JP2003531122A - Method of treatment - Google Patents

Abstract

  (57) [Summary] The present invention relates to the treatment of diseases associated with cathepsin L, especially in the treatment or prevention of rheumatoid arthritis; the treatment or prevention of cancer metastasis; Cathepsin 4- A method using an amino-azepan-3-one protease inhibitor is provided.

Description

Detailed Description of the Invention

[0001] Technical Field The present invention relates generally to 4-amino - azepan-3-one protease inhibitors, particularly, for example, cathepsin L inhibitor treatment of diseases caused by cathepsin L, in particular the treatment or prophylaxis of rheumatoid arthritis In; treatment or prevention of cancer metastasis; treatment or prevention of diseases that require inhibition of tissue destruction by macrophages, particularly lung macrophages, such as asthma, chronic obstructive pulmonary disease (COPD) and emphysema; It relates to the use in the treatment or prevention of diseases which require inhibiting the positive selection of CD4 + T-cells by tissue cells.

BACKGROUND cathepsin of the present invention is directed to a family of enzymes, which is a kind of papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Cathepsins function in normal physiological processes of proteolysis in animals, including humans. However, the high levels of these enzymes in the body can cause disease-causing pathological conditions. Therefore, cathepsins include, but are not limited to, Pneumocystis carini (pneumocy).
malaria in schistosomiasis, as well as infection with stis carinii), trypsanoma cruzi, trypsanoma burucei brucei, and Crithidia fusiculata.
It has been implicated in a variety of pathologies including tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, muscular atrophy and the like. International Publication WO94 / 0417
2 (published March 3, 1994) and references cited therein. See also European patent application EP0603873A1 and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipans, are associated with the pathogenesis of gingivitis. Potempa, J. et al. (1994) Perspect
ives in Drug Discovery and Design, 2,445-458.

Pathological levels of cathepsin L are associated with various pathological conditions. Therefore, by selectively inhibiting cathepsin L, as a treatment or prevention, suppression of rheumatoid arthritis (see Iwata et al. Arthritis and Rheumatism 1997, 40, 499); suppression of cancer metastasis (K. Ishidoh and E. Kominami). Biol. Chem. 1998, 379, 131); for example in diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung tumors,
Suppression of tissue destruction by macrophages, especially lung macrophages (Chapman HA Jr.
; Munger JS; Shi GP American Journal of Respiratory and Critical Care
Medicine 1994, 150 (6 Pt 2), S155-9); and inhibition of CD4 + T- cell positive selection by cortical thymic epithelial tissue cells (Nakagawa Science 1998, 270, 45.
It is possible to provide an effective treatment for diseases requiring 0).

Some cysteine protease inhibitors are known. Palmer, (1995) J.
Med. Chem., 38, 3193 discloses certain vinyl sulfones that irreversibly inhibit cysteine proteases such as cathepsins B, L, S, O2 and cruzane. Other compounds, such as aldehydes, nitriles, α-ketocarbonyl compounds, halomethylketones, diazomethylketones, (acyloxy) methylketones, ketomethylsulnium salts and epoxysuccinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, supra and references cited therein.

US Pat. No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine proteases. International Patent Publication W
O94 / 04172 and European patent applications EP0525420A1, EP060
3873A1 and EP0611756A2 disclose alkoxymethyl and mercaptomethyl ketones that inhibit the cysteine protease cathepsins B, H and L. International patent application PCT / US94 / 08868 and European patent application EP0623592A1 disclose alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-1β convertase.
Alkoxymethyl and mercaptomethyl ketones have also been disclosed as inhibitors of the serine protease quininogenase (International Patent Application PCT / GB91 /
01479).

Azapeptides designed to deliver aza amino acids to the active site of serine proteases and to provide good leaving groups have been described by Elmore et al., Biochem. J., 196.
8, 107, 103, Garker et al., Biochem. J., 1974, 139, 555, Gray et al., Tetrahedron.
, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al.,
J. Biol. Chem., 1984, 259, 4288 and is known to inhibit serine proteases. In addition, J. Med. Chem., 1992, 35, 4279 discloses certain azapeptide esters as cysteine protease inhibitors.

Antipain and leupeptin are disclosed as reversible inhibitors of cysteine proteases in McConnell et al., J. Med. Chem., 33, 86, and as inhibitors of serine proteases in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogues are also well known as cysteine protease inhibitors (Barrett, Biochem. J., 201, 189 and Grinde, Biochem. Biophys.
Acta,, 701,328). 1,3-Diamido-propanone is used as an analgesic in US Pat. No. 4,749,79.
2 and 4,638,010. In particular, various cysteine and serine protease inhibitors of cathepsin K are disclosed in International Publication No. WO 97/16433 (published May 9, 1997). The present inventors have discovered that certain 4-amino-azepan-3-one compounds inhibit cathepsin L and are useful in the treatment of diseases involving cathepsin L.

[0008] SUMMARY OF THE INVENTION An object of the invention is, of cathepsin L of formula (I) 4-Amino - azepane -
A therapeutic method using a 3-one carbonyl protease inhibitor, cathepsin L
It is intended to provide a therapeutic method which is useful for the treatment of diseases which can be therapeutically modified by altering the activity of In a particular embodiment, the methods of the invention are particularly useful in the treatment or prevention of rheumatoid arthritis; the treatment or prevention of cancer metastasis; diseases that require inhibition of tissue destruction by macrophages, especially pulmonary macrophages, eg asthma, chronic obstructive disease. Lung disease (CO
PD) and treatment or prevention of emphysema; useful for the treatment or prevention of diseases which require inhibiting the positive selection of CD4 ⁺ T ⁻ cells by thymic epithelial cells of the cortex for the treatment.

[0009] DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of inhibiting cathepsin L, animal in need of inhibition, in particular a mammal, especially a human, of formula (I):

[Chemical 6] I [in the formula: R ¹ is

[Chemical 7] It is selected from the group consisting of; ^{R 2} is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} alkyl, ^{R 9 _{C (O) -, R 9}} C (S) -, R 9 SO 2 -, R 9 OC (O) -, R 9 R 11 NC (O) -, R 9 R 11 NC (S) -, R 9 ^(R 11) _NSO 2 -,

[Chemical 8] R ³ is selected from the group consisting of: H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and A
selected from the group consisting of rC _0-6 alkyl; R ³ and R ′ may combine to form a pyrrolidine, piperidine or morpholine ring; R ⁴ represents H, C _1-6 alkyl, C _{3 — 6} cycloalkyl-C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁵ C (O)-, R ⁵ C (S)-, R ⁵ SO _2- , R ⁵ OC (O)-, R ⁵ R ¹³ NC (O)-and R ⁵ R ¹³ NC (S)-; R ⁵ 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 and H
It is selected from the group consisting _{et-C 0-6} alkyl; ^{R 6} is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl or Het-C It is selected from the group consisting of _0-6 alkyl; ^{R 7} is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} ^{alkyl, R 10 C (O) -} , R 10 C (S) -, R 10 SO 2 -, R 10 OC (O) -, R 10 R 14 NC (O
)-And R ¹⁰ R ¹⁴ NC (S)-; R ⁸ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl,
Is selected from HetC _0-6 alkyl and _{ArC 0-6} group consisting of alkyl; ^{R 9} _{is, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, A
selected from the group consisting of r-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹⁰ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl,
R ¹¹ is selected from the group consisting of Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹¹ is from H, C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl. R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar—C _0-6 alkyl and Het-C _0-6 alkyl; R ¹³ is H, C _1-6 R ¹⁴ is selected from the group consisting of alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹⁴ is H, C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6. It is selected from the group consisting of alkyl; R 'is, _{H, C 1-6} alkyl is selected from the group consisting of _{Ar-C 0-6} alkyl and _{Het-C 0 -6} alkyl; R''is, H, C _1-6 alkyl, Ar C _0-6 is selected from alkyl or the group consisting of _{Het-C 0 -6} alkyl; R '''is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, Ar-C Selected from the group consisting of _0-6 alkyl and Het-C _0-6 alkyl; X is selected from the group consisting of CH ₂ , S and O; and Z is a group consisting of C (O) and CH _2. The present invention provides a method of administering an effective amount of a compound represented by the formula: and a pharmaceutically acceptable salt, hydrate and solvate thereof.

In the compound of formula (I), preferably R ¹ is

[Chemical 9] Is. In this compound: R ³ is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Het-C _0-6 alkyl and Ar. Selected from the group consisting of _-C0-6alkyl , preferably _C1-6alkyl and Ar- _C0-6alkyl , most preferably isobutylbutyl, naphthalen-2-ylmethyl, benzyl and benzyloxymethyl. R ⁴ is H, C _1-6 alkyl, C _3-6 cycloalkyl-, C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁵ C (O)-. , R ⁵ C (S)-, R ⁵ SO _2- , R ⁵ OC (O)-, R ⁵ R ¹³ NC (O)-and R ⁵ R ¹³ NC (S)-, and preferably Is R ⁵ C (O)-
Is. R ⁵ _{is, 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
Selected from the group consisting of _-C0-6alkyl . Preferably, R ⁵ is selected from the group consisting of C _1-6 alkyl, Ar—C _0-6 alkyl and Het-C _0-6 alkyl. Most preferably R ⁵ is quinolinyl, especially quinolin-2-yl, quinolin-4-yl and quinolin-8-yl; isoquinolinyl, especially isoquinolin-1-yl; naphthalenyl, especially naphthalen-1-yl; and benzofuranyl. Particularly selected from the group consisting of benzofuran-2-yl. R 'is, _H, is selected from _{C 1-6} alkyl, _{Ar-C 0-6} alkyl and _{Het-C 0 -6} group consisting of alkyl, preferably H. R ″ is selected from the group consisting of H, C _1-6 alkyl, Ar—C _0-6 alkyl and Het-C _0-6 alkyl, preferably H.

[0011] In the compounds of formula (I), ^{R 2} is _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} alkyl , R ⁹ C (O)-, R ⁹ C (S)-, R ⁹ SO _2- , R ⁹ OC (O)-, R ⁹ R ¹¹ NC (O)-, R ⁹ R ¹¹ NC (S)-. , R ⁹ R ¹¹ NSO ₂ −,

[Chemical 10] Is selected from the group consisting of Preferably R ² is R ⁹ SO ₂ . R ⁹ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, A
It is selected from the group consisting of r-C _0-6 alkyl and Het-C _0-6 alkyl, preferably Het-C _0-6 alkyl, more preferably pyridinyl and 1-oxy-pyridinyl. When R ² is ^{R 9} SO _2, ^R 9 is more preferably a pyridin-2-yl and 1-oxy - is selected from the group consisting of pyridin-2-yl. Most preferably R ⁹ is 1-oxy-pyridin-2-yl.

Most preferably, formula (I): [wherein R ¹ is

[Chemical 11] R ² is R ⁹ SO ₂ ; R ³ is selected from the group consisting of isobutyl, naphthalen-2-ylmethyl, benzyl and benzyloxymethyl; R ⁴ is R ⁵ C (O) R ⁵ is selected from the group consisting of quinolin-2-yl, quinolin-4-yl, quinolin-8-yl, isoquinolin-1-yl, naphthalen-1-yl and benzofuran-2-yl; R ⁹ is , Pyridin-2-yl and 1-oxy-pyridin-2-yl,
Preferred is 1-oxy-pyridin-2-yl. R ′ is H, R ″ is H; and R ′ ″ is H. ] It is a compound shown by these.

Compounds of formula (I) selected from the following group are particularly preferred embodiments for use in the invention: quinoline-8-carboxylic acid {(S) -3-methyl-1- [ 3-oxo-1- (
Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (
Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1
-(Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; quinolin-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-
Oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide; naphthylene-1-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3
-Oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide; quinoline-8-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2)
-Sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl}
-Amide; naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-
2-Sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide; quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2)
-Sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl}
-Amide; benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide; benzofuran- 2-carboxylic acid {(S) -2-naphthylene-2-yl-1- [
3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide; and benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo -1- (Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl]
-Ethyl} -amide.

Certain compounds used in the present invention are described in Examples 1-12. Compared to the corresponding 5 and 6 membered ring compounds, the 7 membered ring compounds used in the present invention are in the alpha position to the ketone but are structurally stable. The invention also uses deuterated, similar invention compounds. A representative example of such a deuterium compound is described in Example 12. A representative synthetic method for the deuterium compounds of the present invention is described in Example 12 below. The deuterium compound used in the present invention exhibits excellent chiral stability as compared with the protonated isomer.

Definitions The compounds used in the present invention include all hydrates, solvates, complexes and prodrugs. Prodrugs are any covalent compounds that release the active parent drug according to formula (I) in vivo. When other forms of asymmetric centers or isomeric centers are present in the compounds used in the present invention, all forms of the isomers or isomers, including enantiomers and diastereomers, are included herein Be done. The compounds used in the present method containing asymmetric centers can be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using known techniques, with the individual enantiomers being used alone. Good. Both cis (Z) and trans (E) isomers are included in the scope of the present invention when the compound has an unsaturated carbon-carbon double bond. When a compound exists in tautomeric forms, for example keto-enol tautomers, the individual tautomeric forms are considered to be included in the present invention whether they exist predominantly in equilibrium or in one form in the present invention. Unless defined otherwise, the meaning of a substituent occurring in formula (I) or a sub-formula thereof is independent of the meaning of the substituent or the meaning of other substituents that occur in other places.

Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the invention. In general, the abbreviations for amino acids follow the IUPAC-IUB Biochemical Names Union Committee described in Eur. J. Biochem., 158, 9 (1984). A "protease" is an enzyme that catalyzes the cleavage of amide bonds in peptides and proteins with amide bonds, resulting in hydrolysis, through nucleophilic substitution. Such proteases include cysteine proteases, serine proteases, aspartic proteases and metalloproteases. The compounds of the invention can bind to the enzyme more strongly than the substrate and are generally not subject to cleavage after oxygen catalysis by a nucleophile. As such, they competitively inhibit proteases from recognizing and hydrolyzing natural substrates, and thus act as inhibitors.

The term “amino acid” as used in the present invention means alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. Refers to the D- or L-isomer. The term “C _1-6 alkyl” as used in the present invention refers to substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl. , Neopentyl and hexyl and the simple aliphatic isomers thereof. C _1-6 alkyl ^{is OR 12, C (O) R} 12, SR 12, S (O) R 12 NR 12 2, R 1 2 NC (O) OR 5, CO2R 12, CO2R 12, CO2NR 12 2, N (C
═NH) NH ₂ , Het, C _3-6 cycloalkyl and optionally substituted by a group selected from the group consisting of Ar; wherein R ⁵ is H, C _1-6 alkyl, C _2-6. Selected from the group consisting of alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl-C _0-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹² is H, C _{1- 6} alkyl, a group selected from the group consisting of _{Ar-C 0-6} alkyl and _{Het-C 0-6} alkyl.

The term “C _3-6 cycloalkyl” as used in the present invention is intended to include substituted or unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane. The term “C _2-6 alkenyl” as used herein refers to an alkyl group of 2 to 6 carbon atoms in which a carbon-carbon single bond has been replaced with a carbon-carbon double bond. C _2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene, and several isomers of pentene and hexane. The term “C _2-6 alkynyl” as used herein refers to an alkyl group of 2 to 6 carbon atoms in which one carbon-carbon single bond has been replaced with a carbon-carbon triple bond. C _2-6 alkyl includes acetone, 1-propyne, 2-propyne,
Includes 1-butyne, 3-butyne and the simple isomeric pentines and hexenes. “Halogen” refers to fluorine, chlorine, bromine and iodine. "Ar" or "aryl", phenyl or naphthyl, one or more of _{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 15 R 16; O (CH 2) 1-6 NR 15 R 16; C1-6 _{^{alkyl, OR 17, N (R 17}} ) 2 SR 17 , CF ₃ , NO ₂ , CN, CO ₂ R ¹⁷ ,
CON ^{(R 17),} fluorine, chlorine, bromine or iodine (where ^{R 15} and ^{R 1 6} is, _{H, C 1-6} alkyl, _{Ph-C 0-6} alkyl, naphthyl _{-C 0-6} alkyl or Het- R ¹⁷ is phenyl or naphthyl optionally substituted with C _0-6 alkyl; R ¹⁷ is phenyl, naphthyl, or C _1-6 alkyl.

As used herein, the term “Het” or “heterocyclic” refers to a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic or a stable 11-membered. 18-membered tricyclic heterocycles, which are either saturated or unsaturated, containing 1 to 3 heteroatoms selected from the group consisting of carbon atoms and N, O and S, Here, the nitrogen and sulfur heteroatoms may be oxidized and the nitrogen heteroatoms may be quaternized, including bicyclic groups in which the heterocycles described above are fused with a benzene ring. Heterocycle, attached at a heteroatom or a carbon atom becomes a stable _structure, C 0-6 Ar, C1-6 ^{_{alkyl, OR 17, N (R 17}} ) 2, SR 1 7, CF 3, NO 2, CN, CO ₂ R ¹⁷ , CON (R ¹⁷ ), F, Cl, Br
It may be substituted with 1 or 2 groups selected from and I, wherein R ¹⁷ is phenyl, naphthyl or C 1-6 alkyl. Such heterocycles are, for example, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl. , Pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl,
Oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, lyazoridinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzofuranyl, thiophenyl, benzo [b] thiophenyl, thieno. 2-b] thiophenyl, benzo [1,3] dioxolyl,
It contains 1,8 naphthyridinyl, pyranyl, tetrahydrofuranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl, and is available by ordinary chemical synthesis and is stable. The term "heteroatom" as used herein refers to oxygen, nitrogen and sulfur.

In this definition and throughout the present specification, the term “C ₀ ” means the absence of a directly attached substituent. For example, in an ArC _0-6 alkyl group, C
When is 0, the substituent is Ar, for example phenyl. In contrast, certain aromatics ArC _{0- 6} alkyl group, for example, when it is phenyl, it is understood that the value of C is zero. Certain radical groups are abbreviated herein. t-Bu represents a tert-butyl group, Boc represents a t-butyloxycarbonyl group, Fmoc represents a fluorenylmethoxycarbonyl group, Ph represents a phenyl group, and Cbz represents a benzyloxycarbonyl group. Certain reagents are indicated by abbreviations herein. m-CPBA represents 3-chloroperoxybenzoic acid, EDC represents N-ethyl-N '(dimethylaminopropyl) -carbodiimide, DMF represents dimethylformamide, DMSO represents dimethylsulfoxide, TEA represents triethylamine, TFA. Represents trifluoroacetic acid, and THF represents tetrahydrofuran.

Methods of Preparation The compounds of general formula (I) can be prepared by a series of processes outlined in Schemes 1, 2 and 3. Alkylation of benzyl-N-allyl carbamate (1) with a base such as sodium hydride and 5-bromo-1-pentene gave diene (2) (Scheme 1). Treatment of (2) with the bis (tricyclohexylphosphine) benzilidine ruthenium (IV) dichloride catalyst developed by Grubbs gives tetrahydroazepine (3). (3) to m
The epoxide (4) can be obtained by epoxidation using an oxidizing agent commonly used in the art such as -CPBA. Epoxide (4) is subjected to a nucleophilic ring-opening reaction with a reagent such as sodium azide to give azido alcohol (5), which is 1,3-propanedithiol and triethylamine in methanol or triphenylphosphine in THF and water. Under conditions common in the art such as amino alcohols (
It was reduced to 6). The amine of compound (6) can also be protected with di-tert-butyl dicarbonate to give derivative (7) (Scheme 2). 10% Pd / C
The amine (8) can be obtained by treating (7) with hydrogen gas in the presence of a catalyst as described above to remove the benzyloxycarbonyl protecting group. Treatment of the amine (8) with a sulfonyl chloride such as 2-pyridinesulfonyl chloride in the presence of a base such as triethylamine provides the sulfonamide derivative (9). Intermediate (10) can be obtained by removing the tert-butoxycarbonyl protecting group with an acid such as hydrochloric acid. Alcohol derivatives (1) by coupling (10) with an acid such as N-Boc-phenylalanine in the presence of a coupling agent common in the art such as HBTU or polymer-supported EDC.
1) is obtained. Removal of the tert-butoxycarbonyl protecting group under acidic conditions gives (12). Using an acid such as benzofuran-2-carboxylic acid, H
Coupling of (12) in the presence of coupling agents common in the art such as BTU or polymer supported EDC gives alcohol (13). Alcohol (13) may be oxidized with DMSO and triethylamine or oxidizing agents such as pyridine sulfur trioxide in Dess-Martin periodinane, which are common in the art, to give ketone (14). . The diastromer of (14) can be separated by HPLC.

[0022] Scheme 1

[Chemical 12] Reagents and conditions: (a) NaH, 5-bromo-1-pentene, NaH; (b) Bis (tricyclohexylphosphine) benzilidineruthenium (IV) dichloride, CH ₂ Cl ₂ , reflux; (c) m-CPBA, _{CH 2 Cl 2; (d)} NaN 3, NH 4 Cl, CH 3 OH, H 2 O; (e) TEA, 1,3- _{propanedithiol,} CH 3 OH.

[0023] Scheme 2

[Chemical 13] Reagents and conditions: (a) di-tert-butyl dicarbonate, THF; (b)
_{H 2, 10% Pd / C} , EtOAc; (c) 2- pyridine sulfonyl _{chloride, TEA, CH 2 Cl 2;} (d) HCl, EtOAc; (e) N-Boc- phenylalanine, P-EDC, _CH 2 Cl ₂ ; (f) HCl, CH ₂ Cl ₂ ; (
g) benzofuran-2-carboxylic _{acid, P-EDC, CH 2 Cl} 2; (h) des -
Martin Perogenan, methylene chloride.

Alternatively, compounds of general formula (I) can be prepared as shown in Scheme 3. Acylation of the amino alcohol (6) with an acid such as N-Boc-leucine in the presence of a coupling agent such as EDC or HBTU gives the amide (15). Hydrolysis of the carbonylbenzyloxy protecting group using conditions known in the art such as hydrogen gas in the presence of a catalyst such as 10% Pd / C provides amine (16). Treatment of the amine (16) with a sulfonyl chloride such as 2-pyridinesulfonyl chloride in the presence of a base such as triethylamine provides the sulfonamide derivative (17). Using an acid such as hydrochloric acid
Removal of the ert-butoxycarbonyl protecting group gives intermediate (18). With acids such as quinoline-8-carboxylic acid, HBTU or EDC common in the art can be used.
By coupling (18) in the presence of a coupling agent such as
To get The alcohol (19) may be oxidized with an oxidizing agent such as pyridine sulfur trioxide or Dess-Martin periodinane in DMSO or triethylamine as is common in the art to give the ketone (20). The diastereomer of (20) is HP
It can be separated by LC.

[0025] Scheme 3

[Chemical 14] Reagents and conditions: (a) N-Boc-leucine, EDC, HOBt, TEA, C
_{H 2 Cl 2; (b)} H 2, 10% Pd / C, EtOAc; (c) 2- pyridine sulfonyl _{chloride, TEA, CH 2 Cl 2;} (d) HCl, methanol; (e)
Quinoline-8-carboxylic _{acid, EDC, HOBt, TEA, CH} 2 Cl 2; (f)
Pyridine sulfur trioxide complex, TEA, DMSO.

The deuterated compound of Example 12 can be conveniently prepared by Scheme 4 . Those skilled in the art will understand from Example 12 and Scheme 4 how to prepare deuterated compounds of the present invention. Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [2,2 ', 4-trideuterio) -3-oxo-1- (pyridine-2-sulfonyl) -azepan-4-ylcarbamoyl The respective diastereomers of] -butyl} amide (22) and (23) can be prepared as outlined in Scheme 4 .

Scheme 4

[Chemical 15] Reagents and conditions: a) CD ₃ OD; D ₂ O (10: 1), TEA; b. ) HP
LC Separation Ketone (21) was treated with triethylamine in CD ₃ OD; D ₂ O at reflux temperature to give the deuterated analog as a mixture of diastereomers, which was separated by HPLC. Hydrogenated compounds (22) and (23)
To get

The starting materials used herein are either commercially available amino acids or are prepared by conventional methods known to those skilled in the art and are COMPENDIUM OF ORGANIC SYNTHETIC METH.
It can be found in standard reference books such as ODS, Vol. I-VI (published by Wiley-Interscience). Coupling methods to form amide bonds herein are known in the art. In general, Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springe
r-Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol.
1, 1-284 (1979); JM Stewart and JD Young, SOLID PHASE PEPTIDE SYNTH
The peptide synthesis method generally disclosed by ESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill. 1984 is an exemplary method and is hereby incorporated by reference. Synthetic methods of preparing the compounds of the present invention often employ protecting groups to mask reactive functional groups or to minimize unwanted side reactions. Generally, such protecting groups are Green, TW, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
, John Wiley & Sons, New York (1981). The term "amino protecting group" generally refers to Boc, acetyl, benzoyl, Fmoc and Cbz as known in the art.
A group and its derivative are shown. Methods for protecting or deprotecting as well as substituting another group for an amino protecting group are known.

An acid addition salt of a compound of formula (I) is prepared by adding the parent compound and an excess amount of acid in a suitable solvent.
For example, prepared from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid using standard methods. Certain compounds form acceptable inner salts or zwitterions. Kaothine salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide containing a suitable kaolin; or a suitable organic amine. Kaothines such as Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺⁺ , Mg ⁺⁺ and NH ₄ ⁺ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulphates, phosphates, alkanoates (eg acetate and trifluoroacetate), benzoates and sulphonates (eg mesylate) are examples of anions present in pharmaceutically acceptable salts. The method of the present invention can be carried out by administering a pharmaceutical composition comprising one or more compounds of formula I and a pharmaceutically acceptable carrier, diluent or excipient. Therefore, the compounds of formula I can be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as described herein can be formulated as solutions or lyophilized powders for parenteral administration. The powder can be reconstituted before use by adding a suitable diluent or pharmaceutically acceptable carrier.
The liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable dilutions are normal isotonic saline solution, 5% dextrose in water or sodium buffer or ammonium acetate solution. The formulation is particularly suitable for parenteral administration, but can also be used for oral administration, including a metered dose inhaler or nebulizer for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively, these compounds can be encapsulated, tableted, or prepared in suspensions or syrups for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The liquid carrier is syrup, peanut oil,
Includes olive oil, saline and water. The carrier also includes a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier will vary, but is preferably about 20 mg per dose.
Between about 1 g. Pharmaceutical preparations are produced according to conventional methods of pharmacy, including milling, blending, granulating and tabletting, if necessary in tablet form; milling, blending and filling in hard gelatin capsule form. If a liquid carrier is used, the preparation will be in the form of syrup, elixir, emulsion or aqueous or non-aqueous suspension. The liquid formulation can be administered directly orally or can be filled into soft gelatin capsules. For rectal administration, the compounds of the invention can be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and formed into suppositories.

Utility of the Invention The compounds of formula I are useful as inhibitors of cathepsin L. The present invention is a method of treating a disease caused by pathological levels of cathepsin L, which comprises one or more compounds of the present invention in an animal, especially a mammal, most especially a human in need thereof. Provided is a method characterized by administering an effective amount of a cathepsin L inhibitor. The invention is particularly concerned with the following diseases related to cathepsin L: macrophages in diseases such as inhibition of rheumatoid arthritis, inhibition of cancer metastasis, asthma, chronic obstructive pulmonary disease (COPD) and emphysema for treatment. In particular, inhibition of tissue destruction by lung macrophages, CD4 + T- by cortical thymic epithelial tissue cells
Indications for diseases requiring inhibition of positive cell selection;

The present invention contemplates the use of one or more compounds of Formula I, alone or in combination with other therapeutic agents. For emergency treatment, parenteral administration of the compound of formula I is preferred. Intravenous injection of compounds of similar composition in 5% dextrose in water or normal saline or with suitable excipients is most effective, but intramuscular injection is also useful. Typically, parenteral doses are about 0.01 to about 100 mg / kg; preferably 0.1 and 20 mg, in a manner that maintains the concentration of the drug in plasma at a concentration sufficient to inhibit cathepsin LS. / Kg. The compound has a total daily dose of about 0.4
Is administered 1 to 4 times daily at a level of about 400 mg / kg / day. The exact amount of a compound of the invention that is therapeutically effective, and the best route for administration of the compound, is
It can be easily determined by a person skilled in the art by comparing the blood concentration of the drug with the concentration required to have a therapeutic effect. The compounds of formula (I) may also be administered to patients in such a manner that the concentration of the drug inhibits bone resorption or achieves any of the other therapeutic indications described herein. Can be administered orally. Typically, the pharmaceutical composition containing the compound is administered orally in a dose corresponding to the patient's condition at a dose of about 0.1 to about 50 mg / kg. Preferably, the oral dose will be about 0.5 to about 20 mg / kg. It is believed that there are no unacceptable toxic effects when the compounds of formula I are administered according to this method.

Biological Assays Compounds of the invention can be tested in one of several biological assays to determine the concentration of compound required to exert a given pharmacological effect.

Measurement of Cathepsin L Proteolytic Catalytic Activity All assays for cathepsin L were performed with human recombinant enzyme.
Standard assay conditions for determination of rate constants were fluorogenic peptide substrates, typically Cbz-Phe-Arg-AMC, using 20 mM cysteine and 5 m.
Rate constants were measured in 100 mM sodium acetate (pH 5.5) containing M EDTA. 10 in DMSO used at a final substrate concentration of 20 μM in the assay
Alternatively, a stock substrate solution was prepared at a concentration of 20 mM. All assays contained 10% DMSO. Independent experiments have shown that this level of DMSO does not affect enzyme activity or rate constants. All assays were performed at ambient temperature. Perc fluorescence of product (excitation at 360 nm; emission at 460 nm)
It was monitored and observed with an eptive Biosystems Cytofluor II fluorescent pre-reader. A
A reaction progress curve of the product was obtained over 20 to 30 minutes after formation of the MC product.

Inhibition studies The reaction progression curve method was used to evaluate potential inhibitors. Assays were performed in the presence of varying concentrations of test compound. The reaction was initiated by adding the enzyme to a buffered solution of inhibitor and substrate. Data analysis was performed by one of two methods, depending on the morphology of the reaction progression curve in the presence of the inhibitor. For compounds where the reaction progress curve is linear, see Equation 1 (Brandt et al., Biochemistry, 19
89, 28, 140): ν = V _m A / [K _a (1 + I / K _{i, app} ) + A] (1) [wherein, ν is reaction rate, V _m is maximum reaction rate, A is substrate concentration, The apparent inhibition constant (K _{i, app} ) was calculated by K _a is the Michaelis constant and I is the inhibitor concentration.

For compounds with a downward curvature whose reaction progression curve is characteristic of inhibition over time, Equation 2: [AMC] = ν _ss t + (v ₀ −ν _ss ) [1-exp (−k _obs t) ] / K _obs (2), where [AMC] is the concentration of the product formed after the lapse of time t, v ₀ is the initial velocity, and v _ss is the final steady state velocity. The data was analyzed to obtain _kobs . _Then, by analyzing the values for _{k obs} as a linear function of inhibitor concentration, second-order rate constant for the apparent _{(k obs} / inhibitor concentration or _{k ob} s / [I]) was obtained, and the time inhibition explained. A complete description of this kinetic process can be found in Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61.
, 201.

General nuclear magnetic resonance spectra are obtained by Bruker AM250 or Bruker A, respectively.
Recordings were made at either 250 or 400 MHz using a C400 spectrometer. C
DCl ₃ is deuterated chloroform, DMSO-d ₆ is hexadeuteriodimethylsulfoxide, and CD ₃ OD is tetradeuteriomethanol. Chemical shifts are recorded separately per million (d) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are: s = singlet, d
= Doublet, t = triplet, q = quartet, m = multiplet, dd
= Doublet doublet, dt = doublet triplet, app = visual,
br = broad. J indicates the NMR coupling constant measured in Hertz.
Infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, Fourier Transform Infrared (FTIR) spectra were on Nicolet Immmpac.
Recorded on a t400D infrared spectrometer. IR and FTIR spectra are recorded in transmission mode and belt position is recorded as the reciprocal of the wave number (cm ^-1 ). Mass spectra are VG70FE, PE Syx API III, or VG Z
Performed using fast atom bombardment (FAB) or electrospray (ES) ionization methods on either an AB HF instrument. Elemental analysis is Perkin-Elmer
Obtained using a 240C Elemental Analyzer. Melting points were measured on a Thomas-Hoover melting point apparatus and were uncorrected. All temperatures are recorded in degrees Celsius. Analtec Silica Gel CF and E-Merck Silica Gel 60F-25
Four thin layer plates were used for thin layer chromatography. Both flash and specific gravity chromatography are performed by E. Merck Kieselgel 60 (230-
400 mesh) silica gel. Certain materials were purchased from Aldrich Chemical Co., Milwaukee, WI, Chemical Dynamics Corp., South Plainfield, NJ, and Advanced Chemtech, Louisville, KY.

EXAMPLES In the following synthesis examples, temperatures are given in degrees Celsius (° C.). Unless otherwise noted, all starting materials were obtained from commercial sources. A person skilled in the art can make maximum use of the present invention according to the above description without further devising. These examples are provided to illustrate the invention and not limit the scope of the invention. What the applicant should hold is mentioned in the claims.

[0039] Example 1 quinoline-8-carboxylic acid {(S)-3-methyl-1- [3-oxo-1- (Pi-lysine-2-sulfonyl) - azepan-4-ylcarbamoyl] - butyl} amino Preparation of a. ) Allyl-pent-4-enyl-carbamic acid benzyl ester To a suspension of allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF. Was added dropwise. The mixture was stirred at room temperature for about 10 minutes and then 5-bromo-
1-Pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction was heated at 40 ° C. for about 4 hours then the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2 times), washed with brine, dried (MgSO _4), filtered and concentrated. The residue was subjected to column chromatography (10% ethyl acetate: hexane) to obtain 10.3 g of the title compound as an oily substance. MS (EI
) 260 (M + H ⁺ ).

B. ) 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester To a solution of the compound of Example 1a (50 g) in dichloromethane is added bis (tricyclohexylphosphine) benzilidine ruthenium (IV) dichloride (5.0 g).
Was added. The reaction was heated to reflux until the reaction was complete by TLC analysis. The reaction was concentrated under reduced pressure. The residue was subjected to column chromatography (50% dichloromethane: hexane) to give 35 g of the title compound. MS (EI) 232 (
M + H ⁺ ).

C. ) 8-Oxa-3-aza-bicyclo [5.1.0] octane-3-carboxylic acid benzyl ester m-in a solution of the compound of Example 1b (35 g, 1.5 mol) in dichloromethane.
CPBA (78 g, 0.45 mol) was added. The mixture was stirred at room temperature overnight,
The solid was then filtered off. The filtrate was washed with saturated water and saturated NaHCO ₃ (several times). The organic layer was dried (MgSO ₄ ), filtered and concentrated to give 35 g of the title compound, which was a sufficiently pure compound to be used in the next step. MS (EI) 248 (M + H +), 270 (M + Na ⁺ ).

D. ) 4-Azido-3-hydroxy-azepan-1-carboxylic acid benzyl ester Epoxide (2.0 g, 8.1 mmol) from Example 1c in methanol:
To a solution in water (8: 1 solution) was added NH ₄ Cl (1.29 g, 24.3 mmol) and sodium azide (1.58 g, 24.30 mmol). TL the reaction product
65 ° C. to 75 ° C. until complete consumption of the starting epoxide is observed by C analysis.
Heated to ° C. Most of the solvent was removed under reduced pressure and the remaining solution was partitioned between ethyl acetate and pH 4 buffer. The organic layer was washed with saturated NaHCO _3, water, brine, dried (MgSO _4), filtered and concentrated. The residue was subjected to column chromatography (20% ethyl acetate: hexane) to give 1.3 g of the title compound:
MS (EI) 291 (M + H ⁺ ), additionally 0.14 g of trans-4-hydroxy-3-azido-hexahydro-1H-azepine was obtained.

E. ) 4-Amino-3-hydroxy-azepan-1-carboxylic acid benzyl ester To a solution of the azido alcohol (1.1 g, 3.79 mmol) of Example 1d in methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1, 3-
Propanedithiol (1.1 mL, 11.37 mmol) was added. The reaction was stirred until complete consumption of starting material was observed by TLC analysis, then the reaction was concentrated under reduced pressure. The residue was subjected to column chromatography (20% methanol:
Dichloromethane) gave 0.72 g of the title compound: MS (EI) 265.
(M + H ⁺ ).

F. ) 4-((S) -2-tert-butoxycarbonylamino-4-methyl-
Pentanoylamino) -3-hydroxy-azepan-1-carboxylic acid benzyl ester CH ₂ C of the amino alcohol of Example 1e (720 mg, 2.72 mmol).
₁₂ in solution in EDC (521 mg), HOBt (368 mg) and N-Boc
-Leucine (630 mg) was added. The reaction was kept at room temperature until complete consumption of starting material was observed by TLC analysis. Dilute the reaction with ethyl acetate and
Wash with N HCl, saturated K ₂ CO ₃ , water, brine, dry (MgSO ₄ ).
Filtered and concentrated. The residue was subjected to column chromatography (3% methanol: dichloromethane) to give 1.0 g of the title compound: MS (EI) 478 (M +).
H ⁺ ).

G. ) [(S) -1- (3-Hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert butyl ester The compound of Example 1f (1.0 g) and 10% Pd / C ( A hydrogen balloon was attached to a solution of catalyst) in ethyl acetate: methanol (2: 1 solution). The reaction was stirred until complete consumption of starting material was observed by TLC analysis. The reaction was filtered to remove the catalyst and the filtrate was concentrated to give 0.82 g of the title compound: M
S (EI) 344 (M + H ⁺ ).

H. ) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl)-
Azepan-4-ylcarbamoyl] -3-methyl-butyl} -carbamic acid te
Formation of rt-butyl ester 2-pyridinesulfonyl chloride: 2-mercaptopyridine solution (
33 mL 2.23 g in 9N HCl) was cooled to 0 ° C. Chlorine gas was bubbled through the solution for 90 minutes, maintaining the temperature at 0 ° C. Add ice-cold ethyl acetate,
Then ice-cold saturated NaHCO ₃ was slowly added until the pH of the aqueous layer was approximately 9. The organic layer was then washed with brine, dried over MgSO _4. The ethyl acetate was evaporated to give 3.5 g of crude 2-pyridinesulfonyl chloride as a pale yellow liquid. Example 1g of [(S) -1- (3-hydroxy-azepan-4-ylcarbamoyl) -3-methyl-butyl] -carbamic acid tert butyl ester (12
g, 34.93 mmol) in a solution of dichloromethane in triethylamine (5.8
mL, 41.92 mmol) was added, followed by the dropwise addition of 2-pyridinesulfonyl chloride (7.45 g, 41.92 mmol). The reaction was stirred until TLC analysis showed complete consumption of starting material. Then, the mixture saturated NaHCO _3, water, brine, dried _(Na 2 _SO 4), filtered and concentrated. The residue was subjected to column chromatography (75% ethyl acetate: hexane to 100% ethyl acetate) to give 15 g of the title compound. MS 484
(M ⁺ )

I. ) (S) -2-Amino-4-methyl-pentanoic acid- [3-hydroxy-1-
(Pyridin-2-sulfonyl) -azepan-4-yl] -amide {(S) -1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -of Example 1h. To a solution of 3-methyl-butyl} -carbamic acid tert-butyl ester (14.3 g) in methanol was added 4M HCl in dioxane. The reaction was stirred at room temperature until TLC analysis showed complete consumption, then concentrated to give 14 g of the title compound. MS
(EI) 385 (M + H ⁺ ).

J. ) Quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide Compound of Example 1i ( To a solution of 0.15 g, 0.33) in CH ₂ Cl ₂ was added triethylamine (0.11 mL, 0.82 mmol), EDC (69 mg, 0.36).
mmol), HOBt (49 mg, 0.36 mmol) and quinoline-8-carboxylic acid (62 mg, 0.36 mmol). The reaction was stirred until TLC analysis showed complete consumption. Work-up and column chromatography of the residue gave 0.066 g of the title compound. MS (EI) 5
40 (M + H ⁺ ).

K. ) Quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1
-(Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide TEA (0.1 mL) and pyridine sulfur trioxide in a solution of the alcohol of Example 1j (0.066 g, 0.12 mmol) in DMSO. The complex (57 mg) was added. The reaction was stirred at room temperature for about 2 hours then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography _{(5% CH 3 OH: CH} 2 Cl 2) subjected to give the title compound as a mixture of diastereomers. ¹ HNMR (CDCl ₃ ): δ 1.0
(M, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m
, 1H), 3.7 (d, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5
． 0 (m, 1H), 7.5 (m, 4H), 7.6 (m, 1H), 7.7 (m, 3)
H), 8.2 (m, 1H), 8.6 (m, 1H), 8.7 (m, 1H), 8.9.
(M, 1H); MS (EI): 538 (M + H ⁺ , 100%).

[0050] Example 2-4-carboxylic acid {(S)-3-methyl-1- [3-oxo-1- (Pi-lysine-2-sulfonyl) - azepan-4-ylcarbamoyl] - butyl} amino Preparation of the title compound The title compound was prepared according to the method of Example 1j-k except that a substituted quinoline-4-carboxylic acid was used instead of the quinoline-8-carboxylic acid of Example 1j. 1H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.1 (m
5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). Four
． 0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 6.5-7.2
(M, 2H), 7.4 (m, 2H), 7.5 (m, 1H), 7.7 (m, 1H)
, 7.9 (m, 2H), 8.0 (m, 1H), 8.2 (m, 1H), 8.7 (m
1H), 8.9 (m, 1H); MS (EI): 538 (M + H +, 100%) The diastereomeric mixture is separated by HPLC and the faster eluting diastereomers; MS (EI): 538 (M + H). ⁺ , 100%) and a slower eluting diastereomer; MS (EI): 538 (M + H ⁺ , 100%).

Example 3 Isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1-
(Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl}
Preparation of the amide The title compound was prepared according to the procedure of Example 1j-k, except that isoquinoline-1-carboxylic acid was used instead of quinoline-8-carboxylic acid of Example 1j: ¹ HNMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-2.1 (m, 5H
), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (d, 1H). 4.0 (
m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7.3 (m, 1H),
7.5 (m, 1H), 7.7-8.0 (m, 6H), 8.7 (m, 3H), 9.
5 (m, 1H); MS (EI): 538 (M + H ⁺ , 100%). The diastereomeric mixtures were separated by HPLC to give a fast eluting diastereomer; MS (EI): 537 (M ⁺ , 100%) and a slow eluting diastereomer; MS (EI): 537 (M ⁺ , 100). %).

Example 4 Quinoline-8-carboxylic acid {(S) -2-naphthylene-2 -yl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4 -ylcarbamoyl]- Preparation of ethyl} -amide a. ) 4-tert-Butoxycarbonylamino-3-hydroxy-azepane-
1-carboxylic acid benzyl ester 4-amino-3-hydroxy-azepan-1
-Carboxylic acid benzyl ester (Example 1e, 1.04 g, 3.92 mmol)
Di-tert-butyl dicarbonate (0.864 g) was added to a stirred solution of in THF. After stirring for 30 minutes at room temperature, the reaction was diluted with diethyl ester and saturated N 2
Extracted with aHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated,
Purification by silica gel column gave the title compound as a yellow oil (0.9
63 g, 2.64 mmol, 67%). MS (ESI): 365.03 (M + H ⁺ ).

B. ) 3-Hydroxy-azepan-4-yl-carbamic acid-tert-butyl ester 4-tert-butoxycarbonylamino-3-hydroxy-azepan-1-
Carboxylic acid benzyl ester (Example 4a, 0.963 g, 2.64 mmol)
To a solution of in ethyl acetate (16 mL) was added 10% palladium on carbon (500 mg). After stirring at room temperature for 48 hours, the mixture was filtered through Celite. The filtrate was concentrated to give the title compound (0.529 g, 2.29 mmol, 87%): MS (
ESI): 231.92 (M + H ⁺ ).

C. ) 3-Hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-yl-carbamic acid-tert-butyl ester 3-hydroxy-azepan-4-yl-carbamic acid-tert-butyl ester (Example 4b, 0.529, 2.29 mmol) of dichloromethane (20 m
Triethylamine (232 mg) and pyridine-2-sulfonyl chloride (410 mg, 2.32 mmol) were added to the solution in L). After stirring for 30 minutes at room temperature, the mixture was washed with saturated NaHCO ₃ . The organic layer was dried, filtered, concentrated and purified on a silica gel column to give the title compound as a solid (0.583 g,
1.57 mmol, 68%); MS (ESI): 372.95 (M + H ⁺ ).

D. ) 4-Amino-1- (pyridin-2-sulfonyl) -azepan-3-ol 3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-yl-
Carbamic acid-tert-butyl ester (Example 4c, 0.583 g, 1.5
HCI (4 in dioxane) to a stirred solution of 7 mmol) in ethyl acetate (0.5 mL).
M) (3.9 mL) was added. After stirring the reaction mixture at room temperature for 30 minutes, the mixture was concentrated to give a white solid. The solid was treated with NaOH then extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give a yellow solid (0.347g, 1
． 28 mmol, 81%); MS (ESI) 272.93 (M + H ⁺ ).

E. ) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl)-
Azepan-4-ylcarbonyl] -2-naphthylene-2-yl-ethyl} -carbamic acid tert-butyl ester TEA (0.15 mL), HOBt (99 mg) in a solution of the compound of Example 4d (225 mg) in dichloromethane. EDC (
140 mg) and N- (t-butoxycarbonyl) -3- (2-naphthyl)-
L-alanine (230 mg) was added. The reaction was stirred until the reaction was complete. The residue was post-treated and subjected to column chromatography (3% ethanol: dichloromethane) to give 0.35 g of the title compound: MS (ESI) 569 (M +).
H ⁺ ).

F. ) (S) -2-Amino-N- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-yl] -3-naphthylene-2-yl-proprionamide Compound of Example 4e ( 0.35 g) in a solution of methanol (5 mL) in HCl (
5 mL of 4M HCl in dioxane) was added. The reaction was stirred until complete by TLC analysis, then 0.31 g of the title compound was obtained as a white solid.

G. ) Quinoline-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [
3-Hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide A solution of the compound of Example 4f (131 mg) in dichloromethane was taken as TEA, HOB.
t (39 mg), EDC (55 mg) and quinoline-8-carboxylic acid (51 m
g) was added. The reaction was stirred until the reaction was complete. Post-processing the residue,
Column chromatography (5% methanol: dichloromethane) gave the title compound: MS (ESI) 574 (M + H ⁺ ).

H. ) Quinoline-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [
3-Oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbonyl] -ethyl] -amide The title compound was obtained by the procedure of Example 1k using the compound of Example 4g: MS 622 (M + H ⁺ ).

Example 5 Naphthylene-1-carboxylic acid {(S) -2-naphthylene- 2-yl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan- 4-ylcarbonyl]- Preparation of ethyl] -amide The title compound was obtained according to the method of Example 4g-h, except naphthylene-1-carboxylic acid was used instead of quinoline-8-carboxylic acid: MS621 (M
+ H ⁺ ).

Example 6 Naphthylene-1-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3 -oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbonyl ]- Ethyl] -amide N- (t-butoxycarbonyl) -3- (2-naphthyl) -L- of Example 4e.
Example 4e except that N-Boc-phenylalanine was used instead of alanine.
The title compound was prepared according to the method of -h: MS572 (M + H ⁺ ).

Example 7 Naphthylene-1-carboxylic acid {(S) -2-naphthylene- 2-yl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan- 4-ylcarbonyl]- Preparation of ethyl] -amide N- (t-butoxycarbonyl) -3- (2-naphthyl) -L- of Example 4e.
The title compound was obtained according to the method of Examples 4e-h, except that N-Boc-phenylalanine was used in place of alani and naphthoic acid was used in place of the quinoline-8-carboxylic acid of Example 4g: MS571 (M + H ⁺ ).

Example 8 Quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridin-2- sulfonyl) -azepan-4-ylcarbonyl] -2-phenyl-ethyl} -a Preparation of the amide N- (t-butoxycarbonyl) -3- (2-naphthyl) -L- of Example 4e
The title compound was obtained according to the method of Example 4e-h, except that N-Boc-phenylalanine was used instead of alanine and quinoline-2-carboxylic acid was used instead of quinoline-8-carboxylic acid of Example 4g. . The diastereomer was purified by HPLC to give two diastereomers of the title compound as a solid (first diastereomer: 40 mg: second diastereomer: 43 mg): MS (ESI).
537.8 (M + H) ^<+> .

Example 9 Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridin- 2-sulfonyl) -azepan-4-ylcarbonyl] -2-phenyl-ethyl} -amide Preparation of a. ) {(S) -1- [3-hydroxy-1- (pyridine-2-sulfonyl)-
Azepan-4-ylcarbonyl] -2-phenyl-ethyl} -carbamic acid te
rt- compounds butyl ester Example 4d (19mg, 0.070mmol) in _CH 2 Cl ₂ solution in _CH 2 Cl ₂ N-Boc-phenylalanine (27.9 mg, 0.106 mm
ol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmol)
) And P-EDC (140 mg, 0.14 mmol) were added. After shaking at room temperature overnight, it was treated with PS-trisamine. After shaking for a further 2 hours, the mixture was filtered and concentrated to give the title compound as a solid. MS (ESI) 518.87 (M +
H) ⁺ .

B. ) (S) -2-Amino-N- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-yl] -3-phenyl-proprionamide The compound of Example 9a (34 mg, 0. 07 mmol) of CH ₂ Cl ₂ (0.5
HCl (4 M in dioxane) (0.165 mL) was added to the stirred solution in 0 mL. After stirring at room temperature for 30 minutes, a white solid was obtained. The white solid was azeotroped with toluene then treated with MP-carbonate (0.35 mmol) in methanol. After shaking for 4 hours, the mixture was filtered and concentrated to give the title compound as a solid. MS (
ESI) 418.91 (M + H) ^<+> .

C. ) Benzofuran-2-carboxylic acid {(S) -1- [3-hydroxy-1- (
Pyridine-2-sulfonyl) - azepan-4-ylcarbonyl] -2-phenyl - ethyl} - compound amide Example 9b (27 mg, _CH 2 Cl ₂ in a benzofuran _{of CH} 2 in Cl ₂ solution of 0.070 mmol) - 2-carboxylic acid (17.0 mg, 0.106 m
mol), 1-hydroxybenzotriazole (16.1 mg, 0.12 mmo)
1) and P-EDC (140 mg, 0.14 mmol) were added. After shaking overnight at room temperature, the mixture was treated with PS-trisamine. After shaking for a further 2 hours, the mixture was filtered and concentrated to give the title compound as a solid. MS (ESI) 562.73
(M + H) ⁺ .

D. ) Benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbonyl] -2-phenyl-ethyl} -amide Compound of Example 9c (37 mg, 0.07 mmol) CH ₂ Cl ₂ (0.5
mL) to a stirred solution in Dess-Martin reagent (45 mg
, 0.105 mmol) was added. After stirring for 30 minutes, sodium thiosulfate (10% in water, 0.50 mL) and saturated aqueous sodium bicarbonate (0.50 mL) were added to the reaction simultaneously. It was then extracted with the mixture and dichloromethane (twice).
The organic layer was dried, filtered and concentrated. The residue was purified by HPLC to give two diastereomers of the title compound as solids (first eluate: 7 mg, second eluate: 5.5 mg). MS (ESI) 560.81 (M + H) ^<+> .

Example 10 Benzofuran-2-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3 -oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbonyl ]- Preparation of ethyl} -amide N- (t-butoxycarbonyl) -instead of N-Boc-phenylalanine
The title compound was prepared according to the method of Examples 9a-d, except using 3- (2-naphthyl) -L-alanine to give two diastereomers (first eluate: 5
． 3 mg, second eluate: 3.3 mg): MS (ESI): 610.8 (M +
H) ⁺ .

[0069] Example 11 benzofuran-2-carboxylic acid {(S) -2-Benzyl-1- [3- Oki Seo-1- (pyridin-2-sulfonyl) - azepan-4-ylcarbonyl] - an ethyl } -Amide was prepared in Example 9 using N-Boc-O-benzyl-L-serine in Step 9a.
Benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo-1 was obtained as the mixture of diastereomers according to the method of ad.
-(Pyridin-2-sulfonyl) -azepan-4-ylcarbonyl] -ethyl}
-10% Pd / C (50 m in a solution of amide (90 mg) in ethyl acetate (2 mL).
g) was added. About 50% of the starting benzyl ether was hydrogenated and the mixture was filtered and concentrated. The 4-component mixture was purified by HPLC to give the first eluting diastereomer of the title compound (1 mg) and the second eluting diastereomer of the title compound (0.3 mg): MS (ESI). ): 590.94 (M + H) ⁺ .

Example 12 Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(2,2 ', 4 -tridutrio) -3-oxo-1- (pyridine-2-sulfonyl)) - Azepa down-4-ylcarbonyl] - butyl} -amide a. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-hydroxy-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbonyl]
-Butyl} amide (S) -2-amino-4-methyl-pentanoic acid [3-hydroxy-of Example 1i
1- (pyridin-2-sulfonyl) -azepan-4-yl] -amide (0.15
TEA (0.11 mL), HOBt (49 mg) in a solution of g) in dichloromethane.
, EDC (69 mg) and benzofuran-2-carboxylic acid (58 mg) were added. The reaction was stirred until the reaction was complete. Work-up was performed and column chromatography (5% methanol: ethyl acetate) gave the title compound: MS (E
I) 529 (M + H ⁺ ).

B) Benzofuran-2-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbonyl] -butyl} amide Example To a solution of 11a alcohol (0.11 g) in MSO was added TEA (0.17 g).
mL) and pyridine sulfur trioxide complex (99 mg) were added. The reaction was stirred at room temperature for about 2 hours then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated. The residue was subjected to column chromatography (10% CH ₃ OH: EtOAc) to give 75 mg of the title compound as a mixture of diastereomers: ¹ HNMR (CDCl ₃ ): δ 1.0 (m, 6H), 1.5-
2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, 1H), 3.7 (dd
, 1H). 4.0 (m, 1H), 4.7 (m, 2H), 5.0 (m, 1H), 7
． 2-7.3 (m, 3H), 7.4 (m, 4H), 7.6 (m, 1H), 8.0
(M, 2H), 8.7 (m, 1H); MS (EI): 527 (M + H +, 40%
).

C. ) Benzofuran-2-carboxylic acid {(S) -3-methyl-1-[(2,2
′, 4-Triduterio) -3-oxo-1- (pyridine-2-sulfonyl)
-Azepan-4-ylcarbonyl] -butyl} amide Benzofuran-2-carboxylic acid of Example 11b {(S) -3-methyl-1- [
3-oxo-1- (pyridine-2-sulfonyl) - azepan-4-ylcarbonyl] - _D 2 _O butyl} amide (0.03g): CD 3 OD ( 0.4: 4mL)
Triethylamine (0.04 mL) was added to the medium solution. The reaction was heated to reflux for 2 hours, it was concentrated and dried under reduced pressure. The residue was redissolved in the same mixture and heated to reflux overnight. The reaction was concentrated, the residue was purified by column chromatography and purified by (5% methanol in dichloromethane) to give the title compound (0.02 ^g): 1 H
NMR: δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m,
1H), 4.1 (m, 1H), 4.7 (m, 2H), 7.4-8.0 (m, 8H)
), 8.7 (m, 1H); MS (EI): 529 (M +, 45%). The mixture of diastereomers was separated by HPLC to give a faster eluting diastereomer: MS (EI): 530 (M + H ⁺ , 100%) and a slower eluting diastereomer: MS (EI): 530 (M + H +). , 100%).

The above specification and examples fully disclose how to make and use the compounds of this invention. However, the invention is not limited to the particular embodiments described above, but includes all modifications within the scope of the above claims. The various publications, such as magazines, patents and other publications, cited in this specification constitute the state of the art and are incorporated herein by reference.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 105 A61P 43/00 105 111 111 111 C07D 401/12 C07D 401/12 // C07D 401/14 401 / 14 405/14 405/14 C07M 7:00 C07M 7:00 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM) AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EE, ES , FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT , TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Robert W. Marquis, Junia United States 19087 Country Gate Road, Wayne, PA 209 (72) Inventor Le Yu United States 19087 ba Hancock Lane 1509, Wayne, Sylvania (72) Inventor Scott Kay Thompson, United States 19460 Guilford Circle, 75, Phoenixville, Pennsylvania (72) Inventor Daniel F. Baber United States 19002, Ambler, Pennsylvania Batorson Road 290 (72) Inventor Dennis S. Yamashita United States 19087 Walker Road, Wayne, PA 531 F Term (Reference) 4C063 AA01 AA03 BB08 BB09 CC19 CC41 CC76 DD12 EE01 4C086 AA01 AA02 BC31 GA02 GA07 GA08 GA16 MA01 MA04 NA14 ZA51 ZA59 ZA96 ZB15 ZB21 ZB26 ZC20 ZC41

Claims (29)

[Claims] 1. A method of inhibiting cathepsin L, which comprises administering to a patient in need thereof an effective amount of formula (I): I [wherein R ¹ is It is selected from the group consisting of; ^{R 2} is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} alkyl, ^{R 9 _{C (O) -, R 9}} C (S) -, R 9 SO 2 -, R 9 OC (O) -, R 9 R 11 NC (O) -, R 9 R 11 NC (S) -, R 9 (R ¹¹ ) NSO ₂ −, embedded image R ³ is selected from the group consisting of: H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, HetC _0-6 alkyl and A
selected from the group consisting of rC _0-6 alkyl; R ³ and R ′ may be joined to form a pyrrolidine, piperidine or morpholine ring; R ⁴ is H, C _1-6 alkyl, C _{3 − 6} cycloalkyl-C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, R ⁵ C (O)-, R ⁵ C (S)-, R ⁵ SO _2- , R ^{5 OC (O) -, R 5} R 13 NC (O) - , and ^{R 5 R 13 NC (S)} - are selected from the group consisting of; ^{R 5} 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 and H
It is selected from the group consisting _{et-C 0-6} alkyl; ^{R 6} is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl or Het-C It is selected from the group consisting of _0-6 alkyl; ^{R 7} is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} ^{alkyl, R 10 C (O) -} , R 10 C (S) -, R 10 SO 2 -, R 10 OC (O) -, R 10 R 14 NC (O
)-And R ¹⁰ R ¹⁴ NC (S)-; R ⁸ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl,
Is selected from HetC _0-6 alkyl and _{ArC 0-6} group consisting of alkyl; ^{R 9} _{is, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, A
selected from the group consisting of r-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹⁰ is C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl,
R ¹¹ is selected from the group consisting of Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹¹ is from H, C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl. R ¹² is selected from the group consisting of H, C _1-6 alkyl, Ar—C _0-6 alkyl and Het-C _0-6 alkyl; R ¹³ is H, C _1-6 R ¹⁴ is selected from the group consisting of alkyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ¹⁴ is H, C _1-6 alkyl, Ar-C _0-6 alkyl and Het-C _0-6. It is selected from the group consisting of alkyl; R 'is, _{H, C 1-6} alkyl is selected from the group consisting of _{Ar-C 0-6} alkyl and _{Het-C 0 -6} alkyl; R''is, H, C _1-6 alkyl, Ar C _0-6 is selected from alkyl or the group consisting of _{Het-C 0 -6} alkyl; R '''is, _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, Ar-C Selected from the group consisting of _0-6 alkyl and Het-C _0-6 alkyl; X is selected from the group consisting of CH ₂ , S and O; and Z is a group consisting of C (O) and CH _2. Selected from the above] or a pharmaceutically acceptable salt, hydrate or solvate thereof. 2. In the above compound, R ¹ is The method of claim 1, wherein 3. In the above compound, R ³ is C _1-6 alkyl and A
The method of claim 2 selected from the group consisting of r-C _0-6 alkyl. 4. In the above compound, R ³ is isobutyl, naphthalene-
The method of claim 3 selected from the group consisting of 2-ylmethyl, benzyl and benzyloxymethyl. 5. The method according to claim 2, wherein R ⁴ is R ⁵ C (O) — in the above compound. 6. In the above compound, R ⁵ is C _1-6 alkyl, Ar-
The method of claim 5 selected from the group consisting of C _0-6 alkyl and Het-C _0-6 alkyl. 7. The method of claim 6, wherein in said compound R ⁵ is selected from quinolinyl, isoquinolinyl and benzofuranyl. 8. In the above compound, R ^{5 comprises} quinolin-2-yl, quinolin-4-yl, quinolin-8-yl, isoquinolin-1-yl, naphthalen-1-yl and benzofuran-2-yl. 7. The method of claim 6 selected from the group. 9. The method according to claim 1, wherein R ′ in the above compound is H. 10. The method according to claim 1, wherein R ″ is H in the above compound. 11. The method according to claim 1, wherein R ′ ″ is H in the above compound. 12. The method according to claim 1, wherein R ″ and R ′ ″ in the above compound are both H. 13. The method according to claim 1, wherein R ² is R ⁹ SO ₂ in the above compound. 14. The method of claim 13, wherein in said compound R ⁹ is Het-C _0-6 alkyl. 15. The method of claim 14, wherein in said compound R ⁹ is selected from the group consisting of pyridinyl and 1-oxy-pyridinyl. 16. R ⁹ in the above compounds is pyridin-2-yl and 1-
16. The method of claim 15, selected from the group consisting of oxy-pyridin-2-yl. 17. R ¹ in the above compound is R ² is R ⁹ SO ₂ ; R ³ is selected from the group consisting of isobutyl, naphthalen-2-ylmethyl, benzyl and benzyloxymethyl; R ⁴ is R ⁵ C (O) R ⁵ is selected from the group consisting of quinolin-2-yl, quinolin-4-yl, quinolin-8-yl, isoquinolin-1-yl, naphthalen-1-yl and benzofuran-2-yl; R ⁹ is selected from the group consisting of pyridin-2-yl and 1-oxy-pyridin-2-yl; R ′ is H, R ″ is H; and R ″ ′ is H. The method according to claim 1. 18. The quinoline-8-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (
Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; quinoline-4-carboxylic acid {(S) -3-methyl-1- [3-oxo-1- (
Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; isoquinoline-1-carboxylic acid {(S) -3-methyl-1- [3-oxo-1
-(Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -butyl} amide; quinolin-8-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3-
Oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide; naphthylene-1-carboxylic acid {(S) -2-naphthylene-2-yl-1- [3
-Oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide; quinoline-8-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2)
-Sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl}
-Amide; naphthylene-1-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-
2-Sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide; quinoline-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridine-2)
-Sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl}
-Amide; benzofuran-2-carboxylic acid {(S) -1- [3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl] -2-phenyl-ethyl} -amide; benzofuran- 2-carboxylic acid {(S) -2-naphthylene-2-yl-1- [
3-oxo-1- (pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl) -ethyl] -amide; and benzofuran-2-carboxylic acid {(S) -2-benzyloxy-1- [3-oxo -1- (Pyridin-2-sulfonyl) -azepan-4-ylcarbamoyl]
18. The method of claim 17, selected from the group consisting of -ethyl} -amide. 19. A method for treating a disease characterized by cancer metastasis, which comprises inhibiting the above-mentioned cancer metastasis by administering an effective amount of the compound according to claim 1 to a patient in need thereof. A method of treatment including that. 20. A method of treating a disease characterized by positive selection of CD4 ⁺ T ⁻ cells by cortical thymic epithelial tissue cells, which requires an effective amount of the compound of claims 1-18. The method of treatment comprising the step of inhibiting the positive selection of CD4 + T-cells by the cortical thymic epithelial tissue cells described above when administered to a patient. 21. A method of treating a disease characterized by tissue destruction by macrophages, which comprises administering to a patient in need thereof an effective amount of a compound according to claims 1-18. A method of treatment comprising inhibiting. 22. The therapeutic method according to claim 21, wherein the macrophage is a lung macrophage. 23. The method according to claim 21, wherein the disease is a disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and emphysema. 24. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in inhibiting cathepsin L. 25. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in the treatment of diseases characterized by cancer metastasis. 26. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of diseases characterized by the positive selection of CD4 + T-cells by cortical thymic epithelial tissue cells. 27. Use of a compound according to any one of claims 1-18 in the manufacture of a medicament for use in the treatment of diseases characterized by cell destruction by macrophages. 28. The use according to claim 27, wherein the macrophage is a lung macrophage. 29. The use according to claim 28, wherein said disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and emphysema.