KR20050034922A - Caspase inhibitor comprising 2-alkyl-4-oxobutanoyl group and pharmaceutical composition thereof - Google Patents

Abstract

The present invention provides a novel compound of formula (I), a pharmaceutically acceptable salt, a physiologically hydrolysable ester, hydrate, solvate or stereoisomer thereof, which is an inhibitor that interferes with the activity of caspase, and It relates to a pharmaceutical composition containing the same together with a pharmaceutically acceptable carrier. The compound of formula 1 contains a new backbone not known so far, namely a 2-alkyl-4-oxobutanoyl group. The invention also exemplifies a method of synthesizing a compound of Formula 1 and a method of measuring binding. Inhibitors of formula (I) obtained from the method can be effectively used to alleviate or treat various forms of disease resulting from the action of caspase.

Wherein R, R ₁ , R ₂ , R ₃ , X and Ar are as defined in the specification.

Description

CASE phase inhibitors containing 2-alkyl-4-oxobutanoyl groups and pharmaceutical compositions thereof {CASPASE INHIBITOR COMPRISING 2-ALKYL-4-OXOBUTANOYL GROUP AND PHARMACEUTICAL COMPOSITION THEREOF}

The present invention relates to kephases, including caspase-1 [interleukin-1- converting enzyme (ICE)] and kephase-3 [apopine / CPP-32], caspase-8, 9 Novel compounds of formula (1) which can be used as inhibitors, pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, hydrates, solvates or stereoisomers thereof, and pharmaceutical compositions containing them.

Kephase is a new kind of enzyme discovered in the last decade, and about 14 kinds of enzymes are known to date, and it is a cysteine protease which exists in the tetramer form of (alpha) _{2 (} beta) ₂ form. One of them, `` Casephase-1 '' (ICE), is a type of cytokine that is involved in the conversion of biologically inactive prointerleukin-1β into activated interleukin-1β. to be. Interleukin-1 consists of interleukin-1α and interleukin-1β, both of which are synthesized in the form of precursors of 31 KDa in monocytes, of which only proleukin-1β is It is activated by ICE. The sites hydrolyzed by Kephase- ¹ are Asp ²⁷ -Gly ²⁸ and Asp ¹¹⁶ -Ala ^117. Interleukin-1β is obtained if only the latter is hydrolyzed. Interleukin-1β is known to be a major component and to act as an important mediator of inflammation (1, 3). Kephase-1 was first discovered in 1989, and in 1994 three-dimensional structures were independently identified by X-ray crystallographic methods in both groups.

The mechanism, method of action, and role of CSP-32 have been studied a lot, and the three-dimensional structure was discovered in 1996 (2). The site where hydrolyzed kephase-3 (apopine) from prokephase- ₃ is hydrolyzed is a (P ₄ ) Asp-XX-Asp (P ₁ ) motif and known substrates include poly (ADP-ribose) polymerase, Catalytic subunits of U1 70,000 Mr small nuclear ribonucleoprotein and 460,000 Mr DNA-dependent protein kinases. The X-ray structure of Kephase-7 was found to be similar to Kephase-3 (4).

Kephas-8 and 9 are upstream of kephas-3, 6 and 7, all of which are known to be involved in the apoptosis cascade. The X-ray structure of Kephase-8 was discovered in 1999 (5) and can be usefully used to treat diseases associated with apoptosis, particularly by administering inhibitors.

A cease phase inhibitor refers to a compound capable of controlling inflammation or apoptosis caused by the action of the cease phase by inhibiting the activity of the cease phase. There are a number of diseases that can be used to eliminate or alleviate symptoms, such as: dementia, stroke, brain damage from AIDS, diabetes, gastric ulcer, brain damage from hepatitis virus, and liver disease from hepatitis virus. , Acute hepatitis, human abrupt liver failure, sepsis, organ transplant rejection, rheumatoid arthritis, or ischemic heart disease (6).

Among the known cease phase inhibitors to date, many known inhibitors are as follows.

These inhibitors commonly have a mechanism of inhibiting apoptosis by irreversibly inactivating enzymes (irreversible, broad-spectrum inhibitors). Comparing the efficacy of irreversible and reversible inhibitors, it has been reported that irreversible inhibitors show a much more effective inhibitory effect (7). Both IDUN's IDN-1965 and Maxim's MX-1013 have reported efficacy in a model of cell death associated with liver injury (8, 9). These compounds are in preclinical studies. IDN-6556, an irreversible inhibitor whose structure has not yet been announced, is being developed as a liver damage inhibitor in phase II clinical trials.

references:

(1) Inflammation: Basic Principles and Clinical Correlates , 2nd ed., Ed by Gallin, Goldstein and Snyderman. Raven Press Ltd., New York. 1992 , pp 211-232; Blood , 1996 , 87 (6) , 2095-2147.

(2) Wilson, KP et al, Nature , 1994 , 370 . 270; Walker, NPC et al. Cell, 1994 , 78 , 343; Nature Structural Biology , 1996 , 3 (7) , 619.

(3) Thornberry, NA et al, Nature , 1992 , 356 . 768; Nature Biotechnology, 1996, 14 , 297; Protein Science , 1995 , 4 , 3; Nature , 1995 , 376 (July 6) , 37; Protein Science , 1995 , 4 , 2149.

(4) Wei, Y. et al, Chemistry and Biology , 2000 , 7 , 423.

(5) Blanchard H. et al, Structure , 1999 , 7 , 1125; Blanchard H. et al, J. of Mol. Biol ., 2000 , 302 , 9.

(6) Case Papers Related Disease Cases:

Dementia: Arch Neurol 2003 Mar; 60 (3): 369-76, Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Pompl PN, Yemul S, Xiang Z, Ho L, Haroutunian V, Purohit D, Mohs R, Pasinetti GM.

Cerebral stroke: Proc Natl Acad Sci U S A 2002 Nov 12; 99 (23): 15188-93, Caspase activation and neuroprotection in Caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Le DA, Wu Y, Huang Z, Matsushita K, Plesnila N, Augustinack JC, Hyman BT, Yuan J, Kuida K, Flavell RA, Moskowitz MA.

Brain impairment due to AIDS: J Neurosci 2002 May 15; 22 (10): 4015-24, Caspase cascades in human immunodeficiency virus-associated neurodegeneration. Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA.

Diabetes: Diabetes 2002 Jun; 51 (6): 1938-48, Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ.

Gastric ulcer: J Physiol Pharmacol 1998 Dec; 49 (4): 489-500, Role of basic fibroblast growth factor in the suppression of apoptotic caspase-3 during chronic gastric ulcer healing. Slomiany BL, Piotrowski J, Slomiany A.

Cerebral injure by hepatitis: J Viral Hepat 2003 Mar; 10 (2): 81-6, Cerebral dysfunction in chronic hepatitis C infection. Forton DM, Taylor-Robinson SD, Thomas HC.

Fulminant hepatic failure: Gastroenterology 2000 Aug; 119 (2): 446-60, Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Streetz K, Leifeld L, Grundmann D, Ramakers J, Eckert K, Spengler U, Brenner D, Manns M, Trautwein C.

Sepsis: Nat Immunol 2000 Dec; 1 (6): 496-501, Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson DW, Karl IE.

Organ transplantation rejection: Xenotransplantation 2001 May; 8 (2): 115-24, In vitro prevention of cell-mediated xeno-graft rejection via the Fas / FasL-pathway in CrmA-transducted porcine kidney cells. Fujino M, Li XK, Suda T, Hashimoto M, Okabe K, Yaginuma H, Mikoshiba K, Guo L, Okuyama T, Enosawa S, Amemiya H, Amano T, Suzuki S.

Rheumatic arthritis: Prog Med Chem 2002; 39: 1-72, Caspase inhibitors as anti-inflammatory and antiapoptotic agents. Graczyk PP.

Ischemic cardiac diseases: Am J Physiol Heart Circ Physiol 2002 Sep; 283 (3): H990-5, Hypoxia-induced cleavage of caspase-3 and DFF45 / ICAD in human failed cardiomyocytes. Todor A, Sharov VG, Tanhehco EJ, Silverman N, Bernabei A, Sabbah HN.

Anti-inflammation: J Immunol 2003 Mar 15; 170 (6): 3386-91, A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model. Iwata A, Nishio K, Winn RK, Chi EY, Henderson WR Jr, Harlan JM.

(7) Wu J. et al, Methods: A Companion to Methods in Enzymology , 1999 , 17 , 320.

(8) Hoglen NC et al, J. of Pharmacology and Experimental Therapeutics , 2001 , 297 , 811.

(9) Jaeschke H. et al, Toxicology and Applied Pharmacology , 2000 , 169 , 77.

Therefore, the inventors of the present invention have newly designed and synthesized compounds having fundamentally different chemical structures from the inhibitors reported so far, measure binding to caspase, and have high selectivity for similar enzymes. The compound of formula 1 was found to meet the intended purpose of the present invention and to complete the present invention.

[Formula 1]

Wherein R, R ₁ , R ₂ , R ₃ , X and Ar are as defined below.

Accordingly, it is an object of the present invention to provide novel compounds of formula (I), pharmaceutically acceptable salts, physiologically hydrolysable esters, hydrates, solvates or stereoisomers thereof useful as inhibitors for caspases. .

The present invention also provides a pharmaceutical composition comprising the compound of formula (I), a pharmaceutically acceptable salt thereof, physiologically hydrolysable ester, hydrate, solvate or stereoisomer thereof as the active substance For the purpose.

Before limiting the scope of the invention, some of the following important terms will be defined.

a) simple alkyl chain (S imple A lkyl C hain, if necessary, the abbreviation represents a SAC): when made as a hydrocarbon consisting of 1-8 carbon atoms, open-circuit, straight (linear isomeric form) or branched (branched isomeric form) Fig. Include.

b) simple cycloalkyl chain (S imple C yclo A lkyl C hain, if necessary, the abbreviation represents a SCAC): a cyclic compound composed of a carbon number of 3-10 pieces.

c) aryl group (abbreviated as Ar): An aryl group includes both an aromatic group and a heteroaromatic group. Aromatic groups are simple or fused cyclic rings with unsaturated hydrocarbons consisting of 5 to 15 octagons. One or more hydrogens may be substituted with a group selected from: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, Halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, sphere Guanido group. Heteroaromatic groups are aromatic groups having 1 to 5 heteroatoms such as oxygen, sulfur and nitrogen. One or more hydrogens may also be substituted with a group selected from: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano , Halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, Guanido group.

Examples of aryl groups include phenyl, 1-naphtyl, 2-naphtyl, pyridinyl, pyrimidinyl, quinolinyl, Benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthaloxininyl, phthalazinyl (phthalazinyl), imidazolinyl, isoxazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl , Benzothiazolyl, benzimidazolyl, benzofuranyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, thiadiazolyl Triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isozozolyl, cynolinyl innolinyl, carbazolyl, isochromanyl, chromatin, chromanyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrofuranyl, Isobenzotetrahydrothienyl, isobenzothienyl, isobenzothiolyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzotetrahydrothienyl , Purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imida Zodipyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, benzoxazinyl Drobenzisothiopyranyl, benzopyranyl, benzothiopyranyl, benzomarinyl, coumarinyl, isocoumarinyl, chromonyl, chromonyl, chromanonyl, Pyridinyl-N-oxide, tetrahydroquinolinyl-N-oxide, dihydroquinolinyl, dihydroquinolinoneyl, dihydroquinolinonyl, di Dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, Pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide (quinolinyl-N-oxide), indolyl-N-oxide, indolinyl-N -Indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide N-oxide, phthalazinyl-N-oxide, imidazolinyl-N-oxide, isoxazolyl-N-oxide , Oxazolyl-N-oxide, thiazolyl-N-oxide, indolinzinyl-N-oxide, indazolyl-N-oxide (indazolyl-N-oxide), benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl- N-oxide (tetrazolyl-N-oxide) and the like.

d) Aromatically Substituted Alkyl (abbreviated: -SAC-Ar): Represents a chain or branched alkyl group having 1 to 8 carbon atoms substituted with the aryl group mentioned above.

e) Natural amino acids include the following amino acids: glycine, alanine, valine, leucine, isoleucine, serine, threonine Cysteine, Methionine, Proline, Aspartic acid, Asparagine, Glutamic acid, Glutamine, Lysine, Arginine , Histidine, Phenylalanine, Tyrosine, Tryptophan.

f) The protecting groups for esters are hydrocarbons of 1-8 carbon atoms, including those in the linear or branched isomeric form.

Abbreviated terms are as follows.

N-chlorosuccinimide: NCS

N-methylmorporline: NMM

N, N-dimethyl formamide: DMF

Dimethylsulfoxide: DMSO

Triethylamine: TEA

4- (dimethylamino) pyridine [4- (Dimethyamino) pyridine]: DMAP

N, N - dimethyl isopropyl amine (N, N -Diisopropylethylamine): DIPEA

O - (7- aza-benzotriazol-1-yl) - N, N, N, N '- tetramethyl passage nium phosphate in hexafluoro [O- (7-Azabenzotriazole-1 -yl) - N, N, N , N'- tetramethyluronium hexafluorophosphate]: HATU

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide {1- (3-dimethylaminopropyl) -3-ethylcarbodiimide}: EDC

1-hydroxybenzotriazole hydrate: HOBt

Trifluoroacetic acid: TFA

t-butyloxycarbonyl: Boc

Benzyloxycarbonyl: Cbz

Methyl: Me

Ethyl: Et

Equivalent: Eq

The present invention relates to novel compounds of formula (I), pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, hydrates, solvates or stereoisomers thereof, which have an inhibitory effect on caspases.

[Formula 1]

In the above formula, specific definitions for the substituents R, R ₁ , R ₂ , R ₃ , Ar, X are as follows.

I) R is a simple alkyl group (-SAC) or represents cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar) or hydrogen;

II) R ₁ represents -SAC, -SCAC, -Ar or -SAC-Ar, or represents the side chain residues of all natural amino acids, and in two cases where adjacent positions are stereocenters due to R ₁ All three-dimensional compounds of the compound are included, including the case where two types of compounds coexist (referring to diastereomeric mixtures), and when R ₁ is a side chain residue of amino acids and a carboxylic acid, an ester with a protecting group [-CO ₂ R ₄ , wherein R ₄ is -SAC], when substituted with sulfonamide [-CONHSO ₂ R ₅ , wherein R ₅ is -SAC], and a pharmaceutically acceptable salt thereof. And when present in the form of a pharmaceutically acceptable salt, when R ₁ is composed of bases as side chain residues of amino acids;

III) R ₂ represents -SAC, -SCAC, -Ar or -SAC-Ar, or represents the side chain residues of all natural amino acids, two cases where the adjacent position becomes a stereocenter due to R ₂ All of the three-dimensional compounds of, including coexistence of two types of compounds (referring to diastereomeric mixtures), and when R ₂ is a side chain residue of an amino acid and a carboxylic acid, When [-CO ₂ R ₆ , wherein R ₆ is -SAC], when substituted with sulfonamide [-CONHSO ₂ R ₇ , wherein R ₇ is -SAC], and a pharmaceutically acceptable salt form thereof If R ₂ is composed of a base as a side chain residue of the amino acid, also includes the case in the form of a pharmaceutically acceptable salt thereof, or R _{2 -H, - (CH 2) n} OR 8, - (CH 2) n OC (= O) R 8 ( W Standing, R ₈ is -SAC, -SCAC, -Ar, -SAC- Ar: n represents a = 1, 2);

IV) R ₃ represents a simple alkyl group (-SAC), cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC-Ar) or hydrogen;

V) Ar represents aromatic (-Ar);

R adjacent VI) R ₁ are connected to each other _{- (CH 2) n-, -} (CH 2) nO- (CH 2) m- or _{- (CH 2) n-NHR} 9 - (CH 2) m- [ n + m <9, R ₉ = -SAC, -SCAC, Ar, -SAC-Ar, -C (= O) -SAC, -C (= O) -SCAC, -C (= O) -Ar,- C (= 0) -SAC-Ar]; can form a cyclic compound;

VII) X is -CN, -CHO, -C (= 0) OR ₁₀ , -C (= 0) CH ₂ OR ₁₀ , -C (= 0) CH ₂ OC (= 0) R ₁₀ , -CH = CH -CO ₂ R ₁₀ , -CH = CH-SO ₂ R _10, wherein R ₁₀ represents -SAC, -SCAC, -Ar or -SAC-Ar, wherein -CONR ₁₁ R ₁₂ where R ₁₁ and R ₁₂ are Each independently represent -H, -SAC, -SCAC, -Ar, or -SAC-Ar; or -COCH ₂ -W;

W is —N ₂ , —F, —Cl, —Br, —I, —NR ₁₃ R ₁₄ , wherein R ₁₃ and Each R ₁₄ is independently -SAC, -SCAC, -Ar, or -SAC-Ar, or can be joined together to form cyclic compounds, or -SR ₁₅ , wherein R ₁₅ is -SAC, -SCAC,- Ar or -SAC-Ar, or the following structural formulae;

In the above formulas, the substituent Y is -H, -OH, -OR ₁₆ (R ₁₆ = -SAC, -SCAC), -C (= O) R ₁₇ (R ₁₇ = -H, -SAC, -SCAC),- F, -Cl, -Br, -I, -CN, -N ₃ , -CO ₂ H, -CF ₃ , -CO ₂ R ₁₈ , -C (= O) NHR ₁₈ (R ₁₈ = -SAC, -SCAC ), -C (= 0) NR ₁₉ R ₂₀ (R ₁₉ and R ₂₀ each independently represent -SAC, -SCAC, -Ar, -SAC-Ar), and R ₂₁ represents -H or -SAC.

Preferably, the substituent of the compound of Formula 1 may have the following range:

I) R represents H;

II) R ₁ represents-(CH ₂ ) ₂ COOH,-(CH ₂ ) ₂ COOR (where R = -SAC) or-(CH ₂ ) ₂ CONHSO ₂ R ₂₂ , where R ₂₂ = -SAC ;

III) R ₂ is H, -SAC, -Ar,-(CH ₂ ) _n O _m R where R = -SAC, -SCAC, -Ar or -SAC-Ar, and n = 0, 1 or 2; m = 0 or 1;

IV) R ₃ represents -SAC or hydrogen;

V) Ar represents aromatic (-Ar);

VI) X is -COCH ₂ N ₂ , -COCH ₂ F, -COCH ₂ Cl, -COCH ₂ Br, -COCH ₂ I, -COCH ₂ OAr, -COCH ₂ OCOAr or -COCH ₂ SR ₁₅ (where R ₁₅ is Each independently represents -SAC, -SCAC, -Ar, or -SAC-Ar.

Representative examples of the compound of formula 1 according to the present invention are as follows:

(1) 3-{[4- (1,3-dimethyl-1 H -indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid ( La );

(2) ( 3S ) -3-{[4- (1,3-dimethyl-1 H -indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -4-oxo-5- (2,3,5,6-tetrafluorophenoxy) pentanoic acid ( lb );

(3) ( 3S ) -5-[(2,6-dichlorobenzoyl) oxy] -3-{[4- (1,3-dimethyl-1 H -indol-2-yl) -2-ethyl-4 -Oxobutanoyl] amino} -4-oxopentanoic acid ( IC );

(4) 3-{[4- (1,3-dimethyl-1 H -indol-2-yl) -2-isopropyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentano Iksan ( Id );

(5) (3S) -5-[(2,6-dichlorobenzoyl) oxy] -3-[(2-methyl-4-oxo-4-phenylbutanoyl) amino] -4-oxopentanoic acid ( Ie );

(6) (3S) -5- [2,6-dichlorobenzoyl] oxy] -3-[(2-isopropyl-4-oxo-4-phenylbutanoyl) amino] -4-oxopentanoic acid ( If );

(7) (3S) -3-{[(2R) -2-isopropyl-3-methyl-4-oxo-4-phenylbutanoyl] amino} -4-oxo-5- (2,3,5, 6-tetrafluorophenoxy) pentanoic acid ( Ig );

(8) (3S) -3-{[2-ethyl-4- (1-naphthyl) -4-oxobutanoyl] amino} -4-oxo-5- (2,3,5,6-tetrafluoro Rofenoxy) pentanoic acid ( Ih );

(9) 3-{[2-ethyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid ( Ii ); And

(10) 5-fluoro-3-{[2-isopropyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -4-oxopentanoic acid ( Ij ).

The present invention also provides a pharmaceutical composition comprising the compound of formula (I), a pharmaceutically acceptable salt thereof, a physiologically hydrolysable ester, a hydrate, a solvate or a stereoisomer thereof as an active substance. For the purpose of providing it. The pharmaceutical composition of the present invention is dementia, stroke, brain damage caused by AIDS, diabetes, gastric ulcer, brain damage caused by hepatitis virus, liver disease caused by hepatitis virus, acute hepatitis, human sudden liver failure, sepsis, organ transplant rejection, rheumatism It is a cease phase inhibitor composition useful for treating or preventing sexual arthritis or ischemic heart disease. The present invention also provides an anti-inflammatory and apoptosis-preventing method comprising the compound of Formula 1, a pharmaceutically acceptable salt thereof, a physiologically hydrolysable ester, a hydrate, a solvate or a stereoisomer thereof as an active substance. It is an object to provide a composition.

Preferably the composition according to the invention may be prepared and administered in oral, injectable, or patch form.

The compound of formula 1 according to the present invention can be synthesized according to the methods shown in Schemes 1 and 2. However, these methods only show what is most commonly used to prepare the compounds of the present invention, and the order of the unit operations can be changed at any time. First, β-ketophosphonate III was synthesized from aromatic methyl ester II and methyl dimethyl phosphonate, and compound III was reacted with 2-ketoester IV using a Wittig reaction to react with 4-oxo-2. Prepare the alkyl-2-butenoic ester V. Compound V in the trans / cis mixture is hydrogenated to synthesize Derivative VI. When it is necessary to convert protecting group P ₁ into a new substituent, P ₁ is removed and a P ₂ group is introduced again.

VI a) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = Et, P ₁ = Me

b) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = Et, P ₂ = Bn

c) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = i- Pr, P ₁ = Et

d) Ar = phenyl, R ₂ = Me, P ₁ = Me

e) Ar = phenyl, R ₂ = i- Pr, P ₁ = Me

h) Ar = 1-naphthyl, R ₂ = Et, P ₁ = Me

i) Ar = 1-isoquinolinyl, R ₂ = Et, P ₁ = Me

j) Ar = 1-isoquinolinyl, R ₂ = i -Pr, P ₁ = Et

The carboxylic acid derivative VII obtained by hydrolyzing the compound VI was fused with an aspartic acid derivative VIII to obtain a compound IX, which was then subjected to a des martin periodene oxidation reaction followed by a deprotection process to obtain a compound I. Can be prepared.

X, I a) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = Et, W = F

b) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = Et, W = OPh (2,3,5,6-tetrafluoro)

c) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = Et, W = OCOPh (2,6-dichloro)

d) Ar = 2- (1,3-dimethyl) indolyl, R ₂ = i- Pr, W = F

e) Ar = phenyl, R ₂ = Me, W = OCOPh (2,6-dichloro)

f) Ar = phenyl, R ₂ = i- Pr, W = OCOPh (2,6-dichloro)

h) Ar = 1-naphthyl, R ₂ = Et, W = OPh (2,3,5,6-tetrafluoro)

i) Ar = 1-isoquinolinyl, R ₂ = Et, W = F

j) Ar = 1-isoquinolinyl, R ₂ = i- Pr, W = F

Compound Ig can be obtained by dialkylating compound VII to introduce an R ₃ group followed by the same process as in Scheme 2. Alkyl ethers were deprotected with trichloroacetic acid (see Scheme 3).

X, I g) Ar = phenyl, R ₂ = i- Pr, R ₃ = Me, W = OPh (2,3,5,6-tetrafluoro)

Compounds I having a functional group W in Schemes 2 and 3 may be synthesized through several steps after compound VII is fused with aspartic acid (β-t-Bu) methyl ester. Can also be obtained by reacting compound VIII and compound VII in which is already in a state having the desired form (Ref: WO 00/23421). If W is F, it can be synthesized according to known methods (Ref; Tetrahedron Letters , 1994 , 35 (52), 9693-9696).

VIII a) W = OPh (2,3,5,6-tetrafluoro)

b) W = OCOPh (2,6-dichloro)

c) W = F

Hereinafter, structural formulas of representative compounds synthesized by the present invention are described. This is only for the purpose of describing these synthesis in more detail through the examples. The following examples are, therefore, merely illustrative of the fact that the invention has been practiced and possible, and the invention is not so limited.

(One)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

10

EXAMPLES OF SYNTHESIS AND BIND MEASUREMENTS

Preparation Example 1 Methyl 1,3-dimethyl-1 H Indole-2-carboxylate

Dissolve 1,3-dimethyl- 1H -indole 2-carboxylic acid (4.39 g, 23.2 mmol) in 90 mL of DMF, add K ₂ CO ₃ (6.41 g, 2.0 eq) and MeI (9.88 g, 3.0 eq) and add 2 at room temperature. Stirred for time. The residue was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50mlx2), washed with water and saturated aqueous sodium bicarbonate solution and then with brine. Drying (anhydrous Na ₂ SO ₄ ) was concentrated under reduced pressure, and the residue was purified by column chromatography (10% ethyl acetate-hexane) to give 4.36 g (92%) of a slightly yellow solid.

NMR (500 MHz, CDCl ₃ ) δ 7.67 (d, 1H), 7.38 (t, 1H), 7.32 (d, 1H), 7.14 (t, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.80 (s, 3H), 2.66 (s, 3H)

Preparation Example 2 Dimethyl 2- (1,3-dimethyl-1 H -Indol-2-yl) -2-oxoethylphosphonate

Methyl dimethyl phosphonate (2.20 g, 1.89 mL, 3 eq) is dissolved in about 40 mL of anhydrous tetrahydrofuran under nitrogen atmosphere, kept at -78 ^o C and then n-butyllithium (2.5M in hexane, 7.08 mL , 3.0 eq) was added. After stirring for 1 hour at -78 ^o C to -60 ^o C, methyl 1,3-dimethyl-1 H -indole-2-carboxylate (1.20 g, 5.90 mmol) obtained in Preparation Example 1 was added to 10 mL of anhydrous tetra It was dissolved in hydrofuran and added at -60 ^o C, and stirred for 2 hours while slowly raising the temperature to-room temperature at -60 ^o C. Oxalic acid dihydrate (2.45 g, 3.3 eq) was added to the reaction mixture in 6 mL of methanol. The reaction mixture was filtered through celite, and the resulting solution was concentrated under reduced pressure, and then separated by column chromatography (50% -80% ethyl acetate / hexane) to obtain 1.68 g (97%) of a yellow solid.

NMR (500 MHz, CDCl ₃ ) δ 7.67 (d, 1H), 7.38 (t, 1H), 7.32 (d, 1H), 7.14 (t, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.68 (d, 2H), 2.67 (s, 3H)

Preparation Example 3 Methyl 4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxo-2-butenoate

To sodium hydride (60% dispersion in mineral oil, 216 mg, 1.1 eq, pre-washed with anhydrous tetrahydrofuran), about 40 mL of anhydrous tetrahydrofuran was added under 0 ^o C, nitrogen atmosphere, and dimethyl obtained in Preparation Example 2 2- (1,3-dimethyl-1 H -indol-2-yl) -2-oxoethylphosphonate (1.45 g, 4.90 mmol) was added dissolved in 20 mL of anhydrous tetrahydrofuran. After stirring for about 10 minutes was added lithium chloride (415mg, 2.0 eq) and stirred for 10 minutes at 0 ^° C again. Methyl 2-oxobutylate (630 mg, 1.1 eq) was added to the reaction mixture in 10 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 0 ^° C. for 30 minutes and at room temperature for 2 hours. The reaction was completed with saturated ammonium chloride solution and extracted twice with ethyl acetate (100 mL). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution (NaHCO ₃ , 50 mL × 2), saturated sodium chloride solution, and dried (anhydrous Na ₂ SO ₄ ) -concentrated. Separation by column chromatography (10% -20% ethyl acetate / hexanes) gave 1.17 g (83%, cis / trans = 3: 1) of a yellow liquid.

Trans isomer

NMR (500 MHz, CDCl ₃ ) δ 7.67 (d, 1H), 7.56 (s, 1H), 7.39 (t, 1H), 7.34 (d, 1H), 7.14 (t, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 2.65 (qt, 2H), 2.55 (s, 3H), 1.14 (t, 3H)

Cis isomer

NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, 1H), 7.37 (t, 1H), 7.32 (d, 1H), 7.13 (t, 1H), 6.67 (s, 1H), 3.93 (s, 3H), 3.67 (s, 3H), 2.54 (s, 3H), 2.51 (qt, 2H), 1.20 (t, 3H)

Preparation Example 4 Methyl 4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoate (VIa)

The compound obtained in Preparation Example 3 (1.16 g, 4.06 mmol) was dissolved in 30 mL of ethyl acetate, and Pd / C (400 mg, 10%, Aldrich) was added thereto, using a Parr Hydrogenater under 40 psi of hydrogen pressure. The reaction was time. After filtration through celite, the solution was concentrated under reduced pressure. Separation by column chromatography (10% ethyl acetate / hexanes) gave 1.00 g (94%) of a white solid.

NMR (500 MHz, CDCl ₃ ) δ 7.67 (d, 1H), 7.36 (t, 1H), 7.32 (d, 1H), 7.18 (t, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.41 (dd, 1H), 3.08-3.00 (m, 2H), 2.66 (s, 3H), 1.80-1.64 (m, 2H), 0.99 (t, 3H)

Preparation Example 5: 4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoic acid

The compound (500 mg, 1.74 mmol) obtained in Preparation Example 4 was dissolved in a mixture of distilled tetrahydrofuran (10 mL) and MeOH (5 mL), 1N-NaOH (5.2 mL, 3.0 eq) was added, and the mixture was stirred for one day. Neutralize with 1N HCl and distilled under reduced pressure to remove most of the tetrahydrofuran, and the residue was taken up in excess ethyl acetate (50 mL), washed with saturated sodium chloride solution and concentrated to dryness (anhydrous Na ₂ SO ₄ ) -decompression. 500 mg (quantitative yield) of the target compound of the slightly yellow powder obtained were used for the next reaction without further purification.

MS: [M + H] 274

Preparation Example 6 Benzyl 4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoate (VIb)

The compound (360 mg, 1.32 mmol) obtained in Preparation Example 5 was dissolved in 5 mL of DMF, K ₂ CO ₃ (365 mg, 2.0 equivalents) and benzyl bromide (271 mg, 0.19 mL, 1.2 equivalents) were added thereto, and the mixture was stirred at room temperature for 4 hours. Extracted with ethyl acetate, the extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, and dried (anhydrous Na ₂ SO ₄ ) -concentrated. Separation by column chromatography (5-10% ethyl acetate / hexanes) gave 350 mg of a slightly yellow liquid (73%).

NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, 1H), 7.38-7.30 (m, 7H), 7.16 (t, 1H), 5.17 (Abq, 2H), 3.90 (s, 3H), 3.44 (dd, 1H ), 3.11 (m, 1H), 3.03 (m, 1H), 2.66 (s, 3H), 1.84-1.68 (m, 2H), 0.99 (t, 3H)

Preparation Example 7 Benzyl 4- (1,3-dimethyl-1 H Chiral resolution and deprotection of -indol-2-yl) -2-ethyl-4-oxobutanoate

Each enantiomer was separated using a chiral OD column (Daicel Chemical Industries, 2.00 cm × 25 cm, OD00CJ-1C005, 6% i-PrOH in Hexane, 220 nm). The separated enantiomer was deprotected under hydrogen balloon to quantitatively obtain a chiral compound.

MS: [M + H] 274

Preparation Example 8: tert -Butyl 3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoate (Xa)

The carboxylic acid derivative (237 mg, 0.87 mmol) and amino alcohol derivative VIIIc (Ref; Tetrahedron Letters, 1994, 35 (52), 9693, 200 mg, 1.1 eq) obtained in Preparation Example 5 or 7 were mixed with HATU (430 mg, 1.3 eq). Reaction in DMF solvent in a conventional manner using TEA (264 mg, 0.36 mL, 3.0 eq), after workup, and then purified by column chromatography (25-30-40% EA / Hex) 250 mg (62%) of the compound were obtained. Anhydrous dichloromethane (4 mL) was added to this compound and Dess-Martin reagent (687 mg, 3.0 mol eq), and the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (3 mL). After usual treatment, the product was purified by column chromatography (36% ethyl acetate-hexane) to obtain 180 mg (72%) of diastereomeric target product.

NMR (500 MHz, CDCl ₃ ) δ 7.69 (d, 1H), 7.39 (t, 1H), 7.34 (m, 1H), 7.16 (t, 1H), 6.89 & 6.85 (two d, 1H), 5.47-5.05 ( m, 2H), 4.92-4.84 (two m, 1H), 3.96-3.94 (two s, 3H), 3.53-3.41 (m, 1H), 3.08-2.97 (m, 2H), 2.86-2.68 (m, 2H ), 2.68 & 2.67 (two s, 3H), 1.80 (m, 1H), 1.63 (m, 1H), 1.46 (s, 9H), 1.02 (m, 3H)

Example 1: 3-{[(2 R or 2 S ) -4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid (Ia-1 or 2)

Compound (44 mg) synthesized in Preparation Example 8 was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added at 0 ^° C. The mixture was stirred for 2 hours while gradually maintaining the temperature at room temperature, and then concentrated under reduced pressure to quantitatively obtain the desired final compounds ( Ia-1, Ia-2 ).

NMR (400 MHz, DMSO-d ₆ ) δ 8.64 & 8.52 (two br s, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.34 (t, 1H), 7.11 (t, 1H), 5.16 (br, 2H), 4.61 & 4.46 (two m, 1H), 3.84 & 3.83 (two s, 3H), 3.25 (m, 1H), 2.99 (m, 1H), 2.88-2.60 (m, 3H), 2.60 & 2.59 (two s, 3H), 1.54 (m, 2H), 0.90 (m, 3H)

MS: M + H 405

Preparation Example 9: tert -Butyl (3 S ) -3-{[(benzyloxy) carbonyl] amino} -4-hydroxy-5- (2,3,5,6-tetrafluorophenoxy) pentanoate (XIIIa)

To N-benzyloxycarbonyl-β-t-butylaspartic acid (18.5 g, 55.7 mmol) and NMM (6.78 mL, 1.1 equiv) were added anhydrous tetrahydrofuran (180 mL) under nitrogen atmosphere, and the temperature was reduced to -15 ^° C. After maintaining, isobutylchloro formate (7.63 mL, 1.05 mmol) was added thereto, and the resultant was stirred for about 20 minutes. Diazomethane-ether solution (synthesized with 2.0eq of 1-methyl-3-nitro-1-nitrozo-guanidine, 60 mL) while maintaining the reaction at 0 ^o C was added to synthesize a diazoketone derivative ( ~ 30 minutes). 30% HBr / AcOH (23.3 mL, 2.0 eq) was added thereto to synthesize a bromomethylketone derivative (30-60 minutes). Extracted with ethyl acetate, washed twice with saturated aqueous sodium hydrogen carbonate solution and brine. Drying (anhydrous Na ₂ SO ₄ ) -decompression concentration to obtain quantitative bromomethylketone derivative (23 g).

Bromomethylketone derivative (23 g, 55.7 mmol) and 2,3,5,6-tetrafluorophenol (10.2 g, 1.1 eq) were dissolved in dimethylformamide (150 mL) and KF (8.14 g, 2.5 eq) was added. It was added and stirred at room temperature for 2 hours. Treatment was carried out in a conventional manner to obtain 2,3,5,6-tetrafluorophenoxy methyl ketone derivatives. It was dissolved in methanol (150 mL) and reacted by slowly adding NaBH ₄ (4.24 g) (0 ^o C-room temperature, 2 hours). The reaction was stopped with acetic acid and distilled under reduced pressure to remove methanol. Extracted with ethyl acetate (200mlx2), washed with water and brine, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure, purified by column chromatography (15% ethyl acetate / hexane) to give 20.2 g (74%). The compound was obtained in diastereomeric form.

Preparation Example 10 t-butyl (3S) -3-amino-4-hydroxy-5- (2,3,5,6-tetrafluorophenoxy) pentanoate (VIIIa)

The compound obtained in Preparation Example 9 was dissolved in methanol (300 mL), and Pd / C (10%, 1.50 g) was added thereto, followed by debenzyloxycarbonylation (Pd / C) for 3 hours under a hydrogen balloon (95%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.2 (br, 2H), 7.6-7.5 (m, 1H), 5.9 (m, 1H), 4.3-4.1 (m, 3H), 3.6 (m, 1H), 2.7 (m, 1H), 1.4 (s, 9H)

Preparation Example 11: tert -Butyl (3 S ) -3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -4-oxo-5- (2,3,5,6-tetrafluorophenoxy) pentanoate (Xb)

The carboxylic acid derivative (152 mg, 0.557 mmol) obtained in Preparation Example 5 and the amino alcohol derivative VIIIa (216 mg, 1.1 eq) obtained in Preparation Example 10 were subjected to HATU (275 mg, 1.3 eq) and TEA (169 mg, 0.23 mL, 3.0 eq). 246 mg (85%) of a compound by reaction in DMF (2 mL) solvent in a conventional manner, and after workup, purification by column chromatography (20-30-40% EA / Hex) Got. Anhydrous dichloromethane (5 mL) was added to this compound and Dess-Martin reagent (502 mg, 3.0 eq), and the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (1 mL). After usual treatment, the product was purified by column chromatography (20-25% ethyl acetate-hexane) to obtain 183 mg (76%) of diastereomeric target product.

NMR (500 MHz, CDCl ₃ ) δ 7.66 (d, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 7.13 (t, 1H), 6.95 & 6.88 (two d, 1H), 6.71 & 6.63 ( two m, 1H), 5.43-5.06 (2 set of AB, 2H), 4.93 & 4.84 (m, 1H), 3.45 (two set of dd, 1H), 3.08-2.94 (m, 2H), 2.85-2.65 ( m, 2H), 2.65 & 2.64 (two s, 3H), 1.80 (m, 1H), 1.61 (m, 1H), 1.45 & 1.44 (two s, 9H), 1.01 & 0.99 (two t, 3H).

Example 2: (3 S ) -3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -4-oxo-5- (2,3,5,6-tetrafluorophenoxy) pentanoic acid (Ib)

Compound (180 mg) synthesized in Preparation Example 11 was dissolved in dichloromethane (4 mL), and TFA (2 mL) was added at 0 ^° C. The mixture was stirred for 2 hours while gradually maintaining the temperature at room temperature, and then concentrated under reduced pressure to obtain 160 mg (98%) of the desired final compound.

NMR (500 MHz, DMSO-d ₆ ) δ 12.50 (br, 1H), 8.74-8.59 (two d, 1H), 7.73 (d, 1H), 7.52-7.44 (m, 2H), 7.35 (t, 1H), 7.12 (t, 1H), 5.38-5.13 (m, 2H), 4.67 & 4.47 (two m, 1H), 3.82 & 3.79 (two s, 3H), 3.28 (m, 1H), 3.00 (m, 1H), 2.87-2.72 (m, 2H), 2.59 (two s, 3H), 2.55 (m, 1H), 1.54 (m, 2H), 0.88 (two t, 3H)

MS: [M + H] 551

Preparation 12: (3S) -3-{[(benzyloxy) carbonyl] amino} -5- (t-butoxy) -2-hydroxy-5-oxopentyl 2,6-dichlorobenzoate (XIIIb)

To N-benzyloxycarbonyl-β-t-butylaspartic acid (5.03 g, 15.6 mmol) and NMM (1.90 mL, 17.1 mmol) were added anhydrous tetrahydrofuran (60 mL) under nitrogen atmosphere, and then reduced to -15 ^° C. After maintaining, isobutylchloroformate (2.12 mL, 16.3 mmol) was added thereto, followed by stirring for about 20 minutes. Diazomethane-ether solution (synthesized with 2.0eq of 1-methyl-3-nitro-1-nitrozo-guanidine, 60 mL) while maintaining the reaction at 0 ^° C. was added to synthesize a diazoketone derivative ( ~ 30 minutes). 30% HBr / AcOH (6.42 mL, 2.0 eq) was added thereto to synthesize a bromomethylketone derivative (30-60 minutes). Extracted with ethyl acetate, washed twice with saturated aqueous sodium hydrogen carbonate solution and brine. Dry (anhydrous Na ₂ SO ₄ ) -concentration under reduced pressure afforded a bromomethylketone derivative (6.4 g).

Bromomethylketone derivative (4.36 g) and 2,6-dichlorobenzoic acid (2.28 g, 1.1 eq) were dissolved in dimethylformamide (18 mL), KF (1.58 g, 2.5 eq) was added thereto, and the mixture was stirred for 2 hours. Treatment was carried out in a conventional manner to obtain 2,6-dichlorobenzoxymethyl ketone derivatives. This was dissolved in methanol (20 mL) and reacted with NaBH ₄ (412 mg) -methanol solution (40 mL) (-10 ^o C to room temperature, 2 hours). The reaction was stopped with acetic acid and distilled under reduced pressure to remove methanol. Extracted with ethyl acetate (50mlx2), washed with water and brine, dried (anhydrous Na ₂ SO ₄ ), concentrated under reduced pressure, purified by column chromatography (ethyl acetate-hexane, 1: 5) 4.80g (86%) The desired compound of was obtained in diastereomeric form.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.3-7.2 (m, 8H), 5.9 (m, 1H), 5.2 (m, 4H), 4.7 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1 H), 1.4 (s, 9 H)

Preparation Example 13 (3S) -3-Amino-5- (t-butoxy) -2-hydroxy-5-oxopentyl-2,6-dichlorobenzoate (VIIIb)

The compound obtained in Preparation Example 12 was obtained by debenzyloxycarbonylation (Pd / C) for 40 minutes under a hydrogen balloon in a conventional manner (100%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.2 (br, 2H), 7.6-7.5 (m, 3H), 6.1 (m, 1H), 4.4-3.9 (m, 3H), 3.0-2.6 ( m, 2H), 1.4 (s, 9H)

Preparation 14: (3 S ) -5- ( tert -Butoxy) -3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -2,5-ioxopentyl 2,6-dichlorobenzoate (Xc)

The carboxylic acid derivative (250 mg, 0.87 mmol) obtained in Preparation Example 5 or 7 and the amino alcohol derivative VIIIb (398 mg, 1.1 eq) obtained in Preparation Example 13 were prepared by HATU (430 mg, 1.3 eq) and TEA (264 mg, 0.36 mL, 3.0). eq) in a conventional manner in a DMF solvent, after workup, purified by column chromatography (25-30-40% EA / Hex) to give 530 mg (96%) of the compound. Got it. Anhydrous dichloromethane (4 mL) was added to this compound and Dess-Martin reagent (1.06 g, 3.0 eq), and the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (1 mL). After usual treatment, the product was purified by column chromatography (36% ethyl acetate-hexane) to obtain 289 mg (55%) of diastereomeric target.

NMR (500 MHz, CDCl ₃ ) δ 7.69 (d, 1H), 7.40-7.27 (m, 5H), 7.14 (m, 1H), 7.03- 6.69 (two d, 1H), 5.51-5.18 (2 set of ABq, 2H), 5.00 & 4.90 (m, 1H), 3.95 & 3.93 (two s, 3H), 3.53-3.43 (m, 1H), 3.08-2.96 (m, 2H), 2.88-2.70 (m, 2H), 2.68 & 2.66 (two s, 3H), 1.84 (m, 1H), 1.66 (m, 1H), 1.47 & 1.45 (two s, 9H), 1.06 & 1.02 (two t, 3H)

Example 3: (3 S ) -5-[(2,6-dichlorobenzoyl) oxy] -3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -4-oxopentanoic acid (Ic)

Compound (280 mg) synthesized in Preparation Example 14 was dissolved in dichloromethane (4 mL), and TFA (2 mL) was added at 0 ^° C. The mixture was stirred for 2 hours while gradually maintaining the temperature at room temperature, and then concentrated under reduced pressure to quantitatively obtain the desired final compound.

NMR (500 MHz, DMSO-d ₆ ) δ 12.46 (br, 1H), 8.75-8.62 (two br, 1H), 7.74 (two d, 1H), 7.61-7.53 (m, 3H), 7.49 (two d, 1H ), 7.34 (t, 1H), 7.12 (t, 1H), 5.43-5.05 (two br, 2H), 4. 76 & 4.55 (two m, 1H), 3.85 (two s, 3H), 3.29 (m, 1H), 3.04 (m, 1H), 2.92-2.73 (m, 2H), 2.61 (two s, 3H), 2.61 (m, 1H), 1.58 (m, 2H), 0.92 (two t, 3H)

MS: M + H 575

Preparation Example 15 Ethyl 4- (1,3-dimethyl-1 H -Indol-2-yl) -2-isopropyl-4-oxo-2-butenoate

To sodium hydride (60% suspension in mineral oil, 34 mg, 1.1 eq, pre-washed with anhydrous tetrahydrofuran), about 10 mL of anhydrous tetrahydrofuran was added under 0 ^o C, nitrogen atmosphere, and dimethyl 2 in Preparation Example 2 -(1,3-dimethyl-1 H -indol-2-yl) -2-oxoethylphosphonate (230 mg, 0.78 mmol) was added dissolved in 5 mL of anhydrous tetrahydrofuran. After stirring for about 10 minutes lithium chloride (66mg, 2.0 eq) was added and stirred for 10 minutes at 0 ^o C. To the reaction mixture, ethyl 3-methyl-2-oxobutylate (124 mg, 0.13 mL, 1.1 eq) was dissolved in 3 mL of anhydrous tetrahydrofuran, and stirred at 0 ^° C. for 30 minutes and at room temperature for 2 hours. The reaction was completed with saturated ammonium chloride solution and extracted twice with ethyl acetate (30 mL). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, and concentrated to dryness (anhydrous Na ₂ SO ₄ ) -decompression. Separation by column chromatography (10% -20% ethyl acetate / hexanes) gave 241 mg (99%, cis / trans = 235 mg: 7 mg) yellow liquid.

Trans isomer

NMR (500 MHz, CDCl ₃ ) δ 7.66 (d, 1H), 7.38 (t, 1H), 7.33 (d, 1H), 7.32 (s, 1H), 7.13 (t, 1H), 4.29 (qt, 2H), 3.99 (s, 3H), 3.28 (septet, 1H), 2.56 (s, 3H), 1.34 (t, 3H), 1.22 (d, 6H)

Cis isomer

NMR (500 MHz, CDCl ₃ ) δ 7.66 (d, 1H), 7.37 (t, 1H), 7.32 (d, 1H), 7.14 (t, 1H), 6.64 (s, 1H), 4.18 (qt, 2H), 3.92 (s, 3H), 2.83 (septet, 1H), 2.56 (s, 3H), 1.21 (d, 6H), 1.19 (t, 3H)

Preparation Example 16: Ethyl 4- (1,3-dimethyl-1 H -Indol-2-yl) -2-isopropyl-4-oxobutanoate (VIc)

The compound (230 mg, 0.734 mmol) obtained in Preparation Example 15 was dissolved in 10 mL of ethyl acetate, and Pd / C (60 mg, 10%, Aldrich) was added, using Parr Hydrogenater under a hydrogen pressure of 40 psi for one day. Reacted. After filtration through celite, the solution was concentrated under reduced pressure. Separation by column chromatography (10% ethyl acetate / hexanes) gave 151 mg (65%) of a solid.

NMR (500 MHz, CDCl ₃ ) δ 7.69 (d, 1H), 7.37 (t, 1H), 7.33 (d, 1H), 7.15 (t, 1H), 4.19 (m, 2H), 3.94 (s, 3H), 3.45 (dd, 1H), 3.00-2.95 (m, 2H), 2.67 (s, 3H), 2.09 (septet, 1H), 1.28 (t, 3H), 1.03 (d, 3H), 1.02 (d, 3H)

Preparation Example 17 tert -Butyl 3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-isopropyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoate (Xd)

Using the same method as in Preparation Example 8, the title compound was obtained.

NMR (500 MHz, CDCl ₃ ) δ 7.69 (d, 1H), 7.37 (t, 1H), 7.34 (d, 1H), 7.15 (t, 1H), 6.84 & 6.78 (two d, 1H), 5.49-5.05 ( m, 2H), 4.90 & 4.81 (two m, 1H), 3.94 & 3.92 (two s, 3H), 3.54-3.43 (m, 1H), 3.06-2.96 (m, 2H), 2.81-2.65 (m, 2H), 2.69 & 2.67 (two s, 3H), 2.00 (m, 1H), 1.47 & 1.46 (two s, 9H), 1.05 (m, 6H)

Example 4: 3-{[4- (1,3-dimethyl-1 H -Indol-2-yl) -2-isopropyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid (Id)

The title compound was obtained by subjecting the compound obtained in Preparation Example 17 to the same method as in Example 1.

NMR (500 MHz, CDCl ₃ ) δ 7.69 (d, 1H), 7.39 (d, 1H), 7.34 (t, 1H), 7.11 (t, 1H), 4.85-4.67 (two m, 1H), 4.70-4.25 ( m, 2H), 3.90 (three s, 3H), 3.42 (m, 1H), 3.07 (m, 1H), 2.90-2.76 (m, 3H), 2.67 (three s, 3H), 1.96 (septet, 1H) , 1.03 (m, 6H)

MS [M + H] 419

Preparation Example 18 Methyl 2-methyl-4-oxo-4-phenyl-2-butenoate

A phosphate compound was prepared in the same manner as in Preparation Example 2 using methyl benzoate, and then subjected to the same method as Preparation Example 3 (using methyl pyruvate instead of methyl 2-oxobutylate) to obtain the title compound. .

Trans isomer

NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 3.8 (s, 3H), 2.1 (s, 3H)

Cis isomer

NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 6.7 (m, 1H), 3.6 (s, 3H), 2.1 (s, 3H)

Preparation Example 19 Methyl 2-methyl-4-oxo-4-phenylbutanoate (VId)

The cis / trans mixture (220 mg, 1.1 mmol) and Pd / C (50 mg, 5%) obtained in Preparation Example 18 were dissolved in ethyl acetate (3 ml), stirred for 6 hours under a hydrogen balloon atmosphere, and then filtered under reduced pressure using celite. The solid was removed, washed with ethyl acetate (2mlx2), and distilled under reduced pressure to obtain a solid compound (200mg, 88%).

NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 3.7 (s, 3H), 3.4 (m, 1H), 3.1 (q, 1H), 3.0 (m, 1H), 1.2 (d, J = 7.2 Hz, 3H)

Preparation Example 20 2-Methyl-4-oxo-4-phenylbutanoic acid

The compound ( VId , 1.1 g, 5.38 mmol) obtained in Preparation Example 19 was dissolved in distilled tetrahydrofuran (120 mL), and 1N aqueous sodium hydroxide solution (8.1 mL, 1.5 equiv) was added thereto. After about 4 hours, neutralize with 1N aqueous hydrochloric acid solution and distillate under reduced pressure to remove most of the tetrahydrofuran. The residue is dissolved in excess ethyl acetate (> 700 mL), washed with water and dried (anhydrous Na ₂ SO ₄ ) -decompression. Concentrated. The target compound (1.03 g, 99%) of the obtained white powder was used for the next step reaction without further purification.

NMR (400 MHz, DMSO-d ₆ ) δ 12.1 (br, 1H), 7.9 (d, J = 4 Hz, 2H), 7.6 (m, 1H), 7.5 (m, 2H), 3.4 (m, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 1.1 (d, J = 8 Hz, 3H)

Preparation Example 21 (3s) -5- (t-butoxy) -3-[(2-methyl-4-oxo-4-phenylbutanoyl) amino] -2,5-dioxopentyl 2,6-dichloro Benzoate (Xe)

A mixture of the carboxylic acid derivative (1.03 g, 5.38 mmol), the amino alcohol derivative ( VIIIb , 2.68 mg, 1.2 equivalents) and HATU (2.86 g, 1.4 equivalents) obtained in Preparation Example 20 was cooled to 0 ° C. to give DMF (30 ml). Triethylamine (3.0 ml, 4.0 equiv) was added to the solvent for 5 hours, the solvent was distilled under reduced pressure, extracted with ethyl acetate (300 ml × 2), washed with water and aqueous sodium bicarbonate solution, and brine. Drying (anhydrous Na ₂ SO ₄ ) was concentrated under reduced pressure, and then purified by column chromatography (30% ethyl acetate / hexane) to give 2.35 g (79%) of the compound. Anhydrous dichloromethane (50 mL) was added to this compound and Dess-Martin reagent (5.41 g, 3.0 equivalents), the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (6 mL). The solid was removed by filtration under reduced pressure using Celite, followed by extraction with ethyl acetate (50mlx2), water and saturated aqueous sodium hydrogen carbonate solution, followed by brine. Drying (anhydrous Na ₂ SO ₄ ) was concentrated under reduced pressure, and the residue was first purified by column chromatography (36% ethyl acetate-hexane) to obtain 2.11 g of diastereomeric target product.

NMR (400 MHz, CDCl ₃ ) δ 7.9 (t, J = 8 Hz, 2H), 7.6 (m, 1H), 7.5 (m, 2H), 7.4-7.2 (m, 3H), 6.9 (1H, NH), 5.3 -5.1 (m, 1H), 4.9 (m, 1H), 3.0 (m, 2H), 2.7 (m, 1H), 1.4 (s, 9H), 1.3 (m, 3H)

Example 5: (3S) -5-[(2,6-dichlorobenzoyl) oxy] -3-[(2-methyl-4-oxo-4-phenylbutanoyl) amino] -4-oxopentanoic acid ( Ie)

Compound (190 mg) obtained in Preparation 21 was dissolved in dichloromethane (2 mL) and TFA (1 mL) was added at 0 ^° C. The mixture was stirred for 2 hours while gradually maintaining the temperature at room temperature, and then concentrated under reduced pressure. This compound was dissolved in distilled tetrahydrofuran (3 mL) and 1N aqueous sodium hydroxide solution (0.34 ml, 1.0 equiv) was added. After about 1 hour, neutralized with 1N aqueous hydrochloric acid and distilled under reduced pressure to remove most of the tetrahydrofuran. The residue was dissolved in excess ethyl acetate (10 mL), washed with water and dried (anhydrous Na ₂ SO ₄ )- To yield the desired final compound (Ie) quantitatively.

NMR (400 MHz, CDCl ₃ ) δ 8.1 (t, J = 8 Hz, 2H), 7.7 (m, 1H), 7.6 (m, 2H), 7.5-7.4 (m, 3H), 6.9 (1H, NH), 5.4 -5.2 (m, 1H), 5.0 (m, 1H), 3.2 (m, 2H), 2.8 (m, 1H), 1.3 (m, 3H)

MS [M + Na] ⁺ 516

Preparation Example 22 Methyl (E) -2-isopropyl-4-oxo-4-phenyl-2-butenoate

A phosphate compound was prepared in the same manner as in Preparation Example 2 using methyl benzoate, and then the compound was prepared in the same manner as in Preparation Example 3 (using methyl 3-methyl-2-oxobutylate instead of methyl 2-oxobutylate). Was applied to obtain the title compound.

NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 6.7 (s, 1H), 3.6 (s, 3H), 2.8 (m, 1H), 1.2 (d, J = 6.8 Hz, 6H)

Preparation Example 23 Methyl 3-isopropyl-4-oxo-4-phenylbutanoate (VIe)

The desired compound was obtained by applying the same method as Preparation Example 19 to the compound obtained in Preparation Example 22.

NMR (500 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 3.6 (s, 3H), 3.4 (m, 1H), 3.0-2.9 (m, 1H ), 2.9 (m, 1H), 2.0 (m, 1H), 0.9 (m, 6H)

Preparation Example 24 (3S) -5- (t-butoxy) -3-[(2-isopropyl-4-oxo-4-phenylbutanoyl) amino] -2,5-dioxopentyl 2,6- Dichlorobenzoate (Xf)

After applying the method of Preparation 20 to the compound obtained in Preparation Example 23 to obtain a compound, the same method as in Preparation Example 14 was applied to this compound to obtain the title compound.

NMR (500 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 7.3 (m, 3H), 6.9 (1H, NH), 5.4-4.9 (m, 2H ), 4.8 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.0 (m, 1H) , 1.4 (s, 9H), 0.9 (m, 6H)

Example 6: (3S) -5- [2,6-dichlorobenzoyl] oxy] -3-[(2-isopropyl-4-oxo-4-phenylbutanoyl) amino] -4-oxopentanoic acid ( If; diastereomeric mixture)

The desired title compound was obtained in the same manner as in Example 5 with respect to the compound obtained in Preparation Example 24.

NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 7.3 (m, 3H), 6.9 (1H, NH), 5.4-4.9 (m, 2H ), 4.8 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.0 (m, 1H) , 0.9 (m, 6H)

If (single diastereomer)

A chiral carboxylic acid derivative of (2 S) -2- isopropyl-4-oxo-4-phenyl butanoate acid using (J. Med. Chem. 1998, 41, 2461-2480) a chiral compound (If) Was obtained in the same way.

Preparation 25: (2 R , 3 Z ) -2-isopropyl-4-methoxy-3-methyl-4-phenyl-3-butenoic acid

The chiral carboxylic acid derivative (160 mg, 0.726 mmol, J. Med. Chem. 1998 , 41 , 2461-2480) mentioned in Example 6 was dissolved in THF (3 mL) and NaH (60% dispersion in milenal oil, 73 mg, 2.5 eq) was added at -78 ^o C, the temperature was raised to -40 ^o C, and then cooled to -78 ^o C, MeI (0.18 mL, 4.0 eq) was added, and the mixture was stirred for 3 hours while gradually raising the temperature to room temperature. The reaction was stopped with 0.5N aqueous hydrochloric acid solution, extracted with ethyl acetate (10 mL), washed with water and dried (anhydrous Na ₂ SO ₄ ) -decompression concentrated to give the desired compound as 130mg (71%).

Preparation Example 26 tert -Butyl (3 S ) -3-{[(2 R , 3 Z ) -2-isopropyl-4-methoxy-3-methyl-4-phenyl-3-butenoyl] amino} -4-oxo-5- (2,3,5,6-tetrafluorophenoxy) penta No-eight

Compound 35 mg (0.14 mmol) and amino alcohol derivative VIIIa (60 mg, 1.2 eq) prepared in Preparation Example 25 were subjected to DMF in a conventional manner using HATU (80 mg, 1.5 eq) and TEA (57 mg, 0.078 mL, 4.0 eq). After reacting in a solvent, undergoing a workup process, and purified by column chromatography (20% EA / Hex) to give 20.3 mg (25%) of the compound. Anhydrous dichloromethane (1 mL) was added to this compound and Dess-Martin reagent (44 mg, 3.0 eq), and the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (0.05 mL). After usual treatment, purification by Prep TLC (25% ethyl acetate-hexane) afforded 14 mg (69%) of compound.

Preparation Example 27 t-butyl (3S) -3-{[(2R) -2-isopropyl-3-methyl-4-oxo-4-phenylbutanoyl] amino} -4-oxo-5- (2, 3,5,6-tetrafluorophenoxy) pentanoate (Ig)

Trichloroacetic acid (11.8mg, 3.0eq) / CH ₂ Cl ₂ solution was added to the solution obtained by dissolving the compound (14mg, 0.024mmol) in Preparation Example 26 in CH ₂ Cl ₂ (1mL) at 0 ^o C. The mixture was stirred for 3 hours while gradually raising the temperature. After distillation under reduced pressure, the residue was extracted with ethyl acetate (10 mL), washed with water, dried (anhydrous Na ₂ SO ₄ ) -pressure-reduced concentration, and purified by Prep TLC (33% ethyl acetate-hexane) to obtain 7 mg (49 mg) of the title compound. %) Obtained.

NMR (500 MHz, CDCl ₃ ) δ 8.0 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 6.8 (m, 1H), 5.3 (m, 1H), 5.1 (m, 1H), 4.5-4.3 (m, 1H), 3.0-2.9 (m, 1H), 2.6-2.4 (m, 1H), 2.3 (m, 2H), 1.4 (s, 9H), 1.0 (m, 6H), 0.9 ( m, 3H)

MS [M + H] ⁺ 568

Example 7: (3S) -3-{[(2R) -2-isopropyl-3-methyl-4-oxo-4-phenylbutanoyl] amino} -4-oxo-5- (2,3,5 , 6-tetrafluorophenoxy) pentanoic acid (Ig)

The desired title compound was obtained in the same manner as in Example 5 for the compound obtained in Preparation Example 27.

NMR (400 MHz, CDCl ₃ ) δ 7.9 (br, 1H), 7.5-7.1 (m, 5H), 6.7 (m, 1H), 4.9-4.8 (m, 1H), 4.5 (m, 1H), 4.2 (m , 1H), 4.0 (m, 1H), 3.0-2.8 (m, 1H), 2.4 (m, 1H), 2.1 (m, 1H), 1.8 (m, 1H), 1.3 (m, 3H), 0.9 ( m, 6H).

MS [M + Na] ⁺ 534

Preparation Example 28 Methyl 2-ethyl-4- (1-naphthyl) -4-oxobutanoate (VIh)

The title compound was obtained by applying the same method as Preparation Example 1, 2, 3, 4 to 1-naphthylcarboxylic acid.

NMR (500 MHz, CDCl ₃ ) δ 8.5 (d, J = 8.2 Hz, 1H), 8.0-7.8 (m, 3H), 7.6-7.4 (m, 3H), 3.5 (q, J = 10 Hz, 1H), 3.9 (s, 3H), 3.0 (m, 2H), 1.8-1.7 (m, 2H), 0.9 (t, J = 14 Hz, 3H).

Preparation Example 29 t-butyl (3S) -3-{[2-ethyl-4- (1-naphthyl) -4-oxobutanoyl] amino} -4-oxo-5- (2,3,5, 6-tetrafluorophenoxy) pentanoate (Xh)

Using the compound of Preparation Example 28 and the amino alcohol derivative VIIIa, the title compound was obtained in the same manner as in Preparation Examples 5 and 8.

NMR (500 MHz, CDCl ₃ ) δ 8.5 (d, J = 8.7 Hz, 1H), 7.9 (m, 2H), 7.8 (m, 1H), 7.5 (m, 3H), 6.9 (m, 1H), 6.7- 6.5 (m, 1H), 5.3-5.2 (dd, J = 7.2, 17.4 Hz, 1H), 5.1 (m, 1H), 4.9-4.8 (m, 1H), 3.6 (m, 1H), 3.0 (m, 2H), 3.3 (m, 1H), 2.7 (m, 1H), 1.8 (m, 1H), 1.4 (m, 1H), 1.0 (m, 3H)

Example 8: (3S) -3-{[2-ethyl-4- (1-naphthyl) -4-oxobutanoyl] amino} -4-oxo-5- (2,3,5,6-tetra Fluorophenoxy) pentanoic acid (Ih)

The title compound was obtained by subjecting the compound obtained in Preparation Example 29 to the same method as in Example 5.

NMR (400 MHz, DMSO-d ₆ ) δ 8.3 (m, 1H), 8.1 (m, 1H,) 8.0 (m, 1H), 7.9 (m, 1H), 7.6-7.4 (m, 4H), 5.2 (br , 2H), 4.6-4.5 (m, 1H), 3.3 (m, 2H), 2.8 (m, 1H), 2.7-2.5 (m, 2H), 1.5 (m, 1H), 0.9-0.8 (m, 3H )

MS [M + MeOH + Na] ⁺ 588

Preparation Example 30 Dimethyl 2- (1-isoquinolinyl) -2-oxoethyl phosphonate

Methyl dimethyl phosphonate (4.84 g, 4.17 mL, 3.0 eq) is dissolved in about 100 mL of anhydrous tetrahydrofuran under nitrogen atmosphere, kept at -78 ^o C and then n-butyllithium (2.5 M in hexane, 15.6 mL) , 3.0 eq) was added. After stirring for 1 hour at -78 ^o C to -60 ^o C, 20 mL of methyl 1-isoquinolinyl carboxylate (2.44 g, 13.0 mmol, synthesized from 1-isoquinolinecarboxylic acid in the same manner as in Preparation Example 1) It was dissolved in anhydrous tetrahydrofuran and added at -60 ^o C, and stirred for 2 hours while slowly raising the temperature to-room temperature at -60 ^o C. Oxalic acid dihydrate (5.41 g, 3.3 eq) was added to the reaction mixture in 12 mL of methanol. The reaction mixture was filtered through celite, and the resulting solution was concentrated under reduced pressure, and then separated by column chromatography (50% -80% ethyl acetate / hexane) to obtain 3.59 g (99%) of a yellow solid.

NMR (400 MHz, CDCl ₃ ) δ 9.03 (d, 1H), 8.61 (d, 1H), 7.88 (m, 2H), 7.73 (m, 2H), 4.21 (d, J = 24 Hz, 2H), 3.77 & 3.75 (two s, 6H)

Preparation Example 31 Methyl 2-ethyl-4- (1-isoquinolinyl) -4-oxobutanoate (VIi)

To sodium hydride (60% dispersion in mineral oil, 649 mg, 1.1 eq, pre-washed with anhydrous tetrahydrofuran), about 100 mL of anhydrous tetrahydrofuran was added at 0 ^o C under nitrogen atmosphere, and the force obtained in Preparation Example 30 Phonate compound (4.12 g, 14.75 mmol) was added dissolved in 20 mL of anhydrous tetrahydrofuran. After stirring for about 10 minutes lithium chloride (1.25g, 2.0 eq) was added and stirred for 10 minutes at 0 ^° C. Methyl 2-oxobutylate (2.4 g, 1.2 eq) was dissolved in the reaction mixture in 20 mL of anhydrous tetrahydrofuran, added at 0 ^° C., and stirred at room temperature for 2.5 hours. The reaction was completed with saturated ammonium chloride solution and extracted twice with ethyl acetate (100 mL). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution (NaHCO ₃ , 50 mL × 2), saturated sodium chloride solution, and dried (anhydrous Na ₂ SO ₄ ) -concentrated. Separation by column chromatography (20% ethyl acetate / hexanes) gave a yellow liquid having 2.7 g (68%) of cis form.

2.7 g (10.03 mmol) of the cis isomer was dissolved in 50 mL of ethyl acetate and Pd / C (800 mg, 10%, Aldrich) was added and reacted for 2 hours using Parr Hydrogenater under 40 psi of hydrogen pressure. After filtration through celite, the solution was concentrated under reduced pressure. 1.95 g (71%) of overreduced (ketone-reduced) yellow liquid separated by column chromatography (20% ethyl acetate / hexanes) (Methyl 2-ethyl-4- (1-isoquinolinyl) -4-hydroxybutanoate) was obtained.

NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, 1H), 8.28 (d, 1H), 7.85 (d, 1H), 7.73-7.59 (m, 2H), 7.59 (d, 1H), 5.40 (m, 1H ), 3.83 (s, 3H), 3.05 (m, 1H), 2.37 (t, 1H), 1.69-1.46 (m, 3H), 0.89 (t, 3H)

Oxalyl chloride (0.51 mL, 1.6 eq) was dissolved in 30 mL of dichloromethane, and then DMSO (1.04 mL, 4.0eq) was added at −78 ^° C. and stirred for about 10 minutes. 1.0 g (3.66 mmol) of the compound was dissolved in 30 mL of dichloromethane and added slowly and stirred at -78 ^o C for 15 min. DIPEA (3.19 mL, 5.0 eq) was added to the reaction mixture, which was stirred for 10 minutes at -78 ^o C and slowly warmed to room temperature. Ethyl acetate / hexanes (100 mL) were added and the organic layer was washed with 0.5N HCl and saturated sodium chloride solution and dried (anhydrous Na ₂ SO ₄ ) -concentrated. Separation by column chromatography (25-30% ethyl acetate / hexanes) gave 900 mg (91%, yellow liquid) of the title compound. Each enantiomer was separated using a chiral OD column (Daicel Chemical Industries, 2.00 cm × 25 cm, OD00CJ-1C005, 3% i-PrOH in Hexane, 220 nm).

NMR (400 MHz, CDCl ₃ ) δ 8.89 (d, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.73-7.65 (m, 2H), 3.74 (dd, 1H ), 3.70 (s, 3H), 3.54 (dd, 1H), 3.05 (m, 1H), 1.77 (m, 2H), 0.98 (t, 3H)

Preparation Example 32: tert -Butyl 3-{[2-ethyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoate (Xi)

Carboxylic acid derivatives of isomer (160 mg, respectively) obtained by hydrolyzing the compound obtained in Preparation Example 31 0.622 mmol), a mixture of amino alcohol derivative VIIIc (130 mg, 1.05 eq), HOBt (92 mg, 1.1 eq) and DMAP (88 mg, 1.1 eq) was dissolved in THF (8 mL) and cooled to 0 ^° C. to EDC (132 mg, 1.10eq) was added and slowly stirred for one day while raising the temperature to room temperature. Extracted with ethyl acetate (30mlx2), washed with water and aqueous sodium bicarbonate solution, and washed with brine. Drying (anhydrous Na ₂ SO ₄ ) was concentrated under reduced pressure, and then purified by column chromatography (30-40% ethyl acetate / hexane) to give 249 mg (91%) of the compound. Anhydrous dichloromethane (6 mL) was added to this compound and Dess-Martin reagent (450 mg, 2.0 equivalents), the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (1 mL). The solid was removed by filtration under reduced pressure using Celite, followed by extraction with ethyl acetate (30mlx2), water, saturated aqueous sodium bicarbonate solution and then brine. Drying (anhydrous Na ₂ SO ₄ ) was concentrated under reduced pressure, and the residue was first purified by column chromatography (30-40% ethyl acetate-hexane) to obtain 192 mg (80%) of diastereomeric target product.

NMR (400 MHz, CDCl ₃ ) δ 8.88 (two d, 1H), 8.59 (m, 1H), 7.86 (m, 2H), 7.74-7.67 (m, 2H), 6.94 (two d, 1H, NH), 5.44 -5.07 (m, 2H), 4.90 (m, 1H), 3.76 (m, 1H), 3.57 (m, 1H), 3.02 (m, 1H), 2.84-2.77 (m, 2H), 1.81 (m, 1H ), 1.66 (m, 1H), 1.02 (two t, 3H)

Example 9: 3-{[2-ethyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid (Ii-a, b)

Each diastereomer mixture obtained in Preparation Example 32 was obtained in the same manner as in Example 1 to obtain the title compound.

NMR (500 MHz, DMSO-d ₆ ) δ 12.20 (br, 1H), 8.78-8.26 (m, 3H), 8.12-7.73 (m, 4H,) 5.94-4.56 (br m, 2H), 7.9 (m, 1H ), 4.37-4.32 (two m, 1H), 3.12-2.50 (m, 4H), 2.37-2.05 (m, 2H), 1.78-1.29 (m, 2H), 0.88-0.72 (m, 3H)

MS [M + H] 389

Preparation 33: ethyl ( Z ) -2-isopropyl-4- (1-isoquinolinyl) -4-oxo-2-butenoate

To sodium hydride (60% dispersion in mineral oil, 276 mg, 1.1 eq, pre-washed with anhydrous tetrahydrofuran), about 30 mL of anhydrous tetrahydrofuran was added under 0 ^o C, nitrogen atmosphere, and the force obtained in Preparation Example 30 Phonates (1.76 g, 6.27 mmol) were added dissolved in 10 mL of anhydrous tetrahydrofuran. After stirring for about 10 minutes lithium chloride (532mg, 2.0 eq) was added and stirred for 10 minutes at 0 ^o C. To the reaction mixture, ethyl 3-methyl-2-oxobutylate (994 mg, 1.1 eq) was dissolved in 15 mL of anhydrous tetrahydrofuran, added at 0 ^° C., and stirred at room temperature for one day. The reaction was completed with saturated ammonium chloride solution and extracted twice with ethyl acetate (100 mL). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution (NaHCO ₃ , 50 mL × 2), saturated sodium chloride solution, and dried (anhydrous Na ₂ SO ₄ ) -concentrated. Separation by column chromatography (20% ethyl acetate / hexanes) gave a yellow liquid having 1.7 g (91%) of cis structure.

NMR (500 MHz, CDCl ₃ ) δ 8.98 (d, 1H), 8.61 (d, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.74-7.66 (m, 2H), 7.38 (s, 1H ), 4.30 (qt, 2H), 2.84 (m, 1H), 1.29 (t, 3H), 1.16 (d, 6H)

Preparation 34 Ethyl 2-isopropyl-4- (1-isoquinolinyl) -4-oxobutanoate (VIj)

1.45 g (10.03 mmol) of the compound obtained in Preparation Example 33 was dissolved in 50 mL of ethyl acetate, and Pd / C (100 mg, 10%, Aldrich) was added thereto, using a Parr Hydrogenater under 40 psi of hydrogen pressure for 4 hours. Reacted. After filtration through celite, the solution was concentrated under reduced pressure. 1.31 g (71%) of overreduced (reduced ketone) yellow liquid (ethyl 2-isopropyl-4- (1-isoquinolinyl) -4-hydroxybutanoate) was obtained. Anhydrous dichloromethane (10 mL) was added to 400 mg of this compound and Dess-Martin reagent (900 mg, 3.0 eq), the mixture was stirred at room temperature for 1 hour, and the reaction was stopped with isopropyl alcohol (1 mL). After filtration through celite and normal treatment, the residue was purified by column chromatography (10% ethyl acetate-hexane) to obtain the desired 223 mg (56%) of the eninithiomeric mixture.

NMR (500 MHz, CDCl ₃ ) δ 8.85 (d, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.73-7.64 (m, 2H), 4.19 (m, 2H ), 3.74 (dd, 1H), 3.50 (dd, 1H), 2.99 (m, 1H), 2.16 (m, 1H), 1.26 (t, 3H), 1.04 (two d, 6H)

Preparation Example 35: tert -Butyl 5-fluoro-3-{[2-isopropyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -4-oxopentanoate (Xj)

Using the compound of Preparation 34 in place of the compound of Preparation 31 to apply the same method as Preparation 32 to obtain the title compound.

NMR (400 MHz, CDCl ₃ ) δ 8.86 (m, 1H), 8.60 (m, 1H), 7.89-7.82 (m, 2H), 7.74-7.64 (m, 2H), 6.88 (m, 1H), 5.50-5.07 (m, 2H), 4.90 (m, 1H), 3.87-3.74 (m, 1H), 3.61-3.55 (m, 1H), 3.08-2.99 (m, 1H), 2.84-2.66 (m, 2H), 2.04 (m, 1H), 1.48 & 1.46 (two s, 9H), 1.06 (m, 6H)

Example 10: 5-fluoro-3-{[2-isopropyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -4-oxopentanoic acid (Ij)

Using the compound of Preparation 35, the same procedure as in Example 1 was carried out to obtain the title compound.

NMR (500 MHz, DMSO-d ₆ ) δ 8.78-8.26 (m, 3H), 8.12-7.73 (m, 4H,) 5.94-4.56 (br m, 2H), 7.9 (m, 1H), 4.42-4.31 (two m, 1H), 3.12-2.50 (m, 4H), 2.36-2.05 (m, 2H), 2.03 (m, 1H), 0.88-0.72 (m, 6H)

MS [M + H] ⁺ 403

Experimental Example 1: Essay Method

Methods previously reported for cephaze-1 and kephaze-8, known as α ₂ β ₂ forms of cysteine proteases (Thornberry, NA et al, Nature , 1992 , 356 , 768. Thornberry, NA Methods in Enzymology , 1994 , 244 , 615. Walker, NPC et al. Cell , 1994 , 78 , 343) was obtained by the expression, purification and activation step by a modified method, and the kease phase-9 was purified by a similar method and subjected to drug efficacy evaluation. Briefly, p10 and p20 subunits (Thornberry, NA et al, Nature , 1992 , 356 , 768) were expressed in Escherichia coli and purified by nickel column and anion exchange chromatography followed by caspase-1, caspase. -8 and caspase-9 were obtained, and the caspase-1 was fluorescent substrate AcYVAD-AFC, the caspase-8 was AcDEVD-AFC, and the caspase-9 was AcLEHD-AFC, and enzyme inactivation of the inhibitors synthesized was performed. The degree was measured. In the buffer containing 50 mM HEPES (pH 7.50), 10% (w / v) sucrose, 0.1% (w / v) CHAPS, 100 mM NaCl, 1 mM EDTA, 10 mM DTT, Kephase-1 was 10 nM. The concentration of 50 uM AcYVAD-AFC, and the case phase-8 was 2.1 nM, and the 50 uM AcDEVD-AFC and the case phase-9 were enzymatically reacted with 150 uM AcLEHD-AFC at 25 ^o C at a concentration of 200 nM. After the inhibition constant K _i, K _obs values of inhibitors are to track the rate of the reaction with time in fluorescence spectrophotometer obtaining the initial rate constant (initial rate constant), K _i is in the Lineweaver Burk _Plot, K _obs is K _obs = - It was obtained from the formula ln (1-A _t / A _oo ) / t (A _t : cleavage rate (%), A _oo : maximum cleavage rate (%)) at time t. A spectra MAX GeminiXS fluorescence spectrometer manufactured by Molecular Device was used as the fluorescence spectrometer, and an excitation wavelength of 405 nm and an emission wavelength of 505 nm were used.

Intracellular efficacy evaluation of inhibitors was based on WST-1 (Francoeur AM and Assalian A., a method that reported the amount of live juke cells upon treatment with inhibitors after apoptosis of Jukta cells with Fas antibody. 1996) using Biochemica 3, 19-25) were evaluated measuring the color change. The spectra meter, Spectra MAX 340 spectrometer manufactured by Molecular Device, was used, and the absorption wavelength was 440 nm.

Experimental Example 2: Pharmacokinetic Tests in Rats

Mice (250-300 g, Korea, Biogenome) were operated under ether anesthesia to allow polyethylene tubes to be inserted into the jugular vein and carotid artery. The insert tube was pulled out of the body behind the neck to allow the rat to move freely and the end was connected with a long polyethylene tube protected by a spring. After the rats were completely awake from anesthesia in a metabolic cage, intravenous test administered a drug dissolved in a mixed solution of PEG400, EtOH, TWEEN80, phosphate buffer at a dose of 10 mg / kg into the jugular vein. For oral administration, rats were fasted 18 hours prior to drug administration. For oral experiments, drugs dissolved in PEG400, EtOH, TWEEN80, phosphate buffer were administered at a dose of 20 mg / kg using an oral zone. Blood sampling was performed at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes post-dose for control and intravenous injection, and 15, 30, 60, post-dose for oral studies. At 90, 120, 180 and 240 minutes, respectively. In addition, approximately 200 μl of blood was collected from the carotid artery with a heparin-treated syringe, followed by centrifugation to separate plasma, and then the protein was collected and analyzed by HPLC. The calibration curve was performed in the range of 0.2 to 10 μg / ml of drug. Drugs were analyzed on a Shiseido Capcell-Pak C ₁₈ reversed phase column. HPLC is a SIL-10AXL autoinjector (SIL) with Class-LC10A system control software, CBM-10A communication bus module, two LC-10AD pumps, and sample chiller -10AXL autoinjector with sample cooler), SPD-10AV UV detector (Shimadzu, Tokyo, Japan) and GLP-2050 + laser printer (LG Electronics, Seoul, Korea). Compound Ia-2 Was analyzed by an ultraviolet lamp at a wavelength of 329 nm, and the flow rate was 1 ml per minute. Acetonitrile and 20 mM ammonium acetate were used in the mobile phase in 31% and 69%, respectively. The residence time of the drug was approximately 9 minutes. IDN1965 was analyzed with an ultraviolet lamp at a wavelength of 293 nm and the flow rate was 1 ml per minute. Acetonitrile and 20 mM ammonium acetate were used in the mobile phase at 32% and 68%, respectively. The residence time of the drug was approximately 10 minutes. The data were plotted against plasma drug concentration versus time. Half-life (t _1/2 ), peak concentration (C _max ), peak concentration time (T _max ), applied to non-compartment models using the Win-Nonlin program (Scientific Consultion, USA), Pharmacokinetic parameters of AUC _inf , AUC _last , systemic clearance (CL) and volume of distribution (Vd) were calculated (see Table 2: “Pharmacokinetic Parameter Values After Intravenous and Oral Administration in Rats”).

Experimental Example 3: Therapeutic Effect of LPS-Induced Acute Hepatitis in Mice

Step 1: Preparation of Blood Sample

Female Balb / c mice (6 weeks old, Charles River Laboratory, Osaka, Japan) were bred at 12 / day shifts of 12 hours under 22- and 55% relative humidity. At this time, feed and water were supplied freely. LPS (lipopolysaccaride) and D-galactosamine were dissolved in saline, from which pyrogen was removed, at a concentration of 0.4 mg / ml and 280 mg / ml, respectively. Injection. Vehicle containing dissolved test compound (PEG400: ethanol: Tween80 = 15: 7.5: 2.5 in saline 1/5 dilution) or vehicle alone intraperitoneally after injection of LPS and D-galactosamine Injection. Eight hours after drug injection, blood samples were obtained by cardiac drawing.

Stage 2: Plasma Aminotransferase Activity Assay

Plasma ALT activity on the blood samples obtained in step 1 was measured using an ALT assay kit (Asan Pharmaceutical, Seoul, Korea) according to the manufacturer's instructions. In both experiments, administration of LPS and D-galactosamine rapidly increased plasma ALT activity and the test substance was found to inhibit this elevated enzyme activity in a dose-dependent manner. Based on these results, ED50 values were calculated for each test substance using GraphPad's Prism software (see Table 3: “ALT activity inhibited ED50 values”).

Experimental Example 4: Survival effect in acute hepatitis model by LPS

Female Balb / c mice (6 weeks old, Charles River Laboratory, Osaka, Japan) were bred at 12 / day shifts of 12 hours under 22- and 55% relative humidity. At this time, feed and water were supplied freely. LPS (lipopolysaccaride) and D-galactosamine were dissolved in saline, from which pyrogen was removed, at a concentration of 0.4 mg / ml and 280 mg / ml, respectively. Injection. Vehicle containing dissolved test compound (PEG400: ethanol: Tween80 = 15: 7.5: 2.5 in saline 1/5 dilution) or vehicle alone intraperitoneally after injection of LPS and D-galactosamine Injection. Survival was then calculated by investigating mouse survival over 72 hours (see Table 4: “Percent Survival After Acute Hepatitis Induction”).

Progressiveness

As reported previously, the experimental results of compound Ia-2 and IDN-1965 mentioned in patent US 6,200,969 B1 are compared to Table 5 below.

Inhibitory effects on kephas-8 and cells (Jurkat Cell) were more than doubled compared to IDN-1965, and treatment effects in the LPS-induced acute hepatitis model (mouse) were three times higher. Pharmacokinetic studies also show excellent values when comparing the half-life and clearance parameters for intravenous administration. The most outstanding advantages of IDN-1965 are the oral absorption rate and the survival test. In the survival test (during iv administration), all controls died and the group administered Compound Ia-2 showed an astonishing survival rate of 90%. IDN-1965 showed no effect on oral administration of ALT activity in LPS-induced acute hepatitis, but Compound Ia-2 was effective in both intraperitoneal and oral administration. In addition, the solubility is greatly improved in terms of physical properties, so that it can be easily used as an injection.

Compound Ia-2 as shown in Table 5 above Compared with IDN-1965, it shows an excellent improvement in activity and physical properties.

Claims (8)

A compound of formula (I), a pharmaceutically acceptable salt, physiologically hydrolysable ester, hydrate, solvate or stereoisomer thereof: [Formula 1] In the above formula, specific definitions for the substituents R, R ₁ , R ₂ , R ₃ , Ar, X are as follows. I) R is a simple alkyl group (-SAC) or represents cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar) or hydrogen; II) R ₁ represents -SAC, -SCAC, -Ar or -SAC-Ar, or represents the side chain residues of all natural amino acids, and in two cases where adjacent positions are stereocenters due to R ₁ All three-dimensional compounds of the compound are included, including the case where two types of compounds coexist (referring to diastereomeric mixtures), and when R ₁ is a side chain residue of amino acids and a carboxylic acid, an ester with a protecting group [-CO ₂ R ₄ , wherein R ₄ is -SAC], when substituted with sulfonamide [-CONHSO ₂ R ₅ , wherein R ₅ is -SAC], and a pharmaceutically acceptable salt thereof. And when present in the form of a pharmaceutically acceptable salt, when R ₁ is composed of bases as side chain residues of amino acids; III) R ₂ represents -SAC, -SCAC, -Ar or -SAC-Ar, or represents the side chain residues of all natural amino acids, two cases where the adjacent position becomes a stereocenter due to R ₂ All of the three-dimensional compounds of, including coexistence of two types of compounds (referring to diastereomeric mixtures), and when R ₂ is a side chain residue of an amino acid and a carboxylic acid, When [-CO ₂ R ₆ , wherein R ₆ is -SAC], when substituted with sulfonamide [-CONHSO ₂ R ₇ , wherein R ₇ is -SAC], and a pharmaceutically acceptable salt form thereof If R ₂ is composed of a base as a side chain residue of the amino acid, also includes the case in the form of a pharmaceutically acceptable salt thereof, or R _{2 -H, - (CH 2) n} OR 8, - (CH 2) n OC (= O) R 8 ( W Standing, R ₈ is -SAC, -SCAC, -Ar, -SAC- Ar: n represents a = 1, 2); IV) R ₃ represents a simple alkyl group (-SAC), cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted alkyl (-SAC-Ar) or hydrogen; V) Ar represents aromatic (-Ar); R adjacent VI) R ₁ are connected to each other _{- (CH 2) n-, -} (CH 2) nO- (CH 2) m- or _{- (CH 2) n-NHR} 9 - (CH 2) m- [ n + m <9, R ₉ = -SAC, -SCAC, Ar, -SAC-Ar, -C (= O) -SAC, -C (= O) -SCAC, -C (= O) -Ar,- C (= 0) -SAC-Ar]; can form a cyclic compound; VII) X is -CN, -CHO, -C (= 0) OR ₁₀ , -C (= 0) CH ₂ OR ₁₀ , -C (= 0) CH ₂ OC (= 0) R ₁₀ , -CH = CH -CO ₂ R ₁₀ , -CH = CH-SO ₂ R _10, wherein R ₁₀ represents -SAC, -SCAC, -Ar or -SAC-Ar, wherein -CONR ₁₁ R ₁₂ where R ₁₁ and R ₁₂ are Each independently represent -H, -SAC, -SCAC, -Ar, or -SAC-Ar; or -COCH ₂ -W; W is —N ₂ , —F, —Cl, —Br, —I, —NR ₁₃ R ₁₄ , wherein R ₁₃ and Each R ₁₄ is independently -SAC, -SCAC, -Ar, or -SAC-Ar, or can be joined together to form cyclic compounds, or -SR ₁₅ , wherein R ₁₅ is -SAC, -SCAC,- Ar or -SAC-Ar, or the following structural formulae; In the above formulas, the substituent Y is -H, -OH, -OR ₁₆ (R ₁₆ = -SAC, -SCAC), -C (= O) R ₁₇ (R ₁₇ = -H, -SAC, -SCAC),- F, -Cl, -Br, -I, -CN, -N ₃ , -CO ₂ H, -CF ₃ , -CO ₂ R ₁₈ , -C (= O) NHR ₁₈ (R ₁₈ = -SAC, -SCAC ), -C (= 0) NR ₁₉ R ₂₀ (R ₁₉ and R ₂₀ each independently represent -SAC, -SCAC, -Ar, -SAC-Ar), and R ₂₁ represents -H or -SAC. The method of claim 1, I) R represents H; II) R ₁ represents-(CH ₂ ) ₂ COOH,-(CH ₂ ) ₂ COOR (where R = -SAC) or-(CH ₂ ) ₂ CONHSO ₂ R ₂₂ , where R ₂₂ = -SAC ; III) R ₂ is H, -SAC, -Ar,-(CH ₂ ) _n O _m R wherein R = -SAC, -SCAC, -Ar or -SAC-Ar, n = 0, 1 or 2; m = 0 or 1; IV) R ₃ represents -SAC or hydrogen; V) Ar represents aromatic (-Ar); VI) X is -COCH ₂ N ₂ , -COCH ₂ F, -COCH ₂ Cl, -COCH ₂ Br, -COCH ₂ I, -COCH ₂ OAr, -COCH ₂ OCOAr or -COCH ₂ SR ₁₅ (where R ₁₅ is Each independently represent -SAC, -SCAC, -Ar, or -SAC-Ar. The compound of claim 1 wherein 3-{[4- (1,3-Dimethyl-1 H -indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid ( IA ) ; ( 3S ) -3-{[4- (1,3-dimethyl-1 H -indol-2-yl) -2-ethyl-4-oxobutanoyl] amino} -4-oxo-5- (2, 3,5,6-tetrafluorophenoxy) pentanoic acid ( lb ); ( 3S ) -5-[(2,6-dichlorobenzoyl) oxy] -3-{[4- (1,3-dimethyl-1 H -indol-2-yl) -2-ethyl-4-oxobuta Noyl] amino} -4-oxopentanoic acid ( IC ); 3-{[4- (1,3-Dimethyl-1 H -indol-2-yl) -2-isopropyl-4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid ( Id ); (3S) -5-[(2,6-dichlorobenzoyl) oxy] -3-[(2-methyl-4-oxo-4-phenylbutanoyl) amino] -4-oxopentanoic acid ( Ie ); (3S) -5- [2,6-dichlorobenzoyl] oxy] -3-[(2-isopropyl-4-oxo-4-phenylbutanoyl) amino] -4-oxopentanoic acid ( If ); (3S) -3-{[(2R) -2-isopropyl-3-methyl-4-oxo-4-phenylbutanoyl] amino} -4-oxo-5- (2,3,5,6-tetra Fluorophenoxy) pentanoic acid ( IG ); (3S) -3-{[2-ethyl-4- (1-naphthyl) -4-oxobutanoyl] amino} -4-oxo-5- (2,3,5,6-tetrafluorophenoxy ) Pentanoic acid ( Ih ); 3-{[2-ethyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -5-fluoro-4-oxopentanoic acid ( Ii ); And Selected from the group consisting of 5-fluoro-3-{[2-isopropyl-4- (1-isoquinolinyl) -4-oxobutanoyl] amino} -4-oxopentanoic acid ( Ij ) Phosphorus compounds. Characterized in that it contains a compound as defined in claim 1, a pharmaceutically acceptable salt thereof, a physiologically hydrolysable ester, a hydrate, a solvate or a stereoisomer thereof as an active substance together with a pharmaceutically acceptable carrier. A case phase inhibitor composition. Characterized in that it contains a compound as defined in claim 1, a pharmaceutically acceptable salt thereof, a physiologically hydrolysable ester, a hydrate, a solvate or a stereoisomer thereof as an active substance together with a pharmaceutically acceptable carrier. Anti-inflammatory and apoptosis preventing composition. Alzheimer's disease, stroke, AIDS brain injury, diabetes, gastric ulcer, hepatitis virus brain injury, hepatitis virus liver disease, acute hepatitis, human sudden liver failure, sepsis, organ transplant rejection, rheumatoid arthritis, or ischemic heart disease Activating the compound as defined in claim 1, a pharmaceutically acceptable salt thereof, physiologically hydrolysable ester, hydrate, solvate or stereoisomer thereof, together with a pharmaceutically acceptable carrier for treating or preventing A pharmaceutical composition, characterized in that it contains as a substance. The composition of claim 6 for treating or preventing acute hepatitis. 8. A composition according to claim 7, prepared for oral administration, in the form of an injection, or a patch.