)-2-amino-4-oxobutyric acid hydrochloride

[0235] Under N2 atmosphere, L-aspartic acid (10.66g, 80.09mmol) is suspended in allyl alcohol (60.0mL, 880mmol).Trimethylchlorosilane (31.0mL, 240mmol) is added dropwise to the suspension at a rate of 1mL / min via a syringe pump.Reaction mixture is stirred at room temperature for 16h.The reaction is diluted with ice-cold Et2O (100mL) and the suspension is filtered.Solid is washed with ice-cold Et2O (3x 15mL) and dried to obtain (S)-4-(allyloxy)-2-amino-4-oxobutyric acid hydrochloride (intermediate 1, 12.7g, 76% yield) as an amorphous white solid, which is continued without further purification. 1 HNMR(300MHz,D2O)δ3.14(2H,d),4.25(1H,t),4.70(2H,d),5.26-5.48(2H,m),5.89-6.08(1H,m); m / z: (ES + )[M+H] +=174.

[0236] Intermediate 2: (S)-4-allyl 1-tert-butyl 2-(benzyloxycarbonylamino) succinate (S)-4-(allyloxy)-2-amino-4-oxobutyric acid hydrochloride (intermediate 1, 11.58g, 55.24mmol) was dissolved in water (100mL) and 1,4-dioxane (100mL). Sodium carbonate (23.0g, 220mmol) was added in batches at room temperature and the reaction was stirred for 5min. Benzyl chloroformate (8.3mL, 58mmol) was added dropwise to the reaction at a rate of 1mL / min via a syringe pump. The biphasic reaction mixture was stirred at room temperature for 4h. The crude reaction was quenched with concentrated HCl aqueous solution until pH<1. The layers were separated and the aqueous layer was extracted with EtOAc (2x 25mL). The combined organics were dried over MgSO4, filtered and concentrated to give a colorless oil. The crude carboxylic acid was dissolved in DCM (100mL) and cooled to -78°C in a pressure flask. Sulfuric acid (3.0mL, 56mmol) was added, followed by the immediate addition of pre-condensed isobutylene (66.0mL, 710mmol). The flask was sealed and stirred for 3d, while the ice bath was terminated. The reaction was poured into a saturated aqueous sodium bicarbonate solution (200mL) and stirred for 30min. Each layer was separated and the aqueous layer was extracted with DCM (2x 20mL). The combined organic matter was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to obtain (S)-4-allyl 1-tert-butyl 2-(benzyloxycarbonylamino) succinate (intermediate 2, 12.2g, 61% yield) as a colorless oil. 1 H NMR(300MHz, CDCl3)δ1.47(9H,s),2.76-2.93(1H,dd),2.94-3.12(1H,dd),4.48- 4.57(1H,m),4.60(2H,dq),5.14(2H,s),5.26(1H,dq),5.33(1H,dq),5.71(1H,br d),5.91(1H,ddt),7.31-7.48(5H,m); m / z: (ES + )[M+H] + =381.

[0237] Intermediate 3: 2-((S)-1-(Benzyloxycarbonylamino)-2-tert-butoxy-2-oxoethyl)pent-4-enoic acid

[0238] LiHMDS solution (1M, in toluene, 100mL, 100mmol) is added to an oven-dried multi-neck flask (multineck flask), and diluted with THF (50mL) under N2 atmosphere. The solution is cooled to -78 ° C, and (S) -4-allyl 1- tert-butyl 2- (benzyloxycarbonylamino) succinate (intermediate 2, 12.2g, 33.5mmol) is added dropwise to a reaction flask as a solution in THF (50mL). The reaction is stirred at -78 ° C for 80min. Trimethylchlorosilane (17.0mL, 133mmol) is added and the reaction is stirred for another 1h at -78 ° C. The reaction is then heated to 60 ° C for 160min. The reaction mixture is cooled to room temperature, and quenched with a 2M HCl aqueous solution (67mL). After vigorous stirring for 30min, each layer is separated and the aqueous layer is extracted with EtOAc (2x 30mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH) to afford 2-((S)-1-(benzyloxycarbonylamino)-2-tert-butyl-2-oxoethyl)pent-4-enoic acid (Intermediate 3, 12.0 g, 99%) as an inseparable mixture of diastereomers in a ratio of approximately 1.7:1. 1 HNMR(300MHz, CDCl3)δ1.41(3.4H,s)1.43(5.6H,s),2.19-2.43(1H,m),2.44-2.66(1H,m),2.81-2.99(0.65H,m),3.08- 3.25(0.35H,m),4.48-4.63(1H,m),4.97-5.20(4H,m),5.52-5.71(1H,m),5.71-5.94(1H,m),7.25-7.39(5H,m); m / z: (ES + )[M+H] + =364.

[0239] Intermediate 4: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate and

[0240] Intermediate 5: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate

[0241] 2-((S)-1-(Benzyloxycarbonylamino)-2-tert-butoxy-2-oxoethyl)pent-4-enoic acid (Intermediate 3, 12.0 g, 33.0 mmol) was dissolved in THF (60 mL) and cooled to -10 °C under N2 atmosphere. N-Methylmorpholine (3.7 mL, 34 mmol) was added and the reaction was stirred at -10 °C for 5 min, followed by the addition of ethyl chloroformate (3.2 mL, 33 mmol). The reaction mixture was warmed to room temperature and stirred for 40 min. The resulting suspension was filtered directly into a solution of sodium borohydride (3.0 g, 79 mmol) in water (60 mL) at 0 °C. After addition, the reaction was warmed to room temperature and stirred for 3 h. The reaction mixture was cooled to 0 °C and carefully quenched with 2M aqueous HCl (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (Intermediate 4, 5.77 g, 50% yield) and (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (Intermediate 5, 3.96 g, 34% yield) as colorless oils.

[0242] Intermediate 4: 1 H NMR(300MHz, CDCl3)δ1.46(9H,s),1.70-1.85(1H,m),1.85-1.99(1H,m),2.18-2.37(1H, m),3.26(1H,t),3.63(1H,dd),4.58(1H,dd),4.92-5.06(2H,m),5.10(2H,s),5.55(1H,br d),5.60-5.78(1H,m),7.26-7.39(5H,m); m / z: (ES + )[M+H] + =350.

[0243] Intermediate 5: 1 H NMR(300MHz, CDCl3)δ1.45(9H,s),2.03-2.12(1H,m),2.13-2.23(2H,m),3.65(2H,qd),4.34(1H,br dd),5.00-5.15(4H,m),5.62-5.90(2H,m),7.25-7.41(5H,m); m / z: (ES + )[M+H] + =350.

[0244] Intermediate 6: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)hexane- 5-enoate

[0245] At 0 ° C, triethylamine (7.4mL, 53mmol) and methanesulfonyl chloride (2.6mL, 33mmol) were added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl) hex-5-enoate (intermediate 4, 4.61g, 13.2mmol) in DCM (100mL) in sequence. The reaction was warmed to room temperature and stirred for 90min. The crude mixture was diluted with DCM (25mL) and washed with saturated aqueous sodium bicarbonate solution, water and brine (25mL each) in sequence. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to obtain (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl) hex-5-enoate (intermediate 6, 5.3g, 93% yield) as a light yellow oil. 1 HNMR(300MHz, CDCl3)δ1.46(9H,s),1.96-2.19(2H,m),2.36-2.58(1H,m),2.97(3H,s),4.00-4.23(2H,m),4.52(1H,br d),5.00-5.17(4H,m),5.34(1H,br d),5.60-5.83(1H,m),7.27-7.37(5H,m); m / z: (ES + )[M+H] + =445.

[0246] Intermediate 7: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)-6- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0247] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (0.25 g, 0.37 mmol) and bis(diphenylphosphino)methane (0.28 g, 0.74 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (35 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.00 mL, 28.0 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)hex-5-enoate (intermediate 6, 5.27 g, 12.3 mmol) was added to the reaction as a solution in DCM (30 mL), and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0 ° C and quenched with MeOH (6 mL) and water (50 mL). Each layer was separated and the aqueous layer was extracted with DCM (2x 15mL). The combined organic matter was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to give (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 7, 5.84 g, 85% yield) as a yellow jelly. 1 HNMR(300MHz, CDCl3)δ0.73(2H,t),1.20(12H,s),1.24-1.42(4H,m),1.45(9 H,s),2.30-2.50(1H,m),2.97(3H,s),3.98(1H,t),4.18(1H,dd),4.50(1H,br d),5.02-5.15(2H,m),5.35(1H,brd),7.27-7.42(5H,m); m / z: (ES + )[M+NH4] + =573.

[0248] Intermediate 8: (2S,3R)-tert-butyl 3-(azidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0249] Sodium azide (3.3 g, 51 mmol) was added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 7, 5.84 g, 10.5 mmol) in DMF (30 mL). The reaction was heated to 55 ° C and stirred for 16 h under N2 atmosphere. Another portion of sodium azide (200 mg, 3 mmol) was added and the reaction was stirred for another 4 h at 55 ° C. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The layers were separated and the aqueous layer was extracted with ether (3 x 35 mL). The combined organics were washed with brine (50 mL), then dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 3-(azidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 8, 3.52 g, 67% yield) as a colorless oil. 1 HNMR(300MHz, CDCl3)δ0.73(2H,t),1.20(12H,s),1.22-1.40(4H,m),1.45( 9H,s),2.04-2.20(1H,m),3.15-3.30(1H,m),3.31-3.43(1H,m),4.46(1H,br d),5.10(2H,s),5.37(1H,brd),7.26-7.40(5H,m); m / z: (ES + )[M+NH4] + =520. Intermediate 9: (2S,3R)-tert-butyl 2-(tert-butoxycarbonylamino yl)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexane Acid esters

[0250] Pd / C (10% wt, 0.46 g, 0.43 mmol) and di-tert-butyl dicarbonate (2.50 mL, 10.8 mmol) were added to a solution of (2S, 3R)-tert-butyl 3-(azidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 8, 2.16 g, 4.29 mmol) in EtOAc (15 mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature for 2 h. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated to a cloudy, colorless oil, which was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(tert-butoxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 9, 1.65 g, 71% yield) as a white foam. 1 H NMR(300MHz, CDCl3)δ0.67-0.73(2H,m),0.95-1.16(2H,m),1.20(12H,s),1.37-1 .47(29H,m),2.00-2.20(1H,m),2.36-2.56(1H,m),3.31-3.57(1H,m),4.34(1H,br d),5.14(1H,br d),5.68(1H,brs); m / z: (ES - )[M+HCOO - ] - =587.

[0251] Example 1: (2S,3R)-2-amino-3-(aminomethyl)-6-dihydroxyborylhexanoic acid dihydrochloride

[0252] HBr solution (33 wt % in AcOH, 6.0 mL, 36 mmol) was added to a solution of (2S, 3R)-tert-butyl 2-(tert-butoxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 9, 2.2 g, 4.1 mmol) in DCM (32 mL) and the reaction was stirred at room temperature for 1 h. The reaction was diluted with Et2O (10 mL) and concentrated. This step was repeated twice more. The residue was dissolved in Et2O (40 mL) and 2M HCl aqueous solution (40 mL). Phenylboronic acid (0.989 g, 8.11 mmol) was added and the reaction was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 15 mL). The aqueous layer was lyophilized and purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 100% MeCN in water) to afford (2S,3R)-2-amino-3-(aminomethyl)-6-boronyllohexanoic acid dihydrochloride (Example 1, 0.713 g, 64% yield) as a yellow solid. 1 HNMR(300MHz,D2O)δ0.65-0.87(2H,m),1.32-1.56(4H,m),2.35-2.48(1H,m),3.12(2H,qd),4.09(1H,d); m / z: (ES + )[M-H2O+H] + =187.

[0253] (2S, 3R) -2-amino-3- (aminomethyl) -6- dihydroxyboryl hexanoic acid dihydrochloride (Example 1, 713mg, 2.57mmol) was dissolved in MeOH (5mL) and loaded onto a pre-equilibrated Porapak Rxn Cx (60cc) ion exchange column. The resin was washed with MeOH (45mL) and then washed with 5% NH3 in MeOH (45mL) to elute the product. The fractions containing the product were collected and condensed to give (2S, 3R) -2-amino-3- (aminomethyl) -6- dihydroxyboryl hexanoic acid (300mg, 57% yield) as a white powdery residue, which was present as a 4: 1 mixture of acyclic coordination complex and cyclic coordination complex. 1 HNMR(300MHz,D2O)δ0.49-0.92(2H,m),1.17-1.76(4H,m),2.03-2.18(0.8H,m),2.48-2. 58(0.2H,m),3.01(1.6H,d),3.16-3.26(0.4H,m),3.49(0.8H,d),3.71(0.2H,d); m / z: (ES + )[M-H2O+H] + =187.

[0254] (2S,3R)-2-amino-3-(aminomethyl)-6-boronyl hexanoic acid (95 mg, 0.47 mmol) was dissolved in MeOH (3 mL) and p-toluenesulfonic acid monohydrate (266 mg, 1.40 mmol) was added. The reaction was stirred at room temperature for 20 h. The reaction mixture was concentrated and directly purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 100% MeCN in water) to afford (2S,3R)-2-amino-3-(aminomethyl)-6-boronylhexanoic acid ditosylate (180 mg, 71% yield) as a white solid. 1H NMR(300MHz,D2O)δ0.74-0.87(2H,m),1.38-1.61(4H,m),2.40(6H,s),2.45-2.48 (1H,m),3.15(2H,qd),4.01(1H,d),7.27-7.50(4H,m),7.63-7.79(4H,m); m / z: (ES + )[M-H2O-2TsOH+H] + =187.

[0255] Example 2: (2S,3R)-2-amino-6-dihydroxyboryl-3-(morpholinomethyl)hexanoic acid

[0256]

[0257] Intermediate 10: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(morpholinomethyl)hexane-5- Alkenyl esters

[0258] At room temperature, morpholine (1.00 mL, 11.5 mmol) and potassium carbonate (829 mg, 6.00 mmol) were added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)hex-5-enoate (intermediate 6, 513 mg, 1.20 mmol) in DMF (5 mL). The reaction mixture was heated to 80 ° C and stirred for 16 h under N2 atmosphere. The reaction was cooled to room temperature and diluted with water (50 mL). The layers were separated and the aqueous layer was extracted with Et2O (3x 25 mL). The combined organic matter was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(morpholinomethyl)hex-5-enoate (Intermediate 10, 285 mg, 57% yield) as a colorless oil. 1 HNMR (300MHz, CDCl3) δ1.45(9H,s),1.63-2.61(9H,m),3.54-3.79(4H,m),4.44(1H,br d),4.95-5.16(4H,m),5.63-5.87(1H,m),7.05(1H,br d),7.25-7.39(5H,m); m / z: (ES + )[M+H] + =419.

[0259] Intermediate 11: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(morpholinomethyl)-6-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0260] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (14mg, 0.020mmol) and bis(diphenylphosphino)methane (16mg, 0.040mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (3mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22mL, 1.5mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10min. (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(morpholinomethyl) hex-5-enoate (intermediate 10, 285mg, 0.680mmol) was added to the reaction as a solution in DCM (2mL), and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0°C and quenched with MeOH (2mL) and water (10mL). Each layer is separated and aqueous layer is extracted with DCM (2x 10mL).By the organic matter merged through MgSO4 drying, filter and be concentrated to dryness.By silica gel chromatography (hexane / EtOAc) purification of crude material, (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(morpholinomethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 11, 228mg, 61% yield) is obtained. 1 H NMR(300MHz, CDCl3)δ0.64-0.83(2H,brt),1.20(12H,s),1.28-1.53(13H,m),1.93-2.63(4 H,m),3.06-4.00(4H,m),4.26-4.61(1H,m),4.99-5.18(2H,m),7.26-7.39(5H,m); m / z: (ES + )[M+H] + =547.

[0261] Example 2: (2S,3R)-2-amino-6-dihydroxyboryl-3-(morpholinomethyl)hexanoic acid

[0262] (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(morpholinomethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 11, 228 mg, 0.420 mmol) was dissolved in 6M aqueous HCl (4.0 mL) and the solution was heated to 100 ° C for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and washed with Et2O (3 x 10 mL). The aqueous layer was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The resin was washed with MeOH (15 mL) and then washed with 5% NH3 in MeOH (15 mL) to elute the product. Fractions containing the product were collected and concentrated to afford (2S,3R)-2-amino-6-borono-3-(morpholinomethyl)hexanoic acid (Example 2, 69 mg, 60% yield) as a white solid. 1 H NMR(300MHz,D2O)δ0.72-0.88(2H,m),1.24-1.38(1H,m),1.40-1.58(3H,m),2.19-2.34 (1H,m),2.43-2.58(4H,m),2.62-2.77(2H,m),3.71-3.85(4H,m),3.88(1H,d); m / z: (ES + )[M+H] + =275.

[0263] Example 3: (2S,3R)-2-amino-6-dihydroxyboryl-3-(piperidin-1-ylmethyl)hexanoic acid

[0264]

[0265] Intermediate 12: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(piperidin-1-ylmethyl)hex-5-enoic acid ester

[0266] Oxalyl chloride solution (2M in DCM, 0.72mL, 1.4mmol) was added to an oven-dried flask, diluted with DCM (3mL), and cooled to -78°C under N2 atmosphere. DMSO (0.15mL, 2.2mmol) was added dropwise, and the reaction was stirred at -78°C for 10min. (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (Intermediate 4, 250mg, 0.72mmol) was slowly added as a solution in DCM (3mL), and the reaction was stirred at -78°C for 30min. N,N-diisopropylethylamine (0.50mL, 2.9mmol) was added, and the reaction was stirred at -78°C for 1h, then warmed to 0°C and stirred for another 15min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10mL) and diluted with DCM (50mL). Each layer is separated and extracted with DCM (2x 20mL).The organic matter merged is through anhydrous Na2SO4 drying, filter and concentrate, until remaining about 8mL solvent.Crude aldehyde piperidine (0.14mL, 1.4mmol), sodium triacetoxy borohydride (379mg, 1.79mmol) and acetic acid (0.041mL, 0.72mmol) are processed, and the gained suspension is at room temperature stirred to 16h.Reaction mixture is diluted with DCM (50mL) and saturated NaHCO3 aqueous solution (10mL), and each layer is separated.Extracted with DCM (2x 10mL).The organic matter merged is through Na2SO4 drying, filter and be concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(piperidin-1-ylmethyl)hex-5-enoate (Intermediate 12, 269 mg, 90%) as a colorless oil. 1 HNMR(300MHz, CDCl3)δppm1.39-1.53(15H,m),1.86-1.94(1H,m),2.07-2.46(8H,m),4.3 2(1H,d),5.03-5.15(4H,m),5.73-5.85(1H,m),7.26-7.35(5H,m),7.90(1H,d); m / z: (ES + )[M+H] + =417.

[0267] Intermediate 13: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(piperidin-1-ylmethyl)-6-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0268] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (16 mg, 0.022 mmol) and bis(diphenylphosphino)methane (24 mg, 0.062 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (3 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 mL, 1.4 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(piperidin-1-ylmethyl) hex-5-enoate (intermediate 12, 265 mg, 0.636 mmol) was added to the reaction as a solution in DCM (3 mL), and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(piperidin-1-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 13, 240 mg, 69% yield) as a colorless oil. m / z: (ES + )[M+H] + =545.

[0269] Example 3: (2S,3R)-2-amino-6-dihydroxyboryl-3-(piperidin-1-ylmethyl)hexanoic acid

[0270] (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(piperidin-1-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 13, 240 mg, 0.44 mmol) was dissolved in 6M aqueous HCl (12 mL) and the solution was heated to 100 ° C for 16 h. The reaction mixture was cooled to room temperature, diluted with H2O (25 mL) and washed with EtOAc (2 x 15 mL). The aqueous layer was concentrated under reduced pressure and the resulting residue was purified by reverse phase chromatography (RediSepRf C18, 0 to 50% acetonitrile in water) to afford (2S,3R)-2-amino-6-borono-3-(piperidin-1-ylmethyl)hexanoic acid (Example 3, 79 mg, 36% yield) as a white solid. The material obtained was a 5.7:1 mixture of the title product and diastereomer C3. 1H NMR(300MHz,D2O)δ0.81-0.84(2H,m),1.42-1.58(5H,m),1.75-1.86(3H,m),1.93-1.99(2H,m),2.49(0.2H,s,br),2. 62-2.64(0.76H,m),2.92-3.05(2H,m),3.16-3.43(2H,m),3.53-3.66(2H,m),4.15(0.8H,d),4.23(0.2H,d); m / z: (ES + )[M+H] + =273.

[0271] Example 4: (2S,3R)-2-amino-6-dihydroxyboryl-3-((methylamino)methyl)hexanoic acid

[0272]

[0273] Intermediate 14: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((4-methoxybenzyl)(methyl NH 2-(4-(2-amino-4-yl)methyl)hex-5-enoate

[0274] Oxalyl chloride solution (2M in DCM, 0.57mL, 1.1mmol) was added to an oven-dried flask, diluted with DCM (2mL), and cooled to -78°C under N2 atmosphere. DMSO (0.12mL, 1.7mmol) was added dropwise, and the reaction was stirred at -78°C for 10min. (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (Intermediate 4, 200mg, 0.57mmol) was slowly added as a solution in DCM (3mL), and the reaction was stirred at -78°C for 30min. N,N-diisopropylethylamine (0.40mL, 2.3mmol) was added, and the reaction was stirred at -78°C for 1h, then warmed to 0°C and stirred for another 15min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10mL) and diluted with DCM (20mL). Each layer is separated and extracted with DCM (2x 10mL).The organic matter merged is through anhydrous Na SO Drying, filter and concentrate, until remaining about 8mL solvent.Crude aldehyde 1-(4-methoxyphenyl)-N-methylmethylamine (173mg, 1.14mmol), sodium triacetoxyborohydride (415mg, 1.96mmol) and acetic acid (0.033mL, 0.57mmol) are processed, and the gained suspension is at room temperature stirred to 4h.Reaction mixture is diluted with DCM (30mL) and saturated NaHCO The aqueous solution (20mL) is diluted, and each layer is separated.Extracted with DCM (3x 30mL).The organic matter merged is through anhydrous Na SO Drying, filter and be concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((4-methoxybenzyl)(methyl)amino)methyl)hex-5-enoate (Intermediate 14, 221 mg, 80% yield) as a colorless oil. m / z: (ES + )[M+H] + =483.

[0275] Intermediate 15: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((4-methoxybenzyl)(methyl)amino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0276] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (11 mg, 0.017 mmol) and bis(diphenylphosphino)methane (17 mg, 0.046 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (3 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 mL, 1.0 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((4-methoxybenzyl)(methyl)amino)methyl)hex-5-enoate (intermediate 14, 220 mg, 0.46 mmol) was added to the reaction as a solution in DCM (3 mL), and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((4-methoxybenzyl)(methyl)amino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 15, 182 mg, 65% yield) as a colorless oil. m / z: (ES + )[M+H] + =610.

[0277] Example 4: (2S,3R)-2-amino-6-dihydroxyboryl-3-((methylamino)methyl)hexanoic acid

[0278] Pd / C (10% wt, 280 mg, 0.26 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((4-methoxybenzyl)(methyl)amino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 15, 162 mg, 0.27 mmol) in MeOH (10 mL). The suspension was stirred under a hydrogen atmosphere (balloon, flask was evacuated and backfilled with hydrogen 3 times) at room temperature for 4 h. The reaction mixture was diluted with MeOH, filtered through celite, and the filtrate was concentrated to dryness. The resulting residue was dissolved in 6M aqueous HCl solution (10 mL) and heated to 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL) and washed with DCM (2 x 15 mL). The aqueous layer was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography (RediSep Rf C18, 0 to 30% acetonitrile in water) to afford (2S,3R)-2-amino-6-borono-3-((methylamino)methyl)hexanoic acid (Example 4, 33 mg, 43% yield) as a white solid. The material obtained was a 6.1:1 mixture of the title product and diastereomer C3. 1 H NMR(300MHz,D2O)δ0.73-0.81(2H,m),1.35-1.55(4H,m),2.27-2.45(1H,m),2.74(3H,s),3.05 -3.22(1.82H,m),3.29-3.37(0.12H,m),3.85-3.93(0.81H,m),3.99-4.03(0.12H,m); m / z: (ES + )[M+H] + =219.

[0279] Example 5: (2S,3R)-2-amino-6-dihydroxyboryl-3-((dimethylamino)methyl)hexanoic acid

[0280]

[0281] Intermediate 16: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((dimethylamino)methyl)

[0282] Hex-5-enoate

[0283] Oxalyl chloride solution (2M in DCM, 2.54 mL, 5.08 mmol) was added to an oven-dried flask and diluted with DCM (10 mL) and cooled to -78 ° C under N2 atmosphere. DMSO (0.54 mL, 7.6 mmol) was added dropwise and the reaction was stirred at -78 ° C for 10 min. (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (Intermediate 4, 888 mg, 2.54 mmol) was slowly added as a solution in DCM (10 mL) and the reaction was stirred at -78 ° C for 30 min. N, N-diisopropylethylamine (0.50 mL, 2.9 mmol) was added and the reaction was stirred at -78 ° C for 1 h, then warmed to 0 ° C and stirred for another 15 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (20 mL) and diluted with DCM (40 mL). Each layer is separated and extracted with DCM (2x 20mL) aqueous layer.The organic matter merged is through anhydrous Na2SO4 drying, filtered and concentrated to dryness.The crude aldehyde (294mg, 0.847mmol) of a part is dissolved in DCM (20mL), and dimethylamine solution (2M, in THF, 1.70mL, 3.40mmol) is added, sodium triacetoxy borohydride (448mg, 2.12mmol) and acetic acid (0.048mL, 0.85mmol) are added subsequently.The gained suspension is at room temperature stirred to 15h.Reaction mixture is diluted with DCM (50mL) and saturated NaHCO3 aqueous solution (10mL), and each layer is separated.Extracted with DCM (2x 10mL) aqueous layer.The organic matter merged is through Na2SO4 drying, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((dimethylamino)methyl)hex-5-enoate (Intermediate 16, 253 mg, 79% yield) as a colorless oil. m / z: (ES + )[M+H] + =377.

[0284] Intermediate 17: (4R,5S)-5-(benzyloxycarbonylamino)-6-tert-butoxy-4-((dimethylamino)

[0285] (Methyl)-6-oxohexylboronic acid

[0286] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (16 mg, 0.025 mmol) and bis(diphenylphosphino)methane (26 mg, 0.067 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (3 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22 mL, 1.5 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((dimethylamino)methyl)hex-5-enoate (intermediate 16, 253 mg, 0.672 mmol) was added to the reaction as a solution in DCM (3 mL), and the reaction mixture was stirred overnight. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (4R,5S)-5-(benzyloxycarbonylamino)-6-tert-butoxy-4-((dimethylamino)methyl)-6-oxohexylboronic acid (Intermediate 17, 223 mg, 79% yield). m / z: (ES + )[M+H] + =422.

[0287] Example 5: (2S,3R)-2-amino-6-dihydroxyboryl-3-((dimethylamino)methyl)hexanoic acid

[0288] (4R, 5S) -5- (benzyloxycarbonylamino) -6- tert-butoxy -4- ((dimethylamino) methyl) -6- oxohexylboronic acid (intermediate 17, 223mg, 0.528mmol) was dissolved in 6M HCl aqueous solution (15mL), and the solution was heated to 100 ° C for 20h. The reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with water. The aqueous filtrate was washed with DCM (3x 20mL) and concentrated under reduced pressure. The resulting residue was dissolved in MeOH (3mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using a 5% ammonia solution in MeOH (20mL). The fractions containing the product were collected and concentrated to give (2S, 3R) -2- amino -6- dihydroxyboryl -3- ((dimethylamino) methyl) hexanoic acid (Example 5, 68mg, 56% yield) as a white solid. The material obtained was a 10:1 mixture of the title product and diastereomer C3. 1H NMR(300MHz,D2O)δ0.77(2H,m),1.25-1.48(4H,m),2.25(1H,m),2.69(6H,s),2.85-3.05(2H,m),3.62(1H,d); m / z: (ES + )[M+H] + =233.

[0289] Example 6: (2S,3R)-2-amino-6-dihydroxyboryl-3-(guanidinomethyl)hexanoic acid dihydrochloride

[0290]

[0291] Intermediate 18: tert-Butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(((2,2,10,10-tetramethyl base- 4,8-Dioxo-3,9-dioxa-5,7-diazaundecane-6-ylidene)amino)methyl)hex-5-enoate

[0292] (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (Intermediate 4, 500 mg, 1.43 mmol) was dissolved in anhydrous toluene (14 mL). Triphenylphosphine (826 mg, 3.15 mmol) and 1.3-bis(tert-butoxycarbonyl)guanidine (742 mg, 2.86 mmol) were added and the solution was cooled to 0 °C. DIAD (637 mg, 3.15 mmol) was added dropwise and the reaction mixture was warmed to room temperature and then further heated to 100 °C for 30 min. The reaction mixture was cooled to room temperature and washed with water (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give tert-butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(((2,2,10,10-tetramethyl-4,8-dioxo-3,9-dioxa-5,7-diazaundec-6-ylidene)amino)methyl)hex-5-enoate (Intermediate 18, 300 mg, 35.5%) as a viscous oil. 1 HNMR(300MHz, CDCl3)δ1.40(9H,s),1.49-1.61(18H,m),2.11-2.50(3H,m),3.75-4.05(2H,m),4.21(1H,br d),4.97-5.17(4H,m),5.67-5.91(1H,m),6.20(1H,br s),7.27-7.40(5H,m),9.01-9.60(2H,m); m / z: (ES + )[M+H] + =591.

[0293] Intermediate 19: tert-Butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-3-(((2,2,10,10-tetramethyl-4,8-dioxo-3,9-dioxa-5,7-diazepine Undecane-6-ylidene)amino)methyl)hexanoate

[0294] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (13mg, 0.019mmol) and bis(diphenylphosphino)methane (16mg, 0.042mmol) were added to an oven-dried round-bottomed flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (8mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.18mL, 1.3mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10min. Tert-butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(((2,2,10,10-tetramethyl-4,8-dioxo-3,9-dioxa-5,7-diazaundec-6-ylidene)amino)methyl)hex-5-enoate (Intermediate 18, 300 mg, 0.51 mmol) was added to the reaction as a solution in DCM (2 mL), and the reaction was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness and purified directly by silica gel chromatography (hexanes / EtOAc) to give tert-butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(((2,2,10,10-tetramethyl-4,8-dioxo-3,9-dioxa-5,7-diazaundec-6-ylidene)amino)methyl)hexanoate (Intermediate 19, 190 mg, 52% yield) as a colorless oil. 1 HNMR(300MHz, CDCl3)δ0.75(2H,t),1.12-1.24(14H,m),1.33-1.42(10H,m),1.46(9H,s),1.48-1.55(10H,m),2.23-2.42(1H,m),3.54- 3.87(1H,m),3.91-4.09(1H,m),4.13-4.27(1H,m),4.99-5.19(2H,m),6.12-6.50(1H,m),7.27-7.40(5H,m),9.11-9.55(2H,m); m / z: (ES) + )[M+H] + =719.

[0295] Example 6: (2S,3R)-2-amino-6-dihydroxyboryl-3-(guanidinomethyl)hexanoic acid dihydrochloride

[0296] Tert-butyl (2S,3R)-2-(((benzyloxy)carbonyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(((2,2,10,10-tetramethyl-4,8-dioxo-3,9-dioxa-5,7-diazaundecane-6-ylidene)amino)methyl)hexanoate (Intermediate 19, 45 mg, 0.063 mmol) was dissolved in 6M aqueous HCl (2.08 mL, 12.5 mmol) and the reaction mixture was heated to 90 °C for 30 min. The reaction was cooled to 70 °C and stirred for an additional 1 h. The reaction mixture was cooled to room temperature, diluted with water (2 mL) and extracted with EtOAc (3 x 1 mL). The aqueous layer was lyophilized to give (2S,3R)-2-amino-6-borono-3(guanidinomethyl)hexanoic acid dihydrochloride (Example 6, 10 mg, 50% yield) as a white solid. 1 HNMR(300MHz,D2O)δ0.80(2H,br d),1.37-1.62(4H,m),2.41(1H,br d),3.34(2H,dd),4.09(1H,d); m / z: (ES + )[M+H] + =247.

[0297] Example 7: (2S,3R)-2-amino-6-dihydroxyboryl-3-(ureidomethyl)hexanoic acid

[0298]

[0299] Intermediate 20: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2- two Oxaborolan-2-yl)-3-(ureidomethyl)hexanoate

[0300] Pd / C (10% wt, 220 mg, 0.21 mmol) was added to a solution of (2S, 3R)-tert-butyl 3-(azidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 8, 485 mg, 1.04 mmol) and trimethylsilyl isocyanate (0.35 mL, 2.6 mmol) in EtOAc (40 mL). The mixture was evacuated and backfilled with nitrogen three times, then evacuated and backfilled with hydrogen. The suspension was stirred at room temperature for 3 h under a hydrogen atmosphere. A second portion of trimethylsilyl isocyanate (0.15 mL, 1.1 mmol) was added, and the suspension was stirred at room temperature for an additional 20 min. The reaction mixture was diluted with DCM, filtered through celite, and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(ureidomethyl)hexanoate (Intermediate 20, 242 mg, 48% yield) as a white solid. m / z: (ES + )[M+H] + =486.

[0301] Example 7: (2S,3R)-2-amino-6-dihydroxyboryl-3-(ureidomethyl)hexanoic acid

[0302] Trifluoroacetic acid (6.00 mL, 77.9 mmol) was slowly added to a stirred solution of (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(ureidomethyl)hexanoate (intermediate 20, 242 mg, 0.466 mmol) in DCM (6 mL), and the reaction was stirred at room temperature for 6 h. The solution was concentrated under reduced pressure, and the resulting residue was dissolved in 1M HCl aqueous solution (5 mL) and Et2O (5 mL). Phenylboronic acid (117 mg, 0.96 mmol) was added, and the clear biphasic solution was stirred at room temperature for 16 h. The reaction mixture was diluted with Et2O and water, and the layers were separated. The aqueous layer was washed with Et2O (2 x 30 mL), and the aqueous layer was lyophilized. The reaction mixture was purified by reverse phase chromatography (RediSep Rf The crude material was purified by HPLC-MS / MS (50% acetonitrile in water) to afford (2S,3R)-2-amino-6-borono-3-(ureidomethyl)hexanoic acid (Example 7, 5.0 mg, 4% yield) as a white solid.

[0303] 1H NMR(300MHz,D2O)δ0.77-0.82(2H,m),1.24-1.49(4H,m),2.11-2.20(1H,m),3.07-3.22(2H,m),3.71(1H,d); m / z: (ES + )[M+H] + =248.

[0304] Example 8: (2S,3R)-2-amino-3-(((S)-2-amino-3-methylbutyramido)methyl)-6-dihydroxyborylhexane acid

[0305]

[0306] Intermediate 21: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((N-(tert-butyloxycarbonyl)-2-(tri methylsilyl)ethylsulfonamide)methyl)hex-5-enoate

[0307] (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (intermediate 4, 938mg, 2.68mmol) and tert-butyl ((2-(trimethylsilyl)ethyl)sulfonyl)carbamate (1.1g, 3.9mmol) were dissolved in THF (10mL) and cooled to 0°C. Triphenylphosphine (1.06mg, 4.03mmol) and DIAD (1.1mL, 5.7mmol) were added, and the reaction was stirred for 16h while slowly warming to room temperature. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2x 10mL). The combined organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((N-(tert-butoxycarbonyl)-2-(trimethylsilyl)ethylsulfonamido)methyl)hex-5-enoate (Intermediate 21, 1.56 g, 95%) as a colorless gum. 1 H NMR(300MHz, CDCl3)δ0.04(9H,s),0.81-0.99(2H,m),1.46(9H,s),1.49(9H,m),2.0 5-2.29(2H,m),2.44-2.58(1H,m),3.34-3.54(2H,m),3.55-3.81(2H,m),4.35(1H,br dd),4.93-5.20(4H,m),5.42(1H,br d),5.69-5.96(1H,m),7.26-7.45(5H,m); m / z: (ES + )[M+NH4] + =630. Intermediate 22: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino tert-Butyl)-3-((tert-Butyloxycarbonylamino)

[0308] methyl)hex-5-enoate

[0309] (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((N-(tert-butoxycarbonyl)-2-(trimethylsilyl)ethylsulfonamido)methyl)hex-5-enoate (Intermediate 21, 1.40 g, 2.28 mmol) was dissolved in TBAF solution (1 M in THF, 12.0 mL, 12.0 mmol) and the resulting solution was stirred at room temperature for 16 h. The reaction was diluted with Et2O (40 mL) and washed sequentially with water (3 x 25 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)hex-5-enoate (Intermediate 22, 576 mg, 56% yield) as a colorless oil. 1 HNMR(300 MHz, CDCl3)δ1.43(9H,s),1.44(9H,s),1.74-1.88(1H,m),1.89-2.00(1H,m),2.17-2.30(1H,m), 2.41-2.60(1H,m),3.38-3.62(1H,m),4.46(1H,dd),4.98-5.08(2H,m),5.09(2H,s),5.40(1H,br d),5.52-5.88(2H,m),7.27-7.38(5H,m); m / z: (ES + )[M+H] + =449.

[0310] Intermediate 23: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butyloxycarbonylamino)

[0311] methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0312] Bis(1,5-cyclooctadiene)iridium(I)dichloride (13 mg, 0.065 mmol) and bis(diphenylphosphino)methane (49 mg, 0.13 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (4 mL) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 mL, 3.5 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)hex-5-enoate (Intermediate 22, 576 mg, 1.28 mmol) was added to the reaction as a solution in DCM (3 mL) and the reaction was stirred at room temperature for 3 d. The reaction mixture was cooled to 0 °C and quenched with MeOH (2 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 424 mg, 57% yield) as a light yellow gum. 1 HNMR(300MHz, CDCl3)δ0.57-0.81(2H,m),0.94-1.15(2H,m),1.19(12H,s),1.28-1.59(20H,m), 2.05-2.23(1H,m),2.40-2.57(1H,m),3.39-3.60(1H,m),4.43(1H,dd),5.08(2H,s),5.41(1H,br d),5.53-5.78(1H,m),7.27-7.38(5H,m); m / z: (ES + )[M+H] + =577.

[0313] Intermediate 24: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0314] A solution of HCl (4M in dioxane, 1.5 mL, 6.0 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 424 mg, 0.740 mmol) in dioxane (1.5 mL) at 0°C. The reaction was stirred for 6 h while slowly warming to room temperature. The solution was concentrated to give a yellow gum which was used directly without further purification. In a separate flask, HATU (619 mg, 1.63 mmol) was added to a solution of Boc-L-Val-OH (354 mg, 1.63 mmol) in DMF (3.5 mL) and the reaction was stirred at room temperature for 10 min. The crude amine is dissolved in DMF (3.5mL) and added to the second reaction flask. N, N-diisopropylethylamine (0.45mL, 2.6mmol) is added, and the reaction is stirred at room temperature for 16h. The reaction mixture is diluted with EtOAc (15mL) and washed with 1M HCl aqueous solution (60mL) and 5% lithium chloride aqueous solution (10mL). The organic layer is dried with MgSO4, filtered and concentrated to dryness. The crude material is purified by silica gel chromatography (DCM / MeOH) to obtain (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)-3-methylbutyramide)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)hexanoate (intermediate 24, 476mg, 95% yield) in a light yellow jelly. 1 HNMR(300MHz, CDCl3)δ0.59-0.82(2H,m),0.87-0.98(6H,m),1.18(12H,s),1.28-1.55(22H,m),2.07-2.24(2H,m), 2.31-2.51(1H,m),3.38-3.54(1H,m),3.74-3.89(1H,m),3.89-4.06(1H,m),4.35(1H,dd),5.08(2H,s),5.50(1H,br d),6.92(1H,br s),7.26-7.37(5H,m); m / z: (ES - )[M+HCOO - ] - =720.

[0315] Example 8: (2S,3R)-2-amino-3-(((S)-2-amino-3-methylbutyramido)methyl)-6-dihydroxyborylhexane acid

[0316] (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 24, 476 mg, 0.700 mmol) was dissolved in HBr solution (33 wt % in AcOH, 3.5 mL, 21 mmol) and the reaction was stirred at room temperature for 20 min. The reaction was diluted with Et2O (10 mL) and concentrated. This step was repeated twice more. The resulting residue was dissolved in 2M HCl aqueous solution (5 mL) and Et2O (5 mL). Phenylboronic acid (172 mg, 1.41 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 10 mL) and lyophilized. The solid was dissolved in MeOH (1 mL) and purified by ion exchange chromatography (HyperSep Retain CX column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL). The obtained material was purified by reverse phase chromatography (RediSep Rf C18, 0 to 100% acetonitrile in water) to afford (2S,3R)-2-amino-3-(((S)-2-amino-3-methylbutanamido)methyl)-6-boronohexanoic acid (Example 8, 46 mg, 21% yield) as a white solid. 1 H NMR(300MHz,D2O)δ0.70-0.85(2H,m),0.96(6H,dd),1.24-1.59(4H,m),2.00(1H,sextet),2.16-2.35(1H,m),3.23-3.43(3H,m),3.68(1H,d); m / z: (ES - )[MH] - =302.

[0317] Example 9: (2S,3R)-2-amino-3-(((S)-2-aminobutyramido)methyl)-6-dihydroxyborylhexanoic acid

[0318]

[0319] Intermediate 25: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaborolan-2-yl)

[0320] Hexanoate

[0321] A solution of HCl (4M in dioxane, 4.40 mL, 17.6 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 1.27 g, 2.20 mmol) in dioxane (1.5 mL) at 0°C. The reaction was stirred for 4.5 h while slowly warming to room temperature. The solution was concentrated to give a yellow gum which was used directly without further purification. In a separate flask, HATU (619 mg, 1.63 mmol) was added to a solution of Boc-Abu-OH (335 mg, 1.65 mmol) in DMF (5 mL) and the reaction was stirred at room temperature for 10 min. The crude amine from the previous operation was divided into two equal parts (assumed to be 524 mg, 1.10 mmol), and one part was dissolved in DMF (5 mL) and added to the second reaction flask. N, N-diisopropylethylamine (0.60 mL, 3.4 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1M HCl aqueous solution (60 mL) and 5% lithium chloride aqueous solution (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)butanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 25, 516 mg, 71% yield) as a colorless gum. 1 HNMR(300MHz, CDCl3)δ0.58-0.82(2H,m),0.93(3H,t),1.19(12H,s),1.38-1.45(22H,m),1.60-1.76(1H,m),1.77-1.97(2H,m),2 .10-2.26(1H,m),2.40(1H,dt),3.78-3.90(1H,m),4.03-4.16(1H,m),4.34(1H,dd),5.08(2H,s),5.15-5.24(1H,m),5.48(1H,br d),7.27-7.39(5H,m); m / z: (ES + )[M+H] + =662.

[0322] Example 9: (2S,3R)-2-amino-3-(((S)-2-aminobutyramido)methyl)-6-dihydroxyborylhexanoic acid

[0323] (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)butyramido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 25, 516 mg, 0.780 mmol) was dissolved in HBr solution (33 wt % in AcOH, 4.0 mL, 24 mmol) and the reaction was stirred at room temperature for 20 min. The reaction was diluted with Et2O (10 mL) and concentrated. This step was repeated twice more. The resulting residue was dissolved in 2M HCl aqueous solution (5 mL) and Et2O (7 mL). Phenylboronic acid (190 mg, 1.6 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 10 mL) and lyophilized. The obtained solid was dissolved in MeOH (1 mL) and purified by ion exchange chromatography (Silicycle SPE-R51230B-20X column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL). The obtained material was purified by reverse phase chromatography (RediSep Rf C18, 0 to 100% acetonitrile in water) to afford (2S,3R)-2-amino-3-(((S)-2-aminobutanamido)methyl)-6-boronohexanoic acid (Example 9, 101 mg, 45% yield) as a white solid. 1 H NMR(300MHz,D2O)δ0.66-0.85(2H,m),0.92(3H,t),1.24-1.55(4H,m),1.65-1.83 (2H,m),2.16-2.31(1H,m),3.24-3.39(2H,m),3.56(1H,t),3.65(1H,d); m / z: (ES + )[M+H] + =290.

[0324] Example 10: (2S,3R)-2-amino-3-(((S)-2-aminopropionamido)methyl)-6-dihydroxyborylhexanoic acid

[0325]

[0326] Intermediate 26: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaborolan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)

[0327] Hexanoate

[0328] A solution of HCl (4M in dioxane, 0.34 mL, 1.4 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 375 mg, 0.650 mmol) in dioxane (2 mL) at 0°C and the reaction was stirred at 0°C for 50 min. Another portion of HCl (4M in dioxane, 0.34 mL, 1.4 mmol) was added and the reaction was stirred for an additional 1 h. Another portion of HCl (4M in dioxane, 0.70 mL, 2.7 mmol) was added and the reaction was stirred for 1 h and then placed in a -20°C freezer for 16 h. The reaction was allowed to warm to room temperature and stirred for 20 min. The solution was concentrated to give a yellow gum which was used directly without further purification. In a separation flask, HATU (544 mg, 1.43 mmol) was added to a solution of Boc-Ala-OH (271 mg, 1.43 mmol) in DMF (3 mL), and the reaction was stirred at room temperature for 10 min. The crude amine was dissolved in DMF (3 mL) and added to a second reaction flask. N, N-diisopropylethylamine (0.38 mL, 2.2 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl aqueous solution (60 mL) and 5% lithium chloride aqueous solution (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH) to give (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)propionamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 26, 268 mg, 64% yield) as a light yellow gum. 1 H NMR(300MHz, CDCl3)δ0.55-0.84(2H,m),0.96-1.27(14H,m),1.30-1.52(23H,m),2.07-2.27(1H,m),2.34-2.63(1H,m),2.7 4-2.99(1H,m),3.61-3.93(1H,m),3.99-4.23(1H,m),4.23-4.42(1H,m),4.90-5.24(3H,m),5.41-5.60(1H,m),7.33(5H,br s); m / z: (ES) + )[M+H] + =648.

[0329] Example 10: (2S,3R)-2-amino-3-(((S)-2-aminopropionamido)methyl)-6-dihydroxyborylhexanoic acid

[0330] (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)propionamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 26, 268 mg, 0.410 mmol) was dissolved in HBr solution (33 wt % in AcOH, 2.0 mL, 12 mmol) and the reaction was stirred at room temperature for 20 min. The reaction was diluted with Et2O (5 mL) and concentrated. This step was repeated two more times. The resulting residue was dissolved in 2M HCl aqueous solution (2.5 mL) and Et2O (5 mL). Phenylboronic acid (100 mg, 0.83 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 10 mL) and lyophilized. The solid was dissolved in MeOH (1 mL) and purified by ion exchange chromatography (HyperSep Retain CX column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL). The obtained material was purified by reverse phase chromatography (RediSep Rf C18, 0 to 100% acetonitrile in water) to afford (2S,3R)-2-amino-3-(((S)-2-aminopropionamido)methyl)-6-boronohexanoic acid (Example 10, 45 mg, 39% yield) as a white solid. 1 H NMR(300MHz,D2O)δ0.63-0.84(2H,m),1.20-1.55(7H,m),2.14-2.25(1H,m),3.20-3.36(2H,m),3.62(1H,d),3.74(1H,q); m / z(ES + )[M+H] + =276.

[0331] Example 11: (2S,3R)-3-(acetamidomethyl)-2-amino-6-dihydroxyborylhexanoic acid

[0332]

[0333] Intermediate 27: (2S,3R)-tert-butyl 3-(acetamidomethyl)-2-(benzyloxycarbonylamino yl)-6-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0334] A solution of HCl (4M in dioxane, 4.40 mL, 17.6 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 1.27 g, 2.20 mmol) in dioxane (1.5 mL) at 0°C. The reaction was stirred for 4.5 h while slowly warming to room temperature. The solution was concentrated to give a yellow gum which was used directly without further purification. The crude amine was divided into two equal portions (assumed to be 524 mg, 1.10 mmol) and one portion was dissolved in DCM (5 mL). Triethylamine (0.40 mL, 2.9 mmol) was added and the reaction was stirred at room temperature for 10 min. Acetyl chloride (0.10mL, 1.4mmol) was added, and the reaction was stirred for another 2h. The reaction was quenched with water (15mL) and diluted with DCM (20mL). Each layer was separated and the aqueous layer was extracted with DCM (2x10mL). The combined organic layer was washed with saturated sodium bicarbonate aqueous solution (20mL), then dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH) to obtain (2S, 3R)-tert-butyl 3-(acetamidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 27, 538mg, 94% yield) as a colorless oil. 1 H NMR(300MHz, CDCl3)δ0.55-0.81(2H,m),1.19(12H,s),1.26-1.59(13H,m),1.98(3H,s),2. 07-2.20(1H,m),2.33-2.45(1H,m),3.84(1H,ddd),4.36(1H,dd),5.08(2H,s),5.49(1H,br d),6.76-6.90(1H,m),7.26-7.40(5H,m); m / z: (ES + )[M+H] + =519.

[0335] Example 11: (2S,3R)-3-(acetamidomethyl)-2-amino-6-dihydroxyborylhexanoic acid

[0336] (2S, 3R)-tert-butyl 3-(acetamidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 27, 538 mg, 1.04 mmol) was dissolved in HBr solution (33 wt %, in AcOH, 5.0 mL, 30 mmol), and the reaction was stirred at room temperature for 20 min. The reaction was diluted with Et2O (10 mL) and concentrated. This step was repeated twice more. The resulting residue was dissolved in 2M HCl aqueous solution (7 mL) and Et2O (7 mL). Phenylboronic acid (253 mg, 2.08 mmol) was added, and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated, and the aqueous layer was washed with Et2O (3 x 10 mL) and lyophilized. The obtained solid was dissolved in MeOH (1 mL) and purified by ion exchange chromatography (Silicycle SPE-R51230B-20X column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL). The obtained material was purified by reverse phase chromatography (RediSep Rf C18, 0 to 100% acetonitrile in water) to afford (2S,3R)-3-(acetamidomethyl)-2-amino-6-boronohexanoic acid (Example 11, 84 mg, 33% yield) as a white solid. 1 HNMR(300MHz,D2O)δ0.67-0.86(2H,m),1.26-1.59(4H,m),2.01(3H,s),2.14-2.31(1H,m),3.15

[0337] -3.39(2H,m),3.71(1H,d); m / z: (ES + )[M+H] + =247.

[0338] Example 12: (2S,3R)-3-(aminomethyl)-6-dihydroxyboryl-2-(methylamino)hexanoic acid

[0339]

[0340] Intermediate 28: (2S,3R)-tert-butyl 3-(azidomethyl)-2-((benzyloxycarbonyl)(methyl)amino Base)-6- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0341] (2S,3R)-tert-butyl 3-(azidomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 8, 155 mg, 0.310 mmol) was dissolved in DMF (2 mL) and the solution was cooled to 0 °C. Sodium hydride (60% wt dispersion in oil, 15 mg, 0.37 mmol) was added and the reaction was warmed to room temperature and stirred for 15 min. Iodomethane (0.05 mL, 0.8 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with Et2O (3 x 15 mL). The combined organics were washed with 5% aqueous lithium chloride (10 mL), dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 3-(azidomethyl)-2-((benzyloxycarbonyl)(methyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 28, 109 mg, 68% yield) as a colorless oil and a 55:45 mixture of rotamers. 1 H NMR(300MHz, CDCl3)δ0.66-0.82(2H,m),1.21(12H,s),1.23-1.37(3H,m),1.40(5H,s),1.42 (4H,s)1.46-1.53(1H,m),2.06-2.22(1H,m),2.86(3H,s),3.37-3.55(2H,m),4.50(0.55H,br d),4.65(0.45H,br d),4.95-5.30(2H,m),7.26-7.41(5H,m); m / z: (ES + )[M+NH4] + =534.

[0342] Example 12: (2S,3R)-3-(aminomethyl)-6-dihydroxyboryl-2-(methylamino)hexanoic acid

[0343] Pd / C (10% wt, 22 mg, 0.020 mmol) and di-tert-butyl dicarbonate (115 mg, 0.530 mmol) were added to a solution of (2S, 3R)-tert-butyl 3-(azidomethyl)-2-((benzyloxycarbonyl)(methyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 28, 109 mg, 0.210 mmol) in EtOAc (2 mL). The flask was equipped with a H2 balloon, and the suspension was stirred at room temperature for 16 h. The reaction mixture was filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated to dryness and then dissolved in DCM (3 mL). HBr solution (33% in AcOH, 0.50 mL, 3.0 mmol) was added, and the reaction was stirred at room temperature for 20 min. The reaction was diluted with Et2O (5 mL) and concentrated. This step was repeated twice more. The resulting residue was dissolved in 2M aqueous HCl (2 mL) and Et2O (2 mL). Phenylboronic acid (51 mg, 0.42 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 10 mL) and lyophilized. The resulting solid was purified by reverse phase chromatography (RediSep Rf C18, 0 to 100% acetonitrile in water) to give a dark yellow solid. The obtained material was redissolved in MeOH (1 mL) and loaded onto a pre-equilibrated Hypersep Retain CX (2 g) ion exchange column. The resin was washed with MeOH (15 mL) and then with 5% NH3 in MeOH (15 mL) to elute the product. The fractions containing the product were concentrated to a colorless residue, which was purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 100% MeCN in water) to afford (2S,3R)-3-(aminomethyl)-6-borono-2-(methylamino)hexanoic acid (Example 12, 15 mg, 33%) as a white solid. 1 H NMR(300MHz,D2O)δ0.68-0.91(2H,m),1.34-1.59(4H,m),2.11-2.26(1H,m),2.60(3H,s),3.07(2H,qd),3.51(1H,d); m / z: (ES + )[M-H2O+H] + =201.

[0344] Example 13: (2S,3R)-2-((S)-2-amino-3-methylbutyramido)-3-(aminomethyl)-6-dihydroxyboryl Hexanoic acid

[0345]

[0346] Intermediate 29: (2S,3R)-tert-butyl 2-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamide Base)-3- ((tert-Butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0347] Pd / C (10% wt, 180 mg, 0.16 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 950 mg, 1.65 mmol) in EtOAc (12 mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature for 16 h. The reaction mixture was filtered through celite and rinsed with EtOAc (50 mL). The filtrate was concentrated to give a pale yellow oil, which was used directly without further purification. In a separate flask, HATU (363 mg, 0.95 mmol) was added to a solution of Boc-Val-OH (210 mg, 0.95 mmol) in DMF (4 mL) and the reaction was stirred at room temperature for 10 min. The crude amine from the previous operation was divided into two equal parts (assumed to be 364 mg, 0.825 mmol), and one part was dissolved in DMF (5 mL) and added to the second reaction flask. N, N-diisopropylethylamine (0.35 mL, 2.0 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1M HCl aqueous solution (80 mL) and saturated sodium chloride aqueous solution (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH) to give (2S,3R)-tert-butyl 2-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 29, 400 mg, 72% yield) as a colorless gum. 1 H NMR(300MHz,DMSO-d6)δ0.55-0.69(2H,m),0.84(6H,dd),1.16(12H,s),1.31-1. 43(31H,m),1.83-2.07(2H,m),2.55-2.66(1H,m),2.98-3.13(1H,m),3.83(1H,br t),4.30-4.47(1H,m),6.29-6.44(1H,m),6.72(1H,br d),7.83-7.94(1H,m); m / z: (ES - )[M+HCOO- ] - =686.

[0348] Example 13: (2S,3R)-2-((S)-2-amino-3-methylbutyramido)-3-(aminomethyl)-6-dihydroxyboryl Hexanoic acid

[0349] HBr solution (33 wt % in AcOH, 0.75 mL, 4.6 mmol) was added to a solution of (2S,3R)-tert-butyl 2-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 29, 200 mg, 0.31 mmol) in DCM (4 mL) and the reaction was stirred at room temperature for 1 h. The reaction was diluted with Et2O (5 mL) and concentrated. This step was repeated twice more. The resulting residue was dissolved in 1 M aqueous HCl (7 mL) and Et2O (5 mL). Phenylboronic acid (114 mg, 0.940 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 10 mL) and lyophilized. The resulting solid was dissolved in MeOH (1 mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL). The obtained material was purified by reverse phase chromatography (RediSepRf C18, 0 to 100% acetonitrile in water) to afford (2S,3R)-2-((S)-2-amino-3-methylbutanamido)-3-(aminomethyl)-6-boronohexanoic acid (Example 13, 57 mg, 61% yield) as a white solid. 1 HNMR(300MHz,D2O)δ0.67-0.85(2H,m),0.97(6H,dd),1.16-1.56(4H,m),1.95-2.15(1H ,sextet),2.38(1H,td),2.76(1H,dd),3.14(1H,dd),3.47(1H,d),4.41(1H,d); m / z: (ES + )[M+H] + =304.

[0350] Example 14: (2S,3R)-3-(aminomethyl)-2-((S)-2-aminopropionamido)-6-dihydroxyborylhexanoic acid

[0351]

[0352] Intermediate 30: (2S,3R)-tert-butyl 3-((tert-butoxycarbonylamino)methyl)-2-((S)-2-(tert-butoxy Carbonylamino) propionamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) hexanoate

[0353] Pd / C (10% wt, 180 mg, 0.16 mmol) was added to a solution of (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 23, 950 mg, 1.65 mmol) in EtOAc (12 mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature for 16 h. The reaction mixture was filtered through celite and rinsed with EtOAc (50 mL). The filtrate was concentrated to give a pale yellow oil, which was used directly without further purification. In a separate flask, HATU (363 mg, 0.95 mmol) was added to a solution of Boc-Ala-OH (180 mg, 0.95 mmol) in DMF (4 mL) and the reaction was stirred at room temperature for 10 min. The crude amine from the previous operation was divided into two equal parts (assumed to be 364 mg, 0.825 mmol), and one part was dissolved in DMF (5 mL) and added to the second reaction flask. N, N-diisopropylethylamine (0.35 mL, 2.0 mmol) was added, and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1M HCl aqueous solution (80 mL) and saturated sodium chloride aqueous solution (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH) to give (2S,3R)-tert-butyl 3-((tert-butoxycarbonylamino)methyl)-2-((S)-2-(tert-butoxycarbonylamino)propionamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 30, 191 mg, 36% yield) as a colorless oil. 1 H NMR(300MHz, CDCl3)δ0.54-0.82(2H,m),0.84-1.12(2H,m),1.19(12H,s),1.29-1.38(4H,m),1.38-1.58(28H,m),2.07-2.24(1H, m),2.25-2.44(1H,m),3.29-3.61(1H,m),4.05-4.19(1H,m),4.55-4.71(1H,m),4.86-5.14(1H,m),5.60-6.01(1H,m),6.66(1H,br d); m / z: (ES) + )[M+H] + =614.

[0354] Example 14: (2S,3R)-3-(aminomethyl)-2-((S)-2-aminopropionamido)-6-dihydroxyborylhexanoic acid

[0355] HBr solution (33 wt % in AcOH, 0.75 mL, 4.6 mmol) was added to a solution of (2S,3R)-tert-butyl 3-((tert-butoxycarbonylamino)methyl)-2-((S)-2-(tert-butoxycarbonylamino)propionamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 30, 191 mg, 0.310 mmol) in DCM (4 mL) and the reaction was stirred at room temperature for 1.5 h. The reaction was diluted with Et2O (5 mL) and concentrated. This step was repeated twice more. The resulting residue was dissolved in 1 M aqueous HCl (7 mL) and Et2O (7 mL). Phenylboronic acid (114 mg, 0.940 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was washed with Et2O (3 x 5 mL) and lyophilized. The resulting solid was dissolved in MeOH (1 mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20 cc column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL). The obtained material was purified by reverse phase chromatography (RediSep Rf C18, 0 to 100% acetonitrile in water) to afford (2S,3R)-3-(aminomethyl)-2-((S)-2-aminopropionamido)-6-boronohexanoic acid (Example 14, 59 mg, 68% yield) as a white solid. 1 H NMR(300MHz,D2O)δ0.67-0.87(2H,m),1.17-1.55(7H,m),2.39(1H,tq),2.74(1H,dd),3.12(1H,dd),3.79(1H,q),4.40(1H,d); m / z: (ES + )[M+H] + =276.

[0356] Example 15: (2S,3R)-2-amino-3-(2-aminoethyl)-6-dihydroxyborylhexanoic acid dihydrochloride

[0357]

[0358] Intermediate 31: (S,E)-tert-butyl 4-(3-ethoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3- Formate

[0359] At 0 ° C, methyl (triphenylphosphoranylidene) acetate (9.62g, 28.8mmol) was added to a solution of tert-butyl (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (6.00g, 26.2mmol) in toluene (220mL). After addition, the reaction was warmed to room temperature and stirred for 40h. The reaction mixture was concentrated, and the resulting residue was diluted with Et2O (50mL). The solid was removed by filtration and washed with Et2O (20mL). The filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to obtain (S, E)-tert-butyl 4-(3-ethoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3-carboxylate (intermediate 31, 5.74g, 77% yield) as a mixture of rotamers. 1 H NMR(300MHz, CDCl3)δ1.37-1.50(9H,m),1.51-1.57(3H,m),1.63(3H,br s),3.70-3.83(4H,m),4.05-4.12(1H,m),4.33-4.64(1H,m),5.84-6.03(1H,m),6.85(1H,br dd); m / z: (ES + )[M+H] + =286.

[0360] Intermediate 32: (S)-tert-butyl 4-((S)-1-ethoxy-1-oxohex-4-en-3-yl)-2,2-dimethyloxazole Alkane-3-carboxylate

[0361] The three-necked flask was dried under N2. Copper (I) iodide (23.4 g, 123 mmol) was added, and the solid was diluted in THF (100 mL). The suspension was cooled to 5 ° C, and under N2 atmosphere, prop-1-ene-1-yl magnesium bromide solution (0.5 M in THF, 491 mL, 245 mmol) was added dropwise via an additional funnel. The mixture was stirred at 5 ° C for 30 min and then cooled to -78 ° C. After stirring at -78 ° C for 10 min, trimethylsilyl chloride (15.68 mL, 122.7 mmol) was added, followed by a solution of (S, E)-tert-butyl 4-(3-ethoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3-carboxylate (intermediate 31, 7.00 g, 24.5 mmol) in THF (20 mL). After addition, the reaction was stirred at -78 ° C for 30 min, then heated to -30 ° C to -20 ° C, and stirred for another 30 min. At -20 ° C, the reaction was carefully quenched with concentrated NH4OH aqueous solution: saturated NH4Cl aqueous solution (1: 9, 200 mL). The crude mixture was warmed to room temperature, and the solid was removed by vacuum filtration. The two-phase filtrate was separated, and the aqueous phase was extracted with EtOAc (3x 100 mL). The combined organic matter was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to obtain (S)-tert-butyl 4-((S)-1-ethoxy-1-oxohex-4-ene-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (intermediate 32, 6.80 g, 85% yield) as a mixture of rotamers and E / Z olefins. 1 H NMR (300MHz, CDCl3) δ1.40-1.52(12H,m),1.54-1.75(6H,m),2.14-2.36(1H,m),2.42-2.65(1H,m) ,3.29-3.55(1H,m),3.63(3H,m),3.73-4.01(3H,m),5.10-5.37(1H,m),5.46-5.70(1H,m); m / z: (ES + )[M+H] + =328.

[0362] Intermediate 33: (S)-tert-Butyl 4-((S)-1-hydroxyhex-4-en-3-yl)-2,2-dimethyloxazolidine-3-carboxylic acid ester

[0363] (S)-tert-Butyl 4-((S)-1-ethoxy-1-oxohex-4-en-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 32, 3.50 g, 10.7 mmol) was dissolved in anhydrous THF (18 mL), and the solution was cooled to 0 ° C under N2 atmosphere. LAH solution (2M in THF, 5.34 mL, 10.7 mmol) was added dropwise to the reaction, and the reaction mixture was stirred at 0 ° C for 1 h. At 0 ° C, the reaction was carefully quenched with water (0.4 mL), 15% NaOH aqueous solution (0.4 mL) and water (1.2 mL). The resulting suspension was warmed to room temperature and stirred for 10 min. Na2SO4 (5 g) was added, and the suspension was filtered, and the solid filter cake was washed with EtOAc (50 mL). The filtrate was concentrated to dryness. The crude product was purified by silica gel chromatography (hexanes / EtOAc) to give (S)-tert-butyl 4-((S)-1-hydroxyhex-4-en-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 33, 3.10 g, 97% yield) as a mixture of rotamers and E / Z olefins. 1 H NMR (300MHz, CDCl3) δ1.43-1.52(14H,m),1.54-1.72(6H,m),1.73-1.88(1H,m),2.48-3.17( 1H,m),3.50-3.73(2H,m),3.75-4.01(3H,m),5.12-5.38(1H,m),5.43-5.77(1H,m); m / z: (ES + )[M+H] + =300.

[0364] Intermediate 34: (S)-tert-butyl 2,2-dimethyl-4-((S)-1-(methylsulfonyloxy)hex-4-en-3-yl) Oxazolidine-3-carboxylate

[0365] Triethylamine (1.96 mL, 14.0 mmol) and methanesulfonic anhydride (2.27 g, 13.0 mmol) were added sequentially to a solution of (S)-tert-butyl 4-((S)-1-hydroxyhex-4-ene-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (intermediate 33, 3.00 g, 10.0 mmol) in DCM (25 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The crude reaction mixture was diluted with DCM (25 ml) and washed with 1 M aqueous HCl (10 mL) and saturated NaHCO (5 mL). The organics were dried over Na2SO4, filtered and concentrated to dryness to give (S)-tert-butyl 2,2-dimethyl-4-((S)-1-(methylsulfonyloxy)hex-4-en-3-yl)oxazolidine-3-carboxylate (Intermediate 34, as a mixture of rotamers and E / Z olefins) which was used without further purification.1 HNMR(300MHz, CDCl3)δ1.39-1.51(12H,m),1.53-1.64(4H,m),1.66-1.77(3H,m),1.89-2.12(1H,m),2.97(3H,s),3.07 -3.20(1H,m),3.74-4.00(3H,m),4.03-4.17(1H,m),4.22-4.35(1H,m),5.05-5.27(1H,m),5.54-5.84(m,1H); m / z: (ES + )[M+H] + =378. Intermediates 35: (S)-tert-butyl 4-((S)-1-(bis(tert-butoxycarbonyl)amino)hex-4-en-3-yl)-2,2-dimethyloxazolidine-3-yl Formate

[0366] Sodium hydride (60% wt in oil, 427 mg, 10.68 mmol) was added to a solution of di-tert-butyl iminodicarboxylate (2.319 g, 10.68 mmol) in DMF (30 mL) at 0 ° C, and the suspension was stirred at 0 ° C for 20 min, then warmed to room temperature and stirred for another 10 min. A solution of (S)-tert-butyl 2,2-dimethyl-4-((S)-1-(methylsulfonyloxy)hex-4-ene-3-yl)oxazolidine-3-carboxylate (intermediate 34, 2.60 g, 6.89 mmol) in DMF (3 mL) was added, and the reaction was heated to 95 ° C under N2 atmosphere for 3 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was diluted in water (10 mL) and EtOAc (20 mL), and the layers were separated. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (S)-tert-butyl 4-((S)-1-(bis(tert-butoxycarbonyl)amino)hex-4-en-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 35, 2.60 g, 76% yield). 1 HNMR(300MHz, CDCl3)δ1.36-1.52(30H,m),1.53-1.95(8H,m),2.26-2.97(1H,m),3.28-3.44 (1H,m),3.48-3.66(1H,m),3.70-4.00(3H,m),5.14-5.29(1H,m),5.40-5.83(1H,m); m / z: (ES + )[M+Na] + =521.

[0367] Intermediate 36: tert-butyl(tert-butoxycarbonyl)((S)-3-((S)-1-((tert-butoxycarbonyl)amino)-2-hydroxy (4-(2-(2-(ethyl)hex-4-en-1-yl)carbamate)

[0368] At room temperature, cerium (III) chloride heptahydrate (3.36 g, 9.02 mmol) and oxalic acid (0.027 g, 0.30 mmol) were added sequentially to a solution of (S)-tert-butyl 4-((S)-1-(bis(tert-butoxycarbonyl)amino)hex-4-ene-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (intermediate 35, 1.50 g, 3.01 mmol) in acetonitrile (30 mL). The resulting suspension was stirred at room temperature for 2 h. The suspension was filtered and the solid was washed with EtOAc. The filtrate was concentrated, then diluted with EtOAc (50 mL), and washed with water (20 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give tert-butyl(tert-butoxycarbonyl)((S)-3-((S)-1-((tert-butoxycarbonyl)amino)-2-hydroxyethyl)hex-4-en-1-yl)carbamate (Intermediate 36, 830 mg, 60% yield). 1 HNMR(300MHz, CDCl3)δ1.43(9H,s),1.49(18H,s),1.56-1.85(5H,m),2.17-2.77(1H,m ),3.34-3.72(5H,m),4.52-4.76(1H,m),5.13-5.35(1H,m),5.47-5.78(1H,m); m / z: (ES + )[M+H] + =459.

[0369] Intermediate 37: (2S,3S)-3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino 4-enoic acid

[0370] Tert-butyl(tert-butoxycarbonyl)((S)-3-((S)-1-((tert-butoxycarbonyl)amino)-2-hydroxyethyl)hex-4-en-1-yl)carbamate (Intermediate 36, 400 mg, 0.87 mmol) was dissolved in acetone (5 mL) and cooled to -20 °C under N2 atmosphere. Jones reagent (2.37 M in aqueous H2SO4, 1.14 mL, 3.05 mmol) was slowly added and the solution was stirred at -20 °C to -10 °C for 5 h. The reaction mixture was concentrated and the residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino)hex-4-enoic acid (Intermediate 37, 200 mg, 48% yield), which was contaminated with impurities. m / z: (ES + )[M+H] + =471. Intermediate 38: (2S,3S)-tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino (tert-Butyl)ethyl)-2-(tert-butoxycarbonylamino)hex-4-enoate

[0371] 2-tert-Butyl-1,3-diisopropylisourea (0.42 mL, 1.9 mmol) was added to a solution of (2S,3S)-3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino)hex-4-enoic acid (Intermediate 37, 250 mg, 0.53 mmol) in DCM (5 mL), and the reaction was stirred at room temperature under N2 atmosphere for 16 h. The reaction suspension was filtered to remove insoluble solids. 2-tert-Butyl-1,3-diisopropylisourea (0.05 mL, 0.2 mmol) was added to the filtrate, and the reaction was stirred at room temperature for another 48 h. The crude mixture was concentrated to dryness and purified directly by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino)hex-4-enoate (Intermediate 38, 120 mg, 43% yield) as a viscous oil. 1 H NMR (300MHz, CDCl3) δ1.33-1.57(37H,m),1.60-1.68(3H,m),1.71-1.90(1H,m),2.45-3.06(1H,m), 3.37-3.66(2H,m),4.20-4.28(1H,m),4.90-5.08(1H,m),5.18(1H,td),5.44-5.87(1H,m); m / z: (ES + )[M+Na] +=551.

[0372] Intermediate 39: (2S,3R)-tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0373] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (15mg, 0.022mmol) and bis(diphenylphosphino)methane (17mg, 0.046mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (2.6mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.21mL, 1.4mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10min. (2S, 3S)-tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino)hex-4-enoate (intermediate 38, 300mg, 0.57mmol) was added to the reaction as a solution in DCM (2mL), and the reaction was stirred at room temperature for 24h. The reaction mixture was concentrated to dryness and purified directly by silica gel chromatography (hexanes / EtOAc) to give (2S,3R)-tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 39, 100 mg, 27% yield) as a colorless oil. 1 H NMR(300MHz, CDCl3)δ0.73(2H,t),1.22(12H,s),1.43(12H,s),1.46-1.74(30H,m),1.80-1.90(1H,br d),3.42-3.77(2H,m),4.28(1H,brdd),5.03(1H,br d); m / z: (ES + )[M+Na] + =679.

[0374] Example 15: (2S,3R)-2-amino-3-(2-aminoethyl)-6-dihydroxyborylhexanoic acid dihydrochloride

[0375] (2S,3R)-tert-butyl 3-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 39, 230 mg, 0.35 mmol) was dissolved in HCl (4M in dioxane, 1.75 mL, 7.01 mmol) and the reaction was stirred at room temperature under N2 atmosphere for 30 min. The reaction was heated to 60 °C and stirred for 1 h. The reaction was cooled to room temperature and diluted with 1 M aqueous HCl (1 mL). Phenylboronic acid (214 mg, 1.75 mmol) was added and the reaction was heated to 60 °C for 1 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude solution was diluted with water (5 mL) and washed with EtOAc (4 x 3 mL). The aqueous phase was lyophilized to afford (2S,3R)-2-amino-3-(2-aminoethyl)-6-boronohexanoic acid dihydrochloride (Example 15, 80 mg, 78% yield) as a dry film. 1 H NMR(300MHz,D2O)δ0.81(2H,br t),1.35-1.55(4H,m),1.72-1.91(2H,m),2.06-2.30(1H,m),3.05-3.23(2H,m),4.07(1H,d); m / z: (ES + )[M+H] + =219.

[0376] Example 16: (2S,3S)-2-amino-6-dihydroxyboryl-3-carbamoylhexanoic acid

[0377]

[0378] Intermediate 40: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-carbamoyl hex-5-enoate

[0379] HATU (311 mg, 0.818 mmol), ammonium chloride (159 mg, 2.97 mmol) and N,N-diisopropylethylamine (0.78 mL, 4.5 mmol) were added to a solution of 2-((S)-1-(benzyloxycarbonylamino)-2-tert-butoxy-2-oxoethyl)pent-4-enoic acid (Intermediate 3, 270 mg, 0.74 mmol) in DMF (3 mL) and the reaction was stirred at room temperature for 15 h. The mixture was diluted with DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to give the pure diastereomers (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-carbamoyl hex-5-enoate (Intermediate 40, 148 mg, 55% yield) and (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-carbamoyl hex-5-enoate (86 mg, 32% yield). The stereochemistry of the major diastereomer was assigned by analogy with previous analogs. 1 H NMR(500MHz, CDCl3)δ1.39(9H,s),2.26-2.47(2H,m),2.78-3.00(1H,m),4.19-4.43(1H,m),5.01-5.16(4H, m),5.71-5.81(1H,m),5.82-5.87(1H,m),5.96-6.05(1H,m),6.13-6.21(1H,m),7.25-7.37(5H,m); m / z: (ES + )[M+H] + =363.

[0380] Intermediate 41: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-carbamoyl-6-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0381] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (15 mg, 0.022 mmol) and bis(diphenylphosphino)ethane (18 mg, 0.045 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (1.5 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (67 μL, 0.46 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-carbamoyl hex-5-enoate (intermediate 40, 84 mg, 0.23 mmol) was added to the reaction as a solution in DCM (1 mL), and the reaction was stirred at room temperature for 15 h. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (10 mL). Each layer is separated and aqueous layer is extracted with DCM (2x 10mL).By the organic matter merged through MgSO4 drying, filter and be concentrated to dryness.By silica gel chromatography (hexane / EtOAc) purification of crude material, (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-formamyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 41,73mg, 64% yield) is obtained. 1 H NMR(400MHz, CDCl3)δ0.72-0.82(2H,m),1.20(12H,s),1.34-1.41(9H,m),1.43-1.52(2H,m),1.53-1.62(1H,m),1.62-1.72(1H,m),2.68 -2.93(1H,m),4.19-4.40(1H,m),5.01-5.09(1H,m),5.09-5.16(1H,m),5.67-5.94(2H,m),6.04-6.25(1H,m),7.24-7.35(5H,m); m / z: (ES) + )[M+H] + =491.

[0382] Example 16: (2S,3S)-2-amino-6-dihydroxyboryl-3-carbamoylhexanoic acid

[0383] HBr solution (33wt%, in AcOH, 0.5mL, 2.8mmol) is added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-carbamoyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 41, 73mg, 0.15mmol) in DCM (2mL), and the reaction is stirred at room temperature for 1h. The reaction is concentrated and the resulting residue is diluted in Et2O (2mL) and 2M HCl aqueous solution (2mL). Phenylboronic acid (36mg, 0.30mmol) is added, and the clear biphasic solution is stirred at room temperature for 15h. The layers are separated, and the aqueous layer is washed with Et2O (3x10mL) and freeze-dried. The resulting solid is dissolved in MeOH (1mL) and purified by ion exchange chromatography (PoraPakRxn CX20cc column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL) to afford (2S,3S)-2-amino-6-borono-3-carbamoylhexanoic acid (Example 16, 31 mg, 96% yield) as a white solid. 1 HNMR(500MHz,D2O)δ0.79(2H,td),1.44(2H,quin),1.53-1.61(1H,m),1.64-1.73(1H,m),2.87-3.00(1H,m),3.77(1H,d); m / z: (ES + )[M+H] + =219.

[0384] Example 17: (2S,3S)-2-amino-6-dihydroxyboryl-3-(methylcarbamoyl)hexanoic acid

[0385]

[0386] Intermediate 42: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)hexane -5-enoic acid ester

[0387] HATU (266 mg, 0.699 mmol), methylamine hydrochloride (172 mg, 2.54 mmol) and N,N-diisopropylethylamine (0.67 mL, 3.8 mmol) were added to a solution of 2-((S)-1-(benzyloxycarbonylamino)-2-tert-butoxy-2-oxoethyl)pent-4-enoic acid (Intermediate 3, 231 mg, 0.64 mmol) in DMF (3 mL) and the reaction was stirred at room temperature for 15 h. The mixture was diluted with DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to afford the pure diastereomers (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)hex-5-enoate (Intermediate 42, 133 mg, 56% yield) and (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)hex-5-enoate (77 mg, 32% yield). The stereochemistry of the major diastereomer was assigned by analogy with previous analogs. 1 H NMR(500MHz, CDCl3)δ1.37(9H,s),2.24-2.45(2H,m),2.71(3H,d),2.81(1H,td),4.19-4.41(1H,m),4 .96-5.18(4H,m),5.66-5.77(1H,m),5.77-5.84(1H,m),6.09-6.35(1H,m),7.24-7.36(5H,m); m / z: (ES + )[M+H] + =377.

[0388] Intermediate 43: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)-6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0389] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (8.1 mg, 0.012 mmol) and bis(diphenylphosphino)ethane (9.7 mg, 0.024 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (1 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59 μL, 0.40 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)hex-5-enoate (intermediate 42, 76 mg, 0.20 mmol) was added to the reaction as a solution in DCM (1.5 mL), and the reaction was stirred at room temperature for 15 h. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (10 mL). Each layer is separated and aqueous layer is extracted with DCM (2x 10mL).By the organic matter merged through MgSO4 drying, filter and be concentrated to dryness.By silica gel chromatography (hexane / EtOAc) purification of crude material, (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 43,70mg, 69% yield) is obtained. 1 HNMR(500MHz, CDCl3)δ0.64-0.87(2H,m),1.20(13H,s),1.31-1.45(10H,m),1.49-1.60(1H,m),1.63-1.72(1H,m),2.60-2.77(4H,m),4.30(1H,br dd),5.02-5.09(1H,m),5.09-5.16(1H,m),5.75-5.91(1H,m),6.28(1H,br d),7.24-7.35(5H,m); m / z: (ES + )[M+H] + =505.

[0390] Example 17: (2S,3S)-2-amino-6-dihydroxyboryl-3-(methylcarbamoyl)hexanoic acid

[0391] HBr solution (33wt%, in AcOH, 0.5mL, 2.8mmol) was added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(methylcarbamoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 43, 70mg, 0.14mmol) in DCM (2mL), and the reaction was stirred at room temperature for 1h. The reaction was concentrated and the resulting residue was diluted in Et2O (2mL) and 2M HCl aqueous solution (2mL). Phenylboronic acid (34mg, 0.28mmol) was added, and the clear biphasic solution was stirred at room temperature for 15h. The layers were separated, and the aqueous layer was washed with Et2O (3x10mL) and lyophilized. The resulting solid was dissolved in MeOH (1mL) and purified by ion exchange chromatography (PoraPak Rxn CX20cc column). The desired product was eluted from the column using 5% ammonia in MeOH (15 mL) to afford (2S,3S)-2-amino-6-borono-3-(methylcarbamoyl)hexanoic acid (Example 17, 30 mg, 93% yield) as a white solid. 1 H NMR(500MHz,D2O)δ0.71-0.85(2H,m),1.31-1.45(2H,m),1.51-1.60(1H,m),1.62-1.73(1H,m),2.67(3H,s),2.89(1H,dt),3.80(1H,d); m / z: (ES + )[M+H] + =233.

[0392] Example 18: (2S,3S)-2-amino-3-(aminomethyl)-6-dihydroxyborylhexanoic acid dihydrochloride

[0393]

[0394] Intermediate 44: (2S,3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)

[0395] methyl)hex-5-enoate

[0396] At 0 ° C, triethylamine (1.70 mL, 12.2 mmol) and methanesulfonyl chloride (0.60 mL, 7.7 mmol) were added to a solution of (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl) hex-5-enoate (intermediate 5, 1.00 g, 2.86 mmol) in DCM (20 mL). The reaction was warmed to room temperature and stirred for 90 min. The crude mixture was diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate solution, water and brine (25 mL each) in sequence. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to obtain (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl) hex-5-enoate (intermediate 44, 1.17 g, 96% yield) as a light yellow oil. 1 HNMR(300MHz, CDCl3)δ1.46(9H,s),1.94-2.11(1H,m),2.18-2.32(1H,m),2.34-2.53(1H,m),2.97(3H,s),4.12-4.24(2H,m),4.45(1H,br dd),5.00-5.18(4H,m),5.42(1H,brd),5.63-5.89(1H,m),7.25-7.37(5H,m); m / z: (ES + )[M+NH4] + =445.

[0397] Intermediate 45: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((1,3-dioxoisoindoline-2- 2-(4-(2-amino-4-yl)methyl)hex-5-enoate

[0398] Under N2 atmosphere, potassium phthalimide (0.558g, 3.01mmol) and potassium iodide (0.227g, 1.37mmol) were added to an oven-dried flask. (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((methylsulfonyloxy)methyl)hex-5-enoate (intermediate 44, 1.17g, 2.74mmol) was added as a solution in DMF (15mL), and the reaction was heated to 95°C for 3h. The reaction mixture was cooled to room temperature and diluted with water (30mL). The layers were separated and the aqueous layer was extracted with Et2O (3x 20mL). The combined organic matter was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtAOc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((1,3-dioxoisoindolin-2-yl)methyl)hex-5-enoate (Intermediate 45, 0.725 g, 55% yield) as a colorless oil. 1HNMR(300MHz, CDCl3)δ1.20(9H,s),2.04-2.26(2H,m),2.69(1H,pentet),3.61(2H,d),4.47(1H,br d),4.98-5.22(4H,m),5.75-5.94(1H,m),5.99(1H,br d),7.25-7.42(5H,m),7.63-7.72(2H,m),7.77-7.87(2H,m); m / z: (ES + )[M+NH4] + =496.

[0399] Intermediate 46: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((1,3-dioxoisoindoline-2- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0400] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (31 mg, 0.046 mmol) and bis(diphenylphosphino)methane (35 mg, 0.090 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (5 mL) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 mL, 3.5 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((1,3-dioxoisoindolin-2-yl)methyl)hex-5-enoate (Intermediate 45, 725 mg, 1.52 mmol) was added to the reaction as a solution in DCM (4 mL), and the reaction was stirred at room temperature for 15 h. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (10 mL). Each layer was separated and the aqueous layer was extracted with DCM (2x 10 mL). The combined organic matter was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to obtain (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((1,3-dioxoisoindolin-2-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)hexanoate (intermediate 46, 612 mg, 67% yield) as a glassy, ​​colorless residue. 1H NMR(300MHz, CDCl3)δ0.79(2H,brt),1.19(12H,s),1.21(9H,s),1.25-1.54( 3H,m),1.59-1.77(1H,m),2.51-2.66(1H,m),3.49-3.67(2H,m),4.44(1H,br d),5.11(2H,s),5.96(1H,brd),7.26-7.41(5H,m),7.61-7.72(2H,m),7.75-7.85(2H,m); m / z: (ES + )[M+NH4] + =624.

[0401] Example 18: (2S,3S)-2-amino-3-(aminomethyl)-6-dihydroxyborylhexanoic acid dihydrochloride

[0402] (2S,3S)-tert-Butyl 2-(benzyloxycarbonylamino)-3-((1,3-dioxoisoindolin-2-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 46, 315 mg, 0.520 mmol) was dissolved in 6M aqueous HCl (5 mL) and the solution was heated to 100 °C for 16 h. The reaction was cooled to room temperature, diluted with water (10 mL), and washed with ether (3 x 10 mL). The aqueous layer was lyophilized and purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 100% MeCN in water) to afford (2S,3S)-2-amino-3-(aminomethyl)-6-boronyllohexanoic acid dihydrochloride (Example 18, 94 mg, 65% yield) as a yellow solid. 1 H NMR(300MHz,D2O)δ0.73-0.91(2H,m),1.34-1.64(4H,m),2.29-2.45(1H,m),3.27(2H,qd),4.16(1H,d); m / z: (ES + )[M-H2O+H] + =187.

[0403] Example 19: (2S,3S)-2-amino-3-(((S)-2-amino-3-methylbutyramido)methyl)-6-dihydroxyboryl Hexanoic acid

[0404]

[0405] Intermediate 47: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((N-(tert-butyloxycarbonyl)amino)- 2-(trimethyl)- methylsilyl)ethylsulfonamide)methyl)hex-5-enoate

[0406] (2S, 3R)-tert-butyl 2-(benzyloxycarbonylamino)-3-(hydroxymethyl)hex-5-enoate (intermediate 5, 747mg, 2.14mmol) and tert-butyl ((2-(trimethylsilyl)ethyl)sulfonyl)carbamate (602mg, 2.14mmol) were dissolved in THF (10mL) and cooled to 0°C. Triphenylphosphine (842mg, 3.21mmol) and DIAD (0.85mL, 4.4mmol) were added, and the reaction was stirred for 16h while slowly warming to room temperature. The reaction was quenched with saturated sodium bicarbonate aqueous solution (20mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2x 15mL). The combined organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((N-(tert-butoxycarbonyl)-2-(trimethylsilyl)ethylsulfonamido)methyl)hex-5-enoate (Intermediate 47, 860 mg, 66% yield). 1 HNMR(500MHz, CDCl3)0.04(9H,s),0.91-1.01(2H,m),1.46(9H,s),1.50(9H,s),2.0 4-2.13(2H,m),2.41-2.65(1H,m),3.33-3.47(2H,m),3.58-3.81(2H,m),4.40(1H,br d),4.96-5.19(4H,m),5.66(1H,br d),5.72-5.96(1H,m),7.25-7.41(5H,m); m / z: (ES + )[M+NH4] + =630.

[0407] Intermediate 48: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butyloxycarbonylamino)

[0408] methyl)hex-5-enoate

[0409] TBAF solution (1M in THF, 6.0 mL, 6.0 mmol) was added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((N-(tert-butoxycarbonyl)-2-(trimethylsilyl)ethylsulfonamide)methyl)hex-5-enoate (intermediate 47, 1.23 g, 2.01 mmol) in THF (6 mL), and the reaction was stirred at room temperature for 30 min. The reaction was diluted with Et2O (30 mL) and washed with water (3 x 15 mL) in sequence. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to give (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)hex-5-enoate (intermediate 48, 834 mg, 93% yield) as a light yellow oil. 1 HNMR(500MHz, CDCl3)δ1.41(9H,s),1.45(9H,s),1.90-1.99(1H,m),2.06-2.1 6(1H,m),2.17-2.30(1H,m),2.92-3.14(1H,m),3.14-3.27(1H,m),4.36(1H,br dd),4.46-4.69(1H,m),5.03-5.15(4H,m),5.70-5.92(2H,m),7.26-7.39(5H,m); m / z: (ES + )[M+H] + =449. Intermediate 49: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butyloxycarbonylamino)

[0410] methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0411] Bis(1,5-cyclooctadiene)diiridium(I)dichloride (48 mg, 0.071 mmol) and bis(diphenylphosphino)methane (55 mg, 0.14 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solid was dissolved in DCM (7 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.76 mL, 5.2 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)hex-5-enoate (intermediate 48, 1.071 g, 2.39 mmol) was added to the reaction as a solution in DCM (6 mL), and the reaction was stirred at room temperature for 15 h. The reaction mixture was cooled to 0 ° C and quenched with MeOH (2 mL) and water (15 mL). Each layer was separated and the aqueous layer was extracted with DCM (2x 10 mL). The combined organic matter was dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexane / EtOAc) to give (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 49, 1.01 g, 73% yield) as a light yellow jelly. 1 HNMR(500MHz, CDCl3)δ0.75(2H,br t),1.20(12H,s),1.30-1.38(2H,m),1.40(9H,s),1.43(9H,s),1.46-1.51(2H,m),2.09(1H,br s),2.98-3.12(1H,m),3.12-3.25(1H,m),4.30(1H,br dd),4.55-4.79(1H,m),5.01-5.18(2H,m),5.77(1H,br d),7.25-7.38(5H,m); m / z: (ES + )[M+H] + =577.

[0412] Intermediate 50: (2S,3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0413] At 0 ° C, HCl solution (4M in dioxane, 3.35 mL, 13.4 mmol) was added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 49, 773 mg, 1.34 mmol) in dioxane (3.5 mL). The reaction was stirred for 2 h while slowly warming to room temperature. The solution was concentrated to dryness to give (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 50, 639 mg, 100% yield) as an off-white solid, which was used without further purification. m / z:(ES + )[M+H] + =476.

[0414] Intermediate 51: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0415] HATU (385mg, 1.01mmol) is added to a solution of Boc-Val-OH (220mg, 1.01mmol) in DMF (4mL), and the reaction is stirred at room temperature for 10min. Then (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) hexanoate (intermediate 50, 438mg, 0.919mmol) is added to the reaction as a solution in DMF (6mL). N,N-diisopropylethylamine (0.80mL, 4.6mmol) is added, and the reaction is stirred at room temperature for 3h. The reaction mixture is diluted with saturated NH4Cl aqueous solution and DCM, and each layer is separated. The aqueous layer is extracted with DCM (3x 20mL). The combined organic matter is dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 51, 450 mg, 72% yield) as a white foam. 1HNMR(500MHz, CDCl3)δ0.72(2H,br t),0.80-0.97(6H,m),1.13-1.35(13H,m),1.37-1.63(21H,m),1.95(1H,br s),2.07-2.17(1H,m),3.07-3.31(1H,m),3.34-3.54(1H,m),3.80-4.00(1H,m),4.14-4.28( 1H,m),5.00-5.23(3H,m),5.50-5.78(1H,m),6.28-6.70(1H,m),7.25-7.45(5H,m); m / z: (ES + )[M+H] + =676.

[0416] Example 19: (2S,3S)-2-amino-3-(((S)-2-amino-3-methylbutyramido)methyl)-6-dihydroxyboryl Hexanoic acid

[0417] Pd / C (10 wt%, 71 mg, 0.070 mmol) was added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 51, 450 mg, 0.67 mmol) in EtOAc (10 mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature overnight. The reaction mixture was filtered through celite and rinsed with EtOAc and methanol. The filtrate was concentrated to dryness and the resulting residue was dissolved in HCl (4 M in dioxane, 10.0 mL, 40.0 mmol). The reaction was heated to 50 °C and stirred for 1.5 h. The reaction was cooled to room temperature and concentrated. The obtained residue is dissolved in 1M HCl aqueous solution (15ml) and Et2O (15mL).Phenylboric acid (155mg, 1.27mmol) is added, and the reaction is stirred at room temperature for 4h.The reaction mixture is diluted with water and washed with Et2O.The water layer is freeze-dried and purified by ion exchange chromatography (PoraPakRxnCX 20cc columns).2.5M ammonia / methanol is used to elute the desired product from the column, and (2S, 3S) -2- amino -3- (((S) -2- amino -3- methylbutyramide) methyl) -6- dihydroxyboryl hexanoic acid (Example 19, 147mg, 76% yield) as a white solid is obtained. 1HNMR(500MHz,D2O)δ0.70-0.85(2H,m),0.91-1.01(6H,m),1.29-1.56(4H,m), 1.94-2.05(1H,m),2.17-2.31(1H,m),3.26-3.44(3H,m),3.70(1H,d); m / z: (ES + )[M+H] + =304.

[0418] Example 20: (2S,3S)-2-amino-3-(((S)-2-aminopropionamido)methyl)-6-dihydroxyborylhexanoic acid

[0419]

[0420] Intermediate 52: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaborolan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)

[0421] Hexanoate

[0422] HATU (561mg, 1.48mmol) is added to a solution of Boc-Ala-OH (279mg, 1.48mmol) in DMF (4mL), and the reaction is stirred at room temperature for 10min. Then (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) hexanoate (intermediate 50, 639mg, 1.34mmol) is added to the reaction as a solution in DMF (6mL). N,N-diisopropylethylamine (1.17mL, 6.71mmol) is added, and the reaction is stirred at room temperature for 3h. The reaction mixture is diluted with saturated NH4Cl aqueous solution and DCM, and each layer is separated. The aqueous layer is extracted with DCM (3x 30mL). The combined organic matter is dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)propionamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 52, 662 mg, 76% yield) as a white solid. 1H NMR(500MHz,CDCl3)δ0.65-0.78(2H,m),1.19(12H,s),1.32(3H,br d),1.37-1.55(22H,m),1.95-2.07(1H,m),3.10-3.27(1H,m),3.30-3.50(1H,m),3.87-4.45(2H,m),5.08(2H,br s),5.13-5.23(1H,m),5.76(1H,br s),6.52-6.80(1H,m),7.25-7.44(5H,m); m / z: (ES + )[M+H] + =648.

[0423] Example 20: (2S,3S)-2-amino-3-(((S)-2-aminopropionamido)methyl)-6-dihydroxyborylhexanoic acid

[0424] Pd / C (10 wt%, 110 mg, 0.10 mmol) was added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)propionamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 52, 662 mg, 1.02 mmol) in EtO (10 mL). The flask was equipped with a H balloon and the suspension was stirred at room temperature overnight. The reaction mixture was filtered through celite and rinsed with EtOAc and methanol. The filtrate was concentrated to dryness and the resulting residue was dissolved in HCl (4 M in dioxane, 10.0 mL, 40.0 mmol) and the reaction was stirred at room temperature for 3.5 h. The reaction mixture was concentrated and the resulting solid was ground with EtO. Solid is dissolved in 1MHCl aqueous solution (15ml) and Et2O (15mL).Phenylboric acid (245mg, 2.01mmol) is added, and the reaction is stirred at room temperature overnight.The reaction mixture is diluted with water and washed with Et2O.The water layer is freeze-dried and purified by ion exchange chromatography (Silicycle SPE-R51230B-20X column).2.5M ammonia / methanol is used to elute the desired product from the column, and (2S, 3S) -2- amino -3- (((S) -2- aminopropionamido) methyl) -6- dihydroxyboryl hexanoic acid (Example 20, 250mg, 91% yield) is obtained as a white solid. 1 H NMR(500MHz,D2O)δ0.68-0.79(2H,m),1.26(3H,br d),1.29-1.36(2H,m),1.37-1.49(2H,m),2.10-2.27(1H,m),3.16-3.37(2H,m),3.50-3.64(2H,m); m / z: (ES+ )[M+H] + =276.

[0425] Example 21: (2S,3S)-2-amino-3-(((S)-2-aminobutyramido)methyl)-6-dihydroxyboronylhexanoic acid

[0426]

[0427] Intermediate 53: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaborolan-2-yl)

[0428] Hexanoate

[0429] N, N-diisopropylethylamine (0.49mL, 2.8mmol) is added to a suspension of HATU (220mg, 0.58mmol) and Boc-Abu-OH (230mg, 1.13mmol) in DCM (3mL), and the reaction is stirred at room temperature for 10min. DMF (1mL) is added to the suspension, and the reaction is stirred at room temperature for another 5min. A solution of (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) hexanoate (intermediate 50, 238mg, 0.499mmol) in DCM (2mL) is added, and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with water and DCM, and the layers are separated. The aqueous layer is extracted with DCM (2x 20mL). The combined organics were washed with saturated sodium chloride, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)butyramido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 53, 110 mg, 29% yield). 1H NMR(500MHz, CDCl3)δ0.73(2H,br s),0.91(3H,br s),1.21(13H,br s),1.30-1.37(1H,m),1.39-1.43(9H,m),1.45(9H,br s),1.49-1.65(2H,m),1.86(1H,br s),2.00(1H,br s),2.14-2.69(1H,m),3.20(1H,br s),3.31-3.61(1H,m),3.99(1H,br s),4.13-4.34(1H,m),5.09(3H,br s),5.66-5.88(1H,m),6.46-6.72(1H,m),7.28-7.39(5H,m). Example 21: (2S, 3S)- 2-Amino-3-(((S)-2-aminobutyramido)methyl)-6-dihydroxyboronylhexanoic acid

[0430] Pd / C (10wt%, 43mg, 0.040mmol) was added to a solution of (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)butyramido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)hexanoate (Intermediate 53, 107mg, 0.162mmol) in ethyl acetate (5mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature overnight. The reaction mixture was filtered through celite and rinsed with EtOAc and methanol. The filtrate was concentrated and the resulting residue was dissolved in DCM (1mL) and trifluoroacetic acid (3mL), and the reaction was stirred at room temperature overnight. The reaction was concentrated and the residue was dissolved in 1M HCl aqueous solution (2mL) and Et2O (2mL). Phenylboronic acid (38mg, 0.31mmol) was added, and the reaction was stirred at room temperature for 3h. The reaction mixture was diluted with water and washed with EtO. The water layer was freeze-dried and purified by ion exchange chromatography (PoraPak Rxn CX 20cc columns). The desired product was eluted from the column using a methanol solution of 5% ammonia to obtain (2S, 3S) -2- amino -3- (((S) -2- aminobutanamido) methyl) -6- dihydroxyboryl hexanoic acid (Example 21, 40mg, 89% yield) as a white solid. 1 H NMR(500MHz,D2O)δ0.74(2H,td),0.85(3H,brt),1.27-1.36(2H,m),1.37-1.47(2H,m),1. 56-1.71(2H,m),2.11-2.20(1H,m),3.20-3.35(2H,m),3.39(1H,t),3.60(1H,d); m / z: (ES +)[M+H] + =290.

[0431] Example 22: (2S,3S)-2-amino-3-(((2S,3S)-2-amino-3-methylpentanamido)methyl)-6-dihydroxy Boryl hexanoic acid

[0432]

[0433] Intermediate 54: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((2S,3S)-2-(tert-butyloxycarbonylamino) amino)-3-methylpentanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0434] N, N-diisopropylethylamine (0.84mL, 4.8mmol) is added to a suspension of HATU (365mg, 0.960mmol) and Boc-Ile-OH (462mg, 2.00mmol) in DCM (3mL) and DMF (3mL), and the reaction is stirred at room temperature for 10min. (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 50, 336mg, 0.705mmol) in DCM (3mL) is added, and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with water and DCM, and each layer is separated. The aqueous layer is extracted with DCM (2x 20mL). The combined organic matter is washed with saturated sodium bicarbonate, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 54, 260 mg, 47% yield). 1 HNMR(500MHz,CDCl3)δ0.73(2H,brt),0.83-0.97(6H,m),1.08(1H,br s),1.21(13H,br s),1.29-1.63(22H,m),1.82-1.92(1H,m),1.92-2.04(1H,m),3.18(1H,br s),3.43(1H,br d),3.96(1H,br s),4.21(1H,brd),5.09(3H,br s),5.58-5.80(1H,m),6.40-6.69(1H,m),7.29-7.40(5H,m).

[0435] Example 22: (2S,3S)-2-amino-3-(((2S,3S)-2-amino-3-methylpentanamido)methyl)-6-dihydroxy Boryl hexanoic acid

[0436] Pd / C (10wt%, 99mg, 0.093mmol) was added to a solution of (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 54, 256mg, 0.371mmol) in ethyl acetate (8mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature overnight. The reaction mixture was filtered through celite and rinsed with EtOAc and methanol. The filtrate was concentrated and the resulting residue was dissolved in DCM (2mL) and trifluoroacetic acid (6mL), and the reaction was stirred at room temperature for 3h. The reaction was concentrated and the residue was dissolved in 1M HCl aqueous solution (2mL) and Et2O (5mL). Phenylboronic acid (82mg, 0.67mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with EtO. The water layer was freeze-dried and purified by ion exchange chromatography (PoraPakRxnCX 20cc columns). The desired product was eluted from the column using a methanol solution of 5% ammonia to obtain (2S, 3S) -2- amino -3- (((2S, 3S) -2- amino -3- methylpentanamido) methyl) -6- dihydroxyboryl hexanoic acid (Example 22, 93mg, 87% yield) as a white solid. 1 HNMR(500MHz,D2O)δ0.68-0.78(2H,m),0.80-0.91(6H,m),1.07-1.18(1H,m),1.27-1.48(5H,m),1.69(1H,br d),2.14(1H,br d),3.21-3.36(3H,m),3.62(1H,brd); m / z: (ES + )[M+H] + =318. Example 23: (2S,3S)-2- Amino-3-(((S)-2-amino-3,3-dimethylbutyramido)methyl)-6-dihydroxyborylhexanoic acid

[0437]

[0438] Intermediate 55: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butyloxycarbonylamino 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoic acid ester

[0439] N, N-diisopropylethylamine (1.08mL, 6.20mmol) is added to a suspension of HATU (472mg, 1.24mmol) and Boc-Tle-OH (550mg, 2.4mmol) in DCM (3mL) and DMF (3mL), and the reaction is stirred at room temperature for 10min. (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 50, 434mg, 0.911mmol) in DCM (4.5mL) is added, and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with water and DCM, and each layer is separated. The aqueous layer is extracted with DCM (2x20mL). The combined organic matter is washed with saturated sodium bicarbonate, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 55, 560 mg, 79% yield) as a colorless oil. 1 H NMR(500MHz,CDCl3)δ0.75(2H,br t),0.95-1.05(9H,m),1.18-1.25(13H,m),1.32-1.40(1H,m),1.42-1.45(9H,m),1 .46-1.51(9H,m),1.52-1.62(1H,m),1.64-1.73(1H,m),1.88-2.04(1H,m),3.08-3. 27(1H,m),3.39-3.56(1H,m),3.74-3.90(1H,m),4.18-4.30(1H,m),5.05-5.17(2H ,m),5.31(1H,s),5.47-5.80(1H,m),6.14-6.44(1H,m),7.30-7.40(5H,m); m / z: (ES + )[M+H] + =690.

[0440] Example 23: (2S,3S)-2-amino-3-(((S)-2-amino-3,3-dimethylbutyramido)methyl)-6-dihydroxy Boryl hexanoic acid

[0441] Pd / C (10 wt%, 138 mg, 0.130 mmol) was added to a solution of (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-(((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 55, 359 mg, 0.521 mmol) in ethyl acetate (12 mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature overnight. The reaction mixture was filtered through celite and rinsed with EtOAc and methanol. The filtrate was concentrated and the resulting residue was dissolved in DCM (3 mL) and trifluoroacetic acid (9 mL), and the reaction was stirred at room temperature for 3 h. The reaction was concentrated and the residue was dissolved in 1 M aqueous HCl (3 mL) and Et2O (5 mL). Phenylboronic acid (127 mg, 1.04 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with Et2O. The aqueous layer was freeze-dried and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using 5% ammonia in methanol. The obtained material was purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 10% acetonitrile in water) was further purified to afford (2S,3S)-2-amino-3-(((S)-2-amino-3,3-dimethylbutanamido)methyl)-6-boronohexanoic acid (Example 23, 96 mg, 58% yield) as a white solid. 1 H NMR(500MHz,D2O w / TFA)δ0.52-0.73(2H,m),0.90(9H,s),1.17-1.41(4H,m),2.11-2.23(1H,m),3.21-3.34(2H,m),3.49-3.55(1H,m),3.91-4.00(1H,m); m / z: (ES + )[M+H] + =318.

[0442] Example 24: (2S,3S)-2-amino-3-((2-aminoacetamido)methyl)-6-dihydroxyborylhexanoic acid

[0443]

[0444] Intermediate 56: (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((2-(tert-butoxycarbonylamino)ethyl Amino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0445] N, N-diisopropylethylamine (0.92mL, 5.3mmol) is added to a suspension of HATU (434mg, 1.14mmol) and Boc-Gly-OH (400mg, 2.28mmol) in DCM (3mL) and DMF (3mL), and the reaction is stirred at room temperature for 10min. (2S, 3S)-tert-butyl 3-(aminomethyl)-2-(benzyloxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) hexanoate (intermediate 50, 369mg, 0.775mmol) in DCM (3mL) is added, and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with water and DCM, and each layer is separated. The aqueous layer is extracted with DCM (2x 20mL). The combined organic matter is washed with saturated sodium chloride, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((2-(tert-butoxycarbonylamino)acetamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 56, 259 mg, 47% yield). 1 H NMR(500MHz,CDCl3)δ0.72(2H,br s),1.19(13H,br s),1.28-1.36(1H,m),1.36-1.45(18H,m),1.45-1.56(2H,m),2.03-2.13(1H,m),3.12(1H,brs),3.41(1H,br d),3.61-3.89(2H,m),4.16-4.38(1H,m),5.07(2H,br s),5.30-5.43(1H,m),5.95(1H,br s),6.73(1H,br s),7.22-7.36(5H,m).

[0446] Example 24: (2S,3S)-2-amino-3-((2-aminoacetamido)methyl)-6-dihydroxyborylhexanoic acid

[0447] Pd / C (10wt%, 107mg, 0.101mmol) was added to a solution of (2S,3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((2-(tert-butoxycarbonylamino)acetamido)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 56, 256mg, 0.404mmol) in ethyl acetate (8mL). The flask was equipped with a H2 balloon and the suspension was stirred at room temperature overnight. The reaction mixture was filtered through celite and rinsed with EtOAc and methanol. The filtrate was concentrated and the resulting residue was dissolved in DCM (2mL) and trifluoroacetic acid (6mL), and the reaction was stirred at room temperature for 3h. The reaction was concentrated and the residue was dissolved in 1M HCl aqueous solution (3mL) and Et2O (5mL). Phenylboronic acid (98mg, 0.80mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with Et2O. The aqueous layer was freeze-dried and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using 5% ammonia in methanol. The obtained material was purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 5% acetonitrile in water) was further purified to afford (2S,3S)-2-amino-3-((2-aminoacetamido)methyl)-6-boronohexanoic acid (Example 24, 20 mg, 19% yield) as a white solid. 1 H NMR (500MHz, D2O w / TFA) δ0.53-0.74(2H,m),1.16-1.45(4H,m),2.17-2.31(1H,m),3.16-3.36(2H,m),3.57-3.71(2H,m),3.96(1H,d); m / z: (ES + )[M+H] + =262.

[0448] Example 25: (2S,3S)-3-(Aminomethyl)-2-[[(2S)-2-aminopropionyl]amino]-6-dihydroxyboryl-hexane acid

[0449]

[0450] Intermediate 57: tert-butyl (2S,3S)-2-amino-3-[(tert-butoxycarbonylamino)methyl [4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate

[0451] Pd / C (10wt%, 243mg, 0.228mmol) is added to a solution of (2S, 3S)-tert-butyl 2-(benzyloxycarbonylamino)-3-((tert-butoxycarbonylamino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (intermediate 49, 1.40g, 2.43mmol) in EtOAc (50mL). The flask is equipped with a H2 balloon, and the suspension is stirred at room temperature overnight. The reaction mixture is filtered through diatomaceous earth and rinsed with EtOAc. The filtrate is concentrated to dryness to give the crude material as a colorless oil. The crude material was subjected to chiral SFC [Chiral Pak IC column, 21 x 250 mm, 5 μm, temperature = 40°C, mobile phase = 15% isopropanol (with 0.2% NH4OH):CO2, flow rate = 4 mL / min, outlet pressure = 100 bar] to give tert-butyl (2S,3S)-2-amino-3-[(tert-butoxycarbonylamino)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 57, 855 mg, 80% yield, >98:2 dr) as a colorless oil. 1 HNMR(500MHz, CDCl3)δ0.80(2H,t),1.19-1.33(14H,m),1.35-1.56(20H,m),1. 61-1.85(2H,m),1.88-2.00(1H,m),3.10-3.31(2H,m),3.39(1H,d),5.25(1H,br s); m / z: (ES) + )[M+H] + =444.

[0452] Intermediate 58: tert-butyl (2S,3S)-3-[(tert-butoxycarbonylamino)methyl]-2-[[(2S)-2-(tert-butoxy [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate]

[0453] HATU (142mg, 0.373mmol) is added to a solution of Boc-Ala-OH (70mg, 0.37mmol) in DMF (6mL), and the reaction is stirred at room temperature for 10min. Then tert-butyl (2S, 3S) -2- amino -3- [(tert-butoxycarbonylamino) methyl] -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) hexanoate (intermediate 57, 150mg, 0.34mmol) is added to the reaction as a solution in DMF (2mL). N, N- diisopropylethylamine (0.12mL, 0.68mmol) is added, and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with saturated NH4Cl aqueous solution and DCM, and each layer is separated. The aqueous layer is extracted with DCM (3x 20mL). The combined organic matter is dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give tert-butyl (2S,3S)-3-[(tert-butoxycarbonylamino)methyl]-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 58, 125 mg, 60% yield) as a white solid. 1 H NMR(500MHz, CDCl3)δ0.71-0.82(2H,m),1.16-1.36(14H,m),1.37-1.69(34H,m),2.14-2.28(1H,m),3.01-3.10(1H,m ),3.19-3.35(1H,m),4.21-4.36(1H,m),4.52-4.63(1H,m),4.66-4.80(1H,m),5.21-5.32(1H,m),7.13-7.25(1H,m).

[0454] Example 25: (2S,3S)-3-(Aminomethyl)-2-[[(2S)-2-aminopropionyl]amino]-6-dihydroxyboryl-hexane acid

[0455] Tert-butyl (2S, 3S) -3- [(tert-butoxycarbonylamino) methyl] -2- [[(2S) -2- (tert-butoxycarbonylamino) propionyl] amino] -6- (4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl) hexanoate (Intermediate 58, 125 mg, 0.204 mmol) was dissolved in HCl (4M in dioxane, 7.0 mL, 28 mmol) and the reaction was heated to 50 ° C and stirred for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting white solid was dissolved in 1M HCl aqueous solution (10 mL) and Et2O (10 mL). Phenylboronic acid (49 mg, 0.41 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous layer was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX20cc column). The desired product was eluted from the column using 2.5 M ammonia / methanol. The obtained material was purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 20% acetonitrile in water) was further purified to afford (2S,3S)-3-(aminomethyl)-2-[[(2S)-2-aminopropanoyl]amino]-6-borono-hexanoic acid (Example 25, 38 mg, 67% yield) as a white solid. 1 HNMR(500MHz,D2O)δ0.74(2H,t),1.31(3H,d),1.33-1.54(4H,m),2.14-2.25(1 H,m),2.98-3.04(1H,m),3.06-3.15(1H,m),3.64(1H,q),4.36(1H,d); m / z: (ES + )[M+H] + =276.

[0456] Example 26: (2S,3S)-3-(aminomethyl)-2-[[(2S)-2-amino-3-methyl-butyryl]amino]-6-di Boryl-hexanoic acid

[0457]

[0458] Intermediate 59: tert-butyl (2S,3S)-3-[(tert-butoxycarbonylamino)methyl]-2-[[(2S)-2-(tert-butyl Butoxy [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-( ... Hexanoate

[0459] HATU (326mg, 0.857mmol) is added to a solution of Boc-Val-OH (186mg, 0.857mmol) in DMF (10mL), and the reaction is stirred at room temperature for 10min. Then tert-butyl (2S, 3S) -2- amino -3- [(tert-butoxycarbonylamino) methyl] -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) hexanoate (intermediate 57, 345mg, 0.780mmol) is added to the reaction as a solution in DMF (5mL). N, N- diisopropylethylamine (0.27mL, 1.6mmol) is added, and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with saturated NH4Cl aqueous solution and DCM, and each layer is separated. The aqueous layer is extracted with DCM (3x 40mL). The combined organic matter is dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to give tert-butyl (2S,3S)-3-[(tert-butoxycarbonylamino)methyl]-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (Intermediate 59, 422 mg, 84% yield) as a white solid. 1 HNMR(500MHz, CDCl3)δ0.77(2H,m),0.90-1.04(6H,m),1.13-1.36(14H,m),1.37-1.72(31H,m),2.1 2-2.31(2H,m),2.94-3.08(1H,m),3.18-3.37(1H,m),4.00-4.11(1H,m),4.61(1H,brd),4.70(1H,br d),5.22(1H,m),7.08-7.20(1H,m).

[0460] Example 26: (2S,3S)-3-(aminomethyl)-2-[[(2S)-2-amino-3-methyl-butyryl]amino]-6-di Boryl-hexanoic acid

[0461] Tert-butyl (2S, 3S) -3- [(tert-butoxycarbonylamino) methyl] -2- [[(2S) -2- (tert-butoxycarbonylamino) -3-methyl- butanoyl] amino] -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) hexanoate (Intermediate 59, 422, 0.658 mmol) was dissolved in HCl (4M in dioxane, 10.0 mL, 48.0 mmol) and the reaction was heated to 50 ° C and stirred for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting white solid was dissolved in 1M HCl aqueous solution (15 mL) and Et2O (15 mL). Phenylboronic acid (160 mg, 1.32 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous layer was lyophilized and purified by ion exchange chromatography (Silicycle SPE-R51230B-20X column). The desired product was eluted from the column using 2.5M ammonia / methanol. The obtained material was purified by reverse phase chromatography (RediSep Rf C18Aq, 0 to 20% acetonitrile in water) was further purified to afford (2S,3S)-3-(aminomethyl)-2-[[(2S)-2-amino-3-methyl-butyryl]amino]-6-borono-hexanoic acid (Example 26, 162 mg, 81% yield) as a white solid. 1 H NMR(500MHz,D2O)δ0.76(2H,t),0.91(3H,d),0.95(3H,d),1.28-1.52(4H,m),1.99(1H,dq ),2.18(1H,dq),2.98-3.07(1H,m),3.08-3.17(1H,m),3.31(1H,d),4.37(1H,d); m / z: (ES + )[M+H] + =304.

[0462] Example 27: Biological Activity of Examples 1-26

[0463] The inhibitory effect of Examples 1-26 on human arginase 1 and arginase 2 activity was quantified by measuring the formation of thiol groups by thioarginine using recombinant arginase 1 or arginase 2 produced by E. coli. Thiol groups were detected using Ellman's reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). DTNB reacts with thiols to produce mixed disulfides and 2-nitro-5-thiobenzoic acid (TNB), which is detected by the negative ion (TNB) at 412 nm. 2- ) was quantified by absorbance.

[0464] The assay was performed in clear 384-well plates (Greiner Cat. No. 781101). 300 nL of different concentrations of Examples 1-26 in DMSO were dispensed into the assay plates using an Echo acoustic dispenser, followed by immediate plate sealing and centrifugation.

[0465] Two premixes were prepared from reagents thawed just before addition to the assay plate. Premix 1 contained human arginase 1 or human arginase 2 at a final concentration of 5 nM and 0.5 mM DTNB in ​​the following assay buffer: 45 mM HEPES pH 7.5, brij 35 (0.045% (w / v)) and 100 μM MnCl2. Premix 2 contained freshly thawed 0.5 mM thioarginine in assay buffer. 15 microliters of premix 1 were dispensed into the assay plate containing Examples 1-9, centrifuged and incubated at room temperature for 30 minutes, then 15 microliters of premix 2 were added.

[0466] The assay plate was centrifuged, and then the absorbance at 412 nm was read in a Pherastar multi-mode microplate reader to collect the data for time point 0 (T0). The plate was incubated at room temperature for 60 min, and then read again to collect the data for time point 1 (T1). The A412 signal measured by T0 (time point 0) was subtracted from the A412 signal measured by T1 (time point 1) to obtain data. The following equation was used to convert the data into % action:

[0467] Compound effect % = 100*[(X-minimum) / (maximum-minimum)],

[0468] Where X represents the normalized value of the compound based on the minimum (vehicle) and maximum (reference compound) inhibition controls.

[0469] The concentration of Examples 1-26 that inhibited activity by 50% (i.e., IC) was calculated by plotting the % effect versus test compound concentration and fitting the data using the Genedata Screener Smart fitting algorithm. 50 The results of these measurements are shown in Table 2:

[0470] Table 2

[0471]

[0472]

[0473] Example 28: Bioavailability Study

[0474] Example 14 is a prodrug form of Example 1. Examples 19 to 22 and 24 to 26 are prodrugs of Example 18. The following pharmacokinetic studies were performed to demonstrate the bioavailability of Example 18 from Example 19. Example 19 was formulated in 0.9% w / v saline pH 4 (adjusted with 1M HCl) for intravenous (IV) administration. The formulation was administered to two male rats (170 g-250 g each) via femoral catheter at 2 mg / kg. Continuous blood samples were collected from the jugular catheter at 0.033, 0.083, 0.167, 0.5, 1, 2, 4, 8 and 24 hours after administration. For oral (PO) administration, Example 19 was formulated in deionized water pH 4 (adjusted with 1M HCl) and administered to two male rats (170 g-250 g each) via oral gavage at 5 mg / kg. Continuous blood samples were collected by jugular catheter at 0.25, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours after administration. Plasma samples were produced from blood using low-speed centrifugation. A single set of calibration standards containing Example 18 and Example 19 was prepared by spiking blank plasma. Samples and standards were extracted by precipitation with two volumes of acetonitrile and then centrifuged. The results obtained were used to determine Cl (mL / min / kg), Vdss (L / kg), Cmax (μM), AUC (μM h), tmax (h) and %F of Example 18 and Example 19. Absolute bioavailability was determined by comparing the oral dose normalized AUC of Example 18 (when administered as Example 19) with the intravenous dose normalized AUC of Example 18 (when administered as Example 18). When appropriate, the measured dose was used instead of the nominal dose for calculation. In a similar manner, the same procedure was repeated for Examples 14, 20 to 22, and 24 to 26. The results are shown in Tables 3 to 10. These results indicate that bioavailability can be improved by incorporating certain amino acid moieties as prodrugs.

[0475] Table 3

[0476] Example 19 Example 18 Cl(mL / min / kg) <![CDATA[16.40 # ]]> 7.30* Vdss(L / kg) <![CDATA[0.47 # ]]> 0.38* PO Cmax(μM) <![CDATA[0.66 # ]]> <![CDATA[4.40 # ]]> PO AUC (μM.h) <![CDATA[1.40 # ]]> <![CDATA[15.6 # ]]> Tmax(h) <![CDATA[0.50 # ]]> <![CDATA[1.50 # ]]> ％F <![CDATA[8.30 # ]]> <![CDATA[37.00 # ]]>

[0477] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0478] Table 4

[0479] Example 20 Example 18 Cl(mL / min / kg) <![CDATA[12.50 # ]]> 7.30* Vdss(L / kg) <![CDATA[0.21 # ]]> 0.38* PO Cmax(μM) <![CDATA[0.44 # ]]> <![CDATA[8.10 # ]]> PO AUC (μM.h) <![CDATA[1.25 # ]]> <![CDATA[30.90 # ]]> Tmax(h) <![CDATA[0.75 # ]]> <![CDATA[1.25 # ]]> ％F <![CDATA[5.10 # ]]> <![CDATA[54.90 # ]]>

[0480] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0481] Table 5

[0482] Example 21 Example 18 Cl(mL / min / kg) <![CDATA[14.10 # ]]> 7.30* Vdss(L / kg) <![CDATA[0.22 # ]]> 0.38* PO Cmax(μM) <![CDATA[0.23 # ]]> <![CDATA[10.20 # ]]> PO AUC (μM.h) <![CDATA[0.35 # ]]> <![CDATA[32.40 # ]]> Tmax(h) <![CDATA[0.50 # ]]> <![CDATA[1.25 # ]]> ％F <![CDATA[1.50 # ]]> <![CDATA[72.00 # ]]>

[0483] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0484] Table 6

[0485] Example 22 Example 18 Cl(mL / min / kg) <![CDATA[13.10 # ]]> 7.30* Vdss(L / kg) <![CDATA[0.20 # ]]> 0.38* PO Cmax(μM) <![CDATA[0.45 # ]]> <![CDATA[4.70 # ]]> PO AUC (μM.h) <![CDATA[0.92 # ]]> <![CDATA[16.00 # ]]> Tmax(h) <![CDATA[1.00 # ]]> <![CDATA[1.75 # ]]> ％F <![CDATA[4.50 # ]]> <![CDATA[39.00 # ]]>

[0486] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0487] Table 7

[0488] Example 24 Example 18 Cl(mL / min / kg) <![CDATA[8.40 # ]]> 7.30* Vdss(L / kg) <![CDATA[0.20 # ]]> 0.38* PO Cmax(μM) <![CDATA[0.88 # ]]> <![CDATA[1.30 # ]]> PO AUC (μM.h) <![CDATA[2.90 # ]]> <![CDATA[6.40 # ]]> Tmax(h) <![CDATA[1.75 # ]]> <![CDATA[2.50 # ]]> ％F <![CDATA[6.40 # ]]> <![CDATA[11.30 # ]]>

[0489] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0490] Table 8

[0491] Example 26 Example 18 Cl(mL / min / kg) <![CDATA[26.60 # ]]> <![CDATA[7.30 * ]]> Vdss(L / kg) <![CDATA[0.15 # ]]> <![CDATA[0.38 * ]]> PO Cmax(μM) <![CDATA[NV # ]]> <![CDATA[15.30 # ]]> PO AUC (μM.h) <![CDATA[NV # ]]> <![CDATA[37.30 # ]]> Tmax(h) <![CDATA[NV # ]]> <![CDATA[0.75 # ]]> ％F <![CDATA[NV # ]]> <![CDATA[66.30 # ]]>

[0492] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0493] Table 9

[0494] Example 25 Example 18 Cl(mL / min / kg) <![CDATA[28.30 # ]]> 7.30* Vdss(L / kg) <![CDATA[0.18 # ]]> 0.38* PO Cmax(μM) <![CDATA[0.04 # ]]> <![CDATA[8.83 # ]]> PO AUC (μM.h) <![CDATA[NV # ]]> <![CDATA[26.20 # ]]> Tmax(h) <![CDATA[0.25 # ]]> <![CDATA[1.00 # ]]> ％F <![CDATA[NV # ]]> <![CDATA[56.00 # ]]>

[0495] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no reportable value

[0496] Table 10

[0497] Example 14 Example 1 Cl(mL / min / kg) <![CDATA[46.10 # ]]> 8.26* Vdss(L / kg) <![CDATA[0.47 # ]]> 0.46* PO Cmax(μM) <![CDATA[0.13 # ]]> <![CDATA[3.42 # ]]> PO AUC (μM.h) <![CDATA[NV # ]]> <![CDATA[15.50 # ]]> Tmax(h) <![CDATA[0.25 # ]]> <![CDATA[1.75 # ]]> ％F <![CDATA[NV # ]]> <![CDATA[42.30 # ]]>

[0498] #Observed values ​​when prodrug is administered *Observed values ​​when payload is administered. NV has no value to report.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in R 1 is selected from hydrogen, -CH3 and -(C=O)CH(R 1a )NH2; R 1a is a C1-C4 alkyl group; Y is -(CH2) n -or -(C=O)-; n is an integer selected from 1 and 2; R 2 is selected from hydrogen, -CH3 and -(C=X)R 4 , and R 3 is hydrogen or -CH3; or R 2 and R 3 are joined together with the nitrogen to which they are attached to form a 6-membered heterocyclic ring; X is NH or O; R 4 is -CH3 or -[CH(R 4a )] m NH2; m is an integer selected from 0 or 1; and R 4a It is hydrogen or C1-C6 alkyl.

2. The compound of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia):

3. The compound of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib):

4. A compound of formula (II) or a pharmaceutically acceptable salt thereof: in R 11 Selected from hydrogen, -CH3 and Where * indicates (S) stereochemistry; Y 1 Yes - (CH2) p -or-(C=O)-; p is an integer selected from 1 and 2; R 11a is a C1-C4 alkyl group; R 12is selected from hydrogen, -CH3 and -(C=X 1 )R 14 , and R 13 is hydrogen or -CH3; or R 12 and R 13 are joined together with the nitrogen to which they are attached to form a 6-membered heterocyclic ring; X 1 is NH or O; R 14 is -CH3 or Where * indicates (S) stereochemistry; R 14a is C1-C4 alkyl; and q is an integer selected from 0 and 1.

5. A compound having formula (III) or a pharmaceutically acceptable salt thereof: in R 22 is hydrogen or wherein * indicates (S) stereochemistry; and R 24a It is a C1-C4 alkyl group.

6. A compound having formula (IV) or a pharmaceutically acceptable salt thereof: in R 11 Selected from wherein * indicates (S) stereochemistry; and R 11a It is a C1-C4 alkyl group.

7. A compound listed in Table 1 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

9. A method for treating cancer, comprising administering to a subject a therapeutically effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in treating cancer.

11. The pharmaceutical composition according to claim 8, for use in treating cancer.

12. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer.

13. A method for treating respiratory inflammatory diseases, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in treating respiratory inflammatory diseases.

15. The pharmaceutical composition according to claim 8, for use in treating respiratory inflammatory diseases.

16. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating respiratory inflammatory diseases.

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