JP2002539080A - Compounds that inhibit leukocyte adhesion mediated by VLA-4 - Google Patents

Abstract

  (57) [Summary] Disclosed are compounds that bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion, particularly VLA-4 mediated leukocyte adhesion. Such compounds are useful in asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis, and myocardial ischemia in mammalian patients (eg, humans). It is useful in treating inflammatory diseases such as The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to compounds that inhibit leukocyte adhesion, and in particular, VLA-4 mediated leukocyte adhesion.

REFERENCES The following publications, patents and patent applications are cited herein as superscripts:

[0003]

[Table 1]

[0004]

[0005] All of the above publications, patents and patent applications are, to the extent possible, to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference in its entirety. Which is incorporated herein by reference in its entirety.

[0006] (art) was first identified by Hemler and Takada ^1, VLA-4 (also referred to as α ₄ β ₁ integrin and CD49d / CD29) is a β1 integrin member of a family of cell surface receptors, of these Each contains two subunit α and β chains. VLA-4 contains an α4 chain and a β1 chain. There are at least nine β1 integrins, all share the same β1 chain and each have a separate α chain. All nine of these receptors bind to different components of various cell matrix molecules, such as fibronectin, laminin and collagen. For example, VLA-4 is
Binds to fibronectin. VLA-4 also binds to non-matrix molecules expressed by endothelial cells and other cells. These non-matrix molecules include VCAM-1, which is expressed on human umbilical vein endothelial cells activated by cytokines in culture. ² different epitopes of VLA-4, play a fibronectin and VCAM-1 binding activities and each activity is shown to be inhibited independently.

[0007] Cell-cell adhesion mediated by VLA-4 and other cell surface receptors has been implicated in a number of inflammatory responses. At the site of injury or other inflammatory stimuli,
Activated vascular endothelial cells express molecules that are adhesive to leukocytes. The mechanism by which leukocytes adhere to endothelial cells involves, in part, the recognition of cell surface receptors on leukocytes and the binding of this receptor to the corresponding cell surface molecule on endothelial cells. Once bound, the leukocytes move across the vessel wall into the site of injury and release chemical mediators to fight infection. For a review of immune system adhesion receptors see, for example, Springer ³ and Osborn ⁴ .

[0008] Inflammatory encephalopathy (eg, experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (
MS) and meningitis) are examples of central nervous system disorders that result in destruction of otherwise healthy brain tissue as a result of the endothelial / leukocyte adhesion mechanism. Large numbers of leukocytes migrate across the blood-brain barrier (BBB) in subjects with these inflammatory diseases. Leukocytes release mediators of toxicity, which cause extensive tissue damage, resulting in defective nerve conduction and paralysis.

[0009] In other organ systems, tissue damage also occurs via an adhesive mechanism, which results in the migration or activation of leukocytes. For example, it has been shown that the initial injury after myocardial ischemia to heart tissue can be further exacerbated by leukocytes entering the injured tissue, causing even more injury (Vedder et al. ⁵ ). Other inflammatory conditions mediated by adhesion mechanisms include, for example, asthma ^6-8 , Alzheimer's disease, atherosclerosis ^9-10 , AIDS dementia ¹¹ , diabetes ^12-14 (including acute juvenile onset diabetes) , Inflammatory bowel disease ¹⁵ (including ulcerative colitis and Crohn's disease), multiple sclerosis ^16-17 , rheumatoid arthritis ^18-21 , tissue transplantation ²² , tumor metastasis ^23-28 , meningitis,
Encephalitis, seizures and other cerebral trauma, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury such as those occurring in adult respiratory distress syndrome.

In view of the above, in a biological sample containing VLA-4, for example, VL
Assays for determining VLA-4 levels are useful for diagnosing conditions mediated by A-4. Furthermore, despite these advantages in understanding leukocyte adhesion, the art has recently begun to address the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions.29 ^{, 30} . The present invention
Addresses these and other needs.

SUMMARY OF THE INVENTION The present invention provides compounds that bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample, and for VLA-4
-4 can be used in pharmaceutical compositions that inhibit cell adhesion mediated by, for example, VCAM-1 to VLA-4. The compound of the present invention comprises about 1
It has a binding affinity for VLA-4, represented by an IC _{50 of} 5 μM or less (as measured as described in Example A below). This compound has the formula I
:

[0012]

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And R ¹ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, R ¹ and R ² are selected from the group consisting of substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ¹ and R ² together with the nitrogen atom attached to R ² and the SO ₂ group can form a group or a substituted heterocyclic group; R ³ is hydrogen, alkyl, substituted alkyl, A cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic is selected from the group consisting of substituted heterocyclic, and R ² is R ¹ and heterocycles If not forming a Shikimoto, R ² and R ³ form a heterocyclic or substituted heterocyclic group together with the carbon atom bonded to the nitrogen atom and R ³ binds to R ² obtained; R ⁴ is Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and When R ³ does not form a heterocyclic or substituted heterocyclic group with R ² ,
R ³ and R ⁴ together with the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R ⁵ is isopropyl, —CH ₂ — Selected from the group consisting of W and = CH-W, wherein W is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, Aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
Selected from the group consisting of carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxy heterocyclic, carboxy-substituted heterocyclic, and hydroxyl; However, R ⁵ is = CH-W
(H) is omitted from this formula and W is not hydroxyl; and Q is the following (i)-(v): (i)

[0014]

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Wherein X is selected from the group consisting of oxygen, sulfur, and NH; (ii)

[0016]

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[0017] Here, R ⁷ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ⁸ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁷ and R ^8, R Together with the nitrogen atom bonded to ⁷ and the carbon bonded to R ⁸ may form a heterocyclic or substituted heterocyclic ring; (iii)

[0018]

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[0019] Here, R ⁹ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ¹⁰ is hydrogen, or is selected from alkyl and the group consisting of substituted alkyl; is or R ⁹ and R ^10, R nitrogen atom bonded to ^9, carbon atoms and -C bonded to R ¹⁰ (X) - with the group to form a heterocyclic or substituted heterocyclic group obtained; X is comprised of oxygen, sulfur and NH Selected from the group; (iv)

[0020]

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Here, R ¹¹ and R ¹² are bonded to a nitrogen atom bonded to R ¹¹ and R ¹² >
Together with the C = N- group form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and (v)

[0022]

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Wherein R ¹³ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; X is oxygen, sulfur, and Selected from the group consisting of NH.

In another embodiment, the compounds of the invention may also be provided as prodrugs that convert (eg, hydrolyze, metabolize, etc.) in vivo to the compounds of formula I above. In a preferred example of such an embodiment, the carboxylic acid of the compound of formula I is modified to a group that converts to the carboxylic acid (including its salts) in vivo. In a particularly preferred embodiment, such a prodrug has the formula IA:

[0025]

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And pharmaceutically acceptable salts thereof, wherein R ¹ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, R ² is selected from the group consisting of aryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ¹ and R ² together with the nitrogen atom attached to R ² and the SO ₂ group are a heterocyclic group or substituted heterocyclic group to form obtained; R ³ is hydrogen, alkyl, substituted alkyl, consequent Alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic is selected from the group consisting of substituted heterocyclic, and R ² is R ¹ and a heterocyclic If it does not form a group, R ² and R ³ form a heterocyclic or substituted heterocyclic group together with the carbon atom bonded to the nitrogen atom and R ³ binds to R ² obtained; R ⁴ is, Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ³ does not form a heterocyclic or substituted heterocyclic group with R ² ,
R ³ and R ⁴ together with the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R ⁵ is isopropyl, —CH ₂ — Selected from the group consisting of W and = CH-W, wherein W is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, Aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
Selected from the group consisting of carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxy heterocyclic, carboxy-substituted heterocyclic, and hydroxyl; However, R ⁵ is = CH-W
Where (H) is excluded from this formula and W is not hydroxyl; and R ⁶ is amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy ,
Substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, -NHOY (wherein, Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl), and _{-NH (CH 2) p COOY '} ( here , Y ′ is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and p is an integer from 1 to 8); and Q is (i) to (v): (I)

[0027]

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Wherein X is selected from the group consisting of oxygen, sulfur, and NH; (ii)

[0029]

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[0030] Here, R ⁷ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ⁸ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁷ and R ^8, R Together with the nitrogen atom bonded to ⁷ and the carbon bonded to R ⁸ may form a heterocyclic or substituted heterocyclic ring; (iii)

[0031]

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[0032] Here, R ⁹ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ¹⁰ is hydrogen, or is selected from alkyl and the group consisting of substituted alkyl; is or R ⁹ and R ^10, R nitrogen atom bonded to ^9, carbon atoms and -C bonded to R ¹⁰ (X) - with the group to form a heterocyclic or substituted heterocyclic group obtained; X is comprised of oxygen, sulfur and NH Selected from the group; (iv)

[0033]

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Here, R ¹¹ and R ¹² are bonded to a nitrogen atom bonded to R ¹¹ and R ¹² >
Together with the C = N- group form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and (v)

[0035]

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Wherein R ¹³ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; X is oxygen, sulfur, and Selected from the group consisting of NH.

Preferably, in the compounds of formulas I and IA above, R¹Is alkyl, substituted
Alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl
And substituted heteroaryl. Still more preferably, R ¹ Is methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl,
4-methylphenyl, 4-t-butylphenyl, 2,4,6-trimethylphenyl
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2
, 4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluoro
Phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3
, 4-Dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluoro
Rophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl
, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butoxyf
Phenyl, 4- (3'-dimethylamino-n-propoxy) phenyl, 2-carbo
Xyphenyl, 2- (methoxycarbonyl) phenyl, 4- (H_TwoNC (O)-
) Phenyl, 4- (H_TwoNC (S)-) phenyl, 4-cyanophenyl, 4-to
Trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3,5-di (
(Trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4
− (CH_ThreeC (O) NH-) phenyl, 4- (PhNHC (O) NH-) phenyl
4-Amidinophenyl, 4-methylamidinophenyl, 4- (CH_ThreeSC (
= NH)-) phenyl, 4-chloro-3- (H_TwoNS (O)_Two-) Phenyl, 1-
Naphthyl, 2-naphthyl, pyridin-2-yl, pyridin-3-yl, pyrimidi
2-yl, quinolin-8-yl, 2- (trifluoroacetyl) -1,2,2
3,4-tetrahydroisoquinolin-7-yl, morpholin-4-yl, 2-thio
Enyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N
-Methylimidazol-4-yl, 1-N-methylpyrazol-3-yl, 1-
N-methylpyrazol-4-yl, 1-N-butylpyrazol-4-yl, 1-
N-methyl-3-methyl-5-chloropyrazol-4-yl), 1-N-methyl
-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-meth
It is selected from the group consisting of tyl-1,3,4-thiadiazol-2-yl.

Preferably, in the compounds of formulas I and IA above, R ² is hydrogen, methyl,
It is a (CH _{2) 2} -φ - phenyl, benzyl, - (CH _{2) 2} -2- thienyl, and.

In one embodiment, R ¹ and R ² are joined together with a nitrogen atom attached to R ² and a SO ₂ group attached to R ¹ to form a heterocyclic or substituted heterocyclic group I do. Preferred heterocyclic groups and substituted heterocyclic groups include groups having 5 to 7 ring atoms having 2 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the ring. Wherein the ring is optionally fused to another ring such as phenyl or cyclohexyl, and is selected from the group consisting of nitrogen, oxygen and sulfur.
Provided is a fused ring heterocycle of 10 to 14 ring atoms having 4 heteroatoms in the ring. Particularly preferred R ¹ / R ² linking groups include, for example, benzisothiazolonyl (
Saccharin-2-yl), N-2,10-camphorsulfamyl (camph)
orsultamyl) and 1,1-dioxo-2,3-dihydro-3,3-
Dimethyl-1,2-benzisothiazol-2-yl.

In one preferred embodiment, R ² and R ³ together with a nitrogen atom attached to the R ² substituent and a carbon attached to the R ³ substituent, comprise nitrogen, oxygen and sulfur in the ring. To form a heterocyclic or substituted heterocyclic group of 4 to 6 ring atoms having 1 to 2 heteroatoms selected from the group consisting of, optionally, fluoro, methyl, hydroxy , oxo (= O), amino, phenyl, thiophenyl, _{thiobenzyl, O-, CH 3 S (O} ) 2 ( thiomorpholin-4-yl) C (O) - made and CH ₃ S (O) ₂ from O- Selected from the group consisting of nitrogen, oxygen and sulfur in the ring, substituted with one or two substituents selected from the group or fused to another ring such as a phenyl ring or a cycloalkyl ring. With 1 to 2 heteroatoms It may provide 10 to 14 pieces of fused heterocyclic ring atoms. Such heterocyclic rings include azetidinyl (eg, L-azetidinyl), thiazolidinyl (eg, L-thiazolidinyl), piperidinyl (eg, L-piperidinyl), piperazinyl (eg, L-piperazinyl), dihydroindolyl ( For example, L-2,
3-dihydroindol-2-yl), tetrahydroquinolinyl (for example, L-
1,2,3,4-tetrahydroquinolin-2-yl), thiomorpholinyl (eg, L-thiomorpholin-3-yl), pyrrolidinyl (eg, L-pyrrolidinyl), 4-hydroxypyrrolidinyl (eg, 4- α- (or β-) hydroxy-L-pyrrolidinyl), 4-oxopyrrolidinyl (for example, 4-oxo-L-
Pyrrolidinyl), 4-fluoropyrrolidinyl (eg, 4-α- (or β-)
Fluoro-L-pyrrolidinyl), 4,4-difluoropyrrolidinyl (for example, 4
, 4-Difluoro-L-pyrrolidinyl), 4- (thiomorpholin-4-yl C (
O) O-) pyrrolidinyl (e.g., 4-alpha-(or beta -) - (thiomorpholin-4-yl C (O) O -) - L- _{pyrrolidinyl), 4- (CH 3 S (} O) 2 O −)
Pyrrolidinyl (for example, 4-α- (or β-) (CH ₃ S (O) ₂ O-)-L-
Pyrrolidinyl), 3-phenylpyrrolidinyl (for example, 3-α- (or β-)
Phenyl-L-pyrrolidinyl), 3-thiophenylpyrrolidinyl (for example, 3-
α- (or β-) thiophenyl-L-pyrrolidinyl), 4-aminopyrrolidinyl (eg, 4-α- (or β-) amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (eg, 3- substituted pyrrolidinyls such as α- (or β-) methoxy-L-pyrrolidinyl), 4,4-dimethylpyrrolidinyl, 4-N-Cbz
- piperazinyl and _{4- (CH 3 S (O)} 2 -) substituted piperazinyl such as piperazinyl, 5,5-dimethyl thiazolidine (Dimethylthiazoli
substituted thiazolidinyl such as ndin) -4-yl, 1,1-dioxo-thiazolidinyl (eg, L-1,1-dioxo-thiazolidine-2-yl), L-1
Substituted 1,1, such as, 1,1-dioxo-5,5-dimethylthiazolidin-2-yl
-Dioxo-thiazolidinyl, 1,1-dioxothiomorpholinyl (for example, L
-1,1-dioxo-thiomorpholin-3-yl) and the like.

Preferably, in the compounds of formulas I and IA above, R ³ is hydrogen, methyl,
Phenyl, benzyl, _{diphenylmethyl, -CH 2 CH 2 -COOH, -CH} 2 -
Butyl, t- butyl, all isomers arising by substitution with -CH ₂ O-benzyl and hydroxymethyl - COOH, 2-amidoethyl, iso. Further, in another preferred embodiment, R ³ and R ² may form a heterocyclic or substituted heterocyclic group with the nitrogen atom bonded to R ² .

Preferably, in the compounds of formulas I and IA above, R ⁴ is hydrogen, methyl,
Selected from the group consisting of ethyl and phenyl, wherein R ³ and R ⁴ are bonded together with the carbon atom to which they are attached, to a cycloalkyl group of 3 to 6 carbon atoms or 3 to 8 rings Forming a heterocyclic group of atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Q is preferably —C (O) N (O) —, —CH ₂ NH—, —CH (OH)
C (O) NH-, -NHC (O) NH- or tetrazole-1,5-diyl.

R ⁵ is preferably selected from all possible isomers resulting from substitution with the following groups: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl , 4-benzyloxybenzyl, 4- [φ-CH (CH 3) O-] benzyl, 4- [φ-CH (COOH ) O-] _{benzyl, 4- [BocNHCH 2 C (O} ) NH-] benzyl, _{4-chlorobenzyl, 4- [NH 2 CH 2 C} (O) NH-] benzyl, _{4-carboxybenzyl, 4- [CbzNHCH 2 CH 2 NH-} ] benzyl, 3-hydroxy -4- (φ-OC (O ) NH-) _{benzyl, 4- [HOOCCH 2 CH 2 C} (O) NH-] benzyl, benzyl, 4- [2'-carboxy phenoxy -] benzyl, 4- [phi-C ( ) NH-] benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3,5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxyphenyl-] benzyl, φ -CH ₂ CH ₂ -, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] - benzyl, 4 - [(1'-cyclopropylpiperidin-4'-yl) C (O) NH-] benzyl, 4 - [- NHC (O ) CH 2 NHBoc] benzyl, 4-carboxy-benzyl, 4-hydroxy-3-nitrobenzyl, 4 - [- NHC (O ) CH (CH 3) NHBoc] benzyl, 4- [ _{-NHC (O) CH (CH 2} φ) NHBoc] benzyl, isobutyl, _{methyl, 4- [CH 3 C (O} ) NH-] benzyl, -CH ₂ - (3 Indolyl), n-butyl, t- butyl _{-OC (O) CH 2 -,} t- butyl _{-OC (O) CH 2 CH 2} -, H 2 NC (O) CH 2 -, H 2 NC (O) CH _{2 CH 2 -, BocNH- (CH} 2) 4 -, t- butyl _{-OC (O) - (CH 2} ) 2 -, HOOCCH 2 -, HOOC (CH 2) 2 -, H 2 N (CH 2) 4 -, isopropyl, (1-naphthyl) -CH ₂ -, (2-naphthyl) -CH ₂ -, _{(2-thiophenyl) -CH 2 -, (φ-} CH 2 -OC (O) NH- (CH 2) ₄ -, cyclohexyl -CH ₂ -, benzyloxy _{-CH 2 -, HOCH 2 -,} 5- (3-N- benzyl) imidazolyl -CH ₂ -, 2-pyridyl -CH ₂ -, 3- pyridyl -CH ₂ - , 4-pyridyl _{-CH 2 -, 5- (3-} N- methyl) imidazolyl CH ₂ -, N-Benjirupiperido-4-yl -CH ₂ -, N-Boc- piperidin-4-yl -CH ₂ -, N- (phenyl - carbonyl) piperidin-4-yl -CH ₂ -, H ₃ CSCH ₂ CH ₂ -, 1-N- benzyl-imidazol-4-yl -CH ₂ -, iso - propyl _{-C (O) NH- (CH 2} ) 4 -, iso - butyl -C (O) NH- (CH ₂ ) ₄ -, phenyl _{-C (O) NH- (CH 2} ) 4 -, benzyl _{-C (O) NH- (CH 2} ) 4 -, allyl _{-C (O) NH- (CH 2} ) 4 -, 4 - (3-N-methylimidazolyl) -CH ₂ -, _{4-imidazolyl, 4 - [(CH 3)} 2 NCH 2 CH 2 CH 2 -O-] benzyl, 4 - [(benzyl) ₂ N -] - benzyl , 4-aminobenzyl, allyloxy _{-C (O) NH (CH 2} ) 4 , Allyloxy _{-C (O) NH (CH 2} ) 3 -, allyloxy _{-C (O) NH (CH 2} ) 2 -, NH 2 C (O) CH 2 -, φ-CH =, 2- pyridyl -C ( _{O) NH- (CH 2) 4} -, 4- methylpyrid-3-yl _{-C (O) NH- (CH 2} ) 4 -, 3- methylthien-2-yl _{-C (O) NH- (CH 2} ) ₄ -, 2-pyrrolyl _{-C (O) NH- (CH 2} ) 4 -, 2- furanyl _{-C (O) NH- (CH 2} ) 4 -, 4- methylphenyl -SO ₂ -N (CH _{3) CH 2 C (O) NH (} CH 2) 4 -, 4- [ cyclopentyl acetylene Les sulfonyl] - benzyl, 4 - [- NHC (O ) - (N-Boc) - pyrrolidin-2-yl)] - benzyl - , 1-N-methyl-imidazol-4-yl -CH ₂ -, 1-N- methyl-imidazol-5-yl -CH ₂ -, imidazol-5-yl -CH ₂ -, 6- methylpyrid-3-yl _{-C (O) NH- (CH 2} ) 4 -, 4- [2'- carboxymethyl phenyl] - benzyl, 4- [ —NHC (O) NHCH ₂ CH ₂ CH ₂ —φ] -benzyl, 4-[— NHC (O) NHCH ₂ CH ₂ —φ] -benzyl, —CH ₂ C (O) NH (CH ₂ ) ₄ φ, 4- [φ (CH ₂ ) ₄ O-]-benzyl, 4-[-C≡C-φ-4′φ] -benzyl, 4-[-C≡C-CH ₂ -OS (O) ₂ -4'-CH ₃ -φ] - benzyl, 4 - [- C≡C-CH 2 NHC (O) NH 2] - benzyl, 4 - [- C≡C-CH 2 -O-4'-COOCH 2 CH ₃ -.phi] - benzyl, 4 - [- C≡C-CH (NH 2) - cyclohexyl] - _{benzyl, - (CH 2) 4 NHC} (O) CH 2 -3- _{Ndoriru, - (CH 2) 4 NHC} (O) CH 2 CH 2 -3- _{indolyl, - (CH 2) 4 NHC} (O) -3- (5- _{methoxy-indolyl), - (CH 2) 4} NHC ( O) -3- (1-methylindolyl),-(CH ₂ ) ₄ NHC (O) -4-(-SO ₂ (CH ₃ ) -φ),-(CH ₂ ) ₄ NHC (O) -4 _{- (C (O) CH 3} ) - _{phenyl, - (CH 2) 4 NHC} (O) -4- _{fluorophenyl, - (CH 2) 4 NHC} (O) CH 2 O-4- fluorophenyl, 4- [ -C≡C- (2-pyridyl)] benzyl, 4-[— C≡C—CH ₂ —O-phenyl] benzyl, 4-[— C≡C—CH ₂ OCH ₃ ] benzyl, 4-[— C {C- (3-hydroxyphenyl)] benzyl, 4-[— C≡C—CH ₂ —O-4 ′-(— C (O) OC ₂ H ₅ ) Phenyl] benzyl, 4-[— C≡C—CH ₂ CH (C (O) OCH ₃ ) ₂ ] benzyl, 4-[— C≡C—CH ₂ NH— (4,5-dihydro-4-oxo-) 5-phenyl-oxazol-2-yl), 3-aminobenzyl, 4-[— C≡C—CH ₂ CH (NHC (O) CH ₃ ) C (O) OH] -benzyl, —CH ₂ C (O _{) NHCH (CH 3) φ,} -CH 2 C (O) NHCH 2 - (4- _{dimethylamino) -φ, -CH 2 C (O} ) NHCH 2 -4- nitrophenyl, -CH ₂ CH ₂ C (O _{) N (CH 3) CH 2} -φ, -CH 2 CH 2 C (O) NHCH 2 CH 2 - (N- methyl) _{-2-pyrrolyl, -CH 2 CH 2 C (O} ) NHCH 2 CH 2 CH 2 _{CH 3, -CH 2 CH 2 C} (O) NHCH 2 CH 2 -3- _{indolyl, -CH 2 C (O) N} ( H ₃₎ CH _{2 phenyl, -CH 2 C (O) NH} (CH 2) 2 - (N- methyl) _{-2-pyrrolyl, -CH 2 C (O) NHCH} 2 CH 2 CH 2 CH 3, -CH 2 _{C (O) NHCH 2 CH 2} -3- _{indolyl, - (CH 2) 2 C} (O) NHCH (CH 3) φ, - (CH 2) 2 C (O) NHCH 2 -4- dimethylaminophenyl, - _{(CH 2) 2 C (O} ) NHCH 2 -4- _{nitrophenyl, -CH 2 C (O) NH} -4 - [- NHC (O) CH 3 - _{phenyl], -CH 2 C (O)} NH-4 - _{pyridyl, -CH 2 C (O) NH} -4- [ _{dimethylaminophenyl], -CH 2 C (O)} NH-3- _{methoxyphenyl, -CH 2 CH 2 C (O} ) NH-4- chlorophenyl, - _{CH 2 CH 2 C (O)} NH-2- _{pyridyl, -CH 2 CH 2 C (O} ) NH-4 - _{methoxyphenyl, -CH 2 CH 2 C (O} ) NH-3- _{pyridyl, 4 - [(CH 3)} 2 NCH 2 CH 2 O-] _{benzyl, - (CH 2) 3 NHC} (NH) NH-SO 2 _{4-methylphenyl, 4 - [(CH 3)} 2 NCH 2 CH 2 O-] _{benzyl, - (CH 2) 4 NHC} (O) NHCH 2 CH 3, - (CH 2) 4 NHC (O) NH- _{phenyl, - (CH 2) 4 NHC} (O) NH-4- methoxyphenyl, 4- [4'-pyridyl -C (O) NH-] benzyl, 4- [3'-pyridyl -C (O) NH- ] benzyl, 4 - [- NHC (O ) NH-3'- methylphenyl] benzyl, 4 - [- NHC (O ) CH 2 NHC (O) NH-3'- methylphenyl] benzyl, 4 - [- NHC (O)-(2 ', 3'-dihydroindol-2-yl)] benzyl 4 - [- NHC (O) - (2 ', 3'- dihydro -N-Boc-indole -
2-yl)] benzyl, p-[— OCH ₂ CH ₂ -1 ′-(4′-pyrimidinyl) -piperazinyl] benzyl, 4-[— OCH ₂ CH ₂ — (1′-piperidinyl)] benzyl, 4- [-OCH ₂ CH ₂ - (1'- pyrrolidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 - (1'- piperidinyl)] benzyl -, -CH ₂ -3- (1,2,4- _{triazolyl), 4 - [- OCH 2} CH 2 CH 2 -4- (3'- chlorophenyl) - piperazine -
1-yl] benzyl, 4-[— OCH ₂ CH ₂ N (φ) CH ₂ CH ₃ ] benzyl, 4-[— OCH ₂ -3 ′-(N-Boc) -piperidinyl] benzyl, 4- [di- n- pentylamino] benzyl, 4- [n- pentylamino] benzyl, 4- [di - iso - propylamino -CH ₂ CH ₂ O-] _{benzyl, 4 - [- OCH 2 CH} 2 - (n- morpholinyl) ] benzyl, 4 - [- O- (3 '- (N-Boc) - piperidinyl] _{benzyl, 4 - [- OCH 2 CH} (NHBoc) CH 2 cyclohexyl] _{benzyl, p- [OCH 2 CH 2 -} (N- piperidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 - (4-m- chlorophenyl) - piperazine -1
- yl] _{benzyl, 4 - [- OCH 2 CH} 2 - (N- homopiperidinyl)] benzyl, 4 - [- NHC (O ) -3 '- (N-Boc) - piperidinyl] benzyl, 4 - [- OCH ₂ CH ₂ N (benzyl) _2] benzyl, -CH _{2-2-thiazolyl, 3-hydroxybenzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) 2] benzyl, 4 - [- NHC (S ) NHCH ₂ CH ₂ - (N- morpholino)] _{benzyl, 4 - [- OCH 2 CH} 2 N (C 2 H 5) 2] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (C 2 H 5) 2 ] _{benzyl, 4- [CH 3 (CH 2} ) 4 NH-] benzyl, 4- [N-n- butyl, N-n-pentylamino -] benzyl, 4 - [- NHC (O ) -4'- piperidinyl ] Benzyl, 4-[-NHC (O) CH (NHBo ) (CH _{2) 4} NHCbz] benzyl, 4 - [- NHC (O ) - (1 ', 2', 3 ', 4'- tetrahydro -N-Bo
c- isoquinolin-1'-yl] _{benzyl, p - [- OCH 2 CH} 2 CH 2 -1 '- (4'- methyl) - piperazinyl] _{benzyl, - (CH 2) 4 NH} -Boc, 3 - [- _{OCH 2 CH 2 CH 2 N (} CH 3) 2] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) 2] _{benzyl, 3 - [- OCH 2 CH} 2 - (1'- pyrrolidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) benzyl] benzyl, 4 - [- NHC (S ) NHCH 2 CH 2 CH 2 - (N- morpholino)] benzyl, 4 - [- OCH ₂ CH ₂ - (N-morpholino)] _{benzyl, 4 - [- NHCH 2 -} (4'- chlorophenyl)] benzyl, 4 - [- NHC (O ) NH- (4'- cyanophenyl)] benzyl, 4- [ -OCH ₂ COOH] benzyl, 4 - [- OC ₂ COOH-t-butyl] benzyl, 4 - [- NHC (O ) -5'- fluoro-indol-2-yl] benzyl, 4 - [- NHC (S ) NH (CH 2) 2 -1- piperidinyl] benzyl , 4 - [- N (SO 2 CH 3) (CH 2) 3 -N (CH 3) 2] benzyl, 4 - [- NHC (O ) CH 2 CH (C (O) OCH 2 φ) -NHCbz] benzyl, 4 - [- NHS (O ) 2 CF 3] benzyl, 3 - [- O- (N- methylpiperidin-4'-yl] benzyl, 4 - [- C (= NH) NH 2] benzyl, 4 - [NHSO ₂ -CH ₂ Cl] benzyl, 4 - [- NHC (O ) - (1 ', 2', 3 ', 4'- tetrahydroisoquinolin-2'-yl] benzyl, 4 - [- NHC (S ) NH (CH _{2) 3} -N- morpholino] benzyl, 4 - [- NHC (O ) C _{H (CH 2 CH 2 CH 2} CH 2 NH 2) NHBoc] benzyl, 4 - [- C (O ) NH 2] benzyl, 4 - [- NHC (O ) NH-3'- methoxyphenyl] benzyl, 4- [-OCH ₂ CH ₂ - indol-3'-yl] _{benzyl, 4 - [- OCH 2 C} (O) NH- benzyl] _{benzyl, 4 - [- OCH 2 C} (O) O- benzyl] benzyl, 4- _{[-OCH 2 C (O) OH} ] _{benzyl, 4 - [- OCH 2 -2} '- (4', 5'- dihydro) imidazolyl] _{benzyl, -CH 2 C (O) NHCH} 2 - (4- dimethylamino ) _{phenyl, -CH 2 C (O) NHCH} 2 - (4- dimethylamino) phenyl, 4 - [- NHC (O ) -L-2'- pyrrolidinyl -N-SO _{2-4'-methylphenyl]} benzyl, 4 - [- NHC (O) NHCH 2 CH 2 C _3] benzyl, 4- [aminobenzyl] _{benzyl, 4 - [- OCH 2 CH} 2 -1- (4- hydroxy-4- (3-methoxy-pyrrol-2-yl) - piperazinyl] benzyl, 4 - [- O -(N-methylpiperidin-4'-yl)] benzyl, 3-methoxybenzyl, 4-[-NHC (O) -piperidin-3'-yl] benzyl, 4-[-NHC (O) -pyridine-2 '- yl] _{benzyl, 4 - [- NHCH 2 -} (4'- chlorophenyl)] benzyl, 4 - [- NHC (O ) - (N- (4'-CH 3 -φ-SO 2) -L- pyrrolidine 2'-yl)] benzyl, 4 - [- NHC (O ) NHCH 2 CH 2 -φ] _{benzyl, 4 - [- OCH 2 C} (O) NH 2] _{benzyl, 4 - [- OCH 2 C} (O ) NH-t-butyl] benzyl, 4 - [- OCH ₂ C _2-1- (4-hydroxy-4-phenyl) - piperidinyl] _{benzyl, 4 - [- NHSO 2 -CH} = CH 2] _{benzyl, 4 - [- NHSO 2 -CH} 2 CH 2 Cl] benzyl, -CH _{2 C (O) NHCH 2 CH 2} N (CH 3) 2, 4 - [(1'-Cbz- piperidin-4'-yl) C (O) NH-] benzyl, 4 - [(1'-Boc- piperidine -4'-yl) C (O) NH-] benzyl, 4-[(2'-bromophenyl) C (O) NH-] benzyl, 4-[-NHC (O) -pyridin-4'-yl] benzyl, 4 - [(4 '- (CH 3) 2 NC (O) O-) phenyl) -C (O) NH-] benzyl, 4 - [- NHC (O ) -1'- methylpiperidine-4' -Yl-] benzyl, 4- (dimethylamino) benzyl, 4-[-NHC (O)-(1 ' N-Boc) - piperidin-2'-yl] benzyl, 3 - [- NHC (O ) - pyridin-4'-yl] benzyl, 4 - [(tert- butyl -O (O) CCH ₂ -O- benzyl ) -NH-] _{benzyl, [BocNHCH 2 C (O)} NH-] butyl, 4-benzyl benzyl, _{2-hydroxyethyl, 4 - [(Et) 2} NCH 2 CH 2 CH 2 NHC (S) NH-] benzyl 4-[(1'-Boc-4'-hydroxypyrrolidin-2'-yl) C (O)
NH-] _{benzyl, 4- [φCH 2 CH 2 CH} 2 NHC (S) NH-] benzyl, 4 - [(perhydro-indoline-2'-yl) C (O) NH-] benzyl, 2- [4- Hydroxy-4- (3-methoxythien-2-yl) piperidine-
1-yl] ethyl, 4-[(1′-Boc-perhydroindoline-2′-yl) -C (O) NH
-] Benzyl, 4-[(N-3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl, 4-[(N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2] .2] octan-2-yl) ethyl-
O-] benzyl, 4-[(4'-hydroxypyrrolidin-2'-yl) C (O) NH-] benzyl, 4- (φNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl 4- (φCH ₂ NHC (S) NH) benzyl, 3-[(1′-Boc-piperidin-2′-yl) C (O) NH—] benzyl 3- [piperidin-2′-yl-C (O ) NH-] benzyl, 4-[(3'-Boc-thiazolidine-4'-yl) C (O) NH-] benzyl, 4- (pyridin-3'-yl-NHC (S) NH) benzyl, 4 _{- (CH 3 -NHC (S)} NH) _{benzyl, 4- (H 2 NCH 2 CH} 2 CH 2 C (O) NH) _{benzyl, 4- (BocHNCH 2 CH 2 CH} 2 C (O) NH) benzyl, 4 - (pyridin-4'-yl -CH ₂ NH) benzyl, 4- [ N, N-di (4-N, N, - dimethylamino) benzyl) amino] benzyl, 4 - [(1-Cbz- piperidin-4-yl) C (O) NH-] butyl, 4- [φCH _{2 OCH 2 (BocHN) CHC (O} ) NH] benzyl, 4 - [(piperidin-4'-yl) C (O) NH-] benzyl, 4 - [(pyrrolidin-2'-yl) C (O) NH- Benzyl, 4- (pyridin-3'-yl-C (O) NH) butyl, 4- (pyridin-4'-yl-C (O) NH) butyl, 4- (pyridin-3'-yl-C (O) NH) _{benzyl, 4- [CH 3 NHCH 2 CH} 2 CH 2 C (O) NH-] _{benzyl, 4- [CH 3 N (Boc} ) CH 2 CH 2 CH 2 C (O) NH-] benzyl 4- (aminomethyl) _{benzyl, 4- [φCH 2 OCH 2 (} H 2 N) CHC ( ) NH] benzyl, 4 - [(1 ', 4'-di (Boc) piperazin-2'-yl) -C (O) NH
-] Benzyl, 4-[(piperazin-2'-yl) -C (O) NH-] benzyl, 4-[(N-toluenesulfonylpyrrolidin-2'-yl) C (O) NH-]
Butyl, 4-[-NHC (O) -4'-piperidinyl] butyl, 4-[-NHC (O) -1'-N-Boc-piperidin-2'-yl] benzyl, 4-[-NHC (O ) -Piperidin-2'-yl] benzyl, 4-[(1'-N-Boc-2 ', 3'-dihydroindoline-2'-yl)
-C (O) NH] benzyl, 4- (pyridin-3'-yl -CH ₂ NH) benzyl, 4 - [(1'-Cbz- piperidin-4'-yl) C (O) NH-] benzyl, 4 - _{[(piperidin-1'-yl) C (O) CH 2 -O-} ] _{benzyl, 4 - [(CH 3)} 2 CH) 2 NC (O) CH 2 -O-] benzyl, 4-[HO (O) C (Cbz-NH ) CHCH 2 CH 2 -C (O) NH-] _{benzyl, 4- [φCH 2 O (O} ) C (Cbz-NH) CHCH 2 CH 2 -C (O) NH-
] Benzyl, 4-[-NHC (O) -2'-methoxyphenyl] benzyl, 4-[(pyrazin-2'-yl) C (O) NH-] benzyl, 4- [HO (O) C (NH _{2) CHCH 2 CH 2 -C (} O) NH-] benzyl, 4- (2'-formyl-1 ', 2', 3 ', 4'-tetrahydroisoquinolin-3'-yl -CH ₂ NH-) benzyl _{, N-Cbz-NHCH 2 -} , 4 - [(4'- methylpiperazin-1'-yl) C (O) O-] _{benzyl, 4- [CH 3 (N-} Boc) NCH 2 C (O) NH -] Benzyl, 4-[-NHC (O)-(1 ', 2', 3 ', 4'-tetrahydro-N-Bo
c- isoquinolin-3'-yl] _{benzyl, 4- [CH 3 NHCH 2 C} (O) NH-] _{benzyl, (CH 3) 2 NC (} O) CH 2 -, 4- (N- methylacetamido) benzyl, 4- (1 ′, 2 ′, 3 ′, 4′-tetrahydroisoquinolin-3′-yl-C
H ₂ NH-) _{benzyl, 4 - [(CH 3)} 2 NHCH 2 C (O) NH-] benzyl, (1-toluenesulfonyl imidazole (Toluenesulfonyli
midizol) -4-yl) methyl, 4-[(1′-Boc-piperidin-4′-yl) C (O) NH—] benzyl 4-trifluoromethylbenzyl, 4-[(2′-bromophenyl) C (O) NH-] _{benzyl, 4 - [(CH 3)} 2 NC (O) NH-] _{benzyl, 4- [CH 3 OC (O} ) NH-] _{benzyl, 4 - [(CH 3)} 2 NC ( O) O-] _{benzyl, 4 - [(CH 3)} 2 NC (O) N (CH 3) -] _{benzyl, 4- [CH 3 OC (O} ) N (CH 3) -] benzyl, 4-(N -Methyltrifluoroacetamido) benzyl, 4-[(1'-methoxycarbonylpiperidin-4'-yl) C (O) NH-
] Benzyl, 4-[(4'-phenylpiperidin-4'-yl) C (O) NH-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) -C (O
) NH-] benzyl, 4-[(piperidin-4'-yl) C (O) O-] benzyl, 4-[(1'-methylpiperidin-4'-yl) -O-] benzyl, 4- [ (1'-methylpiperidin-4'-yl) C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) NH-] benzyl, 3-[(CH ₃ ) ₂ NC (O) O-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) -C (O
) O-] benzyl, 4-(N-toluenesulfonyl amino) _{benzyl, 4 - [(CH 3)} 3 CC (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (O) NH -] _{benzyl, 4 - [(CH 3 CH} 2) 2 NC (O) NH-] benzyl, 4 - [- C (O) NH- (4'-piperidinyl)] benzyl, 4 - [(2'-tri trifluoromethylphenyl) C (O) NH-] benzyl, 4 - [(2'-methylphenyl) C (O) NH-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 O-] benzyl, 4-[(pyrrolidin-2'-yl) C (O) NH-] benzyl, 4-[-NHC (O) -piperidin-1'-yl] benzyl, 4-[(thiomorpholin-4'-yl) C (O) NH-] benzyl, 4-[(thiomorpholin-4'-ylsulfone)- (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (O) O-] benzyl, 3-nitro _{-4- (CH 3 OC (O)} CH 2 O-) benzyl, (2 -Benzoxazolinone-6-yl) methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-
_{, 4 - [(CH 3)} 2 NS (O) 2 NH-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 N (CH 3) -] benzyl, 4 - [(thiomorpholine-4 ' -Yl) C (O) O-] benzyl, 4-[(thiomorpholin-4'-ylsulfone) -C (O) O-] benzyl, 4-[(piperidin-1'-yl) C (O) O -] Benzyl, 4-[(pyrrolidin-1'-yl) C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) O-] benzyl, 4- [(2'-methylpyrrolidin-1'-yl)-, (pyridin-4-yl) methyl-, 4-[(piperazin-4'-yl) -C (O) O-] benzyl, 4-[( 1'-Boc-piperazin-4'-yl) -C (O) O-] benzyl, 4-[(4'-acetylpiperazin-1'-yl) C ( O) O-] benzyl, p-[(4'-methanesulfonylpiperazin-1'-yl) benzyl, 3-nitro-4-[(morpholin-4'-yl) -C (O) O-] benzyl, 4-{[(CH ₃ ) ₂ NC (S)] ₂ N-｝ benzyl, N-Boc-2-aminoethyl-, 4-[(1,1-dioxothiomorpholin-4-yl) -C ( O) O-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 -] benzyl, 4- (imidazolide -2'-one-1'-yl) benzyl, 4 - [(piperidin-1' yl) C (O) O-] benzyl, 1-N-benzyl-- imidazol-4-yl -CH ₂ -, 3,4-oxyethylene, 3,4 dioxymethylene benzyl, 4 - [- N _{(SO 2) (CH 3)} CH 2 CH 2 CH 2 N (CH 3) 2] benzyl, 4- ( 3'-formyl imidazolide -2'-one-1'-yl) benzyl, 4- [NHC (O) CH (CH 2 CH 2 CH 2 CH 2 NH 2) NHBoc] benzyl, [2 '- [4 " -Hydroxy-4 ″-(3 ′ ″-methoxythien-2 ′ ″
- yl) piperidine -2 "- yl] ethoxy] benzyl, and _{p - [(CH 3) 2} NCH 2 CH 2 N (CH 3) C (O) O-] benzyl.

In a preferred embodiment, R ⁵ is preferably selected from all possible isomers resulting from substitution with the following groups: 3-[(CH ₃ ) ₂ NC (O) O-] benzyl _{, 4 - [(CH 3)} 2 NC (O) O-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 O-] benzyl, 4 - [(piperidin-1'-yl) C (O ) O-] benzyl, 4-[(piperidin-4'-yl) C (O) O-] benzyl, 4-[(1'-methylpiperidin-4'-yl) C (O) -O-] benzyl 4-[(4'-hydroxypiperidin-1'-yl) C (O) O-] benzyl, 4-[(4'-formyloxypiperidin-1'-yl) C (O) O-] benzyl, 4-[(4'-ethoxycarbonylpiperidin-1'-yl) C (O) O-]
Benzyl, 4-[(4'-carboxylpiperidin-1'-yl) C (O) O-] benzyl, 4-[(3'-hydroxymethylpiperidin-1'-yl) C (O) O-] benzyl 4-[(4'-hydroxymethylpiperidin-1'-yl) C (O) O-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) C (O )
O-] benzyl, 4-[(4'-piperidone-1'-yl ethylene ketal) C (O) O-
Benzyl, 4-[(piperazin-4'-yl) -C (O) O-] benzyl, 4-[(1'-Boc-piperazin-4'-yl) -C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) O-] benzyl, 4-[(4'-methylhomopiperazin-1'-yl) C (O) O-] benzyl, 4 -[(4 '-(2-hydroxyethyl) piperazin-1'-yl) C (O)
O-] benzyl, 4-[(4'-phenylpiperazin-1'-yl) C (O) O-] benzyl, 4-[(4 '-(pyridin-2-yl) piperazin-1'-yl) C (O) O
-] Benzyl, 4-[(4 '-(4-trifluoromethylpyridin-2-yl) piperazine-
1'-yl) C (O) O-] benzyl, 4-[(4 '-(pyrimidin-2-yl) piperazin-1'-yl) C (O)
O-] benzyl, 4-[(4'-acetylpiperazin-1'-yl) C (O) O-] benzyl, 4-[(4 '-(phenylC (O)-) piperazin-1'-yl ) C (O) O
-] Benzyl, 4-[(4 '-(pyridin-4-ylC (O)-) piperazin-1'-yl)
C (O) O-] benzyl, 4-[(4 '-(phenylNHC (O)-) piperazin-1'-yl) C (O
) O-] benzyl, 4-[(4 '-(phenylNHC (S)-) piperazin-1'-yl) C (O
) O-] benzyl, 4-[(4'-methanesulfonylpiperazin-1'-ylC (O) O-) benzyl, 4-[(4'-trifluoromethanesulfonylpiperazin-1'-ylC (O
) O-) benzyl, 4-[(morpholin-4'-yl) C (O) O-] benzyl, 3-nitro-4-[(morpholin-4'-yl) -C (O) O-] benzyl 4-[(thiomorpholin-4'-yl) C (O) O-] benzyl, 4-[(thiomorpholin-4'-ylsulfone) -C (O) O-] benzyl, (alternative nomenclature In the method, 4-[(1,1-dioxothiomorpholine-
4-yl) -C (O) O-] benzyl), 4-[(pyrrolidin-1'-yl) C (O) O-] benzyl, 4-[(2'-methylpyrrolidin-1'-yl) C (O) O-] benzyl, 4-[(2 '-(methoxycarbonyl) pyrrolidin-1'-yl) C (O) O
-] Benzyl, 4-[(2 '-(hydroxymethyl) pyrrolidin-1'-yl) C (O) O-
] Benzyl, 4-[(2 ′-(N, N-dimethylamino) ethyl) (CH ₃ ) NC (O) O
-] benzyl, 4 - [(2 '- (N-methyl--N- toluene-4-sulfonylamino) ethyl) (CH ₃₎ NC (O) O-] benzyl, 4 - [(2' - (morpholin - 4'-yl) _{ethyl) (CH 3) NC (O} ) O
-] benzyl, 4 - [(2 '- (hydroxy) ethyl) (CH ₃₎ NC (O) O-] benzyl, 4- [bis (2' - (hydroxy) ethyl) NC (O) O-] benzyl , 4 - [(2 '- (formyloxy) _{ethyl) (CH 3) NC (O} ) O-] _{benzyl, 4 - [(CH 3 OC} (O) CH 2) HNC (O) O-] benzyl, 4 - [2 '- (phenyl NHC (O) O-) ethyl -] HNC (O) O-] benzyl, 3-chloro _{-4 - [(CH 3) 2} NC (O) O-] benzyl, 3-chloro -4-[(4'-methylpiperazin-1'-yl) C (O) O-]
Benzyl, 3-chloro-4-[(4 '-(pyridin-2-yl) piperazin-1'-yl) C (O) O-] benzyl, 3-chloro-4-[(thiomorpholine-4'- yl) C (O) O-] benzyl, and 3-fluoro _{-4 - [(CH 3) 2} ) NC (O) O-] benzyl.

In the compounds of formula IA, R ⁶ is preferably 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy , Cyclopentoxy, neo-pentoxy,
2-α-iso-propyl-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, —NH ₂ , benzyloxy, —NHC
H ₂ COOH, —NHCH ₂ CH ₂ COOH, —NH-adamantyl, —NHCH ₂ CH ₂ COOCH ₂ CH ₃ , —NHSO ₂ —p-CH ₃ —φ, —NHOR ⁸ (where,
R ⁸ is hydrogen, methyl, iso-propyl or benzyl), O- (N-succinimidyl), —O-cholest-5-en-3-β-yl, —OCH ₂ —O
C (O) C (CH ₃ ) ₃ , —O (CH ₂ ) _z NHC (O) W, wherein z is 1 or 2, and W is pyrid-3-yl, N-methylpyridyl , And N-
Methyl-1,4-dihydro-pyrid-3-yl),
-NR "C (O) -R ' ( wherein, R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or _{-CH 2 C (O) OCH 2} CH 3)
It is.

Preferred compounds within the above formulas I and IA include, by way of example: N- [N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl] -L-phenylalanine N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-L-phenylalanine N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-D-phenylalanine N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-
Hydroxyacetyl] -L-4- (N-benzyloxycarbonyl-isonipecotamide) phenylalanine N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-
Hydroxyacetyl] -L-4- (isonipecotamide) phenylalanine (2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidine-2-)
Yl) tetrazol-1-yl] -2- (4-nitrobenzyl) propionic acid (2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidine-2-)
Yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonylisonipecotamide) benzyl) propionic acid methyl ester (2S) -2- [5- (N- (toluene-4-sulfonyl) ) Pyrrolidine-2-
Yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonylisonipecotamide) benzyl) propionic acid N- [N- (toluene-4-sulfonyl) pyrrolidin-2-yl] aminocarbonyl ] -L-phenylalanine, and pharmaceutically acceptable salts thereof, and any ester compounds of the above-listed compounds, wherein one ester is a methyl ester, an ethyl ester, an n-propyl ester , Isopropyl ester, n-butyl ester,
A compound substituted with another ester selected from the group consisting of isobutyl ester, sec-butyl ester, and tert-butyl ester.

The present invention also provides a method for binding VLA-4 in a biological sample, the method comprising: combining the biological sample with a compound of Formula I or IA as described above; Contacting under conditions that bind to VLA-4.

Certain compounds of formula I or IA above are also useful in reducing VLA-4 mediated inflammation in vivo.

The present invention also provides a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I or IA above, wherein R ³ and R ⁵ are derived from L-amino acids or other analogous starting materials. A pharmaceutical composition comprising one or more of the above. Alternatively, a racemic mixture can be used.

[0051] The pharmaceutical composition can be used to treat a VLA-4 mediated disease state. Such disease states include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile-onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), Multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral injuries, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and adult respiratory distress Acute leukocyte-media injury as occurs in the syndrome
ted lung injury).

Thus, the present invention also provides a method for the treatment of an inflammatory disease mediated by VLA-4 in a patient, the method comprising the step of administering to said patient the above pharmaceutical composition. I do.

Preferred compounds of Formulas I and IA above include those set forth in Table I below:

[0054]

[Table 2]

[0055]

DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention relates to compounds that inhibit leukocyte adhesion, specifically VLA-4 mediated leukocyte adhesion. When describing the compounds, compositions, and methods of the present invention, the following terms have the following meanings, unless otherwise indicated.

Definitions As used herein, “alkyl” refers to an alkyl group, preferably having 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms.
This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, and the like.

“Substituted alkyl” refers to an alkyl group, preferably of 1 to 10 carbon atoms.
Having 1 to 5 substituents selected from the group consisting of: alkoxy, substituted
Alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, a
Mino, amidino, alkylamidino, thioamidino, aminoacyl, aminocar
Bonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl
, Substituted aryl, aryloxy, substituted aryloxy, aryloxyali
, Substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro
, Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carbo
Xyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl
Reel, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl
Sil-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocycle
Formula, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone,
Thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl
, Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
Oheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted
Reel, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hete
Rocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxo
Thiothiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution al
Kill, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O) _Two -Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Multiple
Cyclic, -OS (O)_Two-Substituted heterocyclic, -OS (O)_Two-NRR (where R is
Hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substitution
Lucil, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NR
S (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS
(O)_Two-Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS (O)_Two-NR
-Alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (O)_Two-NR-
Aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O)_Two-NR-F
Teloaryl, -NRS (O)_Two-NR-substituted heteroaryl, -NRS (O)_Two -NR-heterocyclic, -NRS (O)_Two-NR-substituted heterocyclic (where R is hydrogen
Or alkyl), mono-alkylamino and di-alkylamino, mono- (
Substituted alkyl) amino and di- (substituted alkyl) amino, mono-arylamido
And di-arylamino, mono-substituted arylamino and di-substituted aryl
Ruamino, mono-heteroarylamino and di-heteroarylamino, mono
-Substituted heteroarylamino and di-substituted heteroarylamino, mono-hetero
Cyclic amino and di-heterocyclic amino, mono-substituted heterocyclic amino and di-position
Substituted heterocyclic amino, (alkyl, substituted alkyl, aryl, substituted aryl, hete
Selected from roaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic
A) asymmetric di-substituted amines having different substituents, as well as conventional blocking groups (eg
For example, Boc, Cbz, formyl, etc.) or alkyl / (— SO_Two-Alkyl
, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl,
-SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl
, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroa
Reel, -SO_Two-Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO_TwoNRR (
Where R is a block by a substituted alkyl group substituted with hydrogen or alkyl).
A substituted alkyl group having an amino group to be protected.

“Alkoxy” refers to an “alkyl-O—” group, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-dimethylbutoxy and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Acyl” refers to the following groups: HC (O)-, alkyl-C (O)-, substituted alkyl-C (O)-, alkenyl-C (O)-, substituted alkenyl-C (O)-,
Alkynyl-C (O)-, substituted alkynyl-C (O)-, cycloalkyl-C (
O)-, substituted cycloalkyl-C (O)-, aryl-C (O)-, substituted aryl-C (O)-, heteroaryl-C (O)-, substituted heteroaryl-C (O).
, Heterocyclic -C (O)-, and substituted heterocyclic -C (O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl , Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Acylamino” refers to the group —C (O) NRR where R is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted Is independently selected from the group consisting of cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and wherein each R is attached to a heterocyclic ring or substituted heterocyclic with a nitrogen atom. Form a ring, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Thiocarbonylamino” refers to the group —C (S) NRR, where each R is
Independent of the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic And each R is linked to form a heterocyclic or substituted heterocyclic ring with the nitrogen atom, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl , Substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Acyloxy” refers to the following groups: alkyl-C (O) O—, substituted alkyl-
C (O) O-, alkenyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl-C (O) O-, substituted alkynyl-C (O) O-, aryl-C (O )
O-, substituted aryl-C (O) O-, cycloalkyl-C (O) O-, substituted cycloalkyl-C (O) O-, heteroaryl-C (O) O-, substituted heteroaryl-C ( O) O-, heterocyclic-C (O) O-, and substituted heterocyclic-C (O) O
Refers to where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are , As defined herein.

“Alkenyl” preferably has 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms, and at least one site of alkenyl unsaturation, and preferably 1 to 2 carbon atoms. An alkenyl group having two sites.

“Substituted alkenyl” refers to one to five substituents selected from the group consisting of
Alkenyl group having: alkoxy, substituted alkoxy, acyl, acylamido
Thio, thiocarbonylamino, acyloxy, amino, amidino, alkylamidi
, Thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbo
Nilamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy
Si, substituted aryloxy, aryloxyaryl, substituted aryloxy aryl
, Halogen, hydroxyl, cyano, nitro, carboxyl, carboxyl
Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carbo
Xyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted ant
, Carboxyl heteroaryl, carboxyl-substituted heteroaryl, cal
Boxyl heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cyclo
Alkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thi
Oalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thio
Cycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic
, Substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted
Cyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted
Substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,
Oxycarbonylamino, oxythiocarbonylamino, -OS (O)_Two-Al
Kill, -OS (O)_Two-Substituted alkyl, -OS (O)_Two-Aryl, -OS (O) _Two -Substituted aryl, -OS (O)_Two-Heteroaryl, -OS (O)_Two-Substitution
Lower aryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OS
O_Two-NRR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl
, -NRS (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O
)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two−
Substituted heteroaryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substituted heterocycle
Formula, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl
, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl,
-NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted hetero
Aryl, -NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted
Cyclic (where R is hydrogen or alkyl), mono-alkylamino and di-
Alkylamino, mono- (substituted alkyl) amino and di- (substituted alkyl) a
Mino, mono-arylamino and di-arylamino, mono-substituted aryl
Mino and di-substituted arylamino, mono-heteroarylamino and di-
Teloarylamino, mono-substituted heteroarylamino and di-substituted heteroaryl
Reelamino, mono-heterocyclic amino and di-heterocyclic amino, mono-substituted
Cyclic amino and di-substituted heterocyclic amino, (alkyl, substituted alkyl,
, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
Asymmetric di-substituted amines having different substituents (selected from substituted heterocyclic)
And conventional blocking groups (eg, Boc, Cbz, formyl, etc.)
Nil / (-SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl,
-SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloa
Lequil, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroary
, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substituted heterocycle
Formula, and -SO_TwoNRR (where R is hydrogen or alkyl)
A substituted alkenyl group having an amino group blocked by a substituted alkenyl group.

“Alkynyl” preferably has 2 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms, and has at least one alkynyl unsaturated site and preferably 1 to 2 Alkynyl group having an alkynyl unsaturated site.

“Substituted alkynyl” refers to alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl , Substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxylcycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl Substituted aryl, carboxyl heteroaryl, carboxyl substituted heteroaryl, carboxyl heterocyclic, Carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,
Thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, Cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ —Substituted alkyl, —OS (O) ₂ —
Aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl,-
OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂
- substituted heterocyclic, -OSO ₂ -NRR (where R is hydrogen or _{alkyl), - NRS (O) 2} - alkyl, -NRS (O) ₂ - substituted alkyl, -NRS (
O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) _2- NR-alkyl, -NR
S (O) _2- NR-substituted alkyl, -NRS (O) _2- NR-aryl, -NRS
(O) _2- NR-substituted aryl, -NRS (O) _2- NR-heteroaryl, -N
RS (O) _2- NR-substituted heteroaryl, -NRS (O) _2- NR-heterocyclic,
-NRS (O) _2- NR-substituted heterocyclic (where R is hydrogen or alkyl), monoalkylamino and dialkylamino, mono- (substituted alkyl) amino and di- (substituted alkyl) amino, mono Arylamino and diarylamino, mono-substituted arylamino and di-substituted arylamino, monoheteroarylamino and diheteroarylamino, mono-substituted heteroarylamino and di-substituted heteroarylamino, monoheterocyclic amino and dihetero Cyclic amino, mono-substituted heterocyclic amino and di-substituted heterocyclic amino, (alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic A) asymmetric di-substituted amines having different substituents And, for example Boc, Cbz, conventional substituted alkynyl group or alkynyl / -SO ₂ having an amino group blocked by a blocking group such as formyl - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl, -SO ₂ - cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ - aryl, -SO ₂ - substituted aryl, -SO ₂ - heteroaryl, -SO ₂ - substituted heteroaryl, -SO ₂ - heterocyclic, -SO ₂ - (wherein, R represents hydrogen or alkyl as) substituted heterocyclic and -SO ₂ NRR 1 to 5 amino selected from the group consisting of substituted alkynyl groups substituted with Refers to an alkynyl group having a substituent.

“Amidino” refers to the group H ₂ NC (＝ NH) —, and the term “alkylamidino” refers to compounds having one to three alkyl groups (eg, alkyl HNC
(= NH)-).

“Thioamidino” refers to the group RSC (＝ NH) — where R is hydrogen or alkyl.

“Aminoacyl” refers to the groups —NRC (O) alkyl, —NRC (O) substituted alkyl, —NRC (O) cycloalkyl, —NRC (O) substituted cycloalkyl,
NRC (O) alkenyl, -NRC (O) -substituted alkenyl, -NRC (O) alkynyl, -NRC (O) -substituted alkynyl, -NRC (O) aryl, -NRC (
O) -substituted aryl, -NRC (O) heteroaryl, -NRC (O) -substituted heteroaryl, -NRC (O) -heterocyclic, and -NRC (O) -substituted heterocyclic (where R is hydrogen or Alkyl), wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted hetero Cyclic is as defined herein.

“Aminocarbonyloxy” refers to a group —NRC (O) O-alkyl, —NRC
(O) O-substituted alkyl, -NRC (O) O-alkenyl, -NRC (O) O-
Substituted alkenyl, -NRC (O) O-alkynyl, -NRC (O) O-substituted alkynyl, -NRC (O) O-cycloalkyl, -NRC (O) O-substituted cycloalkyl, -NRC (O) O- Aryl, -NRC (O) O-substituted aryl, -N
RC (O) O-heteroaryl, -NRC (O) O-substituted heteroaryl, -N
RC (O) O-heterocyclic and -NRC (O) O-substituted heterocyclic (where R
Is hydrogen or alkyl), wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic The formula and the substituted heterocyclic are as defined herein.

“Oxycarbonylamino” refers to a group —OC (O) NH ₂ , —OC (O) NR
R, -OC (O) NR-alkyl, -OC (O) NR-substituted alkyl, -OC (
O) NR-alkenyl, -OC (O) NR-substituted alkenyl, -OC (O) NR
-Alkynyl, -OC (O) NR-substituted alkynyl, -OC (O) NR-cycloalkyl, -OC (O) NR-substituted cycloalkyl, -OC (O) NR-aryl, -OC (O) NR- Substituted aryl, -OC (O) NR-heteroaryl,-
OC (O) NR-substituted heteroaryl, -OC (O) NR-heterocyclic, and-
OC (O) NR-substituted heterocyclic, wherein R is hydrogen, alkyl, or each R is joined together with a nitrogen atom to form a heterocyclic or substituted heterocyclic ring Where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic Is as defined herein.

“Oxythiocarbonylamino” refers to the groups —OC (S) NH ₂ , —OC (S)
NRR, -OC (S) NR-alkyl, -OC (S) NR-substituted alkyl, -O
C (S) NR-alkenyl, -OC (S) NR-substituted alkenyl, -OC (S)
NR-alkynyl, -OC (S) NR-substituted alkynyl, -OC (S) NR-cycloalkyl, -OC (S) NR-substituted cycloalkyl, -OC (S) NR-aryl, -OC (S) NR -Substituted aryl, -OC (S) NR-heteroaryl, -OC (S) NR-substituted heteroaryl, -OC (S) NR-heterocyclic, and -OC (S) NR-substituted heterocyclic (where Wherein R is hydrogen, alkyl or
Or each R is attached together with a nitrogen atom to form a heterocyclic or substituted heterocyclic ring), wherein alkyl, substituted alkyl, alkenyl,
Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the groups —NRC (O) NRR, —NRC (O)
NR-alkyl, -NRC (O) NR-substituted alkyl, -NRC (O) NR-alkenyl, -NRC (O) NR-substituted alkenyl, -NRC (O) NR-alkynyl, -NRC (O) NR-substituted Alkynyl, -NRC (O) NR-aryl,
-NRC (O) NR-substituted aryl, -NRC (O) NR-cycloalkyl,-
NRC (O) NR-substituted cycloalkyl, -NRC (O) NR-heteroaryl, and -NRC (O) NR-substituted heteroaryl, -NRC (O) NR-heterocyclic, and -NRC (O) NR -Refers to substituted heterocyclic. Wherein each R is independently hydrogen, alkyl, or each R is joined with a nitrogen atom to form a heterocyclic or substituted heterocyclic ring, and one of the amino groups is , Boc,
Blocked with conventional blocking groups such as Cbz, formyl and the like, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted hetero Aryl, heterocyclic and substituted heterocyclic are defined herein.

“Aminothiocarbonylamino” refers to an —NRC (S) NRR group, an —NRC (
S) NR-alkyl group, -NRC (S) NR-substituted alkyl group, -NRC (S)
NR-alkenyl group, -NRC (S) NR-substituted alkenyl group, -NRC (S)
NR-alkynyl group, -NRC (S) NR-substituted alkynyl group, -NRC (S) N
R-aryl group, -NRC (S) NR-substituted aryl group, -NRC (S) NR-
Cycloalkyl group, -NRC (S) NR-substituted cycloalkyl group, -NRC (S
A) NR heteroaryl group, and -NRC (S) NR-substituted heteroaryl group, -NRC (S) NR-heterocyclic group, and -NRC (S) NR-substituted heterocyclic group. Wherein each R is independently hydrogen, alkyl, or each R is joined with a nitrogen atom to form a heterocyclic or substituted heterocyclic ring, and one of the amino groups is , Boc, Cbz, blocked with conventional blocking groups such as formyl and the like, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are defined herein.

“Aryl” or “Ar” refers to an unsaturated aromatic carbon of 6-14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl) Refers to a cyclic group. Here, the fused ring is aromatic (for example,
2-benzosazolinone, 2H-1,4-benzosazin-3 (4H) -one-
7 il, etc.) or not. Preferred aryls include phenyl and naphthyl.

The substituted aryl is a hydroxy group, an acyl group, an acylamino group, a thiocarbony
Amino group, acyloxy group, alkyl group, substituted alkyl group, alkoxy group,
Substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkyl
Nyl, amidino, alkylamidino, thioamidino, amino, amino
Acyl group, aminocarbonyloxy group, aminocarbonylamino group, aminothio
Carbonylamino group, aryl group, substituted aryl group, aryloxy group,
Reeloxy group, cycloalkoxy group, substituted cycloalkoxy group, heteroaryl
Group, substituted heteroaryloxy group, heterocyclyloxy group, substituted
Rocyclyloxy, carboxyl, carboxylalkyl, carboxyl
-Substituted alkyl group, carboxyl-cycloalkyl group, carboxyl-substituted cycle
Roalkyl, carboxylaryl, carboxyl-substituted aryl, carbo
Xyl heteroaryl group, carboxyl-substituted heteroaryl group, carboxyl
Heterocyclic group, carboxyl-substituted heterocyclic group, carboxamide group, cyano group
, Thiol group, thioalkyl group, substituted thioalkyl group, thioaryl group, substituted thio
Oaryl group, thioheteroaryl group, substituted thioheteroaryl group, thiocyclo
Alkyl group, substituted thiocycloalkyl group, thioheterocyclic group, substituted thioheterocyclic group
, Cycloalkyl group, substituted cycloalkyl group, guanidino group, guanidino sulfo
Group, halo group, nitro group, heteroaryl group, substituted heteroaryl group, heterocyclic
Group, substituted heterocyclic group, cycloalkoxy group, substituted cycloalkoxy group,
Reeloxy group, substituted heteroaryloxy group, heterocyclyloxy group, substituted
Heterocyclyloxy group, oxycarbonylamino group, oxythiocarbonyla
Mino group, -S (O)_Two-Alkyl group, -S (O)_Two-Substituted alkyl group, -S (O) _Two -Cycloalkyl group, -S (O)_Two-Substituted cycloalkyl group, -S (O)_Two-A
Lucenyl group, -S (O)_Two-Substituted alkenyl group, -S (O)_Two-Aryl group, -S
(O)_Two-Substituted aryl group, -S (O)_Two-Heteroaryl group, -S (O)_Two−
Substituted heteroaryl group, -S (O)_Two-Heterocyclic group, -S (O)_Two-Substituted heterocyclic groups
, -OS (O)_Two-Alkyl group, -OS (O)_Two-Substituted alkyl group, -OS (O) _Two -Aryl group, -OS (O)_Two-Substituted aryl group, -OS (O)_Two-Heteroant
Group, -OS (O)_Two-Substituted heteroaryl group, -OS (O)_TwoA heterocyclic group,
-OS (O)_Two-Substituted heterocyclic group, -OSO_Two-NRR groups (where R is hydrogen or
Or alkyl), -NRS (O)_Two-Alkyl group, -NRS (O)_Two-Substituted alk
Group, -NRS (O)_TwoAryl group, -NRS (O)_Two-Substituted aryl group, -NR
S (O)_Two-Heteroaryl group, -NRS (O)_Two-Substituted heteroaryl group,-
NRS (O)_Two-Heterocyclic group, -NRS (O)_Two-Substituted heterocyclic group, -NRS (O
)_Two-NR-alkyl group, -NRS (O)_Two-NR-substituted alkyl group, -NRS (
O)_Two-NR-aryl group, -NRS (O)_Two-NR-substituted aryl group, -NRS
(O)_Two-NR-heteroaryl group, -NRS (O)_Two-NR-substituted heteroaryl
Group, -NRS (O)_Two-NR-heterocyclic group, -NRS (O)_Two-NR-substituted complex
Cyclic groups (where R is hydrogen or alkyl), mono- and di-alkylamino
, Mono- and di- (substituted alkyl) amino, mono- and di-arylamino,
No- and di-substituted arylamino, mono- and -diheteroarylamino,
Mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino
Mono- and di-substituted heterocyclic amino, asymmetric di-substituted amines (alkyl,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
Having different substituents selected from heterocyclic groups and substituted heterocyclic groups)
Is blocked by conventional blocking groups such as Boc, Cbz, formyl, etc.
Or -SO_TwoAn amino group on the substituted aryl substituted with NRR (where R
Is hydrogen or alkyl).
Refers to a substituted aryl group.

“Aryloxy” refers to an aryl-O— group that includes, for example, phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to the group substituted aryl-O—.

“Aryloxyaryl” refers to the group -aryl-O-aryl.

“Substituted aryloxyaryl” refers to hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl,
Alkoxy group, substituted alkoxy group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, amidino group, alkylamidino group, thioamidino group,
Amino group, aminoacyl group, aminocarbonyloxy, aminocarbonylamino group, aminothiocarbonylamino group, aryl group, substituted aryl group, aryloxy group, substituted aryloxy group, cycloalkoxy group, substituted cycloalkoxy group, heteroaryloxy group , Substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl A carboxyl heteroaryl group, a carboxyl-substituted heteroaryl group, a carboxyl heterocyclic group, a carboxyl-substituted heterocyclic group, a carboxamide group, a cyano group, Thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic Formula group, cycloalkyl group, substituted cycloalkyl group, guanidino group, guanidinosulfone group, halo group, nitro group, heteroaryl group, substituted heteroaryl group, heterocyclic group, substituted heterocyclic group, cycloalkoxy group, substituted Cycloalkoxy group, heteroaryloxy, substituted heteroaryloxy group, heterocyclyloxy group, substituted heterocyclyloxy group, oxycarbonylamino group, oxythiocarbonylamino group, -S (O) ₂ -alkyl group, -S (O) ₂ - substituted alkyl group, -S (O) ₂ - cycloalkyl group, S (O) ₂ - substituted cycloalkyl group, -S
(O) ₂ -alkenyl group, -S (O) ₂ -substituted alkenyl group, -S (O) ₂ -aryl group, -S (O) ₂ -substituted aryl group, -S (O) ₂ -heteroaryl group , -S
(O) ₂ -substituted heteroaryl group, -S (O) ₂ -heterocyclic group, -S (O) ₂ -substituted heterocyclic group, -OS (O) ₂ -alkyl group, -OS (O) ₂ -substituted alkyl group,
—OS (O) ₂ -aryl group, —OS (O) ₂ -substituted aryl group, —OS (O) ₂
—Heteroaryl group, —OS (O) ₂ —substituted heteroaryl group, —OS (O) ₂ —
Heterocyclic group, -OS (O) ₂ - substituted heterocyclic group, -OSO ₂ -NRR group (wherein R
Is hydrogen or an alkyl _{group), - NRS (O) 2} - alkyl group, -NRS (O) ₂ - substituted alkyl group, -NRS (O) ₂ - aryl, -NRS (O) ₂ - substituted aryl group, -NRS (O) ₂ -heteroaryl group, -NRS (O) ₂ -substituted heteroaryl group, -NRS (O) ₂ -heterocyclic group, -NRS (O) ₂ -substituted heterocyclic group,
-NRS (O) _2- NR-alkyl group, -NRS (O) _2- NR-substituted alkyl group, -NRS (O) _2- NR-aryl group, -NRS (O) _2- NR-substituted aryl group, -NRS (O) _2- NR-heteroaryl group, -NRS (O) _2- NR-substituted heteroaryl group, -NRS (O) _2- NR-heterocyclic group, -NRS (O) _2- N
R-substituted heterocyclic groups (where R is hydrogen or alkyl group), mono- and di-alkylamino groups, mono- and di- (substituted alkyl) amino, mono- and di-
Arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic Amino, asymmetric di-substituted amines (with different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups) and Boc, Cbz, or is blocked by conventional blocking groups such as formyl, or substituted with -SO ₂ NRR, (where R is hydrogen or alkyl) amino groups on the substituted aryl are selected from the group consisting of Aryloxyaryl substituted with one to three substituents on either or both of the aryl rings The say.

“Cycloalkyl” refers to a cyclic alkyl group of 3 to 8 carbon atoms having a monocyclic ring including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Polycyclic alkyl groups (for example, adamantanyl (adamant)
anyyl) are excluded from this definition.

“Cycloalkenyl” refers to a single or multiple unsaturated (but not aromatic) cyclic alkenyl groups of 3 to 8 carbon atoms.

“Substituted cycloalkyl” and “substituted cycloalkenyl” are cycloalkyl groups having one to five substituents, preferably three to eight carbon atoms, selected from the group consisting of: And cycloalkenyl groups: oxo (= O), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, amino Thiocarbonylamino,
Aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- Substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, Substituted thioalkyl,
Thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, Cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS
(O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl,
-OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) _2- N
RR (where R is hydrogen or alkyl), -NRS (O) ₂ -alkyl, -N
RS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) _2-
Substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic,-
NRS (O) _2- NR-alkyl, -NRS (O) _2- NR-substituted alkyl, -N
RS (O) _2- NR-aryl, -NRS (O) _2- NR-substituted aryl, -NR
S (O) _2- NR-heteroaryl, -NRS (O) _2- NR-substituted heteroaryl, -NRS (O) _2- NR-heterocyclic, -NRS (O) _2- NR-substituted heterocyclic (Where R is hydrogen or alkyl), monoalkylamino and dialkylamino, mono (substituted alkyl) amino and di (substituted alkyl) amino, monoarylamino and diarylamino, mono-substituted arylamino and di-substituted arylamino Monoheteroarylamino and diheteroarylamino, mono-substituted heteroarylamino and di-substituted heteroarylamino, monoheterocyclic amino and diheterocyclic amino, mono-substituted heterocyclic amino and di-substituted heterocycle Formula amino, below: alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, Conversion heteroaryl, heterocyclic, and asymmetry di having different substituents selected from substituted heterocyclic - substituted amines, arrangement substituted alkenyl group (
Boc, Cbz, conventional block amino groups are blocked by groups such as formyl, or alkynyl group / -SO _2, - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl , -SO ₂ - cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ - aryl, -SO ₂ - substituted aryl, -SO ₂ - heteroaryl, -SO ₂ - substituted heteroaryl, -SO ₂ - heterocyclic wherein, -SO ₂ - substituted heterocyclic, and -SO ₂ NRR (wherein, R represents hydrogen or alkyl) with a substituted alkynyl group substituted with).

“Cycloalkoxy” refers to the group —O-cycloalkyl.

“Substituted cycloalkoxy” refers to the group —O-substituted cycloalkyl.

“Guanidino” refers to a —NRC (（NR) NRR group, a —NRC (＝ NR) NR
-Alkyl group, -NRC (= NR) NR-substituted alkyl group, -NRC (= NR)
NR-alkenyl group, -NRC (= NR) NR-substituted alkenyl group, -NRC (
= NR) NR-alkynyl group, -NRC (= NR) NR-substituted alkynyl group,-
NRC (= NR) NR-aryl group, -NRC (= NR) NR-substituted aryl group, -NRC (= NR) NR-cycloalkyl group, -NRC (= NR) NR-heteroaryl group, -NRC (= NR) NR-substituted heteroaryl group, -NRC (=
NR) NR-heterocyclic groups, and -NRC (= NR) NR-substituted heterocyclic groups, wherein each R is independently hydrogen and alkyl, and one of the amino groups
One is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein).

“Guanidinosulfone” refers to an —NRC (＝ NR) NRSO ₂ -alkyl group,
-NRC (= NR) NRSO ₂ - substituted alkyl _{group, -NRC (= NR) NRSO 2} - _{alkenyl, -NRC (= NR) NRSO 2} - substituted alkenyl group, -NRC
(= NR) NRSO ₂ - _{alkynyl, -NRC (= NR) NRSO 2} - substituted alkynyl _{group, -NRC (= NR) NRSO 2} - aryl, -NRC (= NR) N
RSO ₂ - substituted _{aryl, -NRC (= NR) NRSO 2} - cycloalkyl group,
-NRC (= NR) NRSO ₂ - substituted cycloalkyl group, -NRC (= NR) N
RSO ₂ - heteroaryl, and -NRC (= NR) NRSO ₂ - substituted heteroaryl group, -NRC (= NR) NRSO ₂ - heterocyclic, and -NRC (= N
R) NRSO ₂ -substituted heterocyclic, wherein each R is independently hydrogen and alkyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl Alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein).

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo, and is preferably either chloro or bromo.

“Heteroaryl” refers to an aromatic carbocyclic group having from 2 to 10 carbon atoms and from 1 to 4 heteroatoms (selected from oxygen, nitrogen and sulfur) in the ring. Say. Such heteroaryl groups can have one ring (eg, pyridyl or furyl) or multiple condensed rings (eg, indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl, and furyl.

“Substituted heteroaryl” refers to a heteroaryl group substituted with one to three substituents selected from the group consisting of: hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl , Substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy , Substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, carboxyl, carboxylalkyl Carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, carboxamide, Cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, Guanidino, guanidino sulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonyl amino, -S (O) ₂ - alkyl, -S (O) ₂ - substituted alkyl, -S (O) ₂ - Cycloalkyl, -S (O) ₂ -substituted cycloalkyl, -S (O
) ₂ -alkenyl, -S (O) ₂ -substituted alkenyl, -S (O) ₂ -aryl,-
S (O) ₂ -substituted aryl, -S (O) ₂ -heteroaryl, -S (O) ₂ -substituted heteroaryl, -S (O) ₂ -heterocyclic, -S (O) ₂ -substituted hetero Cyclic, -OS
(O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O
) ₂ - substituted heteroaryl, -OS (O) ₂ - heterocyclic, -OS (O) ₂ - substituted heterocyclic, -OSO ₂ -NRR (wherein, R represents hydrogen or alkyl), - NRS (
O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -N
RS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O
) ₂ -Substituted heterocyclic, —NRS (O) ₂ —NR-alkyl, —NRS (O) ₂ —N
R-substituted alkyl, -NRS (O) _2- NR-aryl, -NRS (O) _2- NR
-Substituted aryl, -NRS (O) _2- NR-heteroaryl, -NRS (O) _2-
NR-substituted heteroaryl, -NRS (O) _2- NR-heterocyclic, -NRS (O
) ₂ -NR-substituted heterocyclic (where R is hydrogen or alkyl), monoalkylamino and dialkylamino, mono (substituted alkyl) amino and di (substituted alkyl) amino, monoarylamino and diarylamino, mono- Substituted arylamino and di-substituted arylamino, monoheteroarylamino and diheteroarylamino, mono-substituted heteroarylamino and di-substituted heteroarylamino, monoheterocyclic amino and diheterocyclic amino, mono-substituted hetero Cyclic amino and di-substituted heterocyclic amino, asymmetric di-substituted amines having different substituents selected from: alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, And substituted heterocyclic,
And Boc, Cbz, amino groups on either protected by a conventional blocking group, or -SO ₂ NRR (wherein, R represents hydrogen or alkyl as) substituted aryl substituted with like formyl.

“Heteroaryloxy” refers to the group —O-heteroaryl, and “substituted heteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle” or “heterocyclic” refers to one to ten carbon atoms and one
Refers to a saturated or unsaturated group having a single ring or multiple condensed rings of one to four heteroatoms (selected from nitrogen, sulfur, or oxygen), wherein 1 in a fused ring system One or more rings can be aryl or heteroaryl).

“Substituted heterocyclic” refers to a heterocyclic group substituted with one to three substituents selected from the group consisting of: oxo (＝ O), thioxo (＝ S). , Alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
Aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxy, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxylcycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl-heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocyclo Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thiohetero Wherein substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy (he
terocyclyloxy), substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O
) ₂ -Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -O
S (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) _2- NRR
(Where R is hydrogen or alkyl), -NRS (O) ₂ -alkyl, -NRS (
O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS ( O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS
(O) _2- NR-alkyl, -NRS (O) _2- NR-substituted alkyl, -NRS (
O) _2- NR-aryl, -NRS (O) _2- NR-substituted aryl, -NRS (O
) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl,-
NRS (O) _2- NR-heterocyclic, -NRS (O) _2- NR-substituted heterocyclic (where R is hydrogen or aryl), mono-alkylamino and di-alkylamino, mono- (substituted Alkyl) amino and di- (substituted alkyl) amino, mono-
Arylamino and di-arylamino, mono-substituted arylamino and di-substituted arylamino, mono-heteroarylamino and di-heteroarylamino, mono-substituted heteroarylamino and di-substituted heteroarylamino, mono-heterocycle Formula amino and di-heterocyclic amino, mono-substituted heterocyclic amino and di-substituted heterocyclic amino, asymmetric di-substituted amines with different substituents selected from: alkyl, substituted alkyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic alkynyl groups having an amino group blocked by conventional blocking groups (eg, Boc, Cbz, formyl, etc.), and substituted alkynyl groups or-. SO ₂ - alkyl, -SO ₂ - substituted A Kill, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl,
-SO ₂ - cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ - aryl, -SO ₂ - substituted aryl, -SO ₂ - heteroaryl, -SO ₂ - substituted heteroaryl, -SO ₂ - heterocyclic , -SO ₂ - substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl) alkynyl / substituted alkynyl groups substituted with.

Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,
Isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carbazole, phenanthridine, acridine, phenanthroline, isothiazole, phenazine,
Isoxazole, phenoxazine, phenothiazine, imidazolidin, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4
-Tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl and the like. Not limited.

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substituted heterocyclyloxy” refers to the group —O-substituted heterocyclic.

“Thiol” refers to the group —SH.

“Thioalkyl” refers to the group —S-alkyl.

“Substituted thioalkyl” refers to the group —S-substituted alkyl.

“Thiocycloalkyl” refers to the group —S-cycloalkyl.

“Substituted thiocycloalkyl” refers to the group —S-substituted cycloalkyl.

“Thioaryl” refers to the group —S-aryl and “substituted thioaryl”
Refers to an -S-substituted aryl group.

“Thioheteroaryl” refers to the group —S-heteroaryl, and “substituted thioheteroaryl” refers to the group —S-substituted heteroaryl.

“Thioheterocyclic” refers to the group —S-heterocyclic and “substituted thioheterocyclic”
Refers to a -S-substituted heterocyclic group.

“Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound of Formula I,
The salts are derived from various organic and inorganic counterions well known in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and When the molecule contains basic functionality, it is a salt of an organic or inorganic acid such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Compound Preparation The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Wherever typical or preferred process conditions (ie, reaction temperatures, times, reactant mole ratios, solvents, pressures, etc.) are set, unless otherwise specified, other process conditions may also be used. It will be appreciated that you get. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one of ordinary skill in the art by routine and optimal procedures.

Further, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from unwanted reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, a number of protecting groups have been described in T.W. W. Greene and G.C. M. Wu
ts, Protecting Groups in Organic Synt
hesis, 2nd edition, Wiley, New York, 1991 and references cited therein.

In addition, compounds of the present invention typically contain one or more chiral centers. Therefore,
If desired, such compounds can be prepared or isolated as pure stereoisomers (ie, as individual enantiomers or diastereomers, or as enriched mixtures of stereoisomers). All such stereoisomers (and enriched mixtures) are included within the scope of the invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well-known in the art. Alternatively, a racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral separating agents, and the like.

In a preferred embodiment, the compounds of Formulas I and IA, wherein Q is a tetrazole-1,5-diyl moiety, is a compound of the corresponding amide (ie, Q is-
C and (O) a NH-), anhydrous inert solvent (e.g., contacted with an equimolar amount of phosphorus pentachloride in benzene) (PCl _5), followed by the imino chloride obtained hydrazoic acid (HN ₃ ) Is easily prepared. Typically, the reaction is performed by contacting the amide with PCl ₅ at ambient temperature for about 90 minutes. The resulting imino chloride is typically not isolated, but is reacted in situ with an equimolar amount of hydrazoic acid at ambient temperature for about 2 hours to give the tetrazole.

The amide intermediate used in this reaction (ie, where Q is —C (
O) NH-) is readily prepared by first coupling an amino acid of formula II:

[0112]

Embedded image

Wherein R ² and R ³ together with the sulfonyl chloride of formula III are as defined herein (eg, of formulas I and IIA):

[0114]

Embedded image

Wherein R ¹ is as defined herein to provide an N-sulfonyl amino acid of formula IV:

[0116]

Embedded image

Here, R ^{1 to} R ³ are as defined in the present specification.

The reaction typically involves reacting an amino acid of formula II with at least one equivalent, preferably from about 1.1 to about 2 equivalents of sulfonyl chloride III in an inert diluent such as dichloromethane. This is done by letting Generally, the reaction is performed at a temperature ranging from about -70C to about 40C for about 1 to about 24 hours. Preferably, the reaction is performed in the presence of a suitable base to remove the acid formed during the reaction. Suitable bases include, by way of example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. Alternatively, the reaction is carried out under Schotten-Baumann type conditions,
It can be performed using an aqueous alkali solution (eg, sodium hydroxide, etc.) as the base. Upon completion of the reaction, the resulting N-sulfonyl amino acid IV is recovered by conventional methods (including neutralization, extraction, precipitation, chromatography, filtration, etc.).

The amino acids of formula II used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Examples of suitable amino acids for use in this reaction include, but are not limited to, L-proline, trans-4-hydroxyl-L-proline,
Cis-4-hydroxyl-L-proline, trans-3-phenyl-L-proline, cis-3-phenyl-L-proline, L- (2-methyl) proline, L-pipecolic acid, L-azetidine-2-
Carboxylic acid, L-indoline-2-carboxylic acid, L-1,
2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-
4-carboxylic acid, L- (5,5-dimethyl) thiazolidine-4-carboxylic acid, L
-Thiamorpholine-3-carboxylic acid, glycine, 2-tert-butylglycine, D, L-phenylglycine, L-alanine, α-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D , L-phenylsarcosine, L-aspartic acid β-tert-butyl ester, L-glutamic acid γ-tert-butyl ester, L- (O-benzyl) serine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid And 1-aminocyclopentanecarboxylic acid (cycloleucine) 1-aminocyclohexanecarboxylic acid, L-serine and the like. If desired, the corresponding carboxylic acid ester of an amino acid of formula II (eg, methyl ester, ethyl ester, etc.) can be used in the above reaction with sulfonyl chloride III. Subsequent hydrolysis of the ester group to a carboxylic acid using conventional reagents and conditions (ie, treatment with an alkali metal hydroxide in an inert diluent such as methanol / water) is then followed by N-sulfonyl amino acid Provide IV.

Similarly, the sulfonyl chlorides of formula III used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid (ie, a compound of the formula R ¹ —SO ₃ H, where R ¹ is as defined above).
From), phosphorus trichloride and phosphorus pentachloride. The reaction generally involves the reaction of sulfonic acid with about 2-5 molar equivalents of phosphorus trichloride and phosphorus pentachloride (either neat or in an inert solvent such as dichloromethane) for about 0 to about 5 mole equivalents. The contacting is carried out at a temperature in the range of from about 0C to about 80C for about 1 to about 48 hours to obtain the sulfonyl chloride. Alternatively, the sulfonyl chloride of formula III can be converted from a corresponding thiol compound (ie, from a compound of formula R ¹ -SH, wherein R ¹ is as defined herein), It can be prepared by treatment with (Cl ₂ ) and water under conventional reaction conditions.

Examples of sulfonyl chlorides suitable for use in the present invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride,
1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-
Toluenesulfonyl chloride, α-toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride,
4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, 3,5
-Dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-
Fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4
6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-
Thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, 1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonyl chloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like. If desired, sulfonyl fluoride, sulfonyl bromide or sulfonic anhydride can be used in the above reaction instead of sulfonyl chloride to form N-sulfonyl amino acids of formula IV.

The intermediate N-sulfonyl amino acid of formula IV can also have the formula V:

[0123]

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A sulfonamide of the formula L (R ³ ) CHCOOR may be prepared by reacting a sulfonamide of the formula L (R ³ ) CHCOOR wherein R ¹ and R ² are as defined herein. Where L is a leaving group (eg, chloro, bromo, iodo, mesylate, tosylate, etc.), and R ³ is as defined herein;
And R is hydrogen or an alkyl group. The reaction typically involves the reaction of sulfonamide V with at least one equivalent (preferably 1.1 to 2 equivalents) of a carboxylic acid derivative in an inert diluent (eg, DMF) and a suitable base (eg, DMF). , Triethylamine) at a temperature in the range of about 24 ° C to about 37 ° C for about 0.5 to about 4 hours. This reaction is further described in Zuckermann.
J. et al. Am. Chem. Soc. , 1992, 114, 10646-1064.
7 is described. Preferred carboxylic acid derivatives for use in this reaction are α-chloro and α-bromocarboxylic esters, such as tert-butyl bromoacetate. If a carboxylic ester is used in this reaction, the ester group is subsequently hydrolyzed using conventional procedures to give the N-sulfonyl amino acid of formula IV.

The amide intermediate, where Q is —C (O) NH—, is then reacted with a compound of formula IV
An intermediate N-sulfonyl amino acid of formula VI:

[0126]

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Wherein R ⁵ and R ⁶ are as defined herein. This coupling reaction is typically performed using a well-known coupling reagent (for example, carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) and the like). Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (DCC), 1- (
3-dimethylamino-propyl) -3-ethylcarbodiimide (EDC) and the like. If desired, polymer-supported forms of the carbodiimide coupling reagent may also be used, including, for example, Tetrahedro
n Letters, 34 (48), 7865 (1993). In addition, well-known coupling promoters (eg, N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.) can be used to facilitate the coupling reaction.

The coupling reaction typically involves the conversion of N-sulfonyl amino acid IV in an inert diluent (eg, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.) from about 1 to about It is carried out by contacting with 2 equivalents of coupling reagent and at least 1 equivalent (preferably about 1 to about 1.2 equivalents) of amino acid derivative VI. Generally, the reaction is carried out at a temperature ranging from about 0C to about 37C for about 12 to about 24 hours. Upon completion of the reaction, the amide is recovered by conventional methods (including neutralization, extraction, precipitation, chromatography, filtration, etc.).

Alternatively, the N-sulfonyl amino acid IV can be converted to an acid halide, which is coupled with the amino acid derivative VI to provide an amide. The acid halide of VI is obtained by contacting VI with an inorganic acid halide (eg, thionyl chloride, phosphorus trichloride, phosphorus tribromide, or phosphorus pentachloride) or, preferably, oxalyl chloride under conventional conditions. Can be prepared by In general, the reaction is carried out using about 1 to 5 molar equivalents of an inorganic acid halide or oxalyl chloride (either in pure or inert solvent such as dichloromethane or carbon tetrachloride) for about 0 to about 5 mole equivalents. At a temperature in the range of about
It takes about 48 hours. A catalyst such as DMF can also be used in this reaction.

The acid halide of the N-sulfonyl amino acid IV is then at least one equivalent (preferably from about 1.1 to about 1.10 equivalents) in an inert diluent (eg, dichloromethane).
5 equivalents) of amino acid derivative VI at a temperature in the range of about -70 ° C to about 40 ° C for about 1 to about 24 hours. Preferably, the reaction is performed in the presence of a suitable base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. Alternatively, the reaction is Sch
It can be performed using an aqueous alkaline solution (eg, sodium hydroxide, etc.) under otten-Baumann-type conditions. Upon completion of the reaction, the amide is recovered by conventional methods, including neutralization, extraction, precipitation, chromatography, filtration, and the like.

Alternatively, the amide intermediate, wherein Q is —C (O) NH—, has the formula V
II:

[0132]

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Can be prepared by first forming a diamino acid derivative of wherein R ² ,
R ³ , R ⁵ and R ⁶ are as defined herein. The diamino acid derivative of Formula VII can be prepared by coupling an amino acid of Formula II with an amino acid derivative of Formula VI using conventional amino acid coupling techniques and reagents (eg, carbodiimide, BOP reagent, etc.). Can be easily prepared as follows. The diamino acid VII can then be sulfonated using the sulfonyl chloride of formula III and using the synthetic procedures described above to provide the amide.

The amino acid derivatives of Formula VI used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. For example, amino acid derivatives of Formula VI can be prepared by C-alkylating commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wis., USA) with an alkyl halide or substituted alkyl halide. The reaction typically involves reacting diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. This is done by processing. The resulting C-alkylated malonate is then deacetylated, hydrolyzed, and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to give the amino acid (typically , Hydrochloride).

Examples of amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to: L-tyrosine methyl ester, L-3,
5-diiodotyrosine methyl ester, L-3-iodotyrosine methyl ester, β- (4-hydroxy-naphth-1-yl) -L-alanine methyl ester,
β- (6-hydroxy-naphth-2-yl) -L-alanine methyl ester and the like. If desired, of course, other esters or amides of the above compounds may also be used.

In another preferred embodiment, the compounds of formula I / IA, wherein Q is —CH
(OH) C (O) NH—) has the formula IVa:

[0137]

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Are readily prepared by coupling an α-hydroxycarboxylic acid of formula VI with an amino acid derivative of formula VI using the coupling reagents and procedures described above.
The α-hydroxycarboxylic acids of formula IVa are either commercially available or can be prepared from readily available starting materials using conventional reagents and reaction conditions well known to those skilled in the art.

Further, in another preferred embodiment, the compound of formula I / IA, wherein Q is -C (O) N (O)-, is a compound of formula IV wherein the N-sulfonyl amino acid is of formula IV I
Vb:

[0140]

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By coupling using the coupling reagents and procedures described above with an N-hydroxy amino acid of formula I wherein R ⁵ and R ⁶ are as defined herein. Is prepared. The N-hydroxy amino acid of formula IVb has the formula IV
From the corresponding amino acid derivative (where R ⁶ is OH) from dilute aqueous sulfuric acid (
Typically reacting with sodium nitrite and potassium bromide in 2.5N)
It can be prepared by subsequent treatment with hydroxylamine. Typically, the reaction involves first contacting excess potassium bromide in solution IV and 2.5N sulfuric acid with excess sodium nitrite at 0 ° C. for about 0.25 to 0.5 hours, The contact is then carried out at ambient temperature for one hour. Then the product is
Esterification is performed using thionyl chloride and methanol under standard conditions to form the methyl ester. The methyl ester is then quickly contacted with hydroxylamine in methanol, and the reaction mixture is refluxed for 6-24 hours to give the N-hydroxy amino acid of formula IVb.

In yet another preferred embodiment, the compound of Formula I / IA, wherein Q is
-NHC (O) NH-) contacts an N-sulfonylamino acid of formula IV with an equimolar amount of diphenylphosphoryl azide in an inert solvent such as toluene, followed by a trialkylamine such as Triethylamine) to form the corresponding isocyanate. The intermediate isocyanate is generally not isolated, but is reacted in situ with an amino acid derivative of Formula VI to form urea. The reaction is typically performed at about 80 ° C. for about 6 to about 2
Performed for 4 hours to provide urea.

In yet another preferred embodiment, compounds of formula I / IA, wherein Q is-
CH (R ⁸ ) NR ⁷ —) is converted to a compound of formula IVc using conventional reductive alkylating reagents and conditions:

[0144]

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It is conveniently prepared by reductive alkylation of an amino acid derivative of Formula VI with a carbonyl compound of the formula Typically, the reaction converts the amino acid derivative VI with excess IVc (preferably, 1.1 to 2 equivalents of IVc) and excess (preferably,
(1.1 to 1.5 equivalents) of a reducing agent (for example, sodium cyanoborohydride). Generally, the reaction is carried out in an essentially inert diluent (eg, methanol) at a temperature in the range of about 0 ° C. to about 50 ° C. (preferably,
(Ambient temperature) for about 0.5-3 hours to produce the desired product.

For ease of synthesis, compounds of Formula I are typically prepared as esters (ie, where R ⁶ is an alkoxy or substituted alkoxy group, etc.). If desired, the ester group can be hydrolyzed using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, the reaction involves reacting the ester with at least one equivalent of an alkali metal hydroxide (eg, lithium hydroxide, sodium hydroxide, or the like) in an inert diluent (eg, methanol or a mixture of methanol and water). Potassium hydroxide) at a temperature in the range of about 0 ° C. to about 24 ° C. for about 1 to about 12 hours. Alternatively, the benzyl ester can be removed by hydrogenolysis using a palladium catalyst (eg, palladium on carbon). The resulting carboxylic acid can, if desired, be reacted with an amine (eg, β-
Alanine ethyl ester), hydroxyamines (e.g., hydroxylamine and N-hydroxysuccinimide), alkoxyamines and substituted alkoxyamines (e.g., O-methylhydroxylamine and O-benzylhydroxylamine), etc. It can be coupled using ring reagents and conditions.

As will be apparent to those skilled in the art, other functional groups present on any of the substituents of the compounds of Formula I can be readily modified either before or after the above coupling reactions using well-known synthetic procedures. Or it can be derivatized. For example, a nitro group present on a substituent of a compound of Formula I or an intermediate thereof can be readily reduced by hydrogenation in the presence of a palladium catalyst (eg, palladium on carbon) to provide the corresponding amino group. Can be done. The reaction is typically carried out at a temperature of about 20 ° C. to about 50 ° C. for about 6 to about 24 hours in an inert diluent (eg, methanol). Compounds having a nitro group on R ⁵ substituent may be prepared, for example, by the use of such as 4-nitro-phenylalanine derivative in the coupling reactions described above.

Similarly, a pyridyl group can be hydrogenated in an acidic diluent in the presence of a platinum catalyst (eg, platinum oxide) to provide the corresponding piperidinyl analog. Generally, the reaction is carried out in the presence of a catalyst at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, at a temperature of about 20 ° C. to about 50 ° C. for about 2 to about 24 hours, using an acidic diluent ( For example, a pyridine compound is treated with hydrogen in a mixture of methanol and an aqueous hydrochloric acid solution). Compounds having a pyridyl group, for example,
In the above coupling reaction, it can be easily prepared by using a β- (2-pyridyl)-, β- (3-pyridyl), or β- (4-pyridyl) -L-alanine derivative.

In addition, if the R ⁵ substituent of the compound of formula I or an intermediate thereof comprises a primary or secondary amino group, such amino groups may be, for example, amides, sulfonamides, ureas, thioureas, carbamates , Either before or after the above coupling reaction to provide a secondary or tertiary amine and the like. Compounds having a primary amino group on the R ⁵ substituents are, for example, may be prepared by reduction of the corresponding nitro compound as described above. Alternatively, such compounds can be prepared in the above coupling reaction by using an amino acid derivative of Formula VI derived from lysine, 4-aminophenylalanine, and the like.

By way of example, a compound of formula I having a substituent comprising a primary or secondary amino group or an intermediate thereof (eg, when R ⁵ is a (4-aminophenyl) methyl group)
It can be easily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide. This acylation reaction typically involves the conversion of an amino compound with at least one equivalent, preferably from about 1.1 to about 1.2 equivalents of a carboxylic acid, using a coupling reagent (eg, carbodiimide, BOP reagent (benzotriazole-1- Yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) in an inert diluent (e.g., dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.) in the presence of about 0 <0> C to about This is accomplished by treating at a temperature in the range of 37 ° C. for about 4 to 24 hours. Preferably, a promoter (eg, N-hydroxysuccinimide, 1-hydroxy-benzotriazole, etc.) is used to facilitate the acylation reaction. Examples of carboxylic acids suitable for use in this reaction include N-tert-
Butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L
-Phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonyl isonipecotic acid, N-methyl isonipecotic acid, N-tert-butyloxycarbonyl Examples include, but are not limited to, nipecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N- (toluene-4-sulfonyl) -L-proline.

Alternatively, a compound of formula I or an intermediate thereof containing a primary or secondary amino group is
It can be N-acylated using an acyl halide or carboxylic anhydride to form the corresponding amide. The reaction is typically carried out with an inert diluent (eg,
Dichloromethane) at a temperature ranging from about -70 ° C to about 40 ° C for about 1 hour to about 24 hours.
This is accomplished by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of an acyl halide or carboxylic anhydride for a period of time.
If desired, an acylation catalyst (eg, 4- (N, N-dimethylamino) pyridine) can be used to facilitate the acylation reaction. The acylation reaction is preferably performed in the presence of a base suitable for removing the acid formed during the reaction. Suitable bases include, for example, tertiary amines (eg, triethylamine, diisopropylethylamine, N-methylmorpholine) and the like. Alternatively, the reaction may be performed using aqueous alkali (eg, sodium hydroxide, etc.) under Schotten-Baumann type conditions.

Examples of acyl halides and carboxylic anhydrides suitable for use in this reaction include 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methyl chloride Examples include, but are not limited to, benzoyl, 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chloride (eg, N, N-dimethylcarbamyl chloride, N, N-diethylcarbamyl chloride, etc.) can also be used in this reaction to provide urea. Similarly, dicarbonates (eg, di-t
tert-butyl dicarbonate) can be used to provide the carbamate.

In a similar manner, compounds of formula I or intermediates thereof containing a primary or secondary amino group are N-sulfonated to form a sulfonamide using a sulfonyl halide or sulfonic anhydride. obtain. Suitable sulfonyl halides and sulfonic anhydrides for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chloride (eg, dimethylsulfamoyl chloride) can be used to provide a sulfamide (eg,> N—SO ₂ —N <).

Furthermore, the primary and secondary amino groups present on the substituents of the compound of the formula I or its intermediates are reacted with isocyanates or thioisocyanates,
Urea or thiourea can be produced. The reaction is typically carried out by subjecting the amino compound to at least 1 equivalent, preferably from about 1.1 to about 1.2 equivalents, of an isocyanate or thioisocyanate and an inert diluent such as toluene at about 24 ° C. ~ About 3
The contacting is performed at a temperature in the range of 7 ° C. for about 12 to about 24 hours. Isocyanates and thioisocyanates used in this reaction are commercially available or
Or it can be prepared from commercially available compounds using well known synthetic procedures. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methylthioisocyanate, ethylthioisocyanate, -Phenylethylthioisocyanate, 3-phenylpropylthioisocyanate, 3- (N, N-diethylamino) propylthioisocyanate, phenylthioisocyanate, benzylthioisocyanate, 3-pyridylthioisocyanate, fluorescein isothiocyanate (isomer I) and the like. But not limited thereto.

Further, if the compound of Formula I or an intermediate thereof contains a primary or secondary amino group, the amino group may be reductively converted using an aldehyde or ketone to form a secondary or tertiary amino group. Can be alkylated. This reaction typically involves the reduction of an amino compound with at least one equivalent, preferably from about 1.1 equivalents to about 1.5 equivalents of an aldehyde or ketone, and at least one equivalent of a metal hydride based on the amino compound. Reagents (eg, sodium cyanoborohydride) and an inert diluent (
For example, in methanol, tetrahydrofuran, a mixture thereof, etc.) at about 0 ° C.
The contacting is performed at a temperature in the range of from about 50C to about 50C for about 1 to about 72 hours. Aldehydes and ketones suitable for use in this reaction include, for example,
Examples include benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like.

In a similar manner, when a compound of Formula I or an intermediate thereof has a substituent comprising a hydroxyl group, the hydroxyl group is added before and after the above coupling reaction to provide, for example, ethers, carbamates, and the like. Can be further modified or derivatized. For example, a compound having a hydroxyl group on R ⁵ substituent may be prepared by using an amino acid derivative of formula VI derived from such tyrosine in the above reaction.

By way of example, a compound of Formula I having a substituent containing a hydroxyl group or an intermediate thereof (eg, where R ⁵ is a (4-hydroxyphenyl) methyl group) is readily converted to form an ether. It can be O-alkylated. The O-alkylation reaction typically involves converting the hydroxyl compound to a suitable alkali metal or alkaline earth metal salt (e.g., carbonate) to form an alkali metal or alkaline earth metal salt of the hydroxyl group. Potassium) and an inert diluent (eg, acetone,
2-butanone). The salt is generally not isolated, but at least one equivalent of an alkyl halide or substituted alkyl halide or alkyl sulfonate or substituted alkyl sulfonate (eg, alkyl chloride, alkyl bromide, alkyl iodide, alkyl mesylate or alkyl Tosylate) to give ether in situ. Generally, the reaction is performed at a temperature ranging from about 60C to about 150C for about 24 hours to about 72 hours. If an alkyl chloride or bromide is used in this reaction, preferably a catalytic amount of sodium or potassium iodide is added to the reaction mixture.

Examples of alkyl or substituted alkyl and alkyl sulfonates or alkyl sulfonates suitable for use in this reaction include tert.
-Butylbromoacetate, N-tert-butylchloroacetamide, 1-bromoethylbenzene, ethyl α-bromophenylacetate, 2- (N-ethyl-N-phenylamino) ethyl chloride, 2- (N, N-ethylamino) Ethyl chloride, 2- (N, N-diisopropylamino) ethyl chloride, 2
-(N, N-dibenzylamino) ethyl chloride, 3- (N, N-ethylamino) propyl chloride, 3- (N-benzyl-N-methylamino) propyl chloride, N- (2-chloroethyl) morpholine 2- (hexamethyleneimino) ethyl chloride, 3- (N-methylpiperazine) propyl chloride, 1
-(3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4
-Hydroxy-4-phenylpiperidine) ethyl chloride, N-tert-butyloxycarbonyl-3-piperidinemethyl tosylate, and the like,
It is not limited to these.

Alternatively, a hydroxyl group present on a substituent of a compound of formula I or an intermediate thereof may be O-alkylated using a Mitsunobu reaction. In this reaction, an alcohol such as 3- (N, N-dimethylamino) -1-propanol is converted from about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of triphenylphosphine.
React with about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent such as tetrahydrofuran at a temperature ranging from about -10C to about 5C for about 0.25 to about 1 hour. Then, N-tert-butyl tyrosine methyl ester (N-ter
about 1. such as t-butyltyrosine methyl ester).
0 to about 1.3 equivalents of the hydroxy compound are added and the reaction mixture is heated to about 0 ° C.
Stir at a temperature of about 30 ° C. for about 2 hours to about 48 hours to obtain the O-alkylated product.

In an analogous manner, a compound of formula I or an intermediate thereof containing an arylhydroxy group can be reacted with an aryl iodide to give a diaryl ether. Generally, the reaction is carried out in an inert diluent such as xylene at a temperature of about -25 ° C to about 10 ° C using a suitable base such as sodium hydride to form an alkali metal salt of a hydroxyl group. It is done by doing. The salt is then added to about 1.1
~ 1.5 equivalents of copper (I) bromide dimethyl sulfide (cupprous brom)
Treatment with an ide sulfide complex at a temperature in the range of about 10 ° C. to about 30 ° C. for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide (e.g., , Sodium 2-iodobenzoate). The reaction is then heated at about 70 ° C. to about 150 ° C. for about 2 hours to about 24 hours to obtain the diaryl ether.

In addition, hydroxy-containing compounds can also be easily derivatized to form carbamates. In one method for preparing such carbamates,
The hydroxy compound of Formula I, or an intermediate thereof, is treated with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent such as dichloromethane at about -25 ° C to about 0 ° C. Contact at a temperature in the range of about 0.5 hours to about 2.0 hours. Treatment of the resulting carbonate with an excess (preferably about 2 to about 5 equivalents) of a trialkylamine (e.g., triethylamine) for about 0.5 to 2 hours, followed by about 1.0 to 2 hours
Treatment with ~ about 1.5 equivalents of a primary or secondary amine gives the carbamate. Examples of suitable amines for use in this reaction include piperazine, 1-
Examples include, but are not limited to, methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine, and the like.

Alternatively, in another method for preparing carbamates, the hydroxy-containing compound is prepared by combining about 1.0 to about 1.5 equivalents of carbamyl chloride with an inert diluent such as dichloromethane at about 25 ° C. to about 70 ° C. Contact at a temperature in the range of about 2 hours to about 72 hours. Typically, the reaction is performed in the presence of a suitable base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines (eg, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like). Furthermore, at least one equivalent (based on the hydroxy compound) of 4
-(N, N-dimethylamino) pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chlorides suitable for use in this reaction include, by way of example, dimethyl carbamyl chloride, diethyl carbamyl chloride, and the like.

Similarly, when a compound of Formula I or an intermediate thereof contains a primary or secondary hydroxyl group, such hydroxyl group is readily converted to a leaving group and is easily displaced. For example, amines, sulfides and fluorides. For example, a derivative of 4-hydroxy-L-proline can be converted to the corresponding 4-amino-L-proline derivative, 4-thio-L-proline derivative or 4- via a nucleophilic substitution reaction of the derivatized hydroxyl group. It can be converted to a fluoro-L-proline derivative. Generally, when chiral compounds are used in these reactions,
The stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically reversed.

Typically, these reactions involve first removing the hydroxyl group by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide (eg, p-toluenesulfonyl chloride, etc.) in pyridine. For example, it is implemented by converting to tosylate. The reaction is generally performed at a temperature from about 0C to about 70C for about 1 hour to about 48 hours. The resulting tosylate can then be added to the tosylate, for example, in an inert diluent such as a mixture of at least one equivalent of sodium azide and N, N-dimethylformamide and water in a range from about 0 ° C to about 37 ° C. Can be easily displaced with sodium azide by contacting at a temperature of about 1 hour to about 12 hours to obtain the corresponding azide compound. The then azido group, for example by reduction by hydrogenation using a palladium on carbon catalyst, amino (-NH ₂₎
Compounds can be obtained.

Similarly, a tosylate group can be easily displaced by a thiol to form a sulfide. The reaction is typically carried out by converting the tosylate with at least one equivalent of a thiol (eg, thiophenol) and a suitable base (eg, 1,8-diazabicyclo [5.4.0] undec-7-ene (1,1). 8-diazabicyclo [5.
4.0] undec-7-ene) (DBU)) in an inert diluent such as N, N-dimethylformamide at a temperature of about 0 ° C. to about 37 ° C. for about 1 hour to about 12 hours. Perform by time contact to obtain sulfide. Further, treatment of the tosylate with morpholinosulfatrifluoride in an inert diluent (eg, dichloromethane) at a temperature ranging from about 0 ° C. to about 37 ° C. for about 12 hours to about 24 hours can be accomplished by converting the corresponding fluoro compound give.

Furthermore, compounds of formula I having a substituent comprising an iodoaryl group or intermediates thereof, for example, when R ⁵ is a (4-iodophenyl) methyl group, before or after the above coupling reaction Can be easily converted to a biaryl compound. Typically, the reaction involves converting the iodoaryl compound to about 1.1 to about 2 equivalents of an arylzinc iodide (e.g.,
-(Methoxycarbonyl) phenylzinc (2- (methoxycarbony)
l) phenylzinc iodide) and the reaction are completed at a temperature ranging from about 24 ° C to about 30 ° C in the presence of a palladium catalyst such as palladium tetra (triphenylphosphine) in an inert diluent such as tetrahydrofuran. This is done by processing up to This reaction is described, for example, in Rieke, J .; Org.
Chem. 1991, 56, 1445.

In some cases, the compound of Formula I or an intermediate thereof may include a substituent having one or more sulfur atoms. For example, the amino acid of formula II used in the above reaction may be L-thiazolidine-4-carboxylic acid, L- (5,5-dimethyl) thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid, etc. , Such a sulfur atom is present. If present, such sulfur atoms can be oxidized using conventional reagents and reaction conditions, either before or after the above coupling reaction, to give the sulfoxide or sulfone compound. Suitable reagents for oxidizing a sulfide compound to a sulfoxide compound include, for example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA),
And sodium periodate. The oxidation reaction typically involves reacting the sulfide compound with about 0.95 to about 1.1 equivalents of an oxidizing reagent in an inert diluent such as dichloromethane at a temperature ranging from about -50C to about 75C. The contact is performed for 1 hour to about 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least a further equivalent of an oxidizing reagent (eg, hydrogen peroxide, MCPBA, potassium permanganate, etc.). Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess of the oxidizing reagent. Such reactions are described in March, "Advanced Organic Chemist."
ry ", 4th edition, pp. 1201-1202, Wiley Publisher, 1
992.

As described above, compounds of formula I having an R ² substituent other than hydrogen can be used in the above coupling reactions to provide N-substituted amino acids of formula II (eg, sarcosine, N-methyl-L-phenylalanine, etc.). ) Can be prepared. Alternatively, such compounds may be prepared by N-alkylation of a sulfonamide of Formula I or IV (where R ² is hydrogen) using conventional synthetic procedures. Typically, this N
The alkylation reaction is carried out with a sulfonamide and at least one equivalent, preferably 1.
One to two equivalents of an alkyl or substituted alkyl halide is added to an inert diluent (e.g., acetone, 2-butanone, etc.) in the presence of a suitable base (e.g., potassium carbonate) at about 25 <0> C to about 25 <0> C. The contacting is performed at a temperature in the range of 70 ° C. for about 2 hours to about 48 hours. Examples of alkyl or substituted alkyl halides suitable for use in this reaction include, but are not limited to, methyl iodide and the like.

Further, a sulfonamide of Formula I or IV, wherein R ² is hydrogen and R ¹ is a 2-alkoxycarbonylaryl group, is a 1,2-benzisothiazol-3-one It can be cyclized within the molecule to form a derivative or analog thereof. The reaction typically involves converting a sulfonamide such as N- (2-methoxycarbonylphenylsulfonyl) glycine-L-phenylalanine benzyl ester to about 1.0 to 1.5 equivalents of a suitable base (e.g., hydrogenation). Alkali metal)
At about 0 ° C. to about 30 ° C. in an inert diluent (eg, tetrahydrofuran).
Performed by treatment at a temperature in the range of about 2 hours to about 48 hours to obtain the cyclized 1,2-benzisothiazol-3-one derivative.

Finally, a compound of formula I wherein Q contains a thiocarbonyl group (C = S)
In the above synthetic procedure, aminothionoic acid (ami
No thionacid) derivatives. Such aminothionoic acid derivatives are described in Shalaky et al. Org. Chem. ,
61: 9045-9048 (1996) and Brain et al. Org. Ch
em. , 62: 3808-3809 (1997) and the references cited therein.

Pharmaceutical Formulations When used as a drug, Formulas I and IA are usually administered in the form of a pharmaceutical composition. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well-known in the pharmaceutical arts and include at least one active compound.

The invention also includes pharmaceutical compositions that include, as an active ingredient, one or more compounds of Formulas I and IA above with a pharmaceutically acceptable carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with, diluted by, or in the form of capsules, sachets, paper or other containers. Encapsulated in a carrier such as When the excipient serves as a diluent, the excipient can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition comprises tablets,
Pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (eg,
Up to 10% by weight of active compound), soft or hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In preparing formulations, it may be necessary to mill the active compound to provide the appropriate particle size before combining with other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. Where the active compound is substantially water-soluble, the particle size can usually be adjusted by milling to provide a substantially uniform distribution in the formulation (e.g.,
About 40 mesh).

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone , Cellulose, water, syrup, and methylcellulose. The formulations may further include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate;
And flavoring agents. The compositions of the present invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by using procedures known in the art.

The compositions are preferably formulated in a unit dosage form, each dosage being from about 5 to about
It contains about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit associated with a suitable pharmaceutical excipient. Contains a predetermined amount of active substance calculated to produce the desired therapeutic effect.

The active compounds are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, the amount of compound actually administered will include the condition to be treated, the route of administration selected, the compound actually administered, the age, weight, and individual patient response, the severity of the patient's symptoms, etc. It is understood that the decision is made by the physician in view of the relevant situation.

For preparation of a solid composition such as a tablet, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of the compound of the invention. . When we refer to these pre-formulated compositions as homogeneous, it is meant that the active ingredients are dispersed homogeneously throughout the composition, so that the compositions are equally effective units, such as tablets, pills and capsules It can be easily subdivided into dosage forms. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill may include an inner dosage component and an outer dosage component, the latter being in the form of a mantle over the former. The two components can be separated by an enteric layer that acts to resist degradation in the stomach and allows the internal components to pass intact into the duodenum or delay release. Various materials may be used for such enteric layers or coatings, such materials with many polymeric acids and polymeric acids, such as shellac, cetyl alcohol, and cellulose acetate. And mixtures with other materials.

The liquid forms of the novel compositions of the present invention include suitably flavored aqueous solutions, aqueous or oily suspensions of syrups, and edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. And orally, or for administration by injection, including flavored emulsions having the formula: and elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid composition may include suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. The composition, a preferred pharmaceutically acceptable solvent, can be nebulized by use of an inert gas. The nebulized solution may be breathed directly from the nebulizer, or the nebulizer may be connected to a face masks tent or an intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

The following formulation examples illustrate the pharmaceutical compositions of the present invention.

[0182] To prepare hard gelatin capsules containing (Formulation Example 1) The following ingredients: the amount component (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed, Then, a hard gelatin capsule is filled in an amount of 340 mg.

Formulation Example 2 A tablet formulation is prepared using the following ingredients: Amount ingredient (mg / tablet) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10. 0 Stearic acid 5.0 The ingredients are mixed and compressed to form tablets, each weighing 240 mg.

Formulation Example 3 A dry powder inhaler formulation containing the following ingredients is prepared: Ingredient % by Weight Active Ingredient 5 Lactose 95 The active mixture is mixed with lactose and the mixture is placed in a dry powder inhaler device. Added.

Formulation Example 4 Tablets each containing 30 mg of active ingredient are prepared as follows: Amount ingredient (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total amount 120 mg The active ingredient, starch and cellulose were prepared as 20 mesh U.S. S. Sieve and mix well. A solution of polyvinylpyrrolidone was mixed with the resulting powder, which was then mixed with a 16 mesh U.S.A. S. Pass through sieve. The granules so formed are dried with the resulting powder at 50 ° -60 ° C. and dried on a 16 mesh U.S.A. S. Pass through sieve. Then, the granules were treated with No. 30 mesh U.S. S. Add sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a sieve, mix and compress on a tablet machine to give tablets each weighing 150 mg.

[0186] As described (Formulation Example 5) Hereinafter, each producing a capsule containing a drug 40 mg: Quantity Ingredient (mg / capsule) Active ingredient 40.0mg Starch 109.0mg Magnesium stearate 1.0mg total amount 150.0mg mix this active ingredient, cellulose, starch, magnesium stearate,
No. 20 mesh U.S. S. Pass through a sieve and fill into hard gelatin capsules in an amount of 150 mg.

Formulation Example 6 Suppositories each containing 25 mg of active ingredient are prepared as follows: Component amount Active ingredient 25 mg Saturated fatty acid glyceride Up to 2,000 mg 60 mesh U.S. S. Pass through a sieve and suspend in the pre-melted saturated fatty acid glyceride using the minimum heat required. The mixture is then poured into a 2.0 g apparent volume suppository mold and allowed to cool.

Formulation Example 7 Suspensions each containing 50 mg of drug per 5.0 ml dose are prepared as follows: Ingredient quantity Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethylcellulose (11%) microcrystalline cellulose (89%) 50.0 mg sucrose 1.75 g sodium benzoate 10.0 mg fragrance and dye optional pure water up to 5.0 ml This drug, sucrose and xanthan gum were mixed. 10 mesh U
. S. Pass through a sieve and then mix in water with a pre-made solution of microcrystalline cellulose and sodium carboxymethylcellulose. Sodium benzoate, flavor and dye are diluted with some of this water and added with stirring. Then enough water is added to produce the required volume.

[0189] mixing (Formulation Example 8) weight component (mg / capsule) Active ingredient 15.0mg Starch 407.0mg Magnesium stearate 3.0mg total amount 425.0mg The active ingredient, cellulose, starch, and magnesium stearate , No. 20 mesh U.S. S. Pass through a sieve and fill into hard gelatin capsules in an amount of 560 mg.

Formulation Example 9 An intravenous formulation may be prepared as follows: Ingredient Amount Active Ingredient 250.0 mg Isotonic Saline 1000 ml Formulation Example 10 A typical formulation may be prepared: Component amount Active ingredient 1-10 g Emulsified wax 30 g Liquid paraffin 20 g White soft paraffin Up to 100 g White soft paraffin is heated until molten. Incorporate liquid paraffin and emulsified wax and stir until dissolved. The active ingredient is added and stirring is continued until dispersion. The mixture is then cooled until it becomes solid.

Another preferred formulation used in the methods of the invention uses a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well-known in the art. See, for example, U.S. Patent No. 5,023,252, published June 11, 1991, which is incorporated herein by reference. Such patches may be configured for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Where it is desired or necessary to introduce a pharmaceutical composition into the brain, direct or indirect placement techniques may be used. Usually, direct techniques involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used to deliver biological agents to specific anatomical regions of the human body is described in US Pat. No. 5,011,472, which is incorporated by reference in its entirety. , Incorporated herein by reference.

A generally preferred indirect technique involves formulating the composition and providing drug lamination, usually by conversion of the hydrophilic drug to a lipid-soluble drug. Latentation is generally achieved by the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug, making it more lipid soluble and following transport across the blood-brain barrier. You. Alternatively, delivery of hydrophilic drugs can be enhanced by intra-arterial infusion of a hypertonic solution that can transiently open the blood-brain barrier.

[0194] Using the (utility) compounds of the present invention, in a biological _{sample, VLA-4 (α 4 β} 1 integrin) and bound obtained, thus, for example, for VLA-4, like this Has utility in assaying samples. In such an assay, the compound may bind to a solid support to which a VLA-4 sample is added. The amount of VLA-4 in the sample can be determined by conventional methods, such as using a sandwich ELISA assay. Alternatively, labeled VLA-4 may be used in a competition assay to determine the presence of VLA-4 in a sample. Other suitable assays are well-known in the art.

In addition, certain compounds of the invention inhibit leukocyte adhesion to endothelial cells mediated by VLA-4 in vivo and can therefore be used in the treatment of diseases mediated by VLA-4. . Such diseases include asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes),
Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral injuries
Acute leukocyte-mediated lung injury as occurs in nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and respiratory distress syndrome in adults
Inflammatory diseases in mammalian patients such as te-mediated lung injury).

The biological activity of the compounds identified above can be assayed in various systems. For example, the compound can be immobilized on a solid surface, and the attachment of cells expressing VLA-4 can be measured. Using such a format, the majority of compounds can be screened. Suitable cells for this assay include any leukocytes known to express VLA-4, such as T cells, B cells, monocytes, eosinophils, and basophils. Numerous leukocyte cell lines can also be used, e.g.
urkat and U937.

A test compound can also be a labeled compound known to bind between VLA-4 and VCAM-1 or to VLA-4 (eg, a compound of the invention or VLA-4).
Antibody against -4) and the ability to competitively inhibit the binding between VLA-4. In these assays, VCAM-1 can be immobilized on a solid surface. VCAM-1 can also be expressed as a recombinant fusion protein with an Ig terminus (eg, IgG), so that binding to VLA-4 can be detected in an immunoassay. Alternatively, activated endothelial cells or VCA
VCAM-1 expressing cells, such as M-1 transfected fibroblasts,
Can be used. As an assay for determining the ability to inhibit the adhesion of brain to endothelial cells, the assay described in International Patent Application Publication No. WO 91/05038 is particularly preferred. This application is incorporated herein by reference in its entirety.

Many assay formats utilize labeled assay components. This marking system can be in various forms. The label can be attached directly or indirectly to the desired components of the assay according to methods well known in the art. A wide variety of labels may be used. This component can be labeled by any one of several methods. The most common method for detection is the use of autoradiography with ³ H, ¹²⁵ I, ³⁵ S, ¹⁴ C, or ³² P labeled compounds and the like. Non-radioactive labels include labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and ligands that bind the antibody, which can serve as specific binding pair members for the labeled ligand. The choice of this label will depend on the sensitivity required, the ease of binding to the compound, the stability required, and the equipment available.

Suitable in vivo models to demonstrate efficacy in treating inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, and α4 integrin Other models of inflammation are dependent.

Compounds having the desired biological activity can be modified, if necessary, to provide improved pharmacological properties (eg, stability in vivo, bioavailability) or the ability to be detected in diagnostic applications. To provide the desired characteristics. For example, encapsulation of one or more D amino acids in a sulfonamide of the invention typically increases stability in vivo. Stability can be assayed in various ways, such as by measuring the half-life of the protein during incubation with peptidases or human plasma or serum. A number of assays for the stability of such proteins have been described (eg, Verhoef et al., Eur. J. Drug).
Metab. Pharmacokinet. , 1990, 15 (2): 83-.
93).

For diagnostic purposes, a wide variety of labels may be attached to the compounds, which may provide, directly or indirectly, a detectable signal. Thus, the compounds of the present invention can be modified in various ways for various end purposes while still retaining biological activity. In addition, various reaction sites can be introduced at the termini to bind to particles, solid substrates, macromolecules, and the like.

The labeled compounds may be used in various in vivo or in vitro applications.
Radionuclide (eg, γ such as technetium-99 or indium-111)
A wide variety of labels can be used, such as radioactive isotopes), fluorescent agents (eg, fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like. One skilled in the art will know of other suitable labels for binding to the complex, or will be able to ascertain such labels using routine experimentation. Binding of these labels is achieved using standard techniques common to those skilled in the art.

[0203] In vitro uses include diagnostic applications such as monitoring an inflammatory response by detecting the presence of leukocytes that express VLA-4. The compounds of the present invention can also be used to isolate or label such cells. In addition, as described above, the compounds of the invention can be used to assay for potential inhibitors of the VLA-4 / VCAM-1 interaction.

For example, for in vivo diagnostic imaging to identify sites of inflammation, radioisotopes are typically used according to well-known techniques. The radioisotope can be attached to the peptide either directly or indirectly using an intermediate functional group. For example, proteins were coupled to metal ion radioisotopes using chelators such as diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules.

The conjugate can also be labeled with a paramagnetic isotope for in vivo diagnostic purposes such as magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known. Generally, any conventional method for visualizing a diagnostic image can be used. Usually, gamma- and positron-emitting radioisotopes are used for camera images, and paramagnetic isotopes are used for MRI. Thus, these compounds can be used to monitor the process of restoring the inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4, it is possible to determine whether a particular treatment regimen for the purpose of ameliorating the disease is effective.

The pharmaceutical compositions of the present invention can be used to block or inhibit cell attachment associated with many diseases and disorders. For example, many inflammatory disorders are associated with integrins or leukocytes. Treatable disorders include, for example, transplant rejection (eg,
Allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile-onset diabetes), retinitis, cancer metastasis, rheumatoid arthritis, acute leukocyte-mediated lung injury (eg, adult respiratory distress) Syndrome)), asthma, nephritis,
And acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease, including Crohn's disease and ulcerative colitis.In a preferred embodiment, the pharmaceutical composition is used. To treat inflammatory brain disorders such as multiple sclerosis (MS), viral meningitis and encephalitis.

Inflammatory bowel disease is a collective term for two similar diseases called Crohn's disease and ulcerative colitis. Crohn's disease is distinctly demarcated, and is typically idiopathic chronic ulceroconstrictive (ulcerostrictive) characterized by involvement of the transmural wall of all layers of the intestinal wall by a granulomatous inflammatory response.
ive) It is an inflammatory disease. Although the disease most commonly affects the terminal ileum and / or colon, any segment of the gastrointestinal tract from mouth to anus may be involved. Ulcerative colitis is an inflammatory response primarily restricted to the colonic mucosa and submucosa. Lymphocytes and macrophages are abundant in inflammatory bowel disease lesions and can contribute to inflammatory injury.

Asthma is a disease characterized by an increased responsiveness of the bronchial tree to various stimuli that enhance paroxysmal narrowing of the bronchial airways. This stimulation causes the release of various mediators of inflammation from IgE-coated mast cells, including histamine, eosinophil and neutrophil chemotactic factors, leukotrienes, prostaglandins, and platelet activating factors. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory disorders.

[0209] Atherosclerosis is a disease of the arteries (eg, coronary, carotid, aortic, and iliac arteries). The basic lesion (atheroma) consists of a swollen, localized plaque in the intima with a lipid nucleus and a covering fibrous cap. Atherosclerosis weakens arterial blood flow and weakens diseased arteries. Myocardial and cerebral infarction are major consequences of the disease. Macrophages and leukocytes are recruited to atheroma and contribute to inflammatory injury.

Rheumatoid arthritis is a chronic, recurrent inflammatory disease that primarily causes joint damage and destruction. Rheumatoid arthritis usually first affects small joints of the hands and feet, but can then involve the wrists, elbows, ankles and knees. This arthritis results from the interaction of synovial cells with leukocytes infiltrating from the circulation behind the synovium of the joint. For example, Paul, Immunology (Third Edition, Raven Pre
ss, 1993).

Another application of the compounds of the invention is in the treatment of organ rejection or graft rejection mediated by VLA-4. Over recent years, tissues and organs (eg, skin, kidneys,
Liver, heart, lung, pancreas and bone marrow) in the effectiveness of surgical techniques for transplantation,
There is considerable progress. Perhaps the major notable problem is the lack of a satisfactory drug to induce the recipient's immune tolerance to the transplanted allograft or organ. When allogeneic cells or organs are transplanted into the host (ie, the donor and recipient are different individuals from the same species), the host's immune system responds to the foreign antigens in the graft by an immune response. Appears to result in destruction of the transplanted tissue (host versus graft disease). CD8 ⁺ cells, CD4 cells and monocytes are all involved in the rejection of transplanted tissues. Compounds of the present invention that bind to alpha-4 integrin, inter alia, block alloantigen-induced immune responses in the recipient, thereby ensuring that such cells are involved in the destruction of the transplanted tissue or organ. Useful to prevent. For example, Paul et al., Transplant In
international 9,420-425 (1996); Georczyn
Ski et al., Immunology 87, 573-580 (1996); Geo.
rcyznski et al., Transplant. Immunol. 3,55-61
(1995); Yang et al., Transplantation 60, 71-7.
6 (1995); Anderson et al., APMIS 102, 23-27 (19
94).

A related use for compounds of the invention that bind to VLA-4 is in modulating the immune response associated with “graft versus host” disease (GVHD). For example, Sc
hlgel et al. Immunol. 155, 3856-3865 (1995
)checking. GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic recipient. In this case, the immunoreactive cells of the donor can attack the tissue of the recipient. Skin, intestinal epithelium and liver tissue are often targeted and can be destroyed during the course of GVHD. The disease represents a particularly severe problem when immune tissue is transplanted (eg, in bone marrow transplants); however, less severe GVHD also affects other cases (heart transplants and liver transplants). Including). Therapeutic agents of the invention are used, inter alia, to block the activation of donor T cells, thereby hindering their ability to lyse target cells of the host.

A further use of the compounds of the invention is for inhibiting tumor metastasis. Several tumor cells express VLA-4 and compounds that bind to VLA-4 have been reported to block the attachment of such cells to endothelial cells. Ste
inback et al., Urol. Res. 23, 175-83 (1995); Oro
sz et al., Int. J. Cancer 60, 867-71 (1995); Fre.
edman et al., Leuk. Lymphoma 13, 47-52 (1994);
Okahara et al., Cancer Res. 54, 3233-6 (1994).

A further use of the compounds of the invention is in treating multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune response that attacks certain leukocytes and causes destruction of myelin, the insulating sheath that covers nerve fibers. In an animal model for multiple sclerosis, a mouse monoclonal antibody directed against VLA-4 blocks leukocyte adhesion to the endothelium, thus inflaming the central nervous system in the animal and subsequent paralysis It has been shown to prevent ¹⁶ .

[0215] The pharmaceutical compositions of the present invention are suitable for use in various drug delivery systems. Suitable formulations for use in the present invention are Remington's
s Pharmaceutical Sciences, Mace Public
shing Company, Philadelphia, PA, 17th edition (1
985).

To improve serum half-life, the compound can be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or provided to provide an extended serum half-life of the compound. Prior art may be used. To prepare liposomes, see, for example, Szoka et al., US Pat.
Various methods are available, such as those described in U.S. Pat. Nos. 501,728 and 4,837,028, each of which is incorporated herein by reference.

The amount administered to a patient will vary depending upon what is being administered, the purpose of the administration (eg, prophylaxis or therapy), the condition of the patient, the manner of administration, and the like. In therapeutic applications, the composition is administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
An amount adequate to accomplish this is defined as "therapeutically effective dose." Effective amounts for this use will depend on the condition to be treated and the severity of the inflammation, the age of the patient,
It depends on the judgment of the attending physician depending on factors such as weight and general condition.

The composition administered to the patient is in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is typically between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It is understood that the use of certain of the aforementioned excipients, carriers, or stabilizers results in the formation of pharmaceutical salts.

Therapeutic dosages of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is to be effected, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dose will typically be in the range of about 20 μg to about 500 μg per kilogram of body weight, preferably in the range of about 100 μg to about 300 μg per kilogram of body weight. Suitable dosage ranges for intranasal administration generally range from about 0.1 pg to 1 gram per kilogram of body weight.
mg. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The following synthetic and biological examples are provided to illustrate the present invention and are not to be construed as limiting the scope of the invention in any way. Unless otherwise stated, all temperatures are degrees Celsius.

EXAMPLES In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

Aq or aq. = Aqueous AcOH = acetic acid bd = broad doublet bm = broad multiplet bs = broad singlet Bn = benzyl Boc = N-tert-butoxycarbonyl Boc ₂ O = di-tert-butyl dicarbonate BOP = benzotriazole -1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate Cbz = carbobenzyloxy CHCl ₃ = chloroform CH ₂ Cl ₂ = dichloromethane (COCl) ₂ = oxalyl chloride d = double line dd = double double line dt = Double triplet DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene DCC = 1,3-dicyclohexylcarbodiimide DMAP = 4-N, N-dimethylaminopyridine DME = ethylene glycol dimethyl ether DMF = N , N Dimethylformamide DMSO = dimethylsulfoxide EDC = 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et ₃ N = Triethylamine Et ₂ O = diethyl ether EtOAc = ethyl acetate EtOH = ethanol eq or eq. = Equivalent Fmoc = N- (9-fluorenylmethoxycarbonyl) FmocONSu = N- (9-fluorenylmethoxycarbonyl) -succinimide g = gram h = time H ₂ O = water HBr = hydrobromic acid HCl = hydrochloric acid HOBT = 1-hydroxybenzotriazole hydrate hr = time K ₂ CO ₃ = potassium carbonate L = liter m = multiplet MeOH = methanol mg = milligram MgSO ₄ = magnesium sulfate mL = milliliter mm = millimeter mM = millimolarity mmol = Mmol mp = melting point N = specified concentration NaCl = sodium chloride Na ₂ CO ₃ = sodium carbonate NaHCO ₃ = sodium hydrogen carbonate NaOEt = sodium ethoxide NaOH = sodium hydroxide NH ₄ Cl = ammonium chloride NMM = N-methyl morpho Phosphorus Phe = L-phenylalanine Pro = L-proline psi = pounds per square inch PtO ₂ = platinum oxide q = quartet quint. = Quintet rt = room temperature s = singlet sat = saturation t = triplet t-BuOH = tert-butanol TFA = trifluoroacetic acid THF = tetrahydrofuran TLC or tlc = thin layer chromatography Ts = tosyl TsCl = tosyl chloride TsOH = Tosylate μL = microliter In the examples below, all temperatures are degrees Celsius (unless otherwise indicated). The following method can be used to prepare the compounds of the present invention shown below.

Method 1 N-Tosylation Procedure N-tosylation of the appropriate amino acids was performed using Cupps, Boutin and Rapo.
port J. Org. Chem. 1985, 50, 3972.

(Method 2) (Procedure for Preparing Methyl Ester) Amino acid methyl ester was prepared according to the method of Brenner and Huber Helv. C
him. Prepared using the method of Acta 1953, 36, 1109.

Method 3 (BOP Coupling Procedure) The desired dipeptide ester was converted to a suitable amino acid ester or amino acid ester hydrochloride (1 equivalent) of a suitable N-protected amino acid (1 equivalent), benzotriazole-1- Prepared by reaction with iloxy-tris (dimethylamino) -phosphonium hexafluorophosphate [BOP] (2.0 eq), triethylamine (1.1 eq), and DMF. The reaction mixture was stirred overnight at room temperature.
This crude product is purified by flash chromatography to give the dipeptide ester.

Method 4 Hydrogenation Procedure I Hydrogenation was carried out using 10% palladium on carbon (10% by weight) in methanol at 30 psi overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the desired amino compound.

Method 5 Hydrolysis Procedure I A cooled (0 ° C.) THF / H ₂ O solution of the appropriate ester (2: 1, 5-10 m)
To L), LiOH (or NaOH) (0.95 eq) was added. The temperature was maintained at 0 ° C and the reaction was completed within 1-3 hours. The reaction mixture was extracted with ethyl acetate and the aqueous phase was lyophilized to give the desired carboxylate.

Method 6 Ester Hydrolysis Procedure II A cooled (0 ° C.) THF / H ₂ O solution of the appropriate ester (2: 1, 5-10 m)
To L), LiOH (1.1 eq) was added. The temperature is maintained at 0 ° C and the reaction is 1-3
Completed in time. The reaction mixture is concentrated, and the residue is dissolved in H ₂ O, pH
Was adjusted to 2-3 with aqueous HCl. The product was extracted with ethyl acetate, and combined organic phases were washed with brine, dried over MgSO _4, filtered, and concentrated,
The desired acid was obtained.

Method 7 Ester Hydrolysis III The appropriate ester was dissolved in dioxane / H ₂ O (1: 1) and 0.9 equivalents of 0.5N NaOH was added. The reaction was stirred for 3-16 hours and then concentrated. The resulting residue was dissolved in H ₂ O, and extracted with ethyl acetate. The aqueous phase was lyophilized to give the desired sodium carboxylate.

Method 8 Sulfonylation Procedure I To a suitably protected aminophenylalanine analog (11.2 mmol) dissolved in methylene chloride (25 ml) and cooled to -78 ° C, the desired sulfonyl chloride (12 mmol) Was added, followed by dropwise addition of pyridine (2 mL). The solution was warmed to room temperature and stirred for 48 hours. The reaction solution was diluted with methylene chloride (100 m
L) with a 250 mL separatory funnel and 1 N HCl (50 mL × 3)
, Brine (50 mL), and water (100 mL). The organic phase was dried (MgSO ₄ ) and the solvent was concentrated to give the desired product.

Method 9 Reductive Amination Procedure Reductive amination of Tos-Pro-p-NH ₂ -Phe with the appropriate aldehyde was performed using acetic acid, sodium triacetoxyborohydride, methylene chloride. And the combined mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography.

Method 10 BOC Removal Procedure Anhydrous hydrogen chloride (HCl) gas was bubbled through a solution of the appropriate Boc-amino acid ester in methanol at 0 ° C. for 15 minutes and the reaction mixture was stirred for 3 hours. The solution was concentrated to a syrup, dissolved in Et ₂ O, and reconcentrated. This procedure was repeated and the resulting solid was left under high vacuum overnight.

(Method 11) (tert-butyl ester hydrolysis procedure I) The tert-butyl ester was dissolved in CH ₂ Cl ₂ and treated with TFA. The reaction is completed in 1-3 hours, the reaction mixture was concentrated at this point and the residue H ₂ O
And lyophilized to give the desired acid.

(Method 12) (EDC Coupling Procedure I) To a solution of N- (toluene-4-sulfonyl) -L-proline (1 equivalent) in CH ₂ Cl ₂ (5-20 mL) was added the appropriate amino acid ester hydrochloride. (1 equivalent), N-methylmorpholine (1.1-2.2 equivalents) and 1-hydroxybenzotriazole (
2 eq.) And placed in an ice bath to give 1- (3-dimethylaminopropyl) -3.
-Ethylcarbodiimide (1.1 eq) was added. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was poured into H ₂ O, the organic phase was washed with saturated NaHCO _3, brine, dried (MgSO ₄ or Na ₂ SO _4), filtered, and concentrated. The crude product was purified by column chromatography.

(Method 13) (EDC Coupling Procedure II) To a solution of the appropriate N-protected amino acid (1 equivalent) in DMF (5-20 mL) was added the appropriate amino acid ester hydrochloride (1 equivalent), Et ₃ N (1 equivalent). .1 eq.) And 1-hydroxybenzotriazole (2 eq.) Were mixed and placed in an ice bath and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.1 eq.) Was added. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H ₂ O, and 0.2N citric acid the organic phase, H ₂ O, saturated N
Washed with aHCO ₃ , brine, dried (MgSO ₄ or Na ₂ SO ₄ ), filtered and concentrated. This crude product was purified by column chromatography or preparative TLC.

Method 14 Sulfonylation Procedure II The appropriate sulfonyl chloride was dissolved in CH ₂ Cl ₂ and placed in an ice bath. LP
was added ro-L-Phe-OMe · HCl (1 eq) and Et ₃ N (1.1 eq) and the reaction allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture is concentrated, and the residue is partitioned between EtOAc and H ₂ O, and the organic phase is washed with saturated NaHCO ₃ , brine and dried (MgSO ₄ or Na ₂
SO ₄ ) filtered and concentrated. The crude product was purified by column chromatography or preparative TLC.

(Method 15) (Sulfonylation Procedure III) L-Pro-L-4- (3-dimethylaminopropyloxy) -Phe-OM
e [prepared using the procedure described in Method 10] in a CH ₂ Cl ₂ solution of the (1 eq), was added Et ₃ N (5 eq), followed by the appropriate sulfonyl chloride (1.1 eq) Was added. The reaction was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was concentrated, dissolved in EtOAc, saturated NaHCO _3, and washed with 0.2N citric acid. The aqueous phase was made basic with solid NaHCO ₃ and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO ₄ or Na ₂ SO _4), filtered and and concentrated. The crude methyl ester was purified by preparative TLC. The corresponding acid was prepared using the procedure described in Method 7.

Method 16 Hydrogenation Procedure II To a solution of azlactone in methanol (10-15 ml) was added NaOAc (1 equivalent) and 10% Pd / C. 40p of this mixture
It was placed on the hydrogenation vessel (hydrogenator) at SiH _2. After 8-16 hours, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the dehydrodipeptide methyl ester. This ester was converted to dioxane / H ₂ O (5
-10 ml) and to this solution was added 0.5 N NaOH (1.05 eq). After concentration 1-3 hours, the reaction mixture was concentrated and the residue redissolved H ₂ O, and washed with EtOAc. The aqueous phase was acidified with 0.2N HCl and the product was extracted with EtOAc. Combine the organic phases with brine (1 × 5
mL), dried (MgSO ₄ or Na ₂ SO ₄ ), filtered and concentrated to give the acid as an approximately 1: 1 mixture of diastereomers.

(Method 17) (tert-butyl ester hydrolysis procedure II) The tert-butyl ester was dissolved in CH ₂ Cl ₂ (5 mL) and TFA (5 mL).
). The reaction is completed in 1-3 hours, the reaction mixture was concentrated at this point and the residue was dissolved to H ₂ O, concentrated. The residue was re-dissolved in H ₂ O, lyophilized to give the desired product.

Example 1 Synthesis of N- [N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl] -L-phenylalanine N- (toluene-4-sulfonyl) -L-pro Linole (358 mg, 1.4
1 mmol) was dissolved in 7 ml of dry DMSO containing Et ₃ N (3.0 eq, 590 ml) at room temperature under nitrogen. In a separate flask, a solution of the pyridine sulfur trioxide complex (3.0 eq, 660 mg) in DMSO (3 mL) was cooled to 15 ° C. under nitrogen. The prolinol solution was added to the latter reaction mixture by syringe and warmed to room temperature. After 2 hours, the reaction was poured into cold brine (10 mL) and then extracted with ether (2 × 50 mL). The organic layer was 10% citric acid (25 mL),
Washed with water, saturated NaHCO ₃ (25 mL), and brine. The desired prolinal was isolated as a fluffy solid by filtration and evaporation of the solvent under reduced pressure. This is then combined with L-phenylalanine benzyl ester and NaC
Dissolved in MeOH (4 mL) containing NBH ₃ (1.0 eq). One drop of AcO
The pH was maintained at 6.0 with H. The reaction mixture was stirred overnight at room temperature. Et
OAc and water and brine were added. Wash the organic layer several times and add Mg
And dried over SO _4. The crude, obtained by filtration and evaporation of the solvent under reduced pressure, was eluted by column chromatography (silica gel) with EtOAc / hexane (1: 1). This ester was combined with EtOAc / EtOH / water (
1: 0.5: 0.5) and hydrogenated using a catalytic amount of 10% Pd / C. After filtration over celite, the title product was isolated as a white foam.

[0241] Physical data were as follows.

[0242]

Embedded image

Mass spec: (FAB) 403 (M + H).

Example 2 (Synthesis of N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-L-phenylalanine) Powdered sodium nitrite (1.27 g) was added at 0 ° C. Divided into potassium bromide (4
. 896 g) and D-phenylalanine (2 g) in 2.5 N sulfuric acid (24.2 m).
L) Added to the solution. The reaction mixture was stirred for 20 minutes at 0 ° C., followed by 1 hour at ambient temperature. The product was extracted with ether (3 × 15 mL), and the combined organic extracts were washed with water, brine, dried over MgSO4, and evaporated to dryness under reduced pressure. This product (2.4 g) was used for the next reaction without further purification. The methyl ester was prepared using thionyl chloride and methanol. This product (2 g) was added in one portion to a solution of hydroxylamine in methanol (10 mL). Hydroxylamine HCl (1.15 g) was added to methanol (
Free hydroxylamine was prepared by treatment with Na (380 mg) in 10 mL). The reaction mixture was refluxed overnight, evaporated under reduced pressure,
And the residue was partitioned between water and chloroform. The separated organic layer is dried,
And it was evaporated. The residue was redistributed between 2N HCl and ether.
The separated aqueous phase was made basic with NaHCO ₃ , extracted with chloroform and extracted with MgSO 4
, Filtered and evaporated under reduced pressure to give 400 mg of N-hydroxy-L-phenylalanine methyl ester. N- (toluene-4-sulfonyl) -L-prolinecarbonyl chloride (412 mg) in THF (10 mL)
The solution was mixed with the product from the previous reaction (280 mg) containing triethylamine (145 mg).
mg) in THF (20 mL) at 0 ° C. This mixture is kept at 0 ° C. for 1 hour.
And stirred at ambient temperature for 1 hour, then evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The separated organic layer was dried over MgSO _4, filtered, and evaporated under reduced pressure. The residue was flash chromatographed on 30 g of silica gel. By eluting with chloroform, 3
60 mg of N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-
Hydroxy-L-phenylalanine methyl ester was obtained. The title compound was purified from the product of the previous reaction (1150 mg) in THF (80 ml) with 1 N NaOH (2
. 57 mL). The mixture was stirred overnight at ambient temperature. The crystallized product is filtered off, washed with ether and 0.1 Torr
Drying over r gave 750 mg of the title compound (mp 202-204 ° C).

Example 3 Synthesis of N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-D-phenylalanine The title compound was described for the preparation of Example 2. According to the procedure, L-phenylalanine was prepared in place of D-phenylalanine.

Physical data are as follows: MS: [(+) FAB], [M + H] ⁺ 433.

Example 4 (N- [2-N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-
Synthesis of hydroxyacetyl] -L-4- (N-benzyloxycarbonyl-isonipecotamide) phenylalanine) 2- (hydroxyacetyl) pyrrolidine (J. Org. Chem. (1991)
), 56, 1624) are N-tosylated using standard peptide synthesis methodology and the resulting product is coupled with an appropriately substituted phenylalanine. The title compound was obtained after basic hydrolysis of the ester (mp 92-95 ° C).

The physical data are as follows: MS (+) FAB [M + H] ⁺ 707.

Example 5 N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-
Synthesis of hydroxyacetyl] -L-4- (isonipecotamido) phenylalanine The product from Example 4 was deprotected by hydrogenation in ethanol over Pd / C for 4 hours. The catalyst was filtered off and the filtrate was dissolved in water and lyophilized to give 240 mg of a white solid.

Physical data are as follows: MS (+) FAB [M + H] +573.

Calculated value for C28H36N4O7S.CF3CO2H.3H2O: C:
48.71; H: 5.73; N: 7.57. Found: C, 48.88; H, 5.
35; N: 7.45. (Example 6) ((2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidine-2)
Synthesis of -yl) tetrazol-1-yl] -2- (4-nitrobenzyl) propionic acid) N- (toluene-4-sulfonyl) -L-prolyl-L- (4-nitro) phenylalanine methyl ester and the like A molar amount of PCl ₅ was mixed in dry benzene and stirred for 90 minutes. The yellow solution was treated with a solution of triazohydric acid in benzene and the mixture was stirred at room temperature for 2 hours, then diluted with benzene and washed with saturated NaHCO ₃ and brine. The organic layer was dried and evaporated to give a pale yellow foam. The title compound was prepared from the product of the previous reaction utilizing standard basic hydrolysis techniques and was applied to an off-white fluffy solid (mp 150-1).
60 ° C.).

Physical data are as follows: MS (+) FAB [M + H] +487.

Example 7 ((2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidine-2)
-Yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonyl-isonipecotamido) benzyl) propionic acid methyl ester) The nitro intermediate described in Example 6 Dissolved in methylene chloride, NB
oc-Hexahydroisonicotinic acid, mixed with HOBT, cooled to 5 ° C and treated with DCC. The reaction mixture was allowed to warm to ambient temperature overnight, filtered, evaporated to dryness, and the residue was dissolved in ethyl acetate. The organic phase is washed as usual, dried and evaporated down to give the title compound (mp 92-10).
2 ° C.).

Physical data are as follows: MS (+) FAB [M + H] 682. Example 8 ((2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidine-2)
Synthesis of -yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonyl-isonipecotoamido) benzyl) propionic acid) Prepared using basic hydrolysis technique (mp 180-189 ° C).

The physical data are as follows: MS (+) FAB [M + Li] ⁺ 674. Example 9 Synthesis of N- [N- (toluene-4-sulfonyl) pyrrolidin-2-yl] aminocarbonyl] -L-phenylalanine N-tosylproline (1 g, 3.71 mmol) was added to diphenylphosphoryl azide. (1.13 g, 3.71 mmol) in toluene (50 mL) was added under an argon atmosphere. Triethylamine (394 mg, 3.9 mmol) was added, and the mixture was heated at 80 C for 2 hours. L-phenylalanine benzyl ester (1.75 g, 4.1 mmol) and triethylamine (394
mg, 3.9 mmol) and heated at 80 ° C. overnight. The toluene was removed under reduced pressure and the residue was purified by flash column chromatography (silica, hexane: EtOAc (2: 1)) to give the benzyl ester as a white solid (54%).
0 mg, 28%). Hydrogenation of benzyl ester (10% Pd / C, E
tOH, 40 psi H ₂ ). The catalyst was removed and the product was recrystallized from EtOH / Et ₂ O to give the title compound as a white solid (75 mg, 40%)
As obtained.

The physical data are as follows: C ₂₁ H ₂₅ N ₃ O ₅ S.0.75H ₂ O. Calculated C: 56.68; H: 6.00;
N: 9.44. Found: C, 56.94; H, 5.68; N, 9.05. Mass Spec [FAB] ^"M-H] - at M / Z430 (100
%) (Using an in vitro assay) in vitro assay for determining the binding of a candidate compound for Example A VLA-4, were evaluated the binding of a candidate compound to the alpha ₄ beta ₁ integrin. Compounds that bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (eg, competition assays). This assay is sensitive to IC ₅₀ values as low as about 1 nM.

[0257] alpha ₄ beta ₁ integrin activity, soluble VCAM-1, Jurkat cells, a human T cell line expressing the alpha ₄ beta ₁ integrin high levels (e.g., American Type Culture Collection No. TIB 152, TIB 153 and C
RL 8163). VCAM-1 is, alpha ₄ beta ₁ integrin-dependent manner by interacting with cell surface (Yednock et al., J.Bio
l. Chem. 1995, 270: 28740).

[0258] Recombinant soluble VCAM-1, seven extracellular domains of VCAM-1 to N-terminus, and the C-terminus is expressed as a chimeric fusion protein containing the human IgG ₁ heavy chain constant region. VCAM-1 fusion proteins were made and purified as described by Yednock (supra).

Jurkat cells were isolated as described by Yednock (supra) for 1 hour.
Grow in RPMI 1640 supplemented with 0% fetal calf serum, penicillin, streptomycin, and glutamine.

Jurkat cells were treated with 1.5 mM MnCl ₂ and 5 μg / mL 15/7.
Incubated with antibody for 30 minutes on ice. Mn ²⁺ is a receptor activated to increase ligand binding, and 15/7 is a alpha ₄ beta ₁ integrin activated / monoclonal antibodies that recognize conformation occupied by ligands, and locks the molecule into this conformation thereby stabilizing the _VCAM-1 / α ₄ β 1 integrin interaction. Yednock
See above. Antibodies similar to the 15/7 antibody have been prepared by other researchers (Lu
que et al., 1996, J. Am. Biol. Chem. 271: 11067), and can be used in this assay.

The cells were then transferred from 66 μM to 0.01 μM using standard 5-point serial dilutions.
Incubated with candidate compounds at various concentrations ranging up to M for 30 minutes at room temperature. Then, 15 μL of soluble recombinant VCAM-1 fusion protein was added to Jurkat cells and incubated on ice for 30 minutes (Yednoc)
k et al., supra).

The cells were then washed twice and placed in PE-conjugated goat F (ab ') ₂ anti-mouse IgG Fc (Immunotech, Westbrook, ME).
: Resuspended at 200 and incubated on ice for 30 minutes in the dark. Ye
Cells were washed twice and analyzed using a standard fluorescence activated cell sorter ("FACS") assay as described in dnock et al. (supra).

[0263] Compounds having an IC ₅₀ less than about 15μM has binding affinity for the alpha ₄ beta _1.

When tested in this assay, each compound of Examples 1-9 had 15 μM
It has the following IC _50.

[0265] (Example vitro saturation assays for determining binding of the candidate compound to the B alpha ₄ beta ₁₎ below, experimental autoimmune encephalomyelitis, which is described in the following examples ( "EAE") model, Or describe an in vitro assay to determine the required plasma levels for compounds that are active in other in vivo models.

Exponentially growing Jurkat cells were washed and resuspended in normal animal plasma containing 20 μg / ml of the 15/7 antibody (described in the Examples above).

The Jurkat cells were prepared using standard 12-point serial dilutions of standard compounds containing known concentrations of the candidate compound at various concentrations ranging from 66 μM to 0.01 μM for the standard curve. Is diluted two-fold into either a plasma sample of, or in a plasma sample obtained from peripheral blood of an animal treated with the candidate compound.

The cells are then incubated at room temperature for 30 minutes and twice with phosphate-buffered saline ("PBS") containing 2% fetal calf serum and 1 mM each of calcium and magnesium chloride (assay medium). Wash to remove unbound 15/7 antibody.

The cells were then transformed with phycoerythrin-conjugated goat F (ab ') ₂ anti-mouse Ig.
1: 200 to G Fc (Immunotech, Westbrook, ME), which has been adsorbed for any non-specific cross-reactivity by co-incubation with 5% serum from the animal species being studied. Expose and incubate at 4 ° C. for 30 minutes in the dark.

The cells are washed twice with assay medium and resuspended in the same assay medium. These are then described in Yednock et al. Biol. Chem. , 1
Analyze using a standard fluorescence activated cell sorter ("FACS") assay as described in 995, 270: 28740.

The data is then combined with fluorescence versus dose (eg, in a normal dose response mode).
As a graph. The dose level that produces a plateau at the top of this curve indicates the level required to obtain efficacy in an in vivo model.

[0272] The assay can also be other integrins (e.g., alpha ₉ beta ₁ integrin (which is the integrin most closely related to α ₄ β ₁₎₎ plasma levels needed to saturate the binding sites of (Palmer et al., 19
93; Cell Bio. , 123: 1289). Such a bond is α ₉
As inflammatory conditions (e.g. mediated by beta ₁ integrin, resulting in chronic asthma,
Airway hyper-responsibleness
And obstruction, proliferation of smooth muscle cells in atherosclerosis, vascular obstruction after angioplasty, fibrosis and glomerular scarring as a result of kidney disease, aortic stenosis,
In vivo utility for synovial hypertrophy in rheumatoid arthritis, and inflammation and scarring resulting from the development of ulcerative colitis and Crohn's disease.

[0273] Thus, the above assays, alpha ₉ in order to measure the beta ₁ integrin binding in place of Jurkat cells, a human colon carcinoma cells transfected with a cDNA encoding alpha ₉ integrin line SW480 (ATCC # CCL228
) (Yokosaki et al., 1994, J. Biol. Chem., 269: 26).
691). As a control, SW480 cells expressing other α and β ₁ subunits can be used.

[0274] Accordingly, another aspect of the present invention relates to a method for treating a disease in a mammalian patient, the disease is mediated by alpha ₉ beta _1, and the method, the present invention a therapeutically effective amount of And administering the compound to the patient. Such compounds are preferably administered in a pharmaceutical composition as described herein above. Effective daily dosing will depend on the patient's age, weight, and condition, which can be readily ascertained by the attending physician. However, in a preferred embodiment, the compound is administered at about 20-500 μg / kg per day.

Example C In Vivo Evaluation A standard multiple sclerosis model, experimental autoimmunity (or allergic)
Encephalomyelitis ("EAE") was used to determine the effect of a candidate compound on reducing motor impairment in rats or guinea pigs. Reduction in dyskinesia is based on blocking adhesion between leukocytes and endothelium and correlates with anti-inflammatory activity in this candidate compound. This model was previously described by Keszthelyi et al., Ne.
urology, 1996, 47: 1053-1059, and measures the delay in the onset of the disease.

The adult Hartley guinea pig brain and spinal cord were homogenized in equal volumes of phosphate buffered saline. An equal volume of Freund's complete adjuvant (100 mg
(ycobacterium tuberculosis and 10 ml Freund's incomplete adjuvant) were added to the homogenate. This mixture is
This was emulsified by circulating this repeatedly using a peristaltic pump through a 20 ml syringe for about 20 minutes.

Female Lewis rats (2-3 months, 170-220 g) or Hartle
Y guinea pigs (20 days old, 180-200 g) were anesthetized with isoflurane and three injections (0.1 ml each) of this emulsion were made in each flank. The onset of movement disorders is observed within about 9 days.

Candidate compound treatment started on day 8 (immediately before the onset of symptoms). Compounds were administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP").
The dose is given twice daily for 5 days in the range of 10 mg / kg to 200 mg / kg;
Typical doses are 10-100 mg / kg SC, 10-50 mg / kg PO
, And 10-100 mg / kg IP.

[0279] α ₄ β ₁ integrin antibody against GG5 / 3 (Keszthelyi, et al., Ne
urology, 1996, 47: 1053-1059), which delays the onset of symptoms, was used as a positive control and injected subcutaneously at 3 mg / kg on days 8 and 11.

[0280] Body weight and movement disorders were measured daily. Motor impairment was evaluated using the following clinical scores: 0 No change 1 Weak or paralyzed tail 2 Weak hind limbs 3 Paralysis of hind limbs 4 Morbidity or death.

A candidate compound was considered active if the candidate compound delayed the onset of symptoms, for example, if it produced a clinical score of 2 or less or slowed weight loss compared to controls.

[0282] Inflammatory conditions mediated by (Example D) (Asthma Model) alpha ₄ beta ₁ integrin, for example, occurs in chronic asthma, airway hyperresponsiveness and occlusion. The following describes an asthma model that can be used to study the in vivo effects of the compounds of the invention for use in treating asthma.

Abraham et al. Clin. Invest, 93: 776-787 (1
994) and Abraham et al., Am J. et al. Respir Crit Car
e Med, 156: 696-703 (1997), both of which are incorporated by reference in their entirety, formulate the compounds of the present invention in an aerosol and prepare the Ascaris suum antigen Administer to sheep that are hypersensitive to Compounds that reduce the early antigen-induced bronchial response and / or block the late airway response (eg, have a protective effect against antigen-induced late response and airway hyperresponsiveness ("AHR")) are described in this model. Are considered active.

Allergic sheep, which have been shown to develop both early and late bronchial responses to inhaled Ascaris suum antigen, are used to study the airway effects of candidate compounds. After topical anesthesia through the nose with 2% lidocaine, the balloon catheter is advanced through one nostril into the lower esophagus. Then
The animal is intubated through the other nostril using a cuffed endotracheal tube with a flexible fiber optic bronchoscope as a guide.

[0285] Intrathoracic pressure is assessed according to Abraham (1994). The aerosol (see formulation below) is dispensed into a disposable medical nebulizer (And
mass median aerodynamic di as 3.2 μm as determined using an erson cascade impactor
aerosol having an aerosol). The nebulizer is connected to a dosimeter system consisting of a solenoid valve and a source of compressed air (20 psi). The output of the nebulizer is directed to a piece of plastic T, one end of which is connected to the inspiratory port of a piston respirator. The solenoid valve is activated for one second at the beginning of the respiratory inspiratory cycle. The aerosol is delivered at a V _{T of} 500 ml and a rate of 20 breaths / min. Only a 0.5% sodium bicarbonate solution is used as a control.

To assess bronchial response, a cumulative enrichment-response curve for carbachol was
Abraham (1994). Bronchial biopsies may be taken before or after the start of treatment and 24 hours after antigen challenge. Bronchial biopsies may be performed according to Abraham (1994).

[0287] Studies of in vitro adhesion of alveolar macrophages were also performed by Abraham (199).
4) and calculate the percentage of adherent cells.

Aerosol Formulation A solution of the candidate compound (concentration 30.0 mg / mL) in 0.5% sodium bicarbonate / saline (w / v) is prepared using the following procedure.

(A. 0.5% sodium bicarbonate / saline stock solution (100.0 mL
Preparation of))

[0290]

[Table 3]

Procedure: 1. Add 0.5 g sodium bicarbonate to a 100 mL volumetric flask. 2. Add about 90.0 mL of saline and sonicate until dissolved. 3. Make up to 100.0 mL with saline and mix thoroughly.

(B. Preparation of 30.0 mg / mL Candidate Compound (10.0 mL))

[0293]

[Table 4]

Procedure: 1. Add 0.300 g of candidate compound to a 10.0 mL volumetric flask. 2. Add about 9.7 mL of 0.5% sodium bicarbonate / saline stock solution. 3. Sonicate until the candidate compound is completely dissolved. 4. 10.0 mL with 0.5% sodium bicarbonate / saline stock solution
And mix thoroughly.

Using conventional oral formulations, compounds of the present invention are active in this model.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 3/10 A61P 3/10 9/10 9/10 11/00 11/00 11/06 11/06 19 / 00 19/00 19/02 19/02 25/00 25/00 25/28 25/28 27/04 27/04 29/00 29/00 101 101 35/04 35/04 37/00 37/00 C07D 207/09 C07D 207/09 401/04 401/04 C07K 5/023 C07K 5/023 5/06 5/06 5/078 5/078 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), E (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR , CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, K Z, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, 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 Ashwell, Susan United States New Jersey 08536, Planes Bureau, Aspen Drive 1015 (72) Inventor Baudi Reinhard Bernhard United States Pennsylvania 18901, Doylestown, Harinton Coat 5281 (72) invention's Place, Michael Aye. United States California 94087-1355, Sunnyvale, Stellacoat 848 (72) Inventor Salantakis, Dimitrios United States Pennsylvania 18940, Newtown, Sentinel Avenue 262 (72) Inventor Sausset, Eugene Dee. United States 94038, Mos Beach, Buena Vista 571 F-term (reference) 4C063 AA01 BB01 CC47 DD03 EE01 4C069 AA23 4C086 AA01 AA02 AA03 BC07 BC21 BC62 GA07 MA01 MA04 NA14 ZA01 ZA15 ZA16 ZA36 ZA51 ZA81 ZAB ZAB ZAB ZAB ZAB ZAB AA30 BA11 EA20 FA30 FA41

Claims (30)

[Claims] 1. Formula I: ## STR1 ## And pharmaceutically acceptable salts thereof, wherein R ¹ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl is selected from the group consisting of heterocyclic and substituted heterocyclic; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic, substituted is selected from the group consisting of heterocyclic, and R ¹ and R ² are heterocyclic group or substituted heterocyclic ring together with the nitrogen atom and an SO ₂ group bound to R ² It can form Shikimoto; R ³ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl Alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic is selected from the group consisting of substituted heterocyclic, and R ² do not form a R ¹ and a heterocyclic group R ² and R ³ may together with the nitrogen atom bonded to R ² and the carbon atom bonded to R ³ form a heterocyclic or substituted heterocyclic group; R ⁴ is hydrogen, alkyl, R ³ is selected from the group consisting of substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; ^If neither a heterocyclic group nor a substituted heterocyclic group is formed with 2,
R ³ and R ⁴ together with the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R ⁵ is isopropyl, —CH ₂ — Selected from the group consisting of W and = CH-W, wherein W is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, Aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
Selected from the group consisting of carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxy-substituted heterocyclic, and hydroxyl, , R ⁵ is −CH—W, (H) is omitted from the formula and W is not hydroxyl; and Q is the following (i)-(v): (i) Wherein X is selected from the group consisting of oxygen, sulfur, and NH; (ii) Here, R ⁷ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ⁸ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁷ and R ⁸ are bonded to R ⁷ A heterocyclic ring or a substituted heterocyclic ring together with the nitrogen atom to be bonded and the carbon attached to R ⁸ ; (iii) Here, R ⁹ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ¹⁰ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁹ and R ¹⁰ are bonded to R ⁹ X may be selected from the group consisting of oxygen, sulfur and NH together with the nitrogen atom, the carbon atom attached to R ¹⁰ and the —C (X) — group. (Iv) embedded image Here, R ¹¹ and R ¹² are bonded to a nitrogen atom bonded to R ¹¹ and R ¹² >
Together with the C = N- group form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and (v) Wherein R ¹³ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; X is oxygen, sulfur, and NH A compound selected from the group consisting of: 2. A compound of formula IA: And pharmaceutically acceptable salts thereof, wherein R ¹ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl is selected from the group consisting of heterocyclic and substituted heterocyclic; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic, substituted is selected from the group consisting of heterocyclic, and R ¹ and R ² are heterocyclic group or substituted heterocyclic ring together with the nitrogen atom and an SO ₂ group bound to R ² It can form Shikimoto; R ³ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl Alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic is selected from the group consisting of substituted heterocyclic, and R ² do not form a R ¹ and a heterocyclic group R ² and R ³ may together with the nitrogen atom bonded to R ² and the carbon atom bonded to R ³ form a heterocyclic or substituted heterocyclic group; R ⁴ is hydrogen, alkyl, R ³ is selected from the group consisting of substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic; ^{If 2} and a heterocyclic group which may not be formed substituted heterocyclic group, R ³
And R ⁴ together with the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R ⁵ is isopropyl, —CH ₂ —W and ＣＨCH—W wherein W is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxy Aryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
Selected from the group consisting of carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxy heterocyclic, carboxy-substituted heterocyclic, and hydroxyl, , R ⁵ is ＣＨCH—W, (H) is omitted from the formula and W is not hydroxyl; R ⁶ is amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy , Substituted aryloxy, heteroaryloxy,
Substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, -NHOY (wherein, Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl), and _{-NH (CH 2) p COOY '} ( here , Y ′ is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and p is an integer from 1 to 8); and Q is (i) to (v): (I) Wherein X is selected from the group consisting of oxygen, sulfur, and NH; (ii) Here, R ⁷ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ⁸ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁷ and R ⁸ are bonded to R ⁷ A heterocyclic ring or a substituted heterocyclic ring together with the nitrogen atom to be bonded and the carbon bonded to R ⁸ ; (iii) Here, R ⁹ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ¹⁰ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁹ and R ¹⁰ are bonded to R ⁹ X may be selected from the group consisting of oxygen, sulfur and NH together with the nitrogen atom, the carbon atom attached to R ¹⁰ and the —C (X) — group. And (iv) Here, R ¹¹ and R ¹² are bonded to a nitrogen atom bonded to R ¹¹ and R ¹² >
Together with the C = N- group form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and (v) Wherein R ¹³ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; X is oxygen, sulfur, and NH A compound selected from the group consisting of: 3. The compound according to claim 1 or 2, wherein R ¹ is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl. A compound selected from the group consisting of: 4. The compound according to claim 1 or 2, wherein R ¹ is methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-
Methylphenyl, 4-t-butylphenyl, 2,4,6-trimethylphenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4
-Difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4
-Dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butoxyphenyl, 4- (3′-dimethylamino-n-propoxy) -phenyl, 2-carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4- _{(H 2 NC (O) -} )
Phenyl, 4- (H ₂ NC (S) -) phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3,5-di (trifluoromethyl) phenyl, 4-nitrophenyl , 4-aminophenyl, 4-
_{(CH 3 C (O) NH-} ) phenyl, 4- (PhNHC (O) NH- ) phenyl, 4-amidinophenyl, 4-methyl-amidinophenyl, 4- (CH ₃ SC (=
NH) -) phenyl, 4-chloro _{-3- (H 2 NS (O)} 2 -) phenyl, 1-naphthyl, 2-naphthyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, Quinolin-8-yl, 2- (trifluoroacetyl) -1,2,3
, 4-Tetrahydroisoquinolin-7-yl, morpholin-4-yl, 2-thienyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-
Methyl imidazol-4-yl, 1-N-methylpyrazol-3-yl, 1-N
-Methylpyrazol-4-yl, 1-N-butylpyrazol-4-yl, 1-N
-Methyl-3-methyl-5-chloropyrazol-4-yl), 1-N-methyl-
A compound selected from the group consisting of 5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl. 5. A compound according to claim 1 or 2, wherein, R ² is hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2-2-thienyl,} and -
A compound selected from the group consisting of (CH ₂ ) ₂ -φ. 6. A compound according to claim 1 or 2, wherein R ² and R ³ are a complex together with a nitrogen atom bonded to the R ² substituent and a carbon bonded to the R ³ substituent. A compound that forms a cyclic or substituted heterocyclic group. 7. The compound according to claim 6, wherein R ² and R ³ are substituted heterocycles together with a nitrogen atom bonded to the R ² substituent and a carbon bonded to the R ³ substituent. A compound that forms a formula ring. 8. The compound according to claim 1 or 2, wherein R ¹ and R ² are bonded together with a nitrogen atom bonded to R ² and a SO ₂ group bonded to R ^1. A compound that forms a heterocyclic ring or a substituted heterocyclic ring. 9. The compound according to claim 1 or 2, wherein R^ThreeBut
, Hydrogen, methyl, phenyl, benzyl, diphenylmethyl, 2-carboxyethyl
, 2-amidoethyl, iso-butyl, t-butyl, carboxymethyl, -CH _Two A compound selected from the group consisting of O-benzyl and hydroxymethyl. 10. The compound according to claim 1 or 2, wherein R ⁴
Is selected from the group consisting of hydrogen, methyl, ethyl and phenyl. 11. A compound according to claim 1 or 2, wherein, Q is, -C (O) N (O ) -, - CH 2 NH -, - CH (OH) C (O) NH-,-
A compound selected from the group consisting of NHC (O) NH— and tetrazol-1,5-diyl. 12. The compound according to claim 1 or 2, wherein R ⁵
Is as follows: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [φ-CH (CH ₃ ) O-] benzyl, 4- [ φ-CH (COOH) O-] benzyl, 4- [BocNHCH ₂ C (O) NH-] benzyl, 4-chlorobenzyl, 4- [NH ₂ CH ₂ C (O) NH-] benzyl, 4-carboxybenzyl _{, 4- [CbzNHCH 2 CH 2 NH-} ] benzyl, 3-hydroxy -4- (φ-OC (O) NH-) _{benzyl, 4- [HOOCCH 2 CH 2 C} (O) NH-] benzyl, benzyl, 4 -[2'-carboxylphenoxy-] benzyl, 4- [φ-C (O) NH-] benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3 5-di-iodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxyphenyl -] _{benzyl, φ-CH 2 CH 2 -} , 4- nitrobenzyl, 2-carboxybenzyl, 4- [dibenzyl Amino] -benzyl, 4-[(1′-cyclopropylpiperidin-4′-yl) C (O) NH—] benzyl, 4-[— NHC (O) CH ₂ NHBoc] benzyl, 4-carboxybenzyl, 4 - hydroxy-3-nitrobenzyl, 4 - [- NHC (O ) CH (CH 3) NHBoc] benzyl, 4 - [- NHC (O ) CH (CH 2 φ) NHBoc] benzyl, isobutyl, methyl, 4- [ CH ₃ C (O) NH-] benzyl, -CH ₂ - (3- indolyl), n-butyl, t- butyl _{-OC (O) CH 2 -,} t- butyl -OC (O) C _{2 CH 2 -, H 2 NC} (O) CH 2 -, H 2 NC (O) CH 2 CH 2 -, BocNH- (CH 2) 4 -, t- butyl _{-OC (O) - (CH 2} ) 2 _{-, HOOCCH 2 -, HOOC (} CH 2) 2 -, H 2 N (CH 2) 4 -, isopropyl, (1-naphthyl) -CH ₂ -, (2-naphthyl) -CH ₂ -, (2-thiophenyl _{) -CH 2 -, (φ-} CH 2 -OC (O) NH- (CH 2) 4 -, cyclohexyl -CH ₂ -, benzyloxy _{-CH 2 -, HOCH 2 -,} 5- (3-N- benzyl ) imidazolyl -CH ₂ -, 2-pyridyl -CH ₂ -, 3- pyridyl -CH ₂ -, 4-pyridyl _{-CH 2 -, 5- (3-} N- methyl) imidazolyl -CH ₂ -, N-Benjirupiperido - 4-yl -CH ₂ -, N-Boc- piperidin-4-y -CH ₂ -, N- (phenyl - carbonyl) piperidin-4-yl _{-CH 2 -, H 3 CSCH 2} CH 2 -, 1-N- benzyl-imidazol-4-yl -CH ₂ -, iso - propyl -C _{(O) NH- (CH 2)} 4 -, iso - butyl _{-C (O) NH- (CH 2} ) 4 -, phenyl _{-C (O) NH- (CH 2} ) 4 -, benzyl -C (O) NH- (CH _{2) 4} -, allyl _{-C (O) NH- (CH 2} ) 4 -, 4- (3-N- methylimidazolyl) -CH ₂ -, 4- imidazolyl, 4 - [(CH _{3) 2 NCH 2 CH 2 CH 2 -O-} ] benzyl, 4 - [(benzyl) ₂ N -] - benzyl, 4-aminobenzyl, allyloxy -C (O) NH (CH _{2) 4} -, allyloxy -C (O _{) NH (CH 2) 3 -} , allyloxy _{-C (O) NH (CH 2} ) 2 _{, NH 2 C (O) CH} 2 -, φ-CH =, 2- pyridyl _{-C (O) NH- (CH 2} ) 4 -, 4- methylpyrid-3-yl -C (O) NH- (CH ₂ ) ₄ -, 3-methylthien-2-yl -C (O) NH- (CH _{2) 4} -, 2-pyrrolyl -C (O) NH- (CH _{2) 4} -, 2-furanyl -C (O) _{NH- (CH 2) 4 -,} 4- methylphenyl _{-SO 2 -N (CH 3) CH} 2 C (O) NH (CH 2) 4 -, 4- [ cyclopentyl acetylene Les sulfonyl] - benzyl, 4- [ -NHC (O) - (N- Boc) - pyrrolidin-2-yl)] - benzyl -, 1-N-methyl-imidazol-4-yl -CH ₂ -, 1-N-methyl-imidazol-5-yl -CH ₂ -, imidazol-5-yl -CH ₂ -, 6- methylpyrid-3-yl -C (O) NH- ( _{H 2) 4 -, 4- [} 2'- carboxymethyl phenyl] - benzyl, 4 - [- NHC (O ) NHCH 2 CH 2 CH 2 -φ] - benzyl, 4 - [- NHC (O ) NHCH 2 CH ₂ -φ] -benzyl, -CH ₂ C (O) NH (CH ₂ ) ₄ φ, 4- [φ (CH ₂ ) ₄ O-]-benzyl, 4-[-C≡C-φ-4′φ ] -Benzyl, 4-[— C≡C—CH ₂ —OS (O) ₂ -4′-CH ₃ —φ] -benzyl, 4-[— C≡C—CH ₂ NHC (O) NH ₂ ] -Benzyl, 4-[— C≡C—CH ₂ —O-4′-COOCH ₂ CH ₃ —φ] -benzyl, 4-[— C≡C—CH (NH ₂ ) -cyclohexyl] -benzyl, — _{(CH 2) 4 NHC (O} ) CH 2 -3- _{indolyl, - (CH 2) 4 NHC} (O) CH 2 CH 2 -3- indolyl, - (CH _{2) 4} NH C (O) -3- (5- _{methoxy-indolyl), - (CH 2) 4} NHC (O) -3- (1- _{methyl-indolyl), - (CH 2) 4} NHC (O) -4- ( —SO ₂ (CH ₃ ) -φ), — (CH ₂ ) ₄ NHC (O) -4- (C (O) CH ₃ ) -phenyl, — (CH ₂ ) ₄ NHC (O) -4-fluorophenyl _{, - (CH 2) 4 NHC} (O) CH 2 O-4- fluorophenyl, 4 - [- C≡C- (2- pyridyl)] benzyl, 4 - [- C≡C-CH 2 -O- phenyl ] Benzyl, 4-[— C≡C—CH ₂ OCH ₃ ] benzyl, 4-[— C≡C— (3-hydroxyphenyl)] benzyl, 4-[— C≡C—CH ₂ —O-4 ′ - (- C (O) OC 2 H 5) phenyl] benzyl, 4 - [- C≡C-CH 2 CH (C (O) OCH 3) 2] benzyl, 4- -C≡C-CH ₂ NH- (4,5- dihydro-4-oxo-5-phenyl - oxazol-2-yl), 3-aminobenzyl, 4 - [- C≡C-CH 2 CH (NHC ( _{O) CH 3) C (O} ) OH] - _{benzyl, -CH 2 C (O) NHCH} (CH 3) φ, -CH 2 C (O) NHCH 2 - (4- dimethylamino) -φ, -CH ₂ C (O) NHCH _2-4 -nitrophenyl, —CH ₂ CH ₂ C (O) N (CH ₃ ) CH ₂ —φ, —CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ — (N-methyl) _{2-pyrrolyl, -CH 2 CH 2 C (O} ) NHCH 2 CH 2 CH 2 CH 3, -CH 2 CH 2 C (O) NHCH 2 CH 2 -3- _{indolyl, -CH 2 C (O) N} ( CH ₃₎ CH _{2 phenyl, -CH 2 C (O) NH} (CH 2) 2 - (N- methyl) -2-pyrrolyl _{-CH 2 C (O) NHCH 2} CH 2 CH 2 CH 3, -CH 2 C (O) NHCH 2 CH 2 -3- _{indolyl, - (CH 2) 2 C} (O) NHCH (CH 3) φ, - _{(CH 2) 2 C (O} ) NHCH 2 -4- _{dimethylaminophenyl, - (CH 2) 2 C} (O) NHCH 2 -4- _{nitrophenyl, -CH 2 C (O) NH} -4 - [- NHC (O) CH ₃ - _{phenyl], -CH 2 C (O)} NH-4- _{pyridyl, -CH 2 C (O) NH} -4- [ _{dimethylaminophenyl], -CH 2 C (O)} NH-3- _{methoxyphenyl, -CH 2 CH 2 C (O} ) NH-4- _{chlorophenyl, -CH 2 CH 2 C (O} ) NH-2- _{pyridyl, -CH 2 CH 2 C (O} ) NH-4- methoxyphenyl, - _{CH 2 CH 2 C (O)} NH-3- _{pyridyl, 4 - [(CH 3)} 2 NC ₂ CH ₂ O-] _{benzyl, - (CH 2) 3 NHC} (NH) NH-SO 2 -4- _{methylphenyl, 4 - [(CH 3)} 2 NCH 2 CH 2 O-] benzyl, - (CH _{2) 4 NHC (O) NHCH 2 CH} 3, - (CH 2) 4 NHC (O) NH- _{phenyl, - (CH 2) 4 NHC} (O) NH-4- methoxyphenyl, 4- [4'-pyridyl -C (O) NH-] benzyl, 4- [3'-pyridyl-C (O) NH-] benzyl, 4-[-NHC (O) NH-3'-methylphenyl] benzyl, 4-[-NHC (O _{) CH 2 NHC (O) NH} -3'- methylphenyl] benzyl, 4 - [- NHC (O ) - (2 ', 3'- dihydro-indol-2-yl)] benzyl, 4 - [- NHC (O )-(2 ', 3'-dihydro-N-Boc-indole-
2-yl)] benzyl, p-[— OCH ₂ CH ₂ -1 ′-(4′-pyrimidinyl) -piperazinyl] benzyl, 4-[— OCH ₂ CH ₂ — (1′-piperidinyl)] benzyl, 4- [-OCH ₂ CH ₂ - (1'- pyrrolidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 - (1'- piperidinyl)] benzyl -, -CH ₂ -3- (1,2,4- _{triazolyl), 4 - [- OCH 2} CH 2 CH 2 -4- (3'- chlorophenyl) - piperazine -
1-yl] benzyl, 4-[— OCH ₂ CH ₂ N (φ) CH ₂ CH ₃ ] benzyl, 4-[— OCH ₂ -3 ′-(N-Boc) -piperidinyl] benzyl, 4- [di- n- pentylamino] benzyl, 4- [n- pentylamino] benzyl, 4- [di - iso - propylamino -CH ₂ CH ₂ O-] _{benzyl, 4 - [- OCH 2 CH} 2 - (n- morpholinyl) ] benzyl, 4 - [- O- (3 '- (N-Boc) - piperidinyl] _{benzyl, 4 - [- OCH 2 CH} (NHBoc) CH 2 cyclohexyl] _{benzyl, p- [OCH 2 CH 2 -} (N- piperidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 - (4-m- chlorophenyl) - piperazine -1
- yl] _{benzyl, 4 - [- OCH 2 CH} 2 - (N- homopiperidinyl)] benzyl, 4 - [- NHC (O ) -3 '- (N-Boc) - piperidinyl] benzyl, 4 - [- OCH ₂ CH ₂ N (benzyl) _2] benzyl, -CH _{2-2-thiazolyl, 3-hydroxybenzyl, 4- [OCH 2 CH 2 CH} 2 N (CH 3) 2] benzyl, 4 - [- NHC (S ) NHCH ₂ CH ₂ - (N- morpholino)] _{benzyl, 4 - [- OCH 2 CH} 2 N (C 2 H 5) 2] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (C 2 H 5) 2] _{benzyl, 4- [CH 3 (CH 2} ) 4 NH-] benzyl, 4- [N-n- butyl, N-n-pentylamino -] benzyl, 4 - [- NHC (O ) -4'- piperidinyl] Benzyl, 4-[-NHC (O) CH (NHBoc (CH _{2) 4} NHCbz] benzyl, 4 - [- NHC (O ) - (1 ', 2', 3 ', 4'- tetrahydro -N-Bo
c- isoquinolin-1'-yl] _{benzyl, p - [- OCH 2 CH} 2 CH 2 -1 '- (4'- methyl) - piperazinyl] _{benzyl, - (CH 2) 4 NH} -Boc, 3 - [- _{OCH 2 CH 2 CH 2 N (} CH 3) 2] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) 2] _{benzyl, 3 - [- OCH 2 CH} 2 - (1'- pyrrolidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) benzyl] benzyl, 4 - [- NHC (S ) NHCH 2 CH 2 CH 2 - (N- morpholino)] benzyl, 4 - [- OCH ₂ CH ₂ - (N-morpholino)] _{benzyl, 4 - [- NHCH 2 -} (4'- chlorophenyl)] benzyl, 4 - [- NHC (O ) NH- (4'- cyanophenyl)] benzyl, 4- [ -OCH ₂ COOH] benzyl, 4 - [- OC ₂ COOH-t-butyl] benzyl, 4 - [- NHC (O ) -5'- fluoro-indol-2-yl] benzyl, 4 - [- NHC (S ) NH (CH 2) 2 -1- piperidinyl] benzyl , 4 - [- N (SO 2 CH 3) (CH 2) 3 -N (CH 3) 2] benzyl, 4 - [- NHC (O ) CH 2 CH (C (O) OCH 2 φ) -NHCbz] benzyl, 4 - [- NHS (O ) 2 CF 3] benzyl, 3 - [- O- (N- methylpiperidin-4'-yl] benzyl, 4 - [- C (= NH) NH 2] benzyl, 4 _{- [- NHSO 2 -CH 2 Cl} ] benzyl, 4 - [- NHC (O ) - (1 ', 2', 3 ', 4'- tetrahydroisoquinolin-2'-yl] benzyl, 4 - [- NHC ( _{S) NH (CH 2) 3} -N- morpholino] benzyl, 4 - [- NHC (O ) _{CH (CH 2 CH 2 CH 2} CH 2 NH 2) NHBoc] benzyl, 4 - [- C (O ) NH 2] benzyl, 4 - [- NHC (O ) NH-3'- methoxyphenyl] benzyl, 4- [-OCH ₂ CH ₂ - indol-3'-yl] _{benzyl, 4 - [- OCH 2 C} (O) NH- benzyl] _{benzyl, 4 - [- OCH 2 C} (O) O- benzyl] benzyl, 4- _{[-OCH 2 C (O) OH} ] _{benzyl, 4 - [- OCH 2 -2} '- (4', 5'- dihydro) imidazolyl] _{benzyl, -CH 2 C (O) NHCH} 2 - (4- dimethylamino ) Phenyl, 4-[— NHC (O) -L-2′-pyrrolidinyl-N—SO ₂ -4′-methylphenyl] benzyl, 4-[— NHC (O) NHCH ₂ CH ₂ CH ₃ ] benzyl, 4 -[Aminobenzyl] benzyl, 4-[-O CH ₂ CH ₂ -1- (4- hydroxy-4- (3-methoxy-pyrrol-2-yl) - piperazinyl] benzyl, 4 - [- O-(N-methylpiperidin-4'-yl)] benzyl, 3 - methoxybenzyl, 4 - [- NHC (O ) - piperidin-3'-yl] benzyl, 4 - [- NHC (O ) - pyridin-2'-yl] _{benzyl, 4 - [- NHCH 2 -} (4 ' - chlorophenyl)] benzyl, 4 - [- NHC (O ) - (N- (4'-CH 3 -φ-SO 2) -L- pyrrolidin-2'-yl)] benzyl, 4 - [- NHC (O ) NHCH ₂ CH ₂ -φ] _{benzyl, 4 - [- OCH 2 C} (O) NH 2] _{benzyl, 4 - [- OCH 2 C} (O) NH-t- butyl] benzyl, 4 - [- OCH ₂ CH _2-1- (4-hydroxy-4-phenyl) - piperidinyl] _{Njiru, 4 - [- NHSO 2 -CH} = CH 2] _{benzyl, 4 - [- NHSO 2 -CH} 2 CH 2 Cl] _{benzyl, -CH 2 C (O) NHCH} 2 CH 2 N (CH 3) 2, 4 -[(1'-Cbz-piperidin-4'-yl) C (O) NH-] benzyl, 4-[(1'-Boc-piperidin-4'-yl) C (O) NH-] benzyl, 4 - [(2'-bromophenyl) C (O) NH-] benzyl, 4 - [- NHC (O) - pyridin-4'-yl] benzyl, 4 - [(4 '- (CH 3) 2 NC ( O) O-) phenyl) -C (O) NH-] benzyl, 4-[-NHC (O) -1'-methylpiperidin-4'-yl-] benzyl, 4- (dimethylamino) benzyl, 4- [-NHC (O)-(1'-N-Boc) -piperidin-2'-yl] benzyl, 3-[-N C (O) - pyridin-4'-yl] benzyl, 4 - [(tert- butyl -O (O) CCH ₂ -O- benzyl) -NH-] _{benzyl, [BocNHCH 2 C (O)} NH-] butyl , 4-benzyl benzyl, _{2-hydroxyethyl, 4 - [(Et) 2} NCH 2 CH 2 CH 2 NHC (S) NH-] benzyl, 4 - [(1'-Boc -4'- hydroxypyrrolidine-2 ' -Il) C (O)
NH-] _{benzyl, 4- [φCH 2 CH 2 CH} 2 NHC (S) NH-] benzyl, 4 - [(perhydro-indoline-2'-yl) C (O) NH-] benzyl, 2- [4- Hydroxy-4- (3-methoxythien-2-yl) piperidine-
1-yl] ethyl, 4-[(1′-Boc-perhydroindoline-2′-yl) -C (O) NH
-] Benzyl, 4-[(N-3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl, 4-[(N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2] .2] octan-2-yl) ethyl-
O-] benzyl, 4-[(4'-hydroxypyrrolidin-2'-yl) C (O) NH-] benzyl, 4- (φNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl 4- (φCH ₂ NHC (S) NH) benzyl, 3-[(1′-Boc-piperidin-2′-yl) C (O) NH—] benzyl 3- [piperidin-2′-yl-C (O ) NH-] benzyl, 4-[(3'-Boc-thiazolidine-4'-yl) C (O) NH-] benzyl, 4- (pyridin-3'-yl-NHC (S) NH) benzyl, 4 _{- (CH 3 -NHC (S)} NH) _{benzyl, 4- (H 2 NCH 2 CH} 2 CH 2 C (O) NH) _{benzyl, 4- (BocHNCH 2 CH 2 CH} 2 C (O) NH) benzyl, 4 - (pyridin-4'-yl -CH ₂ NH) benzyl, 4- [ N, N-di (4-N, N, - dimethylamino) benzyl) amino] benzyl, 4 - [(1-Cbz- piperidin-4-yl) C (O) NH-] butyl, 4- [φCH _{2 OCH 2 (BocHN) CHC (O} ) NH] benzyl, 4 - [(piperidin-4'-yl) C (O) NH-] benzyl, 4 - [(pyrrolidin-2'-yl) C (O) NH- Benzyl, 4- (pyridin-3'-yl-C (O) NH) butyl, 4- (pyridin-4'-yl-C (O) NH) butyl, 4- (pyridin-3'-yl-C (O) NH) _{benzyl, 4- [CH 3 NHCH 2 CH} 2 CH 2 C (O) NH-] _{benzyl, 4- [CH 3 N (Boc} ) CH 2 CH 2 CH 2 C (O) NH-] benzyl 4- (aminomethyl) _{benzyl, 4- [φCH 2 OCH 2 (} H 2 N) CHC ( ) NH] benzyl, 4 - [(1 ', 4'-di (Boc) piperazin-2'-yl) -C (O) NH
-] Benzyl, 4-[(piperazin-2'-yl) -C (O) NH-] benzyl, 4-[(N-toluenesulfonylpyrrolidin-2'-yl) C (O) NH-]
Butyl, 4-[-NHC (O) -4'-piperidinyl] butyl, 4-[-NHC (O) -1'-N-Boc-piperidin-2'-yl] benzyl, 4-[-NHC (O ) -Piperidin-2'-yl] benzyl, 4-[(1'-N-Boc-2 ', 3'-dihydroindoline-2'-yl)
-C (O) NH] benzyl, 4- (pyridin-3'-yl -CH ₂ NH) benzyl, 4 - [(1'-Cbz- piperidin-4'-yl) C (O) NH-] benzyl, 4 - _{[(piperidin-1'-yl) C (O) CH 2 -O-} ] _{benzyl, 4 - [(CH 3)} 2 CH) 2 NC (O) CH 2 -O-] benzyl, 4-[HO (O) C (Cbz-NH ) CHCH 2 CH 2 -C (O) NH-] _{benzyl, 4- [φCH 2 O (O} ) C (Cbz-NH) CHCH 2 CH 2 -C (O) NH-
] Benzyl, 4-[-NHC (O) -2'-methoxyphenyl] benzyl, 4-[(pyrazin-2'-yl) C (O) NH-] benzyl, 4- [HO (O) C (NH _{2) CHCH 2 CH 2 -C (} O) NH-] benzyl, 4- (2'-formyl-1 ', 2', 3 ', 4'-tetrahydroisoquinolin-3'-yl -CH ₂ NH-) benzyl _{, N-Cbz-NHCH 2 -} , 4 - [(4'- methylpiperazin-1'-yl) C (O) O-] _{benzyl, 4- [CH 3 (N-} Boc) NCH 2 C (O) NH -] Benzyl, 4-[-NHC (O)-(1 ', 2', 3 ', 4'-tetrahydro-N-Bo
c- isoquinolin-3'-yl] _{benzyl, 4- [CH 3 NHCH 2 C} (O) NH-] _{benzyl, (CH 3) 2 NC (} O) CH 2 -, 4- (N- methylacetamido) benzyl, 4- (1 ′, 2 ′, 3 ′, 4′-tetrahydroisoquinolin-3′-yl-C
H ₂ NH-) _{benzyl, 4 - [(CH 3)} 2 NHCH 2 C (O) NH-] benzyl, (1-toluenesulfonyl-imidazol-4-yl) methyl, 4 - [(1'-Boc-piperidin - 4'-yl) C (O) NH-] benzyl 4-trifluoromethylbenzyl, 4 - [(2'-bromophenyl) C (O) NH-] _{benzyl, 4 - [(CH 3)} 2 NC (O ) NH-] _{benzyl, 4- [CH 3 OC (O} ) NH-] _{benzyl, 4 - [(CH 3)} 2 NC (O) O-] _{benzyl, 4 - [(CH 3)} 2 NC (O) N (CH ₃₎ -] _{benzyl, 4- [CH 3 OC (O} ) N (CH 3) -] benzyl, 4-(N-methyl trifluoroacetamide) benzyl, 4 - [(1'-methoxycarbonyl-piperidine -4 '-Yl) C (O) NH-
] Benzyl, 4-[(4'-phenylpiperidin-4'-yl) C (O) NH-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) -C (O
) NH-] benzyl, 4-[(piperidin-4'-yl) C (O) O-] benzyl, 4-[(1'-methylpiperidin-4'-yl) -O-] benzyl, 4- [ (1'-methylpiperidin-4'-yl) C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) NH-] benzyl, 3-[(CH ₃ ) ₂ NC (O) O-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) -C (O
) O-] benzyl, 4-(N-toluenesulfonyl amino) _{benzyl, 4 - [(CH 3)} 3 CC (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (O) NH -] _{benzyl, 4 - [(CH 3 CH} 2) 2 NC (O) NH-] benzyl, 4 - [- C (O) NH- (4'-piperidinyl)] benzyl, 4 - [(2'-tri trifluoromethylphenyl) C (O) NH-] benzyl, 4 - [(2'-methylphenyl) C (O) NH-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 O-] benzyl, 4-[(pyrrolidin-2'-yl) C (O) NH-] benzyl, 4-[-NHC (O) -piperidin-1'-yl] benzyl, 4-[(thiomorpholin-4'-yl) C (O) NH-] benzyl, 4-[(thiomorpholin-4'-ylsulfone)- (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (O) O-] benzyl, 3-nitro _{-4- (CH 3 OC (O)} CH 2 O-) benzyl, (2 -Benzoxazolinone-6-yl) methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-
_{, 4 - [(CH 3)} 2 NS (O) 2 NH-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 N (CH 3) -] benzyl, 4 - [(thiomorpholine-4 ' -Yl) C (O) O-] benzyl, 4-[(thiomorpholin-4'-ylsulfone) -C (O) O-] benzyl, 4-[(piperidin-1'-yl) C (O) O -] Benzyl, 4-[(pyrrolidin-1'-yl) C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) O-] benzyl, 4- [(2'-methylpyrrolidin-1'-yl)-, (pyridin-4-yl) methyl-, 4-[(piperazin-4'-yl) -C (O) O-] benzyl, 4-[( 1'-Boc-piperazin-4'-yl) -C (O) O-] benzyl, 4-[(4'-acetylpiperazin-1'-yl) C ( O) O-] benzyl, p-[(4'-methanesulfonylpiperazin-1'-yl) benzyl, 3-nitro-4-[(morpholin-4'-yl) -C (O) O-] benzyl, 4-{[(CH ₃ ) ₂ NC (S)] ₂ N-｝ benzyl, N-Boc-2-aminoethyl-, 4-[(1,1-dioxothiomorpholin-4-yl) -C ( O) O-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 -] benzyl, 4- (imidazolide -2'-one-1'-yl) benzyl, 4 - [(piperidin-1' yl) C (O) O-] benzyl, 1-N-benzyl-- imidazol-4-yl -CH ₂ -, 3,4-oxyethylene, 3,4 dioxymethylene benzyl, 4 - [- N _{(SO 2) (CH 3)} CH 2 CH 2 CH 2 N (CH 3) 2] benzyl, 4- ( 3'-formyl imidazolide -2'-one-1'-yl) benzyl, 4- [NHC (O) CH (CH 2 CH 2 CH 2 CH 2 NH 2) NHBoc] benzyl, [2 '- [4 " -Hydroxy-4 ″-(3 ′ ″-methoxythien-2 ′ ″
- yl) piperidine -2 "- yl] ethoxy] benzyl, and _{p - [(CH 3) 2} NCH 2 CH 2 N (CH 3) C (O) O-] benzyl, selected from the group consisting of Compound . 13. The compound according to claim 2, wherein R ⁶ is 2,
4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4 -Β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, -NH ₂ , benzyloxy, -NHCH ₂ COOH, -NHCH ₂ CH ₂ COOH, -NH-adamantyl, -NHCH ₂ CH ₂ COOCH ₂ CH ₃ , -NHSO ₂ -p-CH ₃ -φ
, -NHOR ⁸ (wherein, R ⁸ is hydrogen, methyl, iso - propyl or benzyl,), O-(N-succinimidyl), - O-cholest-5-en -3-beta
- _{yl, -OCH 2 -OC (O) C} (CH 3) 3, -O (CH 2) z NHC (O) W
(Where z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl ), -NR "C (O) -R 'wherein R' is aryl,
Is heteroaryl or heterocyclic, and R ″ is hydrogen or —CH ₂ C (O
A) OCH ₂ CH ₃ ). 14. The following: N- [N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl] -L-phenylalanine, N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-L-phenylalanine, N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-D-phenylalanine, N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-
Hydroxyacetyl] -L-4- (N-benzyloxycarbonyl-isonipecotamide) phenylalanine, N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-
Hydroxyacetyl] -L-4- (isonipecotamide) phenylalanine, (2S) 2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4-nitro Benzyl) propionic acid, (2S) 2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonylisonipe) Cotamide) benzyl) propionic acid methyl ester, (2S) 2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert -Butoxycarbonylisonipecotamide) benzyl) propionic acid, N- [N- (toluene-4-sulfonyl) pyrrolidin-2-yl] aminocar Bonyl] -L-phenylalanine, and pharmaceutically acceptable salts thereof, and any ester compounds of the above-listed compounds, wherein one ester is methyl A compound substituted with another ester selected from the group consisting of esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters, isobutyl esters, sec-butyl esters, and tert-butyl esters. 15. A pharmaceutically acceptable carrier and a therapeutically effective amount of a formula I.
: And a pharmaceutically acceptable salt thereof, wherein R ¹ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, R ¹ and R ² are selected from the group consisting of substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and R ¹ and R ² together with the nitrogen atom attached to R ² and the SO ₂ group It can form a group or a substituted heterocyclic group; R ³ is hydrogen, alkyl, substituted alkyl, a cycloalkyl Le, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic is selected from the group consisting of substituted heterocyclic, and R ² is R ¹ and a heterocyclic If it does not form a group, R ² and R ³ form a heterocyclic or substituted heterocyclic group together with the carbon atom bonded to the nitrogen atom and R ³ binds to R ² obtained; R ⁴ is, Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and R If ^3, the R ² and the heterocyclic group does not also form a substituted heterocyclic group, R ³
And R ⁴ together with the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R ⁵ is isopropyl, —CH ₂ —W and ＣＨCH—W wherein W is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxy Aryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
Selected from the group consisting of carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxy heterocyclic, carboxy-substituted heterocyclic, and hydroxyl; However, R ⁵ is = CH-W
(H) is excluded from the formula and W is not hydroxyl; and Q is the following (i) to (v): (i) Wherein X is selected from the group consisting of oxygen, sulfur, and NH; (ii) Here, R ⁷ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ⁸ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁷ and R ⁸ are bonded to R ⁷ A heterocyclic ring or a substituted heterocyclic ring together with the nitrogen atom to be bonded and the carbon attached to R ⁸ ; (iii) Here, R ⁹ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ¹⁰ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁹ and R ¹⁰ are bonded to R ⁹ X may be selected from the group consisting of oxygen, sulfur and NH together with the nitrogen atom, the carbon atom attached to R ¹⁰ and the —C (X) — group. (Iv) embedded image Here, R ¹¹ and R ¹² are bonded to a nitrogen atom bonded to R ¹¹ and R ¹² >
Together with the C = N- group form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and (v) Wherein R ¹³ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; X is oxygen, sulfur, and NH A pharmaceutical composition selected from the group consisting of: 16. A pharmaceutically acceptable carrier and a therapeutically effective amount of a formula I.
A: And a pharmaceutically acceptable salt thereof, wherein R ¹ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, R ¹ and R ² are selected from the group consisting of substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and R ¹ and R ² together with the nitrogen atom attached to R ² and the SO ₂ group It can form a group or a substituted heterocyclic group; R ³ is hydrogen, alkyl, substituted alkyl, a cycloalkyl Le, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic is selected from the group consisting of substituted heterocyclic, and R ² is R ¹ and a heterocyclic If it does not form a group, R ² and R ³ form a heterocyclic or substituted heterocyclic group together with the carbon atom bonded to the nitrogen atom and R ³ binds to R ² obtained; R ⁴ is, Selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and R If ^3, the R ² and the heterocyclic group does not also form a substituted heterocyclic group, R ³
And R ⁴ together with the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R ⁵ is isopropyl, —CH ₂ —W and ＣＨCH—W wherein W is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxy Aryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
Selected from the group consisting of carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxy heterocyclic, carboxy-substituted heterocyclic, and hydroxyl; However, R ⁵ is = CH-W
Wherein (H) is omitted from the formula and W is not hydroxyl; and R ⁶ is amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy ,
Substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, -NHOY (wherein, Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl), and _{-NH (CH 2) p COOY '} ( here , Y ′ is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and p is an integer from 1 to 8); and Q is the following (i) to (v): (I) Wherein X is selected from the group consisting of oxygen, sulfur, and NH; (ii) Here, R ⁷ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ⁸ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁷ and R ⁸ are bonded to R ⁷ A heterocyclic ring or a substituted heterocyclic ring together with the nitrogen atom to be bonded and the carbon attached to R ⁸ ; (iii) Here, R ⁹ is hydrogen, is selected from the group consisting of alkyl and substituted alkyl; R ¹⁰ is hydrogen, or is selected from the group consisting of alkyl and substituted alkyl; or R ⁹ and R ¹⁰ are bonded to R ⁹ X may be selected from the group consisting of oxygen, sulfur and NH together with the nitrogen atom, the carbon atom attached to R ¹⁰ and the -C (X)-group (Iv) embedded image Here, R ¹¹ and R ¹² are bonded to a nitrogen atom bonded to R ¹¹ and R ¹² >
Together with the C = N- group form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and (v) Wherein R ¹³ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; X is oxygen, sulfur, and NH A pharmaceutical composition selected from the group consisting of: 17. The pharmaceutical composition according to claim 15 or 16, wherein R ¹ is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic,
A pharmaceutical composition selected from the group consisting of substituted heterocyclic, heteroaryl and substituted heteroaryl. 18. The pharmaceutical composition according to claim 15 or 16, wherein R ¹ is methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-t. -Butylphenyl, 2,4,6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, -Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4
-Fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butoxyphenyl, 4- (3'-dimethylamino-n-propoxy ) -Phenyl,
2-carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4-(H ₂ N
C (O) -) _{phenyl, 4- (H 2 NC (S} ) -) phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3
, 5-di (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH ₃ C (O) NH-) phenyl, 4- (PhNHC (O) NH
-) Phenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- (C
_{H 3 SC (= NH) -} ) phenyl, 4-chloro _{-3- (H 2 NS (O)} 2 -) phenyl, 1-naphthyl, 2-naphthyl, pyridin-2-yl, pyridin-3-yl, pyrimidine -2-yl, quinolin-8-yl, 2- (trifluoroacetyl)
-1,2,3,4-tetrahydroisoquinolin-7-yl, morpholin-4-yl, 2-thienyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methylimidazole -4-yl, 1-N-methylpyrazole-3-
Yl, 1-N-methylpyrazol-4-yl, 1-N-butylpyrazol-4-yl
Yl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl), 1-
A pharmaceutical composition selected from the group consisting of N-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl. 19. A pharmaceutical composition according to claim 15 or 16, wherein, R ² is hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2-2-thienyl,} and - ( A pharmaceutical composition selected from the group consisting of CH ₂ ) ₂ -φ. 20. The pharmaceutical composition according to claim 15 or 16, wherein R ² and R ³ are a nitrogen atom attached to the R ² substituent and a carbon atom attached to the R ³ substituent. Pharmaceutical compositions, which together form a heterocyclic or substituted heterocyclic group. 21. The pharmaceutical composition according to claim 20, wherein R ²
And R ³ together with the nitrogen atom attached to the R ² substituent and the carbon attached to the R ³ substituent form a substituted heterocyclic ring. 22. The pharmaceutical composition according to claim 15 or 16, wherein R ¹ and R ² together with a nitrogen atom bonded to R ² and a SO ₂ group bonded to R ¹ Pharmaceutical compositions which combine to form a heterocyclic or substituted heterocyclic ring. 23. A pharmaceutical composition according to claim 15 or 16, wherein, R ³ is hydrogen, methyl, phenyl, benzyl, diphenylmethyl, 2-carboxyethyl, 2-amidoethyl, iso - butyl, t- butyl, carboxymethyl, are selected from the group consisting of -CH ₂ O-benzyl and hydroxymethyl, pharmaceutical compositions. 24. The pharmaceutical composition according to claim 15 or 16, wherein R ⁴ is selected from the group consisting of hydrogen, methyl, ethyl and phenyl. 25. A pharmaceutical composition according to claim 15 or 16, wherein, Q is, -C (O) N (O ) -, - CH 2 NH -, - CH (OH) C (O)
A pharmaceutical composition selected from the group consisting of NH-, -NHC (O) NH-, and tetrazole-1,5-diyl. 26. A pharmaceutical composition according to claim 15 or 16, wherein, R ⁵ is selected from the group consisting of: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxy Benzyl, 4-benzyloxybenzyl, 4- [φ-CH (CH ₃ ) O-] benzyl, 4- [φ-CH (COOH) O-] benzyl, 4- [BocNHCH ₂ C (O) NH-] benzyl , _{4-chlorobenzyl, 4- [NH 2 CH 2 C} (O) NH-] benzyl, _{4-carboxybenzyl, 4- [CbzNHCH 2 CH 2 NH-} ] benzyl, 3-hydroxy -4- (φ-OC ( O) NH-) _{benzyl, 4- [HOOCCH 2 CH 2 C} (O) NH-] benzyl, benzyl, 4- [2'-carboxy phenoxy -] benzyl, 4- [φ-C (O ) NH- Benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3,5-di-iodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxyphenyl -] benzyl, φ-CH ₂ CH ₂ -, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] - benzyl, 4 - [(1'-cyclopropylpiperidin-4'-yl) C (O) NH-] benzyl, 4- _{[-NHC (O) CH 2 NHBoc} ] benzyl, 4-carboxy-benzyl, 4-hydroxy-3-nitrobenzyl, 4 - [- NHC (O ) CH (CH 3) NHBoc] benzyl, 4 - [- NHC (O _{) CH (CH 2 φ) NHBoc} ] benzyl, isobutyl, _{methyl, 4- [CH 3 C (O} ) NH-] benzyl, -CH ₂ - (3- indol ), N-butyl, t- butyl _{-OC (O) CH 2 -,} t- butyl _{-OC (O) CH 2 CH 2} -, H 2 NC (O) CH 2 -, H 2 NC (O) CH 2 _{CH 2 -, BocNH- (CH 2} ) 4 -, t- butyl _{-OC (O) - (CH 2} ) 2 -, HOOCCH 2 -, HOOC (CH 2) 2 -, H 2 N (CH 2) 4 - , isopropyl, (1-naphthyl) -CH ₂ -, (2-naphthyl) -CH ₂ -, _{(2-thiophenyl) -CH 2 -, (φ-} CH 2 -OC (O) NH- (CH 2) 4 -, cyclohexyl -CH ₂ -, benzyloxy _{-CH 2 -, HOCH 2 -,} 5- (3-N- benzyl) imidazolyl -CH ₂ -, 2-pyridyl -CH ₂ -, 3- pyridyl -CH ₂ -, 4-pyridyl _{-CH 2 -, 5- (3-} N- methyl) imidazolyl -CH ₂ - N- Benjirupiperido-4-yl -CH ₂ -, N-Boc- piperidin-4-yl -CH ₂ -, N- (phenyl - carbonyl) piperidin-4-yl _{-CH 2 -, H 3 CSCH 2} CH 2 - , 1-N-benzyl-imidazol-4-yl -CH ₂ -, iso - propyl _{-C (O) NH- (CH 2} ) 4 -, iso - butyl _{-C (O) NH- (CH 2} ) 4 -, phenyl _{-C (O) NH- (CH 2} ) 4 -, benzyl _{-C (O) NH- (CH 2} ) 4 -, allyl _{-C (O) NH- (CH 2} ) 4 -, 4- (3- N- methylimidazolyl) -CH ₂ -, _{4-imidazolyl, 4 - [(CH 3)} 2 NCH 2 CH 2 CH 2 -O-] benzyl, 4 - [(benzyl) ₂ N -] - benzyl, 4-amino benzyl, allyloxy _{-C (O) NH (CH 2} ) 4 -, allyl Oxy _{-C (O) NH (CH 2} ) 3 -, allyloxy _{-C (O) NH (CH 2} ) 2 -, NH 2 C (O) CH 2 -, φ-CH =, 2- pyridyl -C (O _{) NH- (CH 2) 4 -} , 4- methylpyrid-3-yl _{-C (O) NH- (CH 2} ) 4 -, 3- methylthien-2-yl _{-C (O) NH- (CH 2} ) 4 -, 2-pyrrolyl _{-C (O) NH- (CH 2} ) 4 -, 2- furanyl _{-C (O) NH- (CH 2} ) 4 -, 4- methylphenyl -SO ₂ -N (CH ₃₎ CH _{2 C (O) NH (CH} 2) 4 -, 4- [ cyclopentyl acetylene Les sulfonyl] - benzyl, 4 - [- NHC (O ) - (N-Boc) - pyrrolidin-2-yl)] - benzyl -, 1-N-methyl-imidazol-4-yl -CH ₂ -, 1-N- methyl-imidazol-5-yl -CH ₂ -, Imi 5-yl -CH ₂ -, 6- methylpyrid-3-yl _{-C (O) NH- (CH 2} ) 4 -, 4- [2'- carboxymethyl phenyl] - benzyl, 4 - [- NHC ( O) NHCH ₂ CH ₂ CH ₂ -φ] -benzyl, 4-[— NHC (O) NHCH ₂ CH ₂ -φ] -benzyl, -CH ₂ C (O) NH (CH ₂ ) ₄ φ, 4- [ φ (CH ₂ ) ₄ O —]-benzyl, 4-[— C≡C-φ-4′φ] -benzyl, 4-[— C≡C—CH ₂ —OS (O) ₂ -4 ′ —CH ₃ —φ] -benzyl, 4-[— C≡C—CH ₂ NHC (O) NH ₂ ] -benzyl, 4-[— C≡C—CH ₂ —O-4′-COOCH ₂ CH ₃ — phi] - benzyl, 4 - [- C≡C-CH (NH 2) - cyclohexyl] - _{benzyl, - (CH 2) 4 NHC} (O) CH 2 -3- indolyl _{- (CH 2) 4 NHC (} O) CH 2 CH 2 -3- _{indolyl, - (CH 2) 4 NHC} (O) -3- (5- _{methoxy-indolyl), - (CH 2) 4} NHC (O) 3- _{(1-methyl-indolyl), - (CH 2) 4} NHC (O) -4 - (- SO 2 (CH 3) -φ), - (CH 2) 4 NHC (O) -4- ( C (O) CH ₃₎ - _{phenyl, - (CH 2) 4 NHC} (O) -4- _{fluorophenyl, - (CH 2) 4 NHC} (O) CH 2 O-4- fluorophenyl, 4 - [- C {C- (2-pyridyl)] benzyl, 4-[— C≡C—CH ₂ —O-phenyl] benzyl, 4-[— C≡C—CH ₂ OCH ₃ ] benzyl, 4-[— C≡C - (3-hydroxyphenyl)] benzyl, 4 - [- C≡C-CH 2 -O-4 '- (- C (O) OC 2 H 5) phenyl] Benzyl, 4-[— C≡C—CH ₂ CH (C (O) OCH ₃ ) ₂ ] benzyl, 4-[— C≡C—CH ₂ NH— (4,5-dihydro-4-oxo-5- Phenyl-oxazol-2-yl), 3-aminobenzyl, 4-[— C≡C—CH ₂ CH (NHC (O) CH ₃ ) C (O) OH] -benzyl, —CH ₂ C (O) NHCH _{(CH 3) φ, -CH 2} C (O) NHCH 2 - (4- _{dimethylamino) -φ, -CH 2 C (O} ) NHCH 2 -4- _{nitrophenyl, -CH 2 CH 2 C (O} ) N _{(CH 3) CH 2 -φ,} -CH 2 CH 2 C (O) NHCH 2 CH 2 - (N- methyl) _{-2-pyrrolyl, -CH 2 CH 2 C (O} ) NHCH 2 CH 2 CH 2 CH 3 _{, -CH 2 CH 2 C (O} ) NHCH 2 CH 2 -3- _{indolyl, -CH 2 C (O) N} (CH 3) C _{2-phenyl, -CH 2 C (O) NH} (CH 2) 2 - (N- methyl) _{-2-pyrrolyl, -CH 2 C (O) NHCH} 2 CH 2 CH 2 CH 3, -CH 2 C (O) NHCH ₂ CH ₂ -3- _{indolyl, - (CH 2) 2 C} (O) NHCH (CH 3) φ, - (CH 2) 2 C (O) NHCH 2 -4- dimethylaminophenyl, - (CH _{2) 2} C (O) NHCH ₂ -4- _{nitrophenyl, -CH 2 C (O) NH} -4 - [- NHC (O) CH 3 - _{phenyl], -CH 2 C (O)} NH-4- pyridyl, - _{CH 2 C (O) NH-} 4- [ _{dimethylaminophenyl], -CH 2 C (O)} NH-3- _{methoxyphenyl, -CH 2 CH 2 C (O} ) NH-4- chlorophenyl, -CH ₂ CH ₂ C (O) NH-2- _{pyridyl, -CH 2 CH 2 C (O} ) NH-4- methoxy _{Phenyl, -CH 2 CH 2 C (O} ) NH-3- _{pyridyl, 4 - [(CH 3)} 2 NCH 2 CH 2 O-] _{benzyl, - (CH 2) 3 NHC} (NH) NH-SO 2 -4 - _{methylphenyl, 4 - [(CH 3)} 2 NCH 2 CH 2 O-] _{benzyl, - (CH 2) 4 NHC} (O) NHCH 2 CH 3, - (CH 2) 4 NHC (O) NH- phenyl, _{- (CH 2) 4 NHC (} O) NH-4- methoxyphenyl, 4- [4'-pyridyl -C (O) NH-] benzyl, 4- [3'-pyridyl -C (O) NH-] benzyl , 4 - [- NHC (O ) NH-3'- methylphenyl] benzyl, 4 - [- NHC (O ) CH 2 NHC (O) NH-3'- methylphenyl] benzyl, 4 - [- NHC (O )-(2 ', 3'-dihydroindol-2-yl)] benzyl, 4-[- NHC (O)-(2 ', 3'-dihydro-N-Boc-indole-
2-yl)] benzyl, p-[— OCH ₂ CH ₂ -1 ′-(4′-pyrimidinyl) -piperazinyl] benzyl, 4-[— OCH ₂ CH ₂ — (1′-piperidinyl)] benzyl, 4- [-OCH ₂ CH ₂ - (1'- pyrrolidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 - (1'- piperidinyl)] benzyl -, -CH ₂ -3- (1,2,4- _{triazolyl), 4 - [- OCH 2} CH 2 CH 2 -4- (3'- chlorophenyl) - piperazine -
1-yl] benzyl, 4-[— OCH ₂ CH ₂ N (φ) CH ₂ CH ₃ ] benzyl, 4-[— OCH ₂ -3 ′-(N-Boc) -piperidinyl] benzyl, 4- [di- n- pentylamino] benzyl, 4- [n- pentylamino] benzyl, 4- [di - iso - propylamino -CH ₂ CH ₂ O-] _{benzyl, 4 - [- OCH 2 CH} 2 - (n- morpholinyl) ] benzyl, 4 - [- O- (3 '- (N-Boc) - piperidinyl] _{benzyl, 4 - [- OCH 2 CH} (NHBoc) CH 2 cyclohexyl] _{benzyl, p- [OCH 2 CH 2 -} (N- piperidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 - (4-m- chlorophenyl) - piperazine -1
- yl] _{benzyl, 4 - [- OCH 2 CH} 2 - (N- homopiperidinyl)] benzyl, 4 - [- NHC (O ) -3 '- (N-Boc) - piperidinyl] benzyl, 4 - [- OCH ₂ CH ₂ N (benzyl) _2] benzyl, -CH _{2-2-thiazolyl, 3-hydroxybenzyl, 4- [OCH 2 CH 2 CH} 2 N (CH 3) 2] benzyl, 4 - [- NHC (S ) NHCH ₂ CH ₂ - (N- morpholino)] _{benzyl, 4 - [- OCH 2 CH} 2 N (C 2 H 5) 2] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (C 2 H 5) 2] _{benzyl, 4- [CH 3 (CH 2} ) 4 NH-] benzyl, 4- [N-n- butyl, N-n-pentylamino -] benzyl, 4 - [- NHC (O ) -4'- piperidinyl] Benzyl, 4-[-NHC (O) CH (NHBoc (CH _{2) 4} NHCbz] benzyl, 4 - [- NHC (O ) - (1 ', 2', 3 ', 4'- tetrahydro -N-Bo
c- isoquinolin-1'-yl] _{benzyl, p - [- OCH 2 CH} 2 CH 2 -1 '- (4'- methyl) - piperazinyl] _{benzyl, - (CH 2) 4 NH} -Boc, 3 - [- _{OCH 2 CH 2 CH 2 N (} CH 3) 2] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) 2] _{benzyl, 3 - [- OCH 2 CH} 2 - (1'- pyrrolidinyl)] _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 N (CH 3) benzyl] benzyl, 4 - [- NHC (S ) NHCH 2 CH 2 CH 2 - (N- morpholino)] benzyl, 4 - [- OCH ₂ CH ₂ - (N-morpholino)] _{benzyl, 4 - [- NHCH 2 -} (4'- chlorophenyl)] benzyl, 4 - [- NHC (O ) NH- (4'- cyanophenyl)] benzyl, 4- [ -OCH ₂ COOH] benzyl, 4 - [- OC ₂ COOH-t-butyl] benzyl, 4 - [- NHC (O ) -5'- fluoro-indol-2-yl] benzyl, 4 - [- NHC (S ) NH (CH 2) 2 -1- piperidinyl] benzyl , 4 - [- N (SO 2 CH 3) (CH 2) 3 -N (CH 3) 2] benzyl, 4 - [- NHC (O ) CH 2 CH (C (O) OCH 2 φ) -NHCbz] benzyl, 4 - [- NHS (O ) 2 CF 3] benzyl, 3 - [- O- (N- methylpiperidin-4'-yl] benzyl, 4 - [- C (= NH) NH 2] benzyl, 4 - [NHSO ₂ -CH ₂ Cl] benzyl, 4 - [- NHC (O ) - (1 ', 2', 3 ', 4'- tetrahydroisoquinolin-2'-yl] benzyl, 4 - [- NHC (S ) NH (CH _{2) 3} -N- morpholino] benzyl, 4 - [- NHC (O ) C _{H (CH 2 CH 2 CH 2} CH 2 NH 2) NHBoc] benzyl, 4 - [- C (O ) NH 2] benzyl, 4 - [- NHC (O ) NH-3'- methoxyphenyl] benzyl, 4- [-OCH ₂ CH ₂ - indol-3'-yl] _{benzyl, 4 - [- OCH 2 C} (O) NH- benzyl] _{benzyl, 4 - [- OCH 2 C} (O) O- benzyl] benzyl, 4- _{[-OCH 2 C (O) OH} ] _{benzyl, 4 - [- OCH 2 -2} '- (4', 5'- dihydro) imidazolyl] _{benzyl, -CH 2 C (O) NHCH} 2 - (4- dimethylamino ) Phenyl, 4-[— NHC (O) -L-2′-pyrrolidinyl-N—SO ₂ -4′-methylphenyl] benzyl, 4-[— NHC (O) NHCH ₂ CH ₂ CH ₃ ] benzyl, 4 -[Aminobenzyl] benzyl, 4-[-OC H ₂ CH ₂ -1- (4- hydroxy-4- (3-methoxy-pyrrol-2-yl) - piperazinyl] benzyl, 4 - [- O-(N-methylpiperidin-4'-yl)] benzyl, 3 - methoxybenzyl, 4 - [- NHC (O ) - piperidin-3'-yl] benzyl, 4 - [- NHC (O ) - pyridin-2'-yl] _{benzyl, 4 - [- NHCH 2 -} (4 ' - chlorophenyl)] benzyl, 4 - [- NHC (O ) - (N- (4'-CH 3 -φ-SO 2) -L- pyrrolidin-2'-yl)] benzyl, 4 - [- NHC (O ) NHCH ₂ CH ₂ -φ] _{benzyl, 4 - [- OCH 2 C} (O) NH 2] _{benzyl, 4 - [- OCH 2 C} (O) NH-t- butyl] benzyl, 4 - [- OCH ₂ CH _2-1- (4-hydroxy-4-phenyl) - piperidinyl] base _{Jill, 4 - [- NHSO 2 -CH} = CH 2] _{benzyl, 4 - [- NHSO 2 -CH} 2 CH 2 Cl] _{benzyl, -CH 2 C (O) NHCH} 2 CH 2 N (CH 3) 2, 4 -[(1'-Cbz-piperidin-4'-yl) C (O) NH-] benzyl, 4-[(1'-Boc-piperidin-4'-yl) C (O) NH-] benzyl, 4 - [(2'-bromophenyl) C (O) NH-] benzyl, 4 - [- NHC (O) - pyridin-4'-yl] benzyl, 4 - [(4 '- (CH 3) 2 NC ( O) O-) phenyl) -C (O) NH-] benzyl, 4-[-NHC (O) -1'-methylpiperidin-4'-yl-] benzyl, 4- (dimethylamino) benzyl, 4- [-NHC (O)-(1'-N-Boc) -piperidin-2'-yl] benzyl, 3-[-NH (O) - pyridin-4'-yl] benzyl, 4 - [(tert-butyl -O (O) CCH ₂ -O- benzyl) -NH-] _{benzyl, [BocNHCH 2 C (O)} NH-] butyl, 4-benzyl benzyl, _{2-hydroxyethyl, 4 - [(Et) 2} NCH 2 CH 2 CH 2 NHC (S) NH-] benzyl, 4 - [(1'-Boc -4'- hydroxypyrrolidine-2' Il) C (O)
NH-] _{benzyl, 4- [φCH 2 CH 2 CH} 2 NHC (S) NH-] benzyl, 4 - [(perhydro-indoline-2'-yl) C (O) NH-] benzyl, 2- [4- Hydroxy-4- (3-methoxythien-2-yl) piperidine-
1-yl] ethyl, 4-[(1′-Boc-perhydroindoline-2′-yl) -C (O) NH
-] Benzyl, 4-[(N-3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl, 4-[(N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2] .2] octan-2-yl) ethyl-
O-] benzyl, 4-[(4'-hydroxypyrrolidin-2'-yl) C (O) NH-] benzyl, 4- (φNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl 4- (φCH ₂ NHC (S) NH) benzyl, 3-[(1′-Boc-piperidin-2′-yl) C (O) NH—] benzyl 3- [piperidin-2′-yl-C (O ) NH-] benzyl, 4-[(3'-Boc-thiazolidine-4'-yl) C (O) NH-] benzyl, 4- (pyridin-3'-yl-NHC (S) NH) benzyl, 4 _{- (CH 3 -NHC (S)} NH) _{benzyl, 4- (H 2 NCH 2 CH} 2 CH 2 C (O) NH) _{benzyl, 4- (BocHNCH 2 CH 2 CH} 2 C (O) NH) benzyl, 4 - (pyridin-4'-yl -CH ₂ NH) benzyl, 4- [ N, N-di (4-N, N, - dimethylamino) benzyl) amino] benzyl, 4 - [(1-Cbz- piperidin-4-yl) C (O) NH-] butyl, 4- [φCH _{2 OCH 2 (BocHN) CHC (O} ) NH] benzyl, 4 - [(piperidin-4'-yl) C (O) NH-] benzyl, 4 - [(pyrrolidin-2'-yl) C (O) NH- Benzyl, 4- (pyridin-3'-yl-C (O) NH) butyl, 4- (pyridin-4'-yl-C (O) NH) butyl, 4- (pyridin-3'-yl-C (O) NH) _{benzyl, 4- [CH 3 NHCH 2 CH} 2 CH 2 C (O) NH-] _{benzyl, 4- [CH 3 N (Boc} ) CH 2 CH 2 CH 2 C (O) NH-] benzyl 4- (aminomethyl) _{benzyl, 4- [φCH 2 OCH 2 (} H 2 N) CHC ( ) NH] benzyl, 4 - [(1 ', 4'-di (Boc) piperazin-2'-yl) -C (O) NH
-] Benzyl, 4-[(piperazin-2'-yl) -C (O) NH-] benzyl, 4-[(N-toluenesulfonylpyrrolidin-2'-yl) C (O) NH-]
Butyl, 4-[-NHC (O) -4'-piperidinyl] butyl, 4-[-NHC (O) -1'-N-Boc-piperidin-2'-yl] benzyl, 4-[-NHC (O ) -Piperidin-2'-yl] benzyl, 4-[(1'-N-Boc-2 ', 3'-dihydroindoline-2'-yl)
-C (O) NH] benzyl, 4- (pyridin-3'-yl -CH ₂ NH) benzyl, 4 - [(1'-Cbz- piperidin-4'-yl) C (O) NH-] benzyl, 4 - _{[(piperidin-1'-yl) C (O) CH 2 -O-} ] _{benzyl, 4 - [(CH 3)} 2 CH) 2 NC (O) CH 2 -O-] benzyl, 4-[HO (O) C (Cbz-NH ) CHCH 2 CH 2 -C (O) NH-] _{benzyl, 4- [φCH 2 O (O} ) C (Cbz-NH) CHCH 2 CH 2 -C (O) NH-
] Benzyl, 4-[-NHC (O) -2'-methoxyphenyl] benzyl, 4-[(pyrazin-2'-yl) C (O) NH-] benzyl, 4- [HO (O) C (NH _{2) CHCH 2 CH 2 -C (} O) NH-] benzyl, 4- (2'-formyl-1 ', 2', 3 ', 4'-tetrahydroisoquinolin-3'-yl -CH ₂ NH-) benzyl _{, N-Cbz-NHCH 2 -} , 4 - [(4'- methylpiperazin-1'-yl) C (O) O-] _{benzyl, 4- [CH 3 (N-} Boc) NCH 2 C (O) NH -] Benzyl, 4-[-NHC (O)-(1 ', 2', 3 ', 4'-tetrahydro-N-Bo
c- isoquinolin-3'-yl] _{benzyl, 4- [CH 3 NHCH 2 C} (O) NH-] _{benzyl, (CH 3) 2 NC (} O) CH 2 -, 4- (N- methylacetamido) benzyl, 4- (1 ′, 2 ′, 3 ′, 4′-tetrahydroisoquinolin-3′-yl-C
H ₂ NH-) _{benzyl, 4 - [(CH 3)} 2 NHCH 2 C (O) NH-] benzyl, (1-toluenesulfonyl-imidazol-4-yl) methyl, 4 - [(1'-Boc-piperidin - 4'-yl) C (O) NH-] benzyl 4-trifluoromethylbenzyl, 4 - [(2'-bromophenyl) C (O) NH-] _{benzyl, 4 - [(CH 3)} 2 NC (O ) NH-] _{benzyl, 4- [CH 3 OC (O} ) NH-] _{benzyl, 4 - [(CH 3)} 2 NC (O) O-] _{benzyl, 4 - [(CH 3)} 2 NC (O) N (CH ₃₎ -] _{benzyl, 4- [CH 3 OC (O} ) N (CH 3) -] benzyl, 4-(N-methyl trifluoroacetamide) benzyl, 4 - [(1'-methoxycarbonyl-piperidine -4 '-Yl) C (O) NH-
] Benzyl, 4-[(4'-phenylpiperidin-4'-yl) C (O) NH-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) -C (O
) NH-] benzyl, 4-[(piperidin-4'-yl) C (O) O-] benzyl, 4-[(1'-methylpiperidin-4'-yl) -O-] benzyl, 4- [ (1'-methylpiperidin-4'-yl) C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) NH-] benzyl, 3-[(CH ₃ ) ₂ NC (O) O-] benzyl, 4-[(4'-phenyl-1'-Boc-piperidin-4'-yl) -C (O
) O-] benzyl, 4-(N-toluenesulfonyl amino) _{benzyl, 4 - [(CH 3)} 3 CC (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (O) NH -] _{benzyl, 4 - [(CH 3 CH} 2) 2 NC (O) NH-] benzyl, 4 - [- C (O) NH- (4'-piperidinyl)] benzyl, 4 - [(2'-tri trifluoromethylphenyl) C (O) NH-] benzyl, 4 - [(2'-methylphenyl) C (O) NH-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 O-] benzyl, 4-[(pyrrolidin-2'-yl) C (O) NH-] benzyl, 4-[-NHC (O) -piperidin-1'-yl] benzyl, 4-[(thiomorpholin-4'-yl) C (O) NH-] benzyl, 4-[(thiomorpholin-4'-ylsulfone)- (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (O) O-] benzyl, 3-nitro _{-4- (CH 3 OC (O)} CH 2 O-) benzyl, (2 -Benzoxazolinone-6-yl) methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-
_{, 4 - [(CH 3)} 2 NS (O) 2 NH-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 N (CH 3) -] benzyl, 4 - [(thiomorpholine-4 ' -Yl) C (O) O-] benzyl, 4-[(thiomorpholin-4'-ylsulfone) -C (O) O-] benzyl, 4-[(piperidin-1'-yl) C (O) O -] Benzyl, 4-[(pyrrolidin-1'-yl) C (O) O-] benzyl, 4-[(4'-methylpiperazin-1'-yl) C (O) O-] benzyl, 4- [(2'-methylpyrrolidin-1'-yl)-, (pyridin-4-yl) methyl-, 4-[(piperazin-4'-yl) -C (O) O-] benzyl, 4-[( 1'-Boc-piperazin-4'-yl) -C (O) O-] benzyl, 4-[(4'-acetylpiperazin-1'-yl) C ( O) O-] benzyl, p-[(4'-methanesulfonylpiperazin-1'-yl) benzyl, 3-nitro-4-[(morpholin-4'-yl) -C (O) O-] benzyl, 4-{[(CH ₃ ) ₂ NC (S)] ₂ N-｝ benzyl, N-Boc-2-aminoethyl-, 4-[(1,1-dioxothiomorpholin-4-yl) -C ( O) O-] _{benzyl, 4 - [(CH 3)} 2 NS (O) 2 -] benzyl, 4- (imidazolide -2'-one-1'-yl) benzyl, 4 - [(piperidin-1' yl) C (O) O-] benzyl, 1-N-benzyl-- imidazol-4-yl -CH ₂ -, 3,4-oxyethylene, 3,4 dioxymethylene benzyl, 4 - [- N _{(SO 2) (CH 3)} CH 2 CH 2 CH 2 N (CH 3) 2] benzyl, 4- ( 3'-formyl imidazolide -2'-one-1'-yl) benzyl, 4- [NHC (O) CH (CH 2 CH 2 CH 2 CH 2 NH 2) NHBoc] benzyl, [2 '- [4 " -Hydroxy-4 ″-(3 ′ ″-methoxythien-2 ′ ″
- yl) piperidine -2 "- yl] ethoxy] benzyl, and _{p - [(CH 3) 2} NCH 2 CH 2 N (CH 3) C (O) O-] benzyl, selected from the group consisting of, pharmaceutical Composition. 27. The pharmaceutical composition according to claim 16, wherein R ⁶
Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol),
Methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β- Methylcyclohexoxy, -N
H _{2, benzyloxy, -NHCH 2 COOH, -NHCH 2 CH} 2 COOH, -N
H- _{adamantyl, -NHCH 2 CH 2 COOCH 2 CH} 3, -NHSO 2 -p-C
H ₃ -φ, -NHOR ⁸ (where R ⁸ is hydrogen, methyl, iso-propyl, or benzyl), O- (N-succinimidyl), -O-cholest-5-en-3-β- _{yl, -OCH 2 -OC (O) C} (CH 3) 3, -O (CH 2) z NHC
(O) W wherein z is 1 or 2 and W is pyrid-3-yl,
Selected from the group consisting of N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl), -NR "C (O) -R ', where R' is aryl, Heteroaryl or heterocyclic, and R ″ is hydrogen or —CH ₂
C (O) OCH ₂ CH ₃ ). 28. A method for binding VLA-4 in a biological sample, the method comprising: combining the biological sample with the compound of claim 1 or 2; And contacting under conditions that bind to -4.
Method. 29. A method for treating an inflammatory condition in a mammalian patient, wherein the condition is mediated by VLA-4, wherein the method comprises administering to the patient a therapeutically effective amount of the inflammatory condition. A method comprising administering the pharmaceutical composition of claim 16. 30. The method of claim 29, wherein the inflammatory condition is asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis. A method selected from the group consisting of: tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury.