KR20010012256A - Protease Inhibitors - Google Patents

Abstract

The present invention relates to 3-hydroxy- and 3-keto-cyclohetero-substituted leucine compounds which are inhibitors of cysteine proteases, especially cathepsin K, and which are useful in the treatment of diseases in which inhibition of bone loss is a factor. The 3-hydroxy- or 3-keto- moiety is bound to a tetrahydrothiophene, tetrahydrothiopyran, tetrahydrofuran or tetrahydropyran ring.

Description

Protease Inhibitors

Cathepsin K is a type of enzyme that is part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S are described in the literature. Recently, cathepsin K polypeptides and cDNAs encoding such polypeptides have been disclosed in US Pat. No. 5,501,969 (herein termed cathepsin O). Cathepsin K has recently been expressed, purified and characterized. Bossard, M. J., et al., (1996) J. Boil. Chem. 271, 12517-12524; Drake, F. H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132

Cathepsin K is variously expressed in the literature as cathepsin O, cathepsin X or cathepsin O2. The name cathepsin K is considered to be the most appropriate (as defined by the Nomenclature Committee of the International Association of Biochemical and Molecular Biology).

Cathepsins of the papain superfamily of cysteine proteases act on the normal physiological proteolytic processes in animals, including humans, for example, the degradation of connective tissue. However, increased levels of these enzymes in the body can lead to disease-causing conditions. That is, cathepsins have several disease states, such as but not limited to pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei and creti Infections caused by Crithidia fusiculata, as well as disease states including schistosomiasis, malaria, tumor metastasis, discolored white matter dystrophy, muscular dystrophy, muscular dystrophy and the like. Reference; International Application Publication No. WO94 / 04172 (published March 3, 1994) and references cited therein. Reference; European patent application EP 0 603 873 A1 and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, are involved in the development of gingivitis. Reference; Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.

Cathepsin K is believed to play a causal role in the disease of excessive bone or cartilage loss. Bone is composed of protein substrates incorporating fusiform- or planar-crystals of hydroxyapatite. Type I collagen represents the major structural protein of bone, making up about 90% of structural proteins. The remaining 10% of the substrate consists of a number of non-collagenic proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone cyloproteins. Skeletal bones are remodeled at separate points throughout life. These points or remodeling units follow a cycle consisting of a bone absorption step followed by a bone replacement step.

Bone uptake is carried out by osteoclasts, which are multinuclear cells of the hematopoietic lineage. Osteoclasts attach to the bone's surface to form a tight junction, which then causes extensive membrane folds on their tip (ie, resorption) surface. This creates an extracellular compartment on the bone surface acidified by the proton pump in the corrugated membrane, where the osteoclasts secrete proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while proteolytic enzymes digest the protein substrate. In this way, an absorbent bovine, or bovine, is formed. At the end of the phase of this cycle, osteoclasts form the basis of a new protein substrate, which is subsequently mineralized. In many disease states, such as osteoporosis and Peget's disease, the usual balance between bone absorption and formation is broken and bone loss is lost in each cycle. As a result, the risk of bone weakening and fracture with minimal trauma may be increased.

Many selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, by selectively inhibiting cathepsin K, diseases including excessive bone loss diseases, such as but not limited to gingival diseases such as osteoporosis, gingivitis and periodontitis, peget's disease, malignant hypercalcemia and metabolic bone disease Can provide an effective treatment. It has also been demonstrated that cathepsin K levels are elevated in cartilage absorbing cells of the osteoarthritis synovial membrane. Thus, selective inhibition of cathepsin K may be useful for the treatment of diseases of excessive cartilage or matrix degradation, including but not limited to osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding substrate. Thus, selective inhibition of cathepsin K may also be useful for the treatment of certain neoplastic diseases.

Now, a new class of compounds has been found to be protease inhibitors, most particularly cathepsin K inhibitors, and that these compounds are useful for the treatment of diseases in which inhibition of bone resorption occurs, such as osteoporosis and fasciitis diseases.

The present invention relates to novel protease inhibitors, in particular inhibitors of cysteine and serine proteases, more particularly compounds that inhibit cysteine proteases. The compounds of the present invention more particularly relate to compounds which inhibit cysteine proteases with papain superfamily, in particular cysteine proteases with cathepsin. In the most preferred embodiment, the invention relates to compounds which inhibit cathepsin K. Such compounds are particularly useful for the treatment of diseases involving cysteine proteases, in particular diseases of excessive bone or cartilage loss, such as osteoporosis, fasciitis and arthritis.

It is an object of the present invention to provide protease inhibitors such as inhibitors of cysteine and serine proteases. In particular, the present invention relates to compounds that inhibit cysteine proteases, in particular cysteine proteases with papain. Preferably, the present invention relates to compounds which inhibit cysteine protease with cathepsin, in particular compounds which inhibit cathepsin K. The compounds of the present invention are useful for the treatment of diseases, and these diseases may be therapeutically altered by altering the activity of the protease.

Thus, in a first aspect, the present invention provides a compound of formula (I)

In another aspect, the present invention provides a pharmaceutical composition containing a compound of formula I and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of treating a disease in which the disease lesion may be therapeutically altered by inhibiting proteases such as cysteine and serine proteases. In particular, the method involves treating the disease by inhibiting cysteine proteases, in particular cysteine proteases. More specifically, inhibition of cysteine protease with cathepsin such as cathepsin K is included.

In another aspect, the compounds of the present invention provide for the treatment of diseases characterized by osteoporosis and gingival diseases, such as gingivitis and periodontitis, characterized by bone loss or characterized by the breakdown of excess cartilage or matrix such as osteoarthritis and rheumatoid arthritis. Is especially useful.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

<Formula I>

[Wherein,

R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O);

R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl;

R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl;

R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl;

X is O or S;

n is 1, 2 or 3]

The present invention includes all hydrates, solvates, complexes and drug precursors of the compounds of the present invention. The drug precursor is any covalently linked compound capable of releasing the active parent drug of formula (I) in vivo. If chiral centers or other forms of isomeric centers are present in the compounds of the present invention, it is contemplated that all forms of isomers or isomers, including enantiomers and diastereomers, are included in the present invention. The compounds of the present invention containing chiral centers can be used as racemic mixtures, mixtures rich in enantiomers, or the racemic mixtures can be separated using known techniques or the individual enantiomers can be used alone. According to the invention, the S-form at the furan ring contact of the compound of formula I is preferred.

Where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of the present invention. Where compounds may exist in tautomeric forms, such as keto-enol tautomers, it is contemplated that each tautomeric form, whether present in equilibrium or one form prevails, is included in the present invention.

The meaning of any substituent in any one of formula (I) or subformulae thereof is independent of the meaning of any such substituent or in any other substituent, unless stated otherwise.

In formula (I):

Suitably R ² and R ⁴ are H and R ³ is C _1-6 alkyl or C _2-6 alkenyl. Preferably, R ³ is i-butyl.

Suitably, each R ⁵ is H.

Suitably, R ¹ is R ″ OC (O), R ″ SO ₂ , or R ″ C (O), wherein R ″ is Ar-C _0-6 alkyl or Het-C _0-6 alkyl, Most preferably R "is as follows:

{Where B ₂ is OH, CN, OCF ₃ , OC _1-6 alkyl, OAr, SO ₂ C _1-6 alkyl, C _1-6 alkyl or halogen}

Suitably n is 1 or 2. Preferably, n is one.

Suitably, X is O.

In one particular embodiment, the present invention is a compound of Formula II:

Preferably, the compound of formula I of the present invention is a compound of formula IIa:

Alternatively, the compound of formula I of the present invention is a compound of formula IIb:

In another embodiment, the invention is a compound of Formula IIc:

Specific exemplary compounds of the invention are as follows:

4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -Amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -Amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(2-quinolincarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(8-quinolincarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -2,2-dibenzyl-tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(indol-6-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(5-aminobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(5-chlorobenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -Amino-N-[(3-bromobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(4-bromobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -Amino-N-[(4-fluorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(4-phenoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -Amino-N-[(4-phenylbenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(6-trifluoromethylbenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -Amino-N-[(4-ethylbenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(4- (t-butyl) benzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(5-methoxybenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(4-nitrobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(6-bromobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(5-bromobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(6-methoxybenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(benzo (b) thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-R-amino-N-[(benzo (b) thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(2-naphthoyl) -S-leucine] -tetrahydrofuran-3-one;

4-R-amino-N-[(2-naphthoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(quinolin-2-carbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-R-amino-N-[(quinolin-2-carbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[((4-pyrid-3-yl) benzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[((4-pyrid-2-yl) benzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(4- [6-methylpyrid-3-yl] benzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[((4-pyrid-4-yl) benzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(2-chlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(4-bromobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(4-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(4-benzylpiperidin-1-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4-S-amino-N-[(3-chlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one;

4- (R, S) -amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -tetrahydropyran-3-one;

4- (R, S) -Amino-N-[(4-phenoxybenzoyl) -S-leucine] -tetrahydropyran-3-one;

4- (R, S) -amino-N-[(quinolin-2-ylcarbonyl) -S-leucine] -tetrahydropyran-3-one;

4- (R, S) -Amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydropyran-3-one;

4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydropyran-3-one; And

4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrothiophen-3-one;

Or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides novel intermediates represented by the following formulas (II), (IV) and (V) which are useful in the preparation of compounds of formula (I):

[Wherein,

R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O);

R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl;

R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl;

R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl;

n is 1, 2 or 3]

Or a pharmaceutically acceptable salt thereof, or

[Wherein,

R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O);

R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl;

R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl;

R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl;

n is 1, 2 or 3]

Or a pharmaceutically acceptable salt thereof.

[Wherein,

R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O);

R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl;

R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl;

R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl;

X is O or S;

n is 1, 2 or 3]

Or a pharmaceutically acceptable salt thereof.

Representative intermediates of the invention are as follows:

Trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(t-butoxycarbonyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(2-quinolinecarbonyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran;

Trans-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydropyran;

Trans-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(indol-6-ylcarbonyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4- (R, S) -amino-N-[(5-aminobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydrofuran;

Trans-4-amino-3-hydroxytetrahydrofuran;

Trans-3-hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran;

4-benzyloxycarbonylamino-tetrahydrofuran-3-one;

3,3-dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran;

3,3-dimethoxy-4-amino-tetrahydrofuran;

Trans-4-S-amino-3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(benzyloxycarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N- (S-leucine) -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(2-quinolinecarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(2-naphthoyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(4-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(4-bromobenzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(4- (pyrid-2-yl) benzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(4- (pyrid-3-yl) benzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-S-amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran;

Trans-4-amino-3-hydroxytetrahydropyran;

Trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran;

Trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydropyran;

Trans-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydropyran;

N-benzo [b] thiophen-2-ylcarbonyl-L-leucine methyl ester;

N-benzo [b] thiophen-2-ylcarbonyl-L-leucine;

N-benzo [b] thiophen-2-ylcarbonyl-L-leucine-S- (methoxycarbonylmethyl) -L, D-cysteine ethyl ester; And

2-methoxycarbonyl-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrothiophen-3-one;

Or salts thereof.

These intermediates are prepared according to methods analogous to the reactions described in Schemes 1-4 and the examples described below.

The drug precursors of the compounds of the present invention may be ketone functional precursors of the ketone functional compounds of compounds of formula (I), specifically ketals or hemiketals of formula (VI), or pharmaceutically acceptable salts thereof:

[Wherein,

R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O);

R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl;

R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl;

R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl;

R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl;

X is O or S;

n is 1, 2 or 3;

R ^a and R ^{a '} are independently H or C _1-2 alkyl, provided that when one of R ^a and R ^a' is H, the other is C _1-2 alkyl; Together they form a 5- or 6-membered ring (CH ₂ ) _2-3 ]

Abbreviations and symbols commonly used in the field of peptides and chemistry are used herein to describe the compounds of the invention. In general, amino acid abbreviations comply with the IUPAC-IUB Joint Committee on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). The term "amino acid" as used herein refers to alanine, arginine, asparagine, asparagine, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine Refers to the D- and L-isomers.

As used herein, “C _1-6 alkyl” refers to substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neo Pentyl and hexyl and their simple aliphatic isomers. Any C _1-6 alkyl group optionally contains 1 or 2 halogen, SR ′, OR ′, N (R ′) ₂ , C (O) N (R ′) ₂ , carbamyl or C _1-4 alkyl (wherein R 'may be independently substituted with H or C _1-6 alkyl. C ₀ alkyl means that no alkyl group is present at the residue. That is, Ar-C ₀ alkyl is the same as Ar.

As used herein, "C _3-6 cycloalkyl" means substituted (ie, alkyl, OR, SR or halogen) and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.

As used herein, "C _2-6 alkenyl" refers to an alkyl group having 2 to 6 carbon atoms in which a carbon-carbon single bond is replaced with a carbon-carbon double bond. C _2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and various isomers of pentene and hexene. Both cis and trans isomers are included.

"C _2-6 alkynyl" refers to an alkyl group having 2 to 6 carbon atoms in which a carbon-carbon single bond is replaced with a carbon-carbon triple bond. C _2-6 alkynyl includes isomers of acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and simple pentines and hexynes.

"Halogen" or "halo" means F, Cl, Br and I.

"Ar" or "aryl" means unsubstituted phenyl or naphthyl; Or one or more Ph-C _0-6 alkyl, Het-C _0-6 alkyl, C _1-6 alkoxy, Ph-C _0-6 alkoxy, Het-C _0-6 alkoxy, OH, (CH ₂ ) _1-6 NR'R ', O (CH ₂ ) _1-6 NR'R', wherein each R 'is independently H, C _1-6 alkyl, Ar-C _0-6 alkyl or Het-C _0-6 Phenyl or naphthyl; Or _{1 selected from} C _1-4 alkyl, OR ', N (R') ₂ , SR ', CF ₃ , NO ₂ , CN, CO ₂ R', CON (R ') ₂ , F, Cl, Br and I Phenyl or naphthyl substituted with from 3 substituents or substituted with methylenedioxy.

"Het" or "heterocyclic" as used herein denotes a stable 5- to 7-membered monocyclic or stable 7- to 10-membered bicyclic heterocyclic ring, which are saturated or unsaturated, are carbon atoms and N, Consisting of 1 to 4 heteroatoms selected from the group consisting of O and S, of which nitrogen and sulfur heteroatoms may be optionally oxidized and nitrogen heteroatoms may optionally be quaternized, and any heterocyclic ring as defined above Comprises any bicyclic group fused to a benzene ring. The heterocyclic ring may be bonded to any heteroatom or carbon atom, resulting in a stable structure, optionally C _1-4 alkyl, OR ', N (R') ₂ , SR ', CF ₃ , NO ₂ Or CN, CO ₂ R ', CON (R') ₂ , F, Cl, Br and I, where R 'is as defined above. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, thienyl, Pyrrolyl, 4-piperidoneyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thia Zolidinyl, thiazolinyl, isothiazolyl, thiazolyl, quinucridinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzopyranyl, benzooxazolyl, benzofuranyl , Furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzooxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benziso Oxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,6-naphthyri Carbonyl, 1,7-naphthyridin piperidinyl, 1,8-naphthyridin piperidinyl, there may be mentioned tetrazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl.

Certain radical groups are also abbreviated herein. t-Bu means tertiary butyl radical; Boc or BOC means t-butyloxycarbonyl radical; Fmoc means fluorenylmethoxycarbonyl radical; Ph stands for phenyl radical; Cbz or CBZ means benzyloxycarbonyl radical.

Certain reagents are also abbreviated herein. DCC is dicyclohexylcarbodiimide; EDC or EDCI is N-ethyl-N '(dimethylaminopropyl) carbodiimide. HOBT or HOBt is 1-hydroxybenzotriazole; DMF is dimethyl formamide; DIEA is di-isopropylethylamine; The Lawson reagent is 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide; TFA is trifluoroacetic acid and THF is tetrahydrofuran.

Compounds of formula (I) are generally prepared as follows:

(i) reacting a compound of formula III with an oxidant:

<Formula III>

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in formula (I) and all reactive functional groups are protected; or

(ii) decarboxylation of the compound of formula IV:

<Formula IV>

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in formula (I) and all reactive functional groups are protected; or

(iii) reacting a compound of formula V with an acid:

<Formula V>

Wherein R ¹ , R ³ , R ⁴ , R ⁵ and n are as defined in formula (I) and all reactive functional groups are protected;

The protecting group is then removed and optionally a pharmaceutically acceptable salt is formed.

Compounds of formula (I) are prepared by methods analogous to those described for the solution synthesis method of Scheme 1, or the solid support method of Scheme 2, or the solution synthesis method of Scheme 3.

a) NaN ₃ , ammonium chloride, methanol: water; b) 10% Pd / C, EtOH, H ₂ ; HCl ethanol solution; c) trimethylacetyl chloride, N-BOC-leucine, DIEA, CH ₂ Cl ₂ ; d) TFA, CH ₂ Cl ₂ ; e) RCOCl, sodium hydrogen carbonate, 1,4-dioxane; f) Dess-Martin periodinane reagent, CH ₂ Cl ₂

Compounds of formula (I) wherein n is 1 and R ¹ is R ″ C (O) are prepared by the method shown in Scheme 1. A known epoxide (1 in Scheme 1) is sodium azide and chloride in aqueous methanol at elevated temperature. Treatment with ammonium yields azide (2 in Scheme 1), reducing the azide (2 in Scheme 1) using methods known in the art, such as reduction of palladium on carbon in ethanol under a hydrogen atmosphere. Treatment with an ethanol solution of hydrogen chloride yields an amine salt (3 in Scheme 1.) The amine salt (3 in Scheme 1) is known in the art such as acylation with acid chlorides or binding to acids in the presence of EDC and HOBT. Coupling with a carboxylic acid by known methods yields an amide (4 in Scheme 1.) reaction by removing t-butoxycarbonyl groups by treatment with a strong acid such as TFA in an aprotic solvent such as dichloromethane. 5 of 1 can be obtained 6. The salt (5 of Scheme 1) can be acylated with acid chloride in 1,4-dioxane in the presence of an aqueous base such as saturated sodium hydrogen carbonate to afford 6 of Scheme 1. Alcohols (6 in Scheme 1) can be oxidized by methods known in the art, such as treatment with des-martin periodinan reagent in an aprotic solvent such as dichloromethane.

A compound of formula (I) wherein R ¹ is C (O) R ', R ² is H, R ⁴ is H, R ⁵ is H, X is O and n is 1 is a solid support synthesis shown in Scheme 2. It is manufactured by the (SPS) method. In particular, in the first step, sodium triacetoxyborohydride is added to a stirred solution of Elmans resin in DMF containing 1% HOAc, followed by the addition of α-amino acid methyl ester to form 2 in Scheme 2. . Known methods such as the addition of EDC and carboxylic acids are used to combine amine groups with carboxylic acids to produce amides (3 in Scheme 2). Subsequently, the ester group is hydrolyzed with potassium trimethylsilane in THF, for example, and the free acid group is combined with 3,3-dimethoxy-4-amino-tetrahydrofuran using EDC, for example in NMP. Produces 4 The blocking group is then removed by known cleavage methods such as the addition of 7: 2: 1 TFA / CH ₂ Cl ₂ / H ₂ O to afford the desired compound (5 of Scheme 2).

A compound of formula (I) wherein R ¹ is C (O) R ', R ² is H, R ⁴ is H, R ⁵ is H, X is O, n is 2, 3,3-dimethoxy Except for replacing 4-aminotetrahydrofuran with 3,3-dimethoxy-4-aminotetrahydropyran, it is prepared by the solid support synthesis (SPS) method shown in Scheme 2.

(a) L-Leu methyl ester, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ ; (b) LiOH, THF / H ₂ O; (c) (i) ClCO ₂ ⁱ Pr, Et ₃ N, CH ₂ Cl ₂ (ii) L-Cys ethyl ester (iii) BrCH ₂ CO ₂ Me; (d) (i) NaOMe, MeOH, (ii) AcOH / HCl, H ₂ O

Scheme 4 below shows the preparation of certain compounds of formula I which are S-diastereomers at furan ring junctions.

R-diastereomers are prepared in the same way from the opposite 3-azido-4-hydroxytetrahydrofuran enantiomers:

Intermediates of the invention, such as 3,3-dimethoxy-4-aminotetrahydrofuran, can be prepared according to the method of Scheme 5.

The steps of Scheme 5 are described as follows. First, 3-hydroxy-4-aminotetrahydrofuran is reacted with benzylchloroformate in dioxane containing aqueous sodium carbonate to add a nitrogen protecting group. The alcohol group is then oxidized by known methods such as adding a bleach containing sodium bicarbonate in the presence of sodium bromide and TEMPO in EtOAc, toluene and water. Ketones are converted to dimethylketal by addition of trimethyl-orthoformate in the presence of paratoluenesulfonic acid in methanol. Finally, the protecting group is removed, for example by hydrogenation with palladium on charcoal in the presence of ethanol in a hydrogen atmosphere.

Starting materials used herein are either commercially available or are prepared by routine methods known to those skilled in the art and include ordinary reference books such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (Wiley-Interscience). You can find it at

Bonding methods for forming amide bonds herein are generally known in the art. Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); And peptide synthesis methods generally described by JMStewart and JDYoung, SOLID PHASE PEPTIDES SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111, 1984 are examples of such techniques, which are incorporated herein by reference. It is cited in the literature.

Synthetic methods for preparing compounds of the present invention often use protecting groups to hide reaction functionality or minimize unwanted side reactions. Such protecting groups are generally described in Green, T. W. PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting group" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof known in the art. Methods of protection and deprotection and replacement of amino protecting groups with other residues are known.

Acid addition salts of compounds of formula (I) may be used in the appropriate solvents with a parent compound and with excess acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methane It is prepared from sulfonic acid by conventional methods. Some of the compounds form an acceptable intramolecular salt or zwitterion. Cationic salts are prepared by treating the mother compound with an excess of alkaline reagents, such as hydroxides, carbonates or alkoxides containing appropriate cations, or with appropriate organic amines. Cations such as Li +, Na +, K +, Ca + +, Mg + + and NH 4 + are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfates, phosphates, alkanoates (such as acetates and trifluoroacetates), benzoates and sulfonates (such as mesylates) are examples of anions present in pharmaceutically acceptable salts.

The present invention also provides a pharmaceutical composition containing a compound of formula (I) and a pharmaceutically acceptable carrier. Thus, the compounds of formula (I) can be used in the preparation of medicaments. Pharmaceutical compositions of the compounds of formula (I) prepared as described above may also be formulated as solutions or lyophilized powders for parenteral administration. The powder may be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be an isotonic, buffered aqueous solution. Examples of suitable diluents are conventional isotonic salt solutions, standard 5% dextrose in water, or sodium acetate or ammonium acetate buffer. Such formulations are particularly suitable for parenteral administration but may be used for oral administration or may be contained in metered dose inhalers or nebulizers for aeration. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, gum arabic, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively, the compounds of the present invention may be encapsulated, tableted or prepared as an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may also be added to enhance or stabilize the composition or to facilitate the preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, gum arabic, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also comprise a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax. The amount of solid carrier varies but is preferably about 20 mg to about 1 g per dosage unit. Pharmaceutical formulations may be prepared by conventional pharmaceutical techniques, including grinding, mixing, granulating, and compacting, as necessary, for tablet form; Or for hard gelatin capsule forms, prepared according to conventional pharmaceutical techniques including grinding, mixing and filling. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. Such liquid formulations may be administered directly or may be filled into soft gelatin capsules.

For rectal administration, the compounds of the invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol and molded into suppositories.

Compounds of formula I are protease inhibitors, in particular inhibitors of cysteine and serine proteases, more particularly inhibitors of cysteine proteases, even more particularly inhibitors of cysteine proteases with papain superfamily, even more particularly inhibitors of cysteine proteases with cathepsin, Most particularly useful as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of such compounds, including pharmaceutical compositions and formulations of such compounds.

The compounds of the present invention are not only infected by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata. Diseases involving cysteine proteases including schistosomiasis, malaria, tumor metastasis, discolored white matter dystrophy, muscular dystrophy, muscular dystrophy; And especially diseases associated with cathepsin K, most particularly gingivitis, including osteoporosis, gingivitis and fasciitis, arthritis, more specifically osteoarthritis and rheumatoid arthritis, peget's disease, malignant hypercalcemia and metabolic bone disease It is useful for treating diseases of excessive bone or cartilage loss.

Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding substrate, and certain tumor and metastatic neoplasia can be effectively treated with the compounds of the present invention.

The invention also provides a method for the treatment of diseases caused by pathological levels of proteases, in particular cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases with papain superfamily, even more particularly cysteine proteases with cathepsin. The method comprises the administration of a compound of the invention to an animal, in particular a mammal, most particularly a human, in need thereof. The present invention particularly provides a method for the treatment of a disease caused by a pathological level of cathepsin K, which method comprises an inhibitor of cathepsin K comprising a compound of the invention, in particular an animal, in particular a mammal, most particularly It consists of administration to humans. The present invention particularly relates to pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei and Crithidia fusiculata, as well as infections caused by pneumocystis carinii. Diseases involving cysteine proteases, including malaria, tumor metastasis, discolorated white matter dystrophy, muscular dystrophy, and muscular dystrophy, especially cathepsin K-related diseases, most particularly gingivitis, including osteoporosis, gingivitis and fasciitis, arthritis It provides a method for the treatment of diseases of excessive bone or cartilage loss, including osteoarthritis and rheumatoid arthritis, Peget's disease, malignant hypercalcemia and metabolic bone disease.

The invention also provides for the treatment of osteoporosis, which consists in administering an effective amount of a compound of formula (I) alone or in combination with other bone resorption inhibitors such as bisphosphonates (ie, alendronates), hormone replacement therapy, anti-estrogens, calcitonin Or a method of suppressing bone loss. It may also be treated with anabolic agents such as compounds of the invention and bone morphological proteins, iproflavones, to prevent bone loss or increase bone mass.

According to the present invention, an effective amount of a compound of formula (I) is administered to inhibit proteases associated with a particular condition or disease. Of course, the dosage can vary depending on the dosage form of the compound. For example, an “effective amount” for acute treatment is preferably parenteral administration of a compound of formula (I). Intramuscular mass injection is also useful, but intravenous infusion of the compound in 5% dextrose in water or conventional saline, or a similar formulation with an appropriate excipient, is most effective. Typically, the parenteral dosage is about 0.01 to about 100 mg / kg to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K; Preferably from 0.1 to 20 mg / kg. The compound is administered once to four times daily to a level that achieves a total daily dose of about 0.4 to about 400 mg / kg / day. The exact amount of a compound of the present invention that is therapeutically effective and the best route of administration of this compound is readily determined by one skilled in the art by comparing the blood concentration of the medicament to the concentration required to achieve a therapeutic effect.

Drug precursors of the compounds of the present invention may be prepared by any suitable method. For compounds wherein the drug precursor moiety is a ketone functionality, in particular ketal and / or hemiacetal, the conversion may be carried out according to conventional methods.

The compounds of the present invention may also be administered orally to a patient such that the concentration of the drug is sufficient to inhibit bone absorption or to achieve other therapeutic uses disclosed herein. Typically, pharmaceutical compositions containing a compound are administered at oral dosages of about 0.1 to about 50 mg / kg, depending on the condition of the patient. Preferably, the oral dosage is about 0.5 to about 20 mg / kg.

There is no unacceptable toxic effect when administering a compound of the present invention according to the present invention.

In order to determine the concentration of compound required to have the desired pharmacological effect, the compounds of the present invention may be tested by one to several biological tests.

Determination of Cathepsin K Proteolytic Catalytic Activity

All assays for cathepsin K were performed using human recombinant enzyme. Standard assay conditions for determination of reaction rate constants were used in a fluorescent peptide substrate, typically Cbz-Phe-Arg-AMC, and determined in 100 mM sodium acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. The substrate stock was prepared at a concentration of 10 or 20 mM in DMSO and the final substrate concentration in the assay was 20 μΜ. All assays contained 10% DMSO. Independent experiments showed that this level of DMSO had no effect on enzyme activity or rate constants. All assays were performed at ambient temperature. Fluorescence of the product (excitation at 360 nM; emission at 460 nM) was detected using a Perceptive Biosystems Cytofluor II fluorescent plate reader. Progress curve of the product was generated 20-30 minutes after formation of the AMC product.

Inhibitory test

Progress curve method was used to assess inhibitor potential. The assay was performed in the presence of various concentrations of test compound. The reaction was initiated by adding the enzyme to a buffer solution of the inhibitor and substrate. Data analysis was performed according to one of two procedures depending on the shape of the progress curve in the presence of the inhibitor. For compounds with linear progression curves, the apparent inhibition constant (K _i , app) was calculated according to Equation 1 (Brandt et al., Biochemistry, 1989, 28, 140):

v = V _m A / [K _a (1 + I (K _{i, app} + A)]

Wherein v is the reaction rate, V _m is the maximum reaction rate, A is the concentration of the substrate, K _a is the Michaelis constant, and I is the concentration of the inhibitor.

For compounds where the progress curve exhibits a downward curve characteristic of time-dependent inhibition, the data from each set were analyzed to yield k _obs according to the following equation:

[AMC] = v _ss t + (vo-v _ss ) [1-exp (-k _obs t)] / k _obs

Where [AMC] is the concentration of product formed over time t, vo is the initial reaction rate and v _ss is the final steady state rate. The value for k _obs was then analyzed as a linear function of inhibitor concentration to obtain an apparent second order rate constant (k _obs / inhibitor concentration or k _obs / [I]), indicating time-dependent inhibition. A detailed review of such reaction rate treatments is fully described in Morrison et al., Adv, Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201.

Those skilled in the art will appreciate that compounds having K _i of less than 50 micromolar are potential lead compounds. Preferably, the compounds used in the process of the invention have a K _i value of less than 1 micromolar. Most preferably, the compounds have a K _i value of less than 100 nanomolar. 4- (R, S) -amino-N-[(8-quinolinsulfonyl) -S-leucine] -3-tetrahydrofuran-3-one, a compound of Formula I, has a K _i value of greater than 10 micromolar. Have

Human Osteoclast Uptake Assay

An aliquot of the osteoclast-derived cell suspension was withdrawn from the liquid nitrogen storage, warmed quickly to 37 ° C. and washed once by centrifugation (1000 rpm, 5 min at 4 ° C.) in RPMI-1640 medium. The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1: 3 in RPMI-1640 medium and incubated for 30 minutes on ice. Cell suspensions were mixed frequently.

The cells were washed twice with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 ° C.) and then transferred to sterile 15 mL centrifuge tubes. The number of monocytes was counted in an improved Neubauer counting chamber.

Sufficient magnetic beads (5 per mononuclear cell) coated with goat anti-mouse IgG were removed from the stock bottle and placed in 5 mL fresh medium (this washes out toxic azide preservatives). The medium was removed by immobilizing the beads on the magnet and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was mixed frequently. Bead-coated cells were immobilized on a magnet, and the remaining cells (fractional-rich fractions) were tilted into sterile 50 mL centrifuge tubes. Fresh medium was added to the bead-coated cells to remove the captured osteoclasts. These washing processes were repeated 10 times. Bead-coated cells were discarded.

Samples were placed in the chamber using a disposable plastic Pasteur pipette with a wide inner diameter and the osteoclasts were counted in a counting chamber. The cells were pelleted by centrifugation and the density of osteoclasts in EMEM medium was adjusted to 1.5 × 10 ⁴ / mL and supplemented with 10% fetal bovine serum and 1.7 g / liter of sodium bicarbonate. A 3 mL aliquot of the cell suspension (per treatment) was tilted into a 15 mL centrifuge tube. Cells were pelleted by centrifugation. 3 mL of appropriate treatment was added to each tube (diluted to 50 μM in EMEM medium). Also included were appropriate excipient controls, positive controls (87MEM1 diluted to 100 μg / mL) and isotype controls (IgG2a diluted to 100 μg / mL). The tube was incubated at 37 ° C. for 30 minutes.

0.5 mL aliquots of cells were seeded on sterile dentin slices in 48-well plates and incubated at 37 ° C. for 2 hours. Each treatment was shielded four times. The slices were washed 6 times with warm PBS (10 mL / well in 6-well plates), then placed in new treatments or controls and incubated at 37 ° C. for 48 hours. The slices were then washed with phosphate buffered saline and placed in 2% glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes, then washed with water and incubated for 5 minutes in buffer at 37 ° C. Slices were washed with cold water and incubated for 5 minutes at 4 ° C. in cold acetate buffer / fast red garnet. Excess buffer was aspirated and the slices washed with water and then air dried.

The number of TRAP positive osteoclasts was counted with brightfield microscopy and removed from the dentin surface by sonication. The content of the contents was determined using a Nikon / Lasertec ILM21W confocal microscope.

In the following synthesis, all starting materials were obtained from commercial raw materials unless otherwise indicated. It will be appreciated by those skilled in the art that the present invention may be utilized to a sufficient degree using the above detailed description without further efforts. The following examples are intended to illustrate the invention and do not limit the scope of the invention. Note the following claims regarding rights reserved for the inventors.

Example 1

Preparation of 4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] tetrahydrofuran-3-one

a) trans-4-azido-3-hydroxytetrahydrofuran

To a stirred solution of sodium azide (27 g, 415 mmol) and ammonium chloride (9 g, 159 mmol) in aqueous methanol (95%, 200 ml) was added 3,4-epoxytetrahydrofuran (9 g, 105 mmol). The reaction was heated to 75 ° C and stirred for 20 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was diluted with water, extracted with ethyl acetate, dried and evaporated under reduced pressure to afford the title compound as a colorless oil. 10 g, 74% yield.

¹ H NMR δ (CDCl ₃ ): 4.32 (m, 1H), 4.09 (dd, 1H, J = 4.8, 9.9 Hz), 3.99 (dd, 1H, J = 4.3, 10.1 Hz), 3.94 (m, 1H) , 3.81 (dd, 1H, J = 2.1, 9.9 Hz), 3.73 (dd, 1H, J = 1.8, 10.1 Hz), 2.72 (d, 1H, J = 4.6 Hz)

b) trans-4-amino-3-hydroxytetrahydrofuran hydrochloride

A mixture of trans-4-azido-3-hydroxytetrahydrofuran (10 g, 77 mmol) and 10% palladium on charcoal (1 g) in ethanol (150 ml) was stirred under hydrogen atmosphere (35 psi) for 12 hours. . The mixture was filtered, treated with 100 ml of ethanol hydrochloric acid solution and evaporated under reduced pressure to give the title compound as a brown solid. 10.5 g, 97% yield, melting point 132 ° C.

¹ H NMR δ (d ₆ DMSO): 8.37 (s, 3H), 4.13 (m, 1H), 3.84 (dd, 1H, J = 4.9 and 14.3 Hz), 3.76 (dd, 1H, J = 5.5, 10.0 Hz ), 3.58 (dd, 1H, J = 2.7, 10.0 Hz), 3.34 (m, 3H)

c) trans-4- (R, S) -amino-N-[(t-butoxycarbonyl) -S-leucine] -3-hydroxytetrahydrofuran

Trimethylacetyl chloride (3.5 ml, 29 mmol) was added to a stirred solution of N-Boc-L-leucine (7.3 g, 31 mmol) and diisopropylethylamine (9 ml, 52 mmol) in dichloromethane (200 ml). It was. After 1 hour, trans-4-amino-3-hydroxytetrahydrofuran.HCl (4 g, 28 mmol) was added and the mixture was stirred overnight. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with 0.5N HCl, saturated sodium bicarbonate, brine and dried. Evaporation under reduced pressure gave the title compound as a yellow foam. 5 g, 44% yield.

¹ H NMR δ (CDCl ₃ ): 8.08 (d, 0.5H, J = 4.8 Hz), 7.89 (d, 0.5H, J = 7.4 Hz), 6.20 (d, 0.5H, J = 8.3 Hz), 6.09 ( d, 0.5H, J = 8.7Hz), 4.81 (d, 1H, J = 16.0Hz), 4.40 (m, 2H), 4.20 (m, 2H), 3.77 (m, 2H), 1.60 (m, 3H) , 1.50 (s, 9 H), 0.92 (m, 6 H).

d) trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydrofuran-TFA salt

To a stirred solution of 20% trifluoroacetic acid in dichloromethane (100 ml) trans-4-amino-N-[(t-butoxycarbonyl) -S-leucine] -3-hydroxytetrahydrofuran (2.5 g) , 8.0 mmol) was added. After 2 hours, the reaction mixture was evaporated under reduced pressure to afford the title compound as a white rubber. 2.6 g, 100% yield.

¹ H NMR δ (MeOD): 4.18 (m, 2H), 4.08 (m, 2H), 3.97 (m, 2H), 3.86 (app t, 2H, J = 7.1 Hz), 3.69 (dd, 2H, J = 1.6, 7.4 Hz), 1.68 (m, 3H), 0.99 (d, 6H, J = 2.1 Hz)

e) trans-4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -3-hydroxytetrahydrofuran

Trans-4-amino-N- (S-leucine) -3-hydroxytetrahydrofuran in saturated sodium bicarbonate (10 ml) and 1,4-dioxane (10 ml) .TFA salt (380 mg, 1.1 mmol) To a stirred solution of) was added piperonyl oil (400 mg, 2.2 mmol). The reaction was stirred for 1 hour and then diluted with ether. The organic layer was washed with 1N hydrochloric acid, sodium bicarbonate, brine and dried. Evaporation of the solvent gave the title compound as a white foam. 250 mg, 60% yield.

¹ H NMR δ (CDCl ₃ ): 8.23 (d, 0.5H, J = 4.8 Hz), 8.15 (d, 0.5H, J = 7.4 Hz), 7.85 (d, 0.5H, J = 7.6 Hz), 7.3 ( m, 2H), 6.66 (dd, 1H, J = 8.1, 11.5 Hz), 5.92 (d, 2H, J = 6.2 Hz), 4.78 (m, 1H), 4.50 (s, 1H), 4.2 (s, 1H ), 4.08-3.75 (m, 4H), 3.74-3.48 (m, 3H), 1.82-1.48 (m, 3H), 0.90 (m, 6H).

MS calcd. For (C ₁₈ H ₂₄ N ₂ 0 ₆ + H) ⁺ : 365, found: 365

f) 4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -tetrahydrofuran-3-one

Trans-4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -3-hydroxytetrahydrofuran (220 mg, 0.60) in dichloromethane (10 ml) To the stirred solution was added Dess-Martin periodinane reagent (500 mg, 1.2 mmol). After 1 hour, ether was added followed by sodium thiosulfate (570 mg, 3.6 mmol). After an additional 15 minutes, the reaction was washed with saturated sodium bicarbonate, brine and dried. Evaporation of the solvent gave the title compound as a white foam. 200 mg, 100% yield

¹ H NMR δ (CDCl ₃ ): 8.14 (d, 0.5H, J = 6.2 Hz), 7.90 (d, 0.5H, J = 5.9 Hz), 7.54 (d, 0.5H, J = 7.3 Hz), 7.46 ( d, 0.5H, J = 5.1Hz), 7.23 (d, 1H, J = 6.6Hz), 7.14 (s, 1H), 6.67 (m, 1H), 5.93 (s, 2H), 4.73 (m, 1H) , 4.37-3.71 (m, 5H), 1.68 (m, 3H), 0.85 (m, 6H).

MS calcd. For (C ₁₈ H ₂₂ N ₂ 0 ₅ + H) ⁺ : 363, found: 363

Example 2

Preparation of 4- (R, S) -amino-N-[(3,4-dichlorobenzoyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of e-f of Example 1 except for replacing piperonyloyl chloride with 3,4-dichlorobenzoyl chloride:

¹ H NMR δ (MeOD): 8.01 (d, 1H, J = 2.0 Hz), 7.75 (dd, 1H, J = 2.0, 8.3 Hz), 7.61 (d, 1H, J = 8.3 Hz), 4.60 (m, 1H), 4.50-3.84 (m, 5H), 1.66 (m, 3H), 1.00 (m, 6H)

MS calcd. For (C ₁₇ Cl ₂ H ₂₀ N ₂ O ₄ + H) ⁺ : 387 & 389, found: 387 & 389

Example 3

Preparation of 4- (R, S) -amino-N-[(2-quinolincarbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared as a white foam following the procedure of e-f of Example 1, except replacing piperonyloil chloride with 2-quinolinecarbonyl chloride:

¹ H NMR δ (CDCl ₃ ): 8.57 (dd, 1H, J = 1.5, 5.1 Hz), 8.20 (m, 3H), 7.77 (m, 2H), 7.62 (m, 1H), 7.40 (d, 1H, J = 6.2 Hz), 4.80 (m, 1H), 4.57 (m, 1H), 4.30 (m, 1H), 4.26-3.87 (m, 3H), 1.96-1.71 (m, 3H), 1.00 (m, 6H )

MS calcd. For (C ₂₀ H ₂₃ N ₃ 0 ₄ + H) ⁺ : 370, found: 370

Example 4

Preparation of 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] tetrahydrofuran-3-one

Except for replacing N-BOC-leucine with N-CBZ-leucine, the title compound was prepared as a white foam following the procedure of Example 1:

¹ H NMR δ (CDCl ₃ ): 7.31 (m, 5H), 5.71 (app dd, 1H, J = 8.4, 14.8 Hz), 5.06 (m, 2H), 4.50 (dd, 1H, J = 8.9, 18.0 Hz ), 4.30-3.88 (m, 4H), 3.80 (app t, 1H, J = 9.6 Hz), 1.64 (m, 3H), 0.91 (m, 6H).

MS calcd. For (C ₁₈ H ₂₄ N ₂ 0 ₅ + H) ⁺ : 349, found: 349

Example 5

Preparation of 4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared according to the procedure of Example 1 except for replacing piperoniloyl chloride with 3,4-methylenedioxybenzoyl chloride.

Example 6

Preparation of 4- (R, S) -amino-N-[(8-quinolincarbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared as white foam following the procedure of Example 1 (e-f) except for replacing piperonyloil chloride with 8-quinolinecarbonyl chloride: Melting point 123 ° C. (HCl salt).

¹ H NMR δ (CDCl ₃ ): 11.54 (m, 1H), 8.84 (d, 1H, J = 1.5 Hz), 8.65 (d, 1H, J = 7.2 Hz), 8.17 (d, 1H, J = 8.0 Hz ), 7.86 (d, 1H, J = 8.0 Hz), 7.7 (s, 1H), 7.54 (t, 1H, J = 7.7 Hz), 7.40 (dd, 1H, J = 3.8, 7.7 Hz), 4.78 (dd , 1H, J = 7.5, 13.6 Hz), 4.47 (dd, 1H, J = 8.6, 13.6 Hz), 4.18 (m, 1H), 4.16-3.79 (m, 3H), 1.88 (m, 3H), 0.88 ( m, 6H).

MS calcd. For (C ₂₀ H ₂₃ N ₃ 0 ₄ + H) ⁺ : 370, found: 370

Example 7

Preparation of 4- (R, S) -amino-N-[(8-quinolinsulfonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared as a brown solid following the procedure of Example 1 (e-f) except for replacing piperonyloil chloride with 8-quinolinesulfonyl chloride: melting point 98 ° C. (HCl salt).

¹ H NMR δ (CDCl ₃ ): 9.07 (dd, 1H, J = 1.7 and 4.3 Hz), 8.40 (m, 1H), 8.30 (m, 1H), 8.00 (m, 1H), 7.66 (m, 2H) , 7.11 (d, 0.5H, J = 5.9 Hz), 6.96 (d, 0.5H, J = 5.7 Hz), 4.51 (t, 0.5H, J = 8.8 Hz), 4.39 (t, 0.5H, J = 8.7 Hz), 4.12-3.71 (m, 4.5H), 3.53 (dd, 0.5H, J = 1.0, 5.9 Hz), 1.43 (m, 2H), 0.64 (m, 3H), 0.33 (m, 3H).

MS calcd. For (C ₁₉ H ₂₃ N ₃ 0 ₅ S + H) ⁺ : 406, found: 406

Example 8

Preparation of 4- (R, S) -amino-N-[((4-methyl3-pyridinyl) carbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of Example 1 (e-f), except that piperoniloyl chloride was replaced with (4-methyl-3-pyridinyl) carbonyl chloride.

Example 9

Preparation of 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -2,2-dibenzyl-tetrahydrofuran-3-one

4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] tetrahydrofuran-3-one (300 mg, 0.9 mmol) and benzyl bromide (0.4 ml) in methanol (5 ml) Sodium methoxide (140 mg, 2.6 mmol) was added to a stirred solution of, 3.4 mmol). After 12 hours, the reaction was poured into ether (100 ml) and washed with water, brine and dried. Evaporation under reduced pressure and purification by flash column chromatography (30% ethyl acetate-hexane) afforded the title compound as a colorless rubber. 250 mg, 55% yield.

¹ H NMR δ (CDCl ₃ ): 7.34-7.25 (m, 10H), 7.24-7.0 (brs, 5H), 6.56 (s, 0.5H), 6.37 (s, 0.5H), 5.18 (d, 1H, J = 11.5 Hz), 5.07 (m, 2H), 4.48-4.42 (m, 1H), 4.20-3.98 (m, 4H), 3.12 (dd, 1H, J = 12.5 and 12.5 Hz), 2.88 (dd, 1H, J = 12.5 and 12.5 Hz), 1.72-1.32 (m, 3H), 0.92-0.76 (m, 6H).

MS calcd. For (C ₃₂ H ₃₆ N ₂ O ₅ = C ₇ H ₇ ) ⁺ : 439, found: 439

Example 10

Preparation of 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of Example 1 (e-f), except that piperoniloyl chloride was replaced with benzo [b] thiophen-2-ylcarbonyl.

¹ H NMR δ (CDCl ₃ ): 8.33 (d, 0.5H, J = 6.6 Hz), 8.00 (m, 1H), 7.78 (m, 4H), 7.38 (m, 2.5H), 4.87 (m, 1H) , 4.63-3.88 (m, 5H), 1.88 (m, 3H), 1.00 (m, 6H).

MS calcd. For (C ₁₉ H ₂₂ N ₂ O ₄ SH) ⁺ : 373, found: 373

Example 11

Preparation of 4- (R, S) -amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of Example 1 (e-f), except that piperoniloyl chloride was replaced with 3,4-dimethoxybenzoyl chloride.

¹ H NMR δ (CDCl ₃ ): 7.58 (d, 0.5H, J = 6.7 Hz), 7.47 (d, 0.5H, J = 6.2 Hz), 7.33 (m, 2H), 7.04 (d, 0.5H, J = 8.0 Hz), 6.92 (d, 0.5H, J = 8.0 Hz), 6.83 (d, 0.5H, J = 8.4 Hz), 4.77 (m, 1H), 4.53-3.67 (m, 5H), 1.68 (m , 3H), 0.85 (m, 6H).

_{(C 19 H 26 N 2 O} 6 -H) - MS Calcd: 377, Found: 377

Example 12

Preparation of 4- (R, S) -amino-N-[(indol-6-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of Example 1 (e-f), except replacing piperonyloil chloride with indole-6-ylcarbonyl chloride.

¹ H NMR δ (d ₆ DMSO): 8.57-7.48 (m, 7H), 6.43 (s, 1H), 4.48-3.55 (m, 6H), 1.80-1.48 (m, 3H), 0.98-0.82 (m, 6H).

MS calcd. For (C ₁₉ H ₂₃ N ₃ 0 ₄ -H) ⁺ : 356, found: 356

Example 13

Preparation of 4- (R, S) -amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of Example 1 (e-f), except that piperoniloyl chloride was replaced with benzofuran-2-ylcarbonyl chloride.

¹ H NMR δ (CDCl ₃ ): 8.00-7.25 (m, 7H), 4.90-4.78 (m, 1H), 4.53-4.48 (m, 1H), 4.38-4.21 (m, 1H), 4.25-3.92 (m , 3H), 1.88 (m, 3H), 1.68 (m, 3H), 0.97 (m, 6H).

MS calcd. For (C ₁₉ H ₂₂ N ₂ 0 ₅ -H) ⁺ : 357. Found: 357

Example 14

Preparation of 4- (R, S) -amino-N-[(5-aminobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

The title compound was prepared following the procedure of Example 1 (e-f), except that piperoniloyl chloride was replaced with 5-aminobenzo [b] thiophen-2-ylcarbonyl chloride.

¹ H NMR δ (CDCl ₃ ): 8.00-7.71 (m, 1H), 7.60 (d, 1H, J = 3.3 Hz), 7.53 (dd, 1H, J = 8.5 and 4.0 Hz), 7.47-6.74 (m, 3H), 4.77 (m, 1H), 4.43 (m, 1H), 4.38-3.50 (m, 4H), 1.77 (m, 3H), 0.85 (m, 6H).

MS calcd. For (C ₁₉ H ₂₃ N ₃ 0 ₄ S + H) ⁺ : 390, found: 390

Example 15

Preparation of Cyclic Alkoxyketones by Solid Supported Synthesis

a) 3-trans-hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran

Benzylchloroformate (20 ml) is added dropwise to a stirred solution of trans-4-amino-3-hydroxytetrahydrofuran (5 g, 20.6 mmol) in dioxane (100 ml) containing 10% aqueous sodium carbonate (200 ml). It was. After 3 hours, the mixture was concentrated to remove dioxane and then extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate, brine and dried (MgSO ₄ ). Evaporation under reduced pressure and purification of the residue by column chromatography gave the title compound as white crystals. 8.00 g, 70% yield.

¹ H NMR δ (CDCl ₃ ): 7.35 (s, 5H), 5.30 (s, 2H), 4.91 (br s, 1H), 4.32 (br s, 1H), 4.12-4.00 (m, 3H), 3.71- 3.62 (m, 2 H), 2.72 (s, 1 H).

b) 4-benzyloxycarbonylamino-tetrahydrofuran-3-one

3-hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran (21 g, 88 mmol) in EtOAc (140 ml), toluene (140 ml) and water (40 ml), sodium bromide (9.4 g), TEMPO (50 mg) was added dropwise a bleach solution (100 ml) containing sodium bicarbonate (7.34 g). After a continuous orange appearance, the mixture was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate, brine and dried (MgSO ₄ ). Evaporation under reduced pressure and purification of the residue by column chromatography gave the title compound as white crystals. 18 g, 87% yield.

¹ H NMR δ (CDCl ₃ ): 7.35 (s, 5H), 5.30 (s, 1H), 5.11 (s, 2H), 4.70 (app t, 1H, J = 8.9 Hz), 4.36-4.17 (m, 2H ), 3.96-3.76 (2H).

c) 3,3-dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran

Trimethylorthoformate (29 ml) was added dropwise to a reflux solution of 4-benzyloxycarbonylamino-tetrahydrofuran-3-one (18 g, 78 mmol) and PTSA (500 mg) in MeOH (100 ml). After 3 hours, the reaction mixture was filtered and concentrated and after column chromatography, the title compound was obtained as a yellow oil. 16.2 g, 76% yield.

¹ H NMR δ (CDCl ₃ ): 7.35 (s, 5H), 5.30 (s, 1H), 5.11 (s, 2H), 4.70 (app t, 1H, J = 8.9 Hz), 4.36-4.17 (m, 2H ), 3.96-3.76 (2H).

d) 3,3-dimethoxy-4-amino-tetrahydrofuran

A mixture of 3,3-dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran (16 g, 57 mmol) and 10% palladium on charcoal (2 g) in ethanol (200 ml) under hydrogen atmosphere (50 psi) ) For 12 hours. The mixture was filtered and concentrated to afford the title compound as a yellow oil. 8 g, 100%.

¹ H NMR δ (CDCl ₃ ): 7.04 (s, 5H), 4.22-4.04 (m, 5H), 3.83-3.69 (m, 2H), 3.36 (s, 3H), 3.33 (s, 3H).

e) SPS using Elman linker

Step A:

Sodium triacetoxyborohydride (10 equiv) was added to a stirred solution of Elman resin (CGBoojamra, KMBurow, LAThompson and JAEllman, J. Org. Chem., 1997, 62, 1240) in DMF containing 1% HOAc. It was. After 5 minutes, α-amino acid methylester (10 equiv) was added and the mixture was shaken for 1 hour. The resin was then washed with DMF (× 7), CH ₂ Cl ₂ (× 7), ether (× 2) and dried to constant weight.

Step B:

NMP was added to the mixture of the resin, carboxylic acid (10 equiv) and EDC (10 equiv). The mixture was shaken for 3 hours and then washed with DMF (× 3), CH ₂ Cl ₂ (× 3), MeOH (× 2) and ether (× 2). The resin was then retreated according to the reaction conditions and then washed again after 3 hours.

Step C:

To the shake mixture of this resin in THF was added potassium trimethylsilanoate (10 equiv). After 18 hours, the resin was replaced with 5% citric acid (× 2), THF (× 2), THF-H ₂ O (× 2), H ₂ O (× 2), THF-H ₂ O (× 2) and Finally washed with THF (× 2).

Step D:

3,3-dimethoxy-4-amino-tetrahydrofuran (3 equiv) was added to a mixture of the resin and EDC (3 equiv) in NMP. After 3 hours, the resin was washed with DMF (× 7), CH ₂ Cl ₂ (× 7) and ether (× 2). The resin was then retreated for an additional 3 hours depending on the reaction conditions and washed again as above.

Step E: Cleavage

A mixture of 7: 2: 1 TFA / CH ₂ Cl ₂ / H ₂ O was added to the resin. After 2 hours, the mixture was filtered and the resin further washed with CH ₂ Cl ₂ . The solvent was removed to give the desired tetrahydrofuran-3-one.

Example 16

Preparation of 4- (R, S) -amino-N-[(5-chlorobenzofuran-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

Using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared according to the general section of Example 15:

¹ H NMR δ (CDCl ₃ ): 7.62-7.05 (m, 6H), 4.81-4.64 (m, 1H), 4.62-4.54 (m, 1H), 4.43-3.81 (m, 4H), 1.90-1.60 (m , 3H), 1.08-0.81 (m, 6H).

MS calcd. For (C ₁₉ H ₂₁ N ₂ 0 ₅ Cl + H) ⁺ : 393, found: 393

Example 17

Preparation of 4- (R, S) -amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

Using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared according to the general section of Example 15:

¹ H NMR δ (CDCl ₃ ): 7.65-6.84 (m, 6H), 4.83-4.54 (m, 1H), 4.53-4.48 (m, 1H), 4.46-3.68 (m, 4H), 1.90-1.62 (m , 3H), 1.08-0.81 (m, 6H).

MS calcd. For (C ₂₀ H ₂₄ N ₂ 0 ₆ + H) ⁺ : 389, found: 389

Example 18

Preparation of 4- (R, S) -amino-N-[(4-bromobenzoyl) -S-leucine] tetrahydrofuran-3-one

Using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared according to the general section of Example 15:

¹ H NMR δ (CDCl ₃ ): 7.64 (App d, 2H, J = 8.5 Hz), 7.60 (App d, 2H, J = 8.5 Hz), 4.81-4.67 (m, 1H), 4.62-4.48 (m, 1H), 3.36-4.19 (m, 1H), 4.18-3.78 (m, 3H), 1.81-1.59 (m, 3H), 1.05-0.80 (m, 6H).

MS calcd. For (C ₁₇ H ₂₁ N ₂ O ₄ Br) ⁺ : 397, found: 397

Example 19

Preparation of 4- (R, S) -amino-N-[(4-bromobenzoyl) -S-leucine] tetrahydrofuran-3-one

Using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared according to the general section of Example 15:

¹ H NMR δ (CDCl ₃ ): 7.91 (m, 1H), 7.76-7.59 (m, 2H), 7.39-7.18 (m, 1H), 7.04-6.89 (m, 1H), 7.84-6.68 (m, 1H ), 4.89-4.68 (m, 1H), 4.66-4.56 (m, 1H), 4.27-3.76 (m, 4H), 1.88-1.68 (m, 3H), 1.03-0.78 (m, 6H).

MS calcd. For (C ₁₇ H ₂₁ N ₂ O ₄ Br) ⁺ : 397, found: 397

Example 20

Preparation of 4- (R, S) -amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

Using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared according to the general section of Example 15:

¹ H NMR δ (CDCl ₃ ): 7.88-7.67 (m, 5H), 7.48-7.38 (m, 1H), 4.81 (br d, 1H, J = 6.7 Hz), 4.60 (app t, 1H, J = 8.8) Hz), 4.43-4.30 (m, 1H), 4.28-3.84 (m, 3H), 1.86-1.62 (m, 3H), 1.05-0.82 (m, 6H).

MS calcd. For (C ₁₉ H ₂₁ N ₂ 0 ₄ SCl-H) ⁺ : 408, found: 408

Example 21

Preparation of 4- (R, S) -amino-N-[(4-fluorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] tetrahydrofuran-3-one

Using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared according to the general section of Example 15:

¹ H NMR δ (CDCl ₃ ): 7.96 (s, 1H), 7.68-7.58 (m, 2H), 7.48-7.32 (m, 1H), 7.06 (dd, 1H, J = 9.0 Hz and 9.0 Hz), 4.89 -4.72 (m, 1H), 4.65-4.55 (app t, 1H, J = 8.8 Hz), 4.35 (app q, 1H, J = 8.2 Hz), 4.28-3.82 (m, 3H), 1.88-1.62 (m , 3H), 1.05-0.82 (m, 6H).

MS calcd. For (C ₁₉ H ₂₁ N ₂ 0 ₄ SF + H) ⁺ : 393, found: 393

Examples 22-66

Preparation of Cyclic Alkoxy Ketones

The compounds of Table 1 were prepared following procedures analogous to those described in Example 1 or Example 15 using appropriate amino acids and acid or acid chloride reagents consistent with the final product. ¹ H NMR spectra and / or mass spectra were consistent with the structures in Table 1.

Example R ³ R " Synthesis method 22 3,4-difluorophenyl solution 23 〃 4-benzylpiperidin-1-yl solution 24 〃 4-benzylpiperazin-1-yl solution 25 〃 4- (3,4-methylenedioxybenzyl) piperazin-1-yl solution 26 〃 4- (t-butoxycarbonyl) piperazin-1-yl solution 27 〃 Piperazin-1-yl solution 28 〃 Benzimidazol-5-yl solution 29 〃 6-quinolyl solution 30 〃 5-indolyl solution 31 〃 2-naphthyl solution 32 〃 2-pyridyl solution 33 〃 4-benzyloxyphenyl solution 34 〃 3-benzyloxyphenyl solution 35 〃 4-hydroxyphenyl solution 36 〃 5-nitrobenzo [b] thiophen-2-yl solution 37 〃 2- (thien-2-yl) ethen-1-yl solution 38 〃 4-methoxyphenyl SPS

39 〃 3-methoxyphenyl SPS 40 〃 7-ethoxybenzofuran-1-yl SPS 41 〃 5-nitrobenzofuran-1-yl SPS 42 〃 4- (2-methoxyphenyl) phenyl SPS 43 〃 3- (2-methoxyphenyl) phenyl SPS 44 〃 4-cyanophenyl SPS 45 〃 3-nitrophenyl SPS 46 〃 3- (dimethylaminoethyl) -4-methoxyphenyl SPS 47 〃 2- (2-chlorophenyl) ethen-1-yl SPS 48 〃 4-trifluoromethoxyphenyl SPS 49 〃 4-methanesulfonylphenyl SPS 50 〃 4-iodophenyl SPS 51 〃 4-chlorobenzo [b] thiophen-2-yl SPS 52 〃 5,6-dimethoxybenzo [b] thiophen-2-yl SPS 53 〃 5,6-methylenedioxybenzo [b] thiophen-2-yl SPS 54 〃 7-chlorobenzo [b] thiophen-2-yl SPS 55 Benzo [b] thiophen-2-yl SPS 56 〃 2-thienyl SPS 57 〃 3,4-dimethoxyphenyl SPS 58 〃 4-bromophenyl SPS 59 〃 Quinolin-2-yl SPS 60 2-thienyl SPS 61 〃 CH ₃ SPS 62 Benzo [b] thiophen-2-yl SPS 63 〃 2-thienyl SPS 64 〃 3,4-dimethoxyphenyl SPS 65 〃 4-bromophenyl SPS 66 〃 Quinolin-2-yl SPS

Example 67

Preparation of 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydropyran-3-one

a) trans-4-amino-3-hydroxytetrahydropyran hydrochloride

The title compound was prepared following the procedure of Examples 1 (a) and 1 (b) by replacing 3,4-epoxytetrahydrofuran with 3,4-epoxytetrahydropyran.

b) trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran

Pivaloyl chloride (5.28 ml, 43 mmol) was added to a solution of N-carbobenzyloxy-L-leucine (12.48 g, 47 mmol) in dichloromethane (300 ml). After 1 hour, a mixture of trans-4-amino-3-hydroxytetrahydropyran hydrochloride (6 g, 39 mmol) and triethylamine (10.8 ml, 79 mmol) in dichloromethane (100 ml) is added and the mixture Was stirred overnight. The reaction mixture was washed with 1N HCl, saturated sodium hydrogen carbonate and dried. Evaporation under reduced pressure gave a pale oil. Purification by chromatography (ethyl acetate / hexane eluent) trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran as white paste Obtained. 5.5 g, 39% yield.

¹ H NMR δ (CDCl ₃ ): 7.35 (s, 5H), 5.0 (m, 3H), 4.16-3.89 (m, 4H), 3.44-3.36 (m, 2H), 3.13 (t, 1H), 1.84- 1.53 (m, 2H), 1.28-1.22 (m, 3H), 0.93 (m, 6H).

c) 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] tetrahydropyran-3-one

4- (R, S) -Amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -3-hydroxytetrahydrofuran to 4- (R, S) -amino-N- [ The title compound was prepared according to the procedure of Example 1 (f), except for replacing with (benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran:

¹ H NMR δ (d ₆ DMSO): 8.15 (d, 1H), 7.39-7.29 (m, 5H), 5.02 (d, 2H), 4.63 (m, 1H), 4.14-4.10 (m, 2H), 3.97 -3.83 (m, 3H), 2.10 (m, 1H), 1.92 (m, 1H), 1.61 (m, 1H), 1.45 (m, 1H), 0.95 (m, 6H).

MS calcd. For (C ₁₉ H ₂₆ N ₂ 0 ₅ + H) ⁺ : 363, found: 363

Example 68

Preparation of 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydropyran-3-one

a) trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydropyran hydrochloride

4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran (2.8 g, 7.75 mmol) and 10% charcoal in ethanol (100 ml) A mixture of palladium (300 mg) was stirred under hydrogen atmosphere (50 psi) for 12 hours. The mixture was filtered, treated with HCl ether solution and the title compound as a brown solid after evaporation under reduced pressure. 1.40 g, 68% yield

¹ H NMR δ (CDCl ₃ ): 8.30 (m, 2H), 8.02 (m, 1 H), 4.06-3.92 (m, 4H), 3.50-3.35 (m, 2H), 3.12 (t, 1H), 1.89- 1.54 (m, 2H), 1.23 (m, 3H), 0.93 (m, 6H).

b) trans-4- (R, S) -amino-N-[(benzothiophen-2-carbonyl) -S-leucine] -3-hydroxytetrahydropyran

Trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydropyran (133 mg, 0.5 mmol) in dioxane (7 ml) and saturated sodium bicarbonate (7 ml) To a solution of benzothiophene-2-carbonyl chloride (442 mg, 2.25 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated sodium hydrogen carbonate, dried and evaporated under reduced pressure to give a white solid. Purification by chromatography (ethylacetate / hexane eluent) to give trans-4- (R, S) -amino-N-[(benzothiophene-2-carbonyl) -S-leucine] -3- as a white solid. Hydroxytetrahydropyran was obtained. 160 mg, 84% yield.

c) 4- (R, S) -amino-N-[(benzothiophen-2-carbonyl) -S-leucine] -tetrahydropyran-3-one

4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -3-hydroxytetrahydrofuran trans-4- (R, S) -amino-N The title compound was prepared according to the procedure of Example 1 (f), except that the compound was replaced with-[(benzothiophene-2-carbonyl) -S-leucine] -3-hydroxytetrahydropyran:

¹ H NMR δ (CDCl ₃ ): 7.84-7.76 (m, 2H), 7.41 (m, 2H), 7.05 (m, 1H), 4.83-4.61 (m, 2H), 4.18-3.77 (m, 4H), 2.73-2.53 (m, 1H), 1.98-1.75 (m, 2H), 1.26 (m, 3H), 0.92 (m, 6H).

MS calcd. For (C ₂₀ H ₂₄ N ₂ 0 ₄ S + H) ⁺ : 389, found: 389

Example 69

Preparation of 4- (R, S) -amino-N-[(4-phenoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.74 (d, 2H, J = 10.9 Hz), 7.37 (dd, 2H, J = 7.7 and 7.7 Hz), 7.20 (dd, 1H, J = 7.5 and 7.5 Hz) , 7.03 (d, 2H, J = 7.7 Hz), 7.0 (d, 2H, J = 7.7 Hz) 6.98-6.82 (m, 2H), 4.83-4.68 (m, 1H), 4.66-4.45 (m, 1H) , 4.34-3.70 (m, 4H), 1.98-1.54 (m, 3H), 1.08-0.78 (m, 6H).

MS calcd. For (C ₂₃ H ₂₆ N ₂ 0 ₅ -H) ⁺ : 409. Found: 409

Example 70

Preparation of 4- (R, S) -amino-N-[(4-phenylbenzoyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.83 (d, 2H, J = 8.2 Hz), 7.70-50 (m, 4H), 7.48-32 (m, 4H), 7.30-7.12 (m, 1H), 6.88-6.72 (m, 1H), 4.88-4.70 (m, 1H), 4.65-52 (m, 1H), 4.38-3.78 (m, 4H), 1.92-1.60 (m, 3H), 1.08-0.78 (m , 6H).

MS calcd. For (C ₂₃ H ₂₆ N ₂ 0 ₄ -H) ⁺ : 393, found: 393

Example 71

Preparation of 4- (R, S) -amino-N-[(6-trifluoromethylbenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (DMSO d ₆ , 250 MHz): 8.82 (d, 1H, J = 6.0 Hz), 8.43 (s, 1H), 8.48-8.44 (m, 0.5H), 8.34 (d, 0.5H, J = 7.8 Hz), 8.23 (s, 1H), 8.04 (d, 1H, J = 8.4 Hz), 7.60 (dd, 1H, J = 1.5 and 8.5 Hz), 4.49-4.38 (m, 1H), 4.26-3.68 ( m, 5H), 1.70-1.36 (m, 3H), 0.80 (d, 3H, J = 6 Hz), 0.76 (d, 3H, J = 6.0 Hz)

MS calcd. For (C ₂₀ H ₂₁ F ₃ N ₂ O ₄ SH) ⁺ : 443, found: 443

Example 72

Preparation of 4- (R, S) -amino-N-[(4-ethylbenzoyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.76 (d, 2H, J = 8.0 Hz), 7.62-7.42 (m, 1H), 7.22 (d, 2H, J = 7.8 Hz), 7.04-6.80 (m, 1H), 4.91-4.73 (m, 1H), 4.61-4.45 (m, 1H), 4.36-3.72 (m, 4H), 2.68 (q, 2H, J = 7.6 Hz), 1.88-1.58 (m, 3H) , 1.23 (t, 3H, J = 7.6 Hz), 0.98-0.88 (m, 6H)

MS calcd. For (C ₁₉ H ₂₆ N ₂ 0 ₄ -H) ⁺ : 345, Found: 345

Example 73

Preparation of 4- (R, S) -amino-N-[(4- (t-butyl) benzoyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.76 (br d, 2H, J = 7.5 Hz), 7.46 (br d, 2H, J = 7.5 Hz), 6.92-6.76 (m, 2H), 4.88-4.68 ( m, 1H), 4.58-4.43 (m, 1H), 4.37-3.71 (m, 4H), 1.82-1.57 (m, 3H), 1.32 (s, 9H), 1.00-0.82 (m, 6H)

MS calcd. For (C ₂₁ H ₃₀ N ₂ 0 ₄ + H) ⁺ : 375, found: 375

Example 74

Preparation of 4- (R, S) -amino-N-[(5-methoxybenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.84-7.54 (m, 2H), 7.20 (d, 1H, J = 2.0 Hz), 7.10 (d, 1H, J = 2.3 Hz), 7.06 (d, 1H, J = 2.3Hz), 6.78 (d, 1H, J = 8.1Hz), 4.82-4.68 (m, 1H), 4.59 (app t, 1H, J = 8.8Hz), 4.49-3.61 (m, 4H), 3.84 (s, 3H), 1.82-1.58 (m, 3H), 1.08-0.72 (m, 6H)

MS calcd. For (C ₂₀ H ₂₄ N ₂ 0 ₅ SH) ⁺ : 403, Found: 403

Example 75

Preparation of 4- (R, S) -amino-N-[(4-nitrobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 8.31 (s, 1H), 7.96 (d, 1H, J = 7.2 Hz), 7.62-7.18 (m, 4H), 4.84 (app d, 1H, J = 7.5 Hz) ), 4.70-3.72 (m, 5H), 1.94-1.60 (m, 3H), 1.11-0.80 (m, 6H).

MS calcd. For (C ₁₉ H ₂₁ N ₃ O ₆ S-NO ₂ ) ⁺ : 373. Found: 373

Example 76

Preparation of 4- (R, S) -amino-N-[(6-bromobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 8.03 (s, 1H), 7.81-7.58 (m, 2H), 7.54-7.40 (m, 1H), 7.22-6.98 (m, 2H), 4.74 (app d, 1H, J = 7.5 Hz), 4.59 (app q, 1H, J = 7.5 and 14.0 Hz), 4,48-3.74 (m, 4H), 1.85-1.58 (m, 3H), 1.10-0.78 (m, 6H )

MS calcd. For (C ₁₉ H ₂₁ BrN ₂ O ₄ SH) ⁺ : 452, found: 452

Example 77

Preparation of 4- (R, S) -amino-N-[(5-bromobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 8.04-7.90 (m, 1H), 7.88-7.18 (m, 5H), 4.88-4.68 (m, 1H), 4.68-4.52 (m, 1H), 4.46-3.88 (m, 4H), 1.92-1.52 (m, 3H), 1.08-0.80 (m, 6H)

MS calcd. For (C ₁₉ H ₂₁ BrN ₂ O ₄ SH) ⁺ : 452, found: 452

Example 78

Preparation of 4- (R, S) -amino-N-[(6-methoxybenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared by a method similar to that detailed in Example 15.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.79-7.61 (m, 2H), 7.32-7.14 (m, 2H), 7.00 (dd, 1H, J = 1.5 and 8.8 Hz), 6.89-6.67 (m, 1H ), 4.75 (app q, 1H, J = 8.2 and 16.2 Hz), 4.57 (app t, 1H, J = 8.6 and 17.4 Hz), 4.49-3.71 (m, 4H), 3.85 (s, 3H), 1.92- 1.52 (m, 3 H), 1.08-0.78 (m, 6 H).

MS calcd. For (C ₂₀ H ₂₄ N ₂ 0 ₅ SH) ⁺ : 403, Found: 403

Examples 79-93

The compounds of Table 2 were prepared by a procedure similar to that described in Example 15, using appropriate amino acids and acid or acid chloride reagents consistent with the final product. ¹ H NMR spectrum and / or mass spectrum was consistent with the structure in Table 2.

Example R ³ R " Synthesis method 79 Phenyl SPS 80 〃 3-chlorophenyl SPS 81 〃 2-phenylethen-1-yl SPS 82 〃 3-fluorophenyl SPS 83 〃 3-hydroxyphenyl SPS 84 〃 4-methylphenyl SPS 85 〃 4-isopropylphenyl SPS 86 〃 4-trifluoromethylphenyl SPS 87 〃 4-methylthiophenyl SPS 88 〃 4- (benzylsulfonylamino) phenyl SPS 89 〃 4- (diethylaminosulfonyl) phenyl SPS 90 〃 4- (acetylamino) phenyl SPS 91 〃 4-benzoylphenyl SPS 92 〃 4-acetylphenyl SPS 93 〃 4- (4-oxopent-1-yl) phenyl SPS

Example 94

Preparation of 4-S-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

(a) trans-4-S-amino-3-R-hydroxytetrahydrofuran hydrochloride

Trans-4-S-azido-3-R-hydroxytetrahydrofuran in ethanol (150 ml) (cf. LEMartinez, JLLeighton, DECarsten and ENJacobsen, J. Amer. Chem. Soc., 1995, 117, 5897) (10 g, 77 mmol) and a mixture of 10% palladium on charcoal (1 g) were stirred under hydrogen atmosphere (50 psi) for 12 hours. The mixture was filtered, treated with 100 ml of HCl ethanol solution and evaporated under reduced pressure to afford the title compound as a brown solid. 10.5 g, 97% yield, melting point 132 ° C.

¹ H NMR δ (D ₂ O): 4.54-4.52 (m, 1 H), 4.24-4.13 (m, 2H), 3.98-3.61 (m, 3H).

(b) trans-4-S-amino-N-[(benzyloxycarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran

To a stirred solution of N-Cbz-L-leucine (12.7 g, 48 mmol) and triethylamine (14 ml, 52 mmol) in THF (200 ml) was added trimethylacetyl chloride (5.4 ml, 44 mmol). After 1 hour, trans-4-S-amino-3-R-hydroxytetrahydrofuran.HCl (5.58 g, 40 mmol) was added and the mixture was stirred at reflux for 16 hours. The reaction mixture was filtered and evaporated under reduced pressure. Flash column chromatography (80% ethyl acetate-hexanes) gave the title compound as a white foam. 10.6 g, 76% yield.

¹ H NMR δ (CDCl ₃ ): 7.76 (d, 1H, J = 5.3 Hz), 7.33-7.20 (m, 5H), 6.43 (d, 1H, J = 8.9 Hz), 5.01 (app d, 2H, J) = 3.0 Hz), 4.60-3.65 (m, 6H), 1.61-1.42 (m, 3H), 0.93-0.88 (m, 6H).

(c) trans-4-S-amino-N- (S-leucine) -3-R-hydroxytetrahydrofuran hydrochloride

Trans-4-S-amino-N-[(carbenzyloxy) -S-leucine] -3-R-hydroxytetrahydrofuran (2.0 g, 5.7 mmol) and 10% charcoal in ethanol (100 ml) A mixture of palladium (500 mg) was stirred under hydrogen atmosphere (50 psi) for 12 hours. The reaction mixture was filtered and diluted with HCl ether solution (100 ml, 1 mol) and the evaporation under reduced pressure gave the title compound as a white foam. 1.5 g, 100% yield

¹ H NMR δ (D ₂ O): 4.20-4.05 (m, 2H), 4.06-4.00 (m, 1H), 3.90-3.83 (m, 2H), 3.68-3.52 (m, 2H), 1.65-1.47 ( m, 3H), 0.86-0.78 (m, 6H).

(d) trans-4-S-amino-N-[(2-benzo (b) thiophencarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran

N, N- to a stirred solution of trans-4-S-amino-N- (S-leucine) -3-R-hydroxytetrahydrofuran-HCl salt (380 mg, 1.1 mmol) in dichloromethane (10 ml) Diisopropylethylamine (0.4 ml, 2.0 mmol) was added. After 5 minutes, benzo [b] thiophene-2-carbonyl chloride (196 mg, 1.0 mmol) was added and the mixture was stirred for 1 hour and then evaporated under reduced pressure. Flash column chromatography (40% acetone-hexane) afforded the title compound as a white foam. 271 mg, 75% yield

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.72 (d, 1H, J = 8.5 Hz), 8.25 (s, 1H), 8.04 (d, 1H, J = 8.5 Hz), 7.95 (d, 1H, J = 8.5 Hz), 7.46-7.43 (m, 2H), 5.23 (d, 1H, J = 3.94 Hz), 4.54-4.47 (m, 1H), 4.03-4.00 (m, 2H), 3.90 (dd, 1H, J = 5.4 and 8.9 Hz), 3.82 (dd, 1H, J = 4.4 and 9.3 Hz), 3.53-3.48 (m, 2H), 1.72-1.66 (m, 2H), 1.52-1.48 (m, 1H), 0.91 (d, 3H, J = 6.4 Hz), 0.88 (d, 3H, J = 6.4 Hz).

MS calcd. For (C ₁₈ H ₂₄ N ₂ 0 ₅ + H) ⁺ : 365, found: 365

(e) 4-S-amino-N-[(2-benzo (b) thiophencarbonyl) -S-leucine] -tetrahydrofuran-3-one

Trans-4-S-amino-N-[(2-benzo (b) thiophencarbonyl) -S-leucine-3-R-hydroxytetrahydrofuran (150 mg, 0.40 mmol) in dichloromethane (10 ml) To a stirred solution of Dess-Martin Periodinane Reagent (200 mg, 0.5 mmol) was added. After 1 hour, ether (20 ml) was added followed by sodium thiosulfate (1 g). After an additional 15 minutes, the reaction was washed with saturated sodium bicarbonate, brine and dried. Evaporation of the solvent gave the title compound as a white foam. 147 mg, 100% yield

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.82 (d, 1H, J = 4.0 Hz), 8.46 (d, 1H, J = 4.0 Hz), 8.28 (s, 1H), 8.05 (d, 1H, J = 4.0 Hz), 7.98 (d, 1H, J = 4.0 Hz), 7.47-7.44 (m, 2H), 4.54-4.51 (m, 1H), 4.33-4.18 (m, 3H), 4.08-3.80 (m, 3H), 1.74-1.67 (m, 2H), 1.58-1.56 (m, 1H), 0.92 (d, 3H, J = 6.4 Hz), 0.88 (d, 3H, J = 6.4 Hz).

MS calcd. For (C ₁₉ H ₂₂ N ₂ 0 ₄ -H) ⁺ : 373, found: 373

Example 95

Preparation of 4-R-amino-N-[(2-benzo (b) thiophencarbonyl) -S-leucine] -tetrahydrofuran-3-one

The starting material in the method of Example 94 (a) was trans-4-R-azido-3-S-hydroxytetrahydrofuran (see LE Martinez, JLLeighton, DECarsten and EN, Jacobsen, J. Amer. The title compound was prepared following the procedure of Example 94 (ae), except for replacing with Chem. Soc., 1995, 117, 5897).

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.82 (d, 1H, J = 4.0 Hz), 8.52 (d, 1H, J = 4.0 Hz), 8.28 (s, 1H), 8.01 (d, 1H, J = 4.0 Hz), 7.95 (d, 1H, J = 4.0 Hz), 7.47-7.44 (m, 2H), 4.54-4.51 (m, 1H), 4.33-4.18 (m, 3H), 4.33 (app t, 1H , J = 8.5 Hz), 4.22 (dd, 1H, J = 8.7 and 16.0 Hz), 4.07 (app d, 1H, J = 16.6 Hz), 3.90 (app d, 1H, J = 16.6 Hz), 3.81 (app t, 1H, J = 8.5 Hz), 1.74-1.67 (m, 2H), 1.58-1.56 (m, 1H), 0.92 (d, 3H, J = 6.4 Hz), 0.88 (d, 3H, J = 6.4 Hz ).

MS calcd. For (C ₁₉ H ₂₂ N ₂ 0 ₄ -H) ⁺ : 373, found: 373

Example 96

Preparation of 4-S-amino-N-[(2-naphthoyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared according to the procedure of Example 94 using 4-azido-3-hydroxytetrahydrofuran with the appropriate carboxylic acid chloride and the required stereochemistry consistent with the final product.

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.64 (d, 1H, J = 3.8 Hz), 8.54 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 8.03 (d, 1H, J = 3.8 Hz), 8.02-7.95 (m, 3H), 7.62-7.58 (m, 2H), 4.63-4.60 (m, 1H), 4.35-4.27 (m, 2H), 4.08 (app d, 1H, J = 16.8 Hz), 3.86 (app d, 1H, J = 16.8 Hz), 3.82 (app t, 1H, J = 8.0 Hz), 1.75-1.64 (m, 2H), 1.62-1.55 (m, 1H), 0.92 ( d, 3H, J = 6.0 Hz), 0.88 (d, 3H, J = 6.0 Hz).

MS calcd. For (C ₂₁ H ₂₄ N ₂ 0 ₄ -H) ⁺ : 367, found: 367

Example 97

Preparation of 4-R-N-[(2-naphthoyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared according to the procedure of Example 94 using 4-azido-3-hydroxytetrahydrofuran with the appropriate carboxylic acid chloride and the required stereochemistry consistent with the final product.

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.62 (d, 1H, J = 3.8 Hz), 8.52 (s, 1H), 8.50 (d, 1H, J = 3.8 Hz), 8.04 (d, 1H, J = 3.8 Hz), 8.02-7.95 (m, 3H), 7.62-7.58 (m, 2H), 4.63-4.60 (m, 1H), 4.32 (app t, 1H, J = 8.8Hz), 4.23 (ddd, 1H , J = 8.8 and 16.0 Hz), 4.04 (app d, 1H, J = 16.4 Hz), 3.86 (app d, 1H, J = 16.4 Hz), 3.81 (app t, 1H, J = 8.0 Hz), 1.75- 1.64 (m, 2H), 1.62-1.55 (m, 1H), 0.92 (d, 3H, J = 6.0 Hz), 0.88 (d, 3H, J = 6.0 Hz).

MS calcd. For (C ₂₁ H ₂₄ N ₂ 0 ₄ -H) ⁺ : 367, found: 367

Example 98

Preparation of 4-S-amino-N-[(quinolin-2-carbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared according to the procedure of Example 94 using 4-azido-3-hydroxytetrahydrofuran with the appropriate carboxylic acid chloride and the required stereochemistry consistent with the final product.

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.80 (d, 1H, J = 9.0 Hz), 8.70 (d, 1H, J = 6.9 Hz), 8.63 (d, 1H, J = 8.5 Hz), 8.39 ( d, 1H, J = 2.5 Hz), 8.27 (d, 1H, J = 2.5 Hz), 8.21 (d, 1H, J = 7.9 Hz), 7.95 (app t, 1H, J = 8.2 Hz), 7.77 (app t, 1H, J = 7.1 Hz), 4.75-4.66 (m, 1H), 4.41-4.26 (m, 2H), 4.16-3.79 (m, 3H), 1.82-1.63 (m, 3H), 0.97-0.88 ( m, 6H).

MS calcd. For (C ₂₀ H ₂₃ N ₃ 0 ₄ + H) ⁺ : 370, found: 370

Example 99

Preparation of 4-R-amino-N-[(quinolin-2-carbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared according to the procedure of Example 94 using 4-azido-3-hydroxytetrahydrofuran with the appropriate carboxylic acid chloride and the required stereochemistry consistent with the final product.

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.88 (d, 1H, J = 9.0 Hz), 8.82 (d, 1H, J = 6.7 Hz), 8.70 (d, 1H, J = 8.5 Hz), 8.30 ( d, 1H, J = 2.5 Hz), 8.27 (d, 1H, J = 2.5 Hz), 8.21 (d, 1H, J = 7.9 Hz), 8.02 (app t, 1H, J = 7.0 Hz), 7.87 (app t, 1H, J = 7.0 Hz), 4.82-4.73 (m, 1H), 4.48-3.88 (m, 5H), 1.88-1.70 (m, 3H), 1.05-1.02 (m, 6H).

MS calcd. For (C ₂₀ H ₂₃ N ₃ 0 ₄ + H) ⁺ : 370, found: 370

Example 100

Preparation of 4-S-amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

The title compound was prepared according to the procedure of Example 94 using 4-azido-3-hydroxytetrahydrofuran with the appropriate carboxylic acid chloride and the required stereochemistry consistent with the final product.

¹ H NMR δ (d ₆ DMSO, 400 MHz): 8.73 (d, 1H, J = 8.4 Hz), 8.52 (d, 1H, J = 7.0 Hz), 7.65-7.62 (m, 2H), 7.33 (d, 1H , J = 2.6 Hz), 7.12 (dd, 1H, J = 2.6 and 9.2 Hz), 4.64-4.55 (m, 1H), 4.42-4.30 (m, 2H), 4.18-3.87 (m, 3H), 3.86 ( s, 3H), 1.84-1.57 (m, 3H), 0.98-0.87 (m, 6H).

MS calcd. For (C ₂₀ H ₂₄ N ₂ 0 ₆ + H) ⁺ : 389, found: 389

Examples 101 to 108

The compounds of Table 3 were prepared by a procedure similar to that described in Example 15, using appropriate amino acids and acid or acid chloride reagents consistent with the final product. ¹ H NMR spectrum and / or mass spectrum was consistent with the structure in Table 3.

Example R ³ R " Synthesis method 101 6-hydroxybenzo [b] thiophen-2-yl SPS 102 〃 5-hydroxybenzo [b] thiophen-2-yl SPS 103 〃 4- (3- (hydroxymethyl) phenyl) phenyl SPS 104 〃 3-phenylphenyl SPS 105 〃 4- (3-oxophenyl) phenyl SPS 106 〃 4- (3- (aminosulfonyl) phenyl) phenyl SPS 107 Benzo [b] thiophen-2-yl SPS 108 Benzo [b] thiophen-2-yl SPS

Examples 109-126

The compounds of Examples 109-126 were prepared according to the procedure of Example 94 using 4-azido-3-hydroxytetrahydrofuran with the appropriate carboxylic acid chloride and the required stereochemistry consistent with the final product. ¹ H NMR spectrum and / or mass spectrum was consistent with the structure in Table 4.

Example R ³ R " Stereochemistry at 4-position 109 4- (pyrid-3-yl) phenyl S 110 〃 4- (pyrid-2-yl) phenyl S 111 〃 4-acetylphenyl S 112 〃 Benzyloxy S 113 〃 3,4-dimethoxyphenyl S 114 〃 Benzofuran-2-yl S 115 〃 4- (6-methylpyrid-3-yl) phenyl S 116 〃 5-chlorobenzo [b] thiophen-2-yl S 117 〃 4- (pyrid-4-yl) phenyl S 118 〃 2-chlorophenyl S 119 〃 4-bromophenyl S 120 〃 4-chlorobenzo [b] thiophen-2-yl S 121 〃 4-benzylpiperidin-1-yl S 122 〃 3,4-dichlorophenyl S 123 〃 3,4-dimethoxyphenyl R 124 〃 Benzofuran-2-yl R 125 〃 3-chlorophenyl S 126 〃 5-chlorobenzo [b] thiophen-2-yl R

Examples 127-129

3,3-dimethoxy-4-aminotetrahydropyran is used instead of 3,3-dimethoxy-4-aminotetrahydrofuran, except that the appropriate amino acid and carboxylic acid reagents match the final product. The compounds of Examples 127-129 were prepared using the SPS method of Example 15. ¹ H NMR spectrum and / or mass spectrum was consistent with the structure in Table 5.

Example R ³ R " Synthesis method 127 4-phenoxyphenyl SPS 128 〃 Quinolin-2-yl SPS 129 〃 3,4-dimethoxyphenyl SPS

Example 130

Preparation of 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrothiophen-3-one

(a) N-benzo [b] thiophen-2-ylcarbonyl-L-leucine methyl ester

To a stirred solution of L-leucine methyl ester (4.5 g, 25 mmol) and diisopropylethylamine (9 ml, 51 mmol) in DCM (200 ml) was added benzo [b] thiophene-2-carbonyl chloride (4.9 g). , 25 mmol) was added. After stirring for 2 hours at room temperature, the mixture was poured into water, washed with brine and dried (MgSO ₄ ). Evaporation under reduced pressure gave the title compound as a white solid. 7.6 g, 100% yield

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.88-7.78 (m, 3H), 7.44-7.38 (m, 2H), 6.53 (d, 1H, J = 7.6 Hz), 4.91-4.82 (m, 1H), 3.78 (s, 3H), 1.82-1.60 (m, 3H), 1.00 (appt, 6H, J = 5.9 Hz).

(b) N-benzo [b] thiophen-2-ylcarbonyl-L-leucine

Lithium hydroxide (1.41 g) in a stirred solution of N-benzo [b] thiophen-2-ylcarbonyl-L-leucine methyl ester (8.99 g, 29.4 mmol) in THF / H ₂ O (1/1, 300 ml) 59 mmol) was added in one portion. After stirring for 12 hours at room temperature, the mixture was poured into water, acidified to pH 1 with cHCl and extracted with Et ₂ O (× 2). Evaporation under reduced pressure gave the title compound as a yellow solid. 6.1 g, 71% yield

¹ H NMR δ (d ₆ DMSO, 250 MHz): 8.78 (d, 1H, J = 9.1 Hz), 8.12 (s, 1H), 7.92-7.83 (m, 2H), 7.36-7.30 (m, 2H), 4.37 -4.28 (m, 1H), 1.88-1.47 (m, 3H), 0.82 (d, 3H, J = 6.0 Hz), 0.78 (d, 3H, J = 6.0 Hz).

(c) N-benzo [b] thiophen-2-ylcarbonyl-L-leucine-S- (methoxycarbonylmethyl) -L, D-cysteine ethyl ester

Iso-propyl chloro in a stirred solution of N-benzo [b] thiophen-2-ylcarbonyl-L-leucine (1.65 g, 5.7 mmol) and triethylamine (1.6 ml, 11.8 mmol) in DCM (20 ml) Formate (5.9 ml, 1.0 M in toluene) was added. After 1 hour at room temperature, L-cysteine ethyl ester was added followed by triethylamine (1.6 ml, 11.8 mmol) and the mixture was further stirred for 6 hours. Methyl bromoacetate (0.6 ml, 6.3 mmol) was added and the mixture was left to stand for 0.5 h more before pouring into water, then extracted with EtOAc (× 3). The combined organic layers were washed with brine, dried (MgSO ₄ ) and evaporated under reduced pressure. Flash column chromatography (40% hexanes-Et ₂ O) gave the title compound as a white solid. 1.6 g, 70%.

¹ H NMR δ (CDCl ₃ , 250 MHz): 7.84-7.77 (m, 3H), 7.66 (d, 0.5H, J = 8.4 Hz), 7.52 (d, 0.5H, J = 8.4 Hz), 7.40-7.35 ( m, 2H), 7.24 (d, 0.5H, J = 8.4 Hz), 7.16 (d, 0.5H, J = 8.4 Hz), 4.88-4.82 (m, 2H), 4.23-4.15 (m, 2H), 3.70 (s, 1.5H), 3.69 (s, 1H), 3.36-3.22 (m, 2H), 3.15-3.08 (m, 2H), 1.82-1.75 (m, 3H), 1.28 (t, 1.5H, J = 4.5 Hz), 1.23 (t, 1.5H, J = 4.5 Hz), 0.98-0.95 (m, 6H).

(d) 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one

To N-benzo [b] thiophen-2-ylcarbonyl-L-leucine-S- (carbomethoxymethyl) -L, D-cysteine ethyl ester (1.5 g, 3.2 mmol) in methanol (2 ml) Freshly prepared sodium methoxide solution from 75 mg of sodium and 2 ml of methanol was added at room temperature. After 1 hour, Et ₂ O (80 ml) was added and the solution was cooled to 0 ° C. and the white solid obtained was filtered off. The solid was dissolved in 15 ml of acetic acid, 10 ml of cHCl and 15 ml of H ₂ O. The mixture was stirred at reflux for 0.5 h and then cooled to rt and extracted with CHCl ₃ (× 5). The combined organic layers were washed with NaHCO ₃ , brine, dried (MgSO ₄ ) and evaporated under reduced pressure. Flash column chromatography (40% hexanes-Et ₂ O) gave the title compound as a white solid. 120 mg, 10% yield

¹ H NMR δ (CDCl ₃ , 400 MHz): 7.88-7.78 (m, 3H), 7.58 (d, 0.5H, J = 6.4 Hz), 7.54 (d, 0.5H, J = 6.4 Hz), 7.42-7.35 ( m, 3H), 4.85-4.80 (m, 1H), 4.43-4.34 (m, 1H), 3.34-3.23 (m, 3H), 3.02-2.91 (m, 1H), 1.76-1.74 (m, 3H), 0.98-0.85 (m, 6 H).

MS calcd. For (C ₁₉ H ₂₂ N ₂ 0 ₃ S + H) ⁺ : 391, found: 391

Example 131

Preparation of 4-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3,3-dimethoxytetrahydrofuran diastereomer 1

(a) 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3,3-dimethoxytetrahydrofuran

4- (R, S) -amino-3,3-dimethoxytetrahydrofuran (2.2 g, 15 mmol), N-benzyloxycarbonyl-L-leucine (3.98 g, 15 mmol), EDC (3.17 g, 16.5 mmol) and hydroxyaminobenztriazole (0.45 g, 3.3 mmol) were stirred together in a mixture of dichloromethane and tetrahydrofuran (1: 1, 100 ml) at ambient temperature for 12 hours. The mixture was added to ethyl acetate (300 ml), washed with water (2 × 100 ml), dried (MgSO ₄ ) and evaporated to dryness. The resulting oil was chromatographed on silica gel (ethyl acetate / hexane 1: 3 to 1: 1 gradient) to afford the title compound as an oil (5.27 g, 89%).

¹ H NMR δ (CDCl ₃ ): 7.34 (s, 5H), 6.55 (d, 1H), 5.11 (m, 3H), 4.34 (q, 1H, J = 6.7 Hz), 4.20 (m, 2H), 3.77 (m, 2H), 3.51 (m, 1H), 3.26 (d, 3H, J = 2.3 Hz), 3.20 (d, 3H, J = 4.7 Hz), 1.54 (m, 3H), 0.95 (s, 3H) , 0.93 (s, 3 H).

(b) the respective diastereomers of 4-amino-N- (S-leucine) -3,3-dimethoxytetrahydrofuran

4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3,3-dimethoxytetrahydrofuran (5.27 g, 13.4 mmol) containing 10% palladium on charcoal Hydrogenation at 50 psi in methanol. After 3.5 hours, the mixture was filtered through celite and the solvent was removed under reduced pressure. The resulting oil (3.5 g) was chromatographed on silica gel (CH ₂ Cl ₂ with a 0-4% gradient of MeOH) to separate the title compound into two pure single diastereomers:

Diastereomer 1 (fast flow) (0.63 g). ¹ H NMR δ (CDCl ₃ ): 7.76 (d, 1H, J = 7.3 Hz), 4.36 (dd, 1H, J = 6.3, 7.2 Hz), 4.21 (dd, 1H, J = 6.4, 9.0 Hz), 3.80 (s, 2H), 3.57 (dd, 1H, J = 5.3, 9.1 Hz), 3.41 (dd, 1H, J = 3.8, 10.1 Hz), 3.30 (s, 3H), 3.24 (s, 3H), 1.73 ( m, 2H), 1.35 (m, 1H), 0.96 (d, 3H, J = 6.7 Hz), 0.94 (d, 3H, J = 6.6 Hz).

Diastereomer 2 (slow flow) (0.91 g). ¹ H NMR δ (CDCl ₃ ): 7.77 (d, 1H, J = 7.1 Hz), 4.36 (dd, 1H, J = 6.4, 12.9 Hz), 4.21 (dd, 1H, J = 6.5, 9.1 Hz), 3.80 (s, 2H), 3.55 (dd, 1H, J = 5.3, 9.0 Hz), 3.38 (dd, 1H, J = 4.0, 10.0 Hz), 3.30 (s, 3H), 3.25 (s, 3H), 1.72 ( m, 2H), 1.38 (m, 1H), 0.96 (d, 3H, J = 6.7 Hz), 0.94 (d, 3H, J = 6.8 Hz).

(c) 4-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3,3-dimethoxytetrahydrofuran diastereomer 1

Saturated sodium bicarbonate solution in a solution of 4-amino-N- (S-leucine) -3,3-dimethoxytetrahydrofuran diastereomer 1 (0.13 g, 0.5 mmol) in 1,4-dioxane (5 ml) (5 ml) was added followed by benzo [b] thiophen-2-ylcarbonyl chloride (0.39 g, 2 mmol). After 45 minutes, the mixture was added to ethyl acetate and washed with water, sodium bicarbonate solution and water. The organic solution was dried (MgSO ₄ ) and evaporated to give a white solid (0.47 g). Chromatography on silica gel (CH ₂ Cl ₂ with 0-5% gradient of MeOH) afforded the title compound as a white solid (0.18 g, 89%).

¹ H NMR δ (CDCl ₃ ): 7.88 (s, 1H), 7.74 (m, 3H), 7.34 (m, 2H), 7.18 (d, 1H, J = 7.1 Hz), 4.82 (m, 1H), 4.38 (dd, 1H, J = 6.4, 12.3 Hz), 4.21 (dd, 1H, J = 6.5, 9.2 Hz), 3.78 (ABq, 2H, J = 3.8, 9.8 Hz), 3.62 (dd, 1H, J = 5.2 , 9.1 Hz), 1.78 (m, 3H), 0.99 (s, 3H), 0.96 (s, 3H).

Examples 132-142

Using a diastereomer of suitable 4-amino-N- (S-leucine) -3,3-dimethoxytetrahydrofuran and a carboxylic acid halide reagent consistent with the final product, a procedure similar to that described in Example 131 was used. The compound of Table 6 was prepared by the above. ¹ H NMR and mass spectra were consistent with the structures in Table 6.

Example R ³ R " R ^a R ^b Diastereomers 132 Benzo [b] thiophen-2-yl Me Me 2 133 〃 Indole-5-day 〃 〃 One 134 〃 〃 〃 〃 2 135 〃 Quinolin-2-yl 〃 〃 One 136 〃 〃 〃 〃 2 137 〃 3-bromophenyl 〃 〃 One 138 〃 〃 〃 〃 2 139 〃 4-phenoxyphenyl 〃 〃 One 140 〃 〃 〃 〃 2 141 〃 Indole-6-day 〃 〃 2 142 〃 Benzimidazol-5-yl One

Example 143

Preparation of 4-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3,3-dimethoxytetrahydropyran diastereomer 1

(a) 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3,3-dimethoxytetrahydropyran

4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydropyran-3-one (Example 67c, 3.1 g, 8.6 mmol) in methanol (50 ml) Heated under reflux for 12 h with trimethylorthoformate (2.8 ml) and p-toluenesulfonic acid (0.080 g). After removal of the solvent under reduced pressure, the resulting oil was chromatographed on silica gel (ethyl acetate / hexane gradient) to afford the title compound as a white solid (2.89 g, 80%).

¹ H NMR δ (CDCl ₃ ): 7.29 (s, 5H), 6.99 (m, 1H), 6.15 (m, 1H), 5.07 (s, 2H), 4.28 (m, 1H), 4.18 (m, 1H) , 3.52 (m, 4H), 3.19 (s, 3H), 3.14 (s, 3H), 1.85 (m, 1H), 1.63 (m, 4H), 0.93 (s, 6H).

(b) each diastereomer of 4-amino-N- (S-leucine) -3,3-dimethoxytetrahydropyran

4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3,3-dimethoxytetrahydropyran was hydrogenated as in Example 131b and titled after chromatography Pure single diastereomers of the compounds were obtained:

Diastereomer 1: ¹ H NMR δ (CDCl ₃ ): 7.75 (d, 1H, J = 8.1 Hz), 4.17 (m, 1H), 3.58 (m, 3H), 3.41 (dd, 1H, J = 3.5, 9.7 Hz), 3.28 (s, 3H), 3.24 (s, 3H), 1.92 (m, 1H), 1.71 (m, 4H), 1.30 (m, 1H), 0.97 (d, 3H, J = 6.4 Hz) , 0.94 (d, 3H, J = 6.3 Hz).

Diastereomer 2: ¹ H NMR δ (CDCl ₃ ): 7.8 (s, 1H), 4.16 (m, 1H), 3.59 (m, 3H), 3.49 (m, 1H), 3.28 (s, 3H), 3.24 (s, 3H), 1.92 (m, 1H), 1.72 (m, 4H), 1.41 (m, 1H), 0.97 (d, 3H, J = 6.1 Hz), 0.95 (d, 3H, J = 6.0 Hz) .

(c) 4-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3,3-dimethoxytetrahydropyran diastereomer 1

4-Amino-N- (S-leucine) -3,3-dimethoxytetrahydropyran diastereomer 1 was reacted with benzo [b] thiophen-2-ylcarbonyl chloride as in Example 131c to give the title compound Obtained.

¹ H NMR δ (CDCl ₃ ): 7.98 (d, 1H, J = 8.3 Hz), 7.93 (s, 1H), 7.78 (d, 1H, J = 7.7 Hz), 7.71 (d, 1H, J = 8.3 Hz ), 7.33 (m, 3H), 4.83 (m, 1H), 4.19 (m, 1H), 3.69 (m, 1H), 3.57 (m, 2H), 3.40 (d, 1H, J = 13 Hz), 3.23 ( s, 3H), 3.13 (s, 3H), 1.85 (m, 5H), 0.98 (d, 3H, J = 4.8 Hz), 0.96 (d, 3H, J = 5.2 Hz).

Example 144

Preparation of 4-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3,3-dimethoxytetrahydropyran diastereomer 2

The title compound was prepared using diastereomer 2 of 4-amino-N- (S-leucine) -3,3-dimethoxytetrahydropyran in the procedure of Example 143c.

The above specification and examples fully disclose the preparation and use of the compounds of the present invention. However, the invention is not limited to the specific embodiments described above and includes all variations thereof within the scope of the following claims. Various references to periodicals, patents, and other publications cited herein include aspects of the art, and are incorporated herein by reference as indicated above.

Claims (36)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: <Formula I> [Wherein, R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O); R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl; R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl; R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl; X is O or S; n is 1, 2 or 3] 2. Compounds according to claim 1, wherein R ² and R ⁴ are each H. The compound of claim 1, wherein R ³ is C _1-6 alkyl or C _2-6 alkenyl. The compound of claim 3, wherein R ³ is i-butyl. The compound of claim 1, wherein R ¹ is R ″ OC (O), R ″ SO ₂ or R ″ C (O), wherein R ″ is Ar-C _0-6 alkyl or Het-C _0-6 alkyl Phosphorus compounds. The group according to claim 5, wherein the R ″ group is: Wherein B ₂ is OH, CN, OCF ₃ , OC _1-6 alkyl, OAr, SO ₂ C _1-6 alkyl, C _1-6 alkyl or halo] Phosphorus compounds. 2. Compounds according to claim 1, wherein n is 1 or 2. 8. A compound according to claim 7, wherein n is one. The compound of claim 1, wherein X is O. 2. Compounds according to claim 1, wherein each R ⁵ is H. A compound of formula IIa: <Formula IIa> The compound of claim 1 wherein <Formula IIb> A compound of formula IIc according to claim 1: <Formula IIc> The method of claim 1, 4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -Amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -Amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(2-quinolincarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(8-quinolincarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -2,2-dibenzyl-tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(indol-6-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(5-aminobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(5-chlorobenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -Amino-N-[(3-bromobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(4-bromobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -Amino-N-[(4-fluorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(4-phenoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -Amino-N-[(4-phenylbenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(6-trifluoromethylbenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -Amino-N-[(4-ethylbenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(4- (t-butyl) benzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(5-methoxybenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(4-nitrobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(6-bromobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(5-bromobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(6-methoxybenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(benzo (b) thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-R-amino-N-[(benzo (b) thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(2-naphthoyl) -S-leucine] -tetrahydrofuran-3-one; 4-R-amino-N-[(2-naphthoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(quinolin-2-carbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-R-amino-N-[(quinolin-2-carbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyrid-3-yl) benzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyrid-2-yl) benzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(4- [6-methylpyrid-3-yl] benzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[((4-pyrid-4-yl) benzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(2-chlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(4-bromobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(4-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(4-benzylpiperidin-1-ylcarbonyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4-S-amino-N-[(3-chlorobenzoyl) -S-leucine] -tetrahydrofuran-3-one; 4- (R, S) -amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -tetrahydropyran-3-one; 4- (R, S) -Amino-N-[(4-phenoxybenzoyl) -S-leucine] -tetrahydropyran-3-one; 4- (R, S) -amino-N-[(quinolin-2-ylcarbonyl) -S-leucine] -tetrahydropyran-3-one; 4- (R, S) -Amino-N-[(benzyloxycarbonyl) -S-leucine] -tetrahydropyran-3-one; 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydropyran-3-one; And 4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrothiophen-3-one; Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier. A method of inhibiting cysteine protease, comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof. The method of claim 16, wherein the cysteine protease is cathepsin K. A method of inhibiting bone loss, comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof. A method of treating osteoporosis comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. A method of treating gingival or periodontal disease comprising administering an effective amount of a compound according to claim 1 to a patient in need thereof. A method for treating a disease characterized by excessive cartilage or matrix degradation comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. The method of claim 21, wherein the disease is osteoarthritis or rheumatoid arthritis. The compound according to claim 1, for use as a medicament. Use of a compound of formula (I) as defined in claim 1 for the manufacture of a medicament for the treatment of a disease in which the inhibition of cysteine protease is effective. The use of compounds according to claim 24, wherein the cysteine protease is cathepsin K. Use of a compound of formula (I) as defined in claim 1 for the preparation of a medicament for inhibiting bone loss. Use of a compound of formula (I) as defined in claim 1 for the manufacture of a medicament for the treatment of osteoporosis. Use of a compound of formula (I) as defined in claim 1 for the manufacture of a medicament for the treatment of gingival or periodontal disease. Use of a compound of formula (I) as defined in claim 1 for the manufacture of a medicament for the treatment of a disease characterized by excessive cartilage or matrix degradation. The use of a compound according to claim 29, wherein the disease characterized by excessive cartilage or matrix degradation is osteoarthritis or rheumatoid arthritis. (i) reacting a compound of formula III with an oxidant: <Formula III> [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in formula I of claim 1 and all reactive functional groups are protected]; or (ii) decarboxylation of the compound of formula IV: <Formula IV> [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in formula I of claim 1 and all reactive functional groups are protected]; or (iii) reacting a compound of formula V with an acid: <Formula V> Wherein R ¹ , R ³ , R ⁴ , R ⁵ and n are as defined in formula I of claim 1 and all reactive functional groups are protected; A process for preparing a compound of formula (I) as defined in claim 1 which then comprises removing the protecting group and optionally forming a pharmaceutically acceptable salt. A compound of formula III or a pharmaceutically acceptable salt thereof: <Formula III> [Wherein, R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O); R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl; R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl; R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl; n is 1, 2 or 3] A compound of formula IV or a pharmaceutically acceptable salt thereof: <Formula IV> [Wherein, R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O); R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl; R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl; R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl; n is 1, 2 or 3] A compound of formula (V) or a pharmaceutically acceptable salt thereof: <Formula V> [Wherein, R ¹ is R ", R" C (O), R "C (S), R" SO ₂ , R "OC (O), R"R'NC (O) or R "OC (O) NR'CH (R ⁶ ) C (O); R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl; R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl; R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl; X is O or S; n is 1, 2 or 3] A compound selected from the group consisting of: Trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(t-butoxycarbonyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(3,4-methylenedioxybenzoyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(2-quinolinecarbonyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran; Trans-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydropyran; Trans-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(indol-6-ylcarbonyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4- (R, S) -amino-N-[(5-aminobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydrofuran; Trans-4-amino-3-R-hydroxytetrahydrofuran; Trans-3-hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran; 4-benzyloxycarbonylamino-tetrahydrofuran-3-one; 3,3-dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran; 3,3-dimethoxy-4-amino-tetrahydrofuran; Trans-4-S-amino-3-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(benzyloxycarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N- (S-leucine) -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(3,4-dichlorobenzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(2-quinolinecarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(benzofuran-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(2-naphthoyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(5-methoxybenzofuran-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(5-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(4-chlorobenzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(4-bromobenzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(4- (pyrid-2-yl) benzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(4- (pyrid-3-yl) benzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-S-amino-N-[(3,4-dimethoxybenzoyl) -S-leucine] -3-R-hydroxytetrahydrofuran; Trans-4-amino-3-hydroxytetrahydropyran; Trans-4- (R, S) -amino-N-[(benzyloxycarbonyl) -S-leucine] -3-hydroxytetrahydropyran; Trans-4- (R, S) -amino-N- (S-leucine) -3-hydroxytetrahydropyran; Trans-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -3-hydroxytetrahydropyran; N-benzo [b] thiophen-2-ylcarbonyl-L-leucine methyl ester; N-benzo [b] thiophen-2-ylcarbonyl-L-leucine; N-benzo [b] thiophen-2-ylcarbonyl-L-leucine-S- (methoxycarbonylmethyl) -L, D-cysteine ethyl ester; or 2-methoxycarbonyl-4- (R, S) -amino-N-[(benzo [b] thiophen-2-ylcarbonyl) -S-leucine] -tetrahydrothiophen-3-one; Or salts thereof. A compound of formula (VI) or a pharmaceutically acceptable salt thereof: <Formula VI> [Wherein R ¹ is R ″, R ″ C (O), R ″ C (S), R ″ SO ₂ , R ″ OC (O), R ″ R′NC (O) or R ″ OC (O ) NR'CH (R ⁶ ) C (O); R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ³ is H, C _1~6 alkyl, C _2~6 alkenyl, C _2~6 alkynyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0-6 alkyl; R ⁴ is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; Each R ⁵ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ⁶ is H, C _1~6 alkyl, C _2~6 alkenyl, C _3~6 cycloalkyl, -C _0~6 alkyl, Ar-C _0~6 alkyl, or Het-C _0~6 alkyl; R 'is H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl, or Het-C _0-6 alkyl; R ″ is C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, Ar-C _2-6 alkenyl, or Het-C _2-6 alkenyl; X is O or S; n is 1, 2 or 3; R ^a and R ^{a '} are independently H or C _1-2 alkyl, provided that when one of R ^a and R ^a' is H, the other is C _1-2 alkyl; Or R ^a and R ^{a '} together are (CH ₂ ) _2-3 forming a 5- or 6-membered ring]