HK1044549A1

HK1044549A1 - Compounds with inhibit leukocyte adhesion mediated by vla-4

Info

Publication number: HK1044549A1
Application number: HK02106216A
Authority: HK
Inventors: S‧阿什威尔; R‧B‧鲍迪; M‧A‧普雷斯; D‧萨兰塔基斯; E‧D‧索塞特
Original assignee: 依兰制药公司; Wyeth公司
Priority date: 1999-01-25
Filing date: 2000-01-21
Publication date: 2002-10-25
Also published as: HK1044549B; MXPA01007394A; JP2002539080A; WO2000043415A1; AR029611A1; AU3348700A; EP1150997A1; CN1340058A; CN1185250C; CA2359114A1

Abstract

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

Compounds that inhibit leukocyte adhesion mediated by VLA-4

Background

Technical Field

The present invention relates to compounds that inhibit leukocyte adhesion, particularly leukocyte adhesion mediated by VLA-4.

Reference to the literature

The following listed versions, patents and patent applications are incorporated herein by reference in their entirety:

¹hemler and Takada, European patent application publication No. 330,506, published on 8/30 1989

²Elices, et al, Cell (Cell), 60: 577-584(1990)

³Springer, Nature, 346: 425-434(1990)

⁴Osborn, Cell (Cell), 62: 3-6(1990)

⁵Vedder et al, Surgery, 106: 509(1989)

⁶Pretolani et al, j.exp.med. (journal of experimental medicine), 180: 795(1994)

⁷Abraham et al, j.clin.invest. (journal of clinical research), 93: 776(1994)

⁸Mulligan et al, j. immunology, 150: 2407(1993)

⁹Cybutsky et al, Science, 251: 788(1991)

¹⁰Li et al, ariterioscler. 197(1993)

¹¹Sasseville et al, am.j.path, (journal of american pathology), 144: 27(1994)

¹²Yang et al, proc.nat.acad.science (USA) (proceedings of the national academy of sciences USA), 90: 10494(1993)

¹³Burkly et al, Diabetes, 43: 529(1994)

¹⁴Baron et al, j.clin.invest. (journal of clinical research), 93: 1700(1994)

¹⁵Hamann et al, j. immunology, 152: 3238(1994)

¹⁶Yednock et al, Nature (Nature), 356: 63(1992)

¹⁷Baron et al, j.exp.med. (journal of experimental medicine), 177: 57(1993)

¹⁸van Dinther-Janssen et al, j.immunology, 147: 4207(1991)

¹⁹van Dinther-Janssen et al, annals. 672(1993)

²⁰Elices et al, j.clin.invest. (journal of clinical research), 93: 405(1994)

²¹Nesto et al, j.clin.invest. (journal of clinical research), 89: 1445(1991)

²²Paul et al, transpl. proceed., 25: 813(1993)

²³Okarrara et al, can.res, (cancer research), 54: 3233(1994)

²⁴Paavonen et al, int.j.can. (journal of international cancer), 58: 298(1994)

²⁵Schadendorf et al, j. path (journal of pathology), 170: 429(1993)

²⁶Bao et al, diff., 52: 239(1993)

²⁷Lauri et al, British j. cancer (British journal of cancer), 68: 862(1993)

²⁸Kawaguchi et al, japan j. cancer Res. (japan journal of cancer research), 83: 1304(1992)

²⁹Kogan et al, U.S. Pat. No. 5,510,332, granted on 23/4/1996

³⁰International patent application publication No. WO 96/01644

All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Prior Art

VLA-4 (also referred to as alpha)₄β₁Integrin and CD49d/CD29), originally composed of Hemler and Takada¹Determined to be a cell surface receptorA member of the β 1 integrin family, the cellular receptors each comprising two subunits, the α chain and the β chain. VLA-4 contains one α 4 chain and one β 1 chain. There are at least 9 β 1 integrins, all of which share a common β 1 chain and each contain a different α chain. These 9 receptors all bind to different complements of various cell matrix molecules such as fibronectin, laminin, and collagen. For example, VLA-4 may bind to fibronectin. VLA-4 may also bind to non-matrix molecules expressed by endothelial cells and other cells. These non-matrix molecules include VCAM-1, which is expressed in culture on cytokine-activated human umbilical vein endothelial cells. The different epitopes of VLA-4 are associated with the binding activity of fibronectin and VCAM-1, and each activity can be inhibited independently of the other.²

Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a variety of inflammatory responses. At the site of injury or other inflammatory stimuli, activated vascular endothelial cells express molecules that can adhere to leukocytes. The mechanism of leukocyte adhesion to endothelial cells is in part involved in the recognition and binding of corresponding cell surface molecules on endothelial cells by cell surface receptors on leukocytes. Once bound, leukocytes migrate through the vessel wall into the damaged epitope and release chemical mediators that fight infection. For a review of immune system adhesion receptors see, e.g., Springer³And Osborn⁴。

Inflammatory brain diseases, such as Experimental Autoimmune Encephalomyelitis (EAE), Multiple Sclerosis (MS) and meningitis, are examples of central nervous system diseases in which endothelial/leukocyte adhesion mechanisms lead to destruction of healthy brain tissue. In individuals with these inflammatory diseases, a large number of leukocytes migrate across the Blood Brain Barrier (BBB). Leukocytes release toxic mediators that can cause extensive tissue damage, leading to impaired nerve conduction and paralysis.

In other organs, tissue damage also occurs through adhesion mechanisms that cause leukocyte migration or activation. For example, it has been demonstrated that initial injury to cardiac tissue following myocardial ischemia can further complicate leukocyte entryInto damaged tissue and cause further damage (Vedder et al)⁵). Other inflammatory conditions caused by adhesion mechanisms include, for example, asthma^6-8Alzheimer's disease^9-11AIDS dementia¹¹Diabetes mellitus^12-14(including acute juvenile onset diabetes), inflammatory bowel disease¹⁵(including ulcerative colitis and Crohn's disease), multiple sclerosis^16-17Rheumatoid arthritis, and rheumatoid arthritis^18-21Tissue transplantation²²Tumor metastasis^23-28Meningitis, encephalitis, stroke and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that seen in adult respiratory distress syndrome.

In view of the above, assays for determining VLA-4 levels in a biological sample containing VLA-4 would be useful, for example, in diagnosing VLA-4 mediated disorders. Furthermore, despite advances in understanding leukocyte adhesion, the use of adhesion inhibitors in the treatment of inflammatory brain diseases and other inflammatory conditions has not been recently elucidated in the art^29-30. The present invention addresses these and other needs.

Summary of The Invention

The present invention provides compounds that can bind to VLA-4. The compounds are useful, for example, for detecting the presence of VLA-4 in a sample and for pharmaceutical compositions to inhibit VLA-4 mediated cell adhesion, such as the binding of VCAM-1 to VLA-4. IC for binding affinity of the inventive compounds to VLA-4₅₀Expressed as about 15 μ M or less (measured as described in example a below), the compound is defined by the following formula I:

wherein

R¹Selected from alkyl, substituted alkyl, cyclicAlkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;

R²selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and R¹And R²To the connection R²Nitrogen atom and SO₂The groups together may form a heterocyclic or substituted heterocyclic group;

R³selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and when R is²Not with R¹When forming a heterocyclic group, R²And R³And is attached to R²To the nitrogen atom and bound to R³The carbon atoms on the above may together form a heterocyclic group or a substituted heterocyclic group;

R⁴selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and when R is³Not with R²When a heterocyclic or substituted heterocyclic group is formed, then R³And R⁴May form, together with the carbon atom to which they are attached, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic ring, or a substituted heterocyclic group;

R⁵selected from isopropyl, -CH₂-W and ═ CH-W, wherein W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acylamino, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkylCarboxy aryl, carboxy-substituted aryl, carboxy heteroaryl, carboxy-substituted heteroaryl, carboxy heterocycle, carboxy-substituted heterocycle, and hydroxy, with the proviso that when R is⁵(ii) when is ═ CH-W, then (H) is removed from formula (hi) and W is not hydroxy;

q is selected from:

(i)

wherein X is selected from oxygen, sulfur and NH;

(ii)

wherein R is⁷Selected from the group consisting of hydrogen, alkyl, and substituted alkyl;

R⁸selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or R⁷And R⁸And is attached to R⁷To the nitrogen atom and bound to R⁸The carbon atoms on the above may together form a heterocyclic ring or a substituted heterocyclic ring;

(iii)

wherein R is⁹Selected from the group consisting of hydrogen, alkyl, and substituted alkyl;

R¹⁰selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or R⁹And R¹⁰And is attached to R⁹To the nitrogen atom of R¹⁰The carbon atom and the-c (x) -group together may form a heterocyclic or substituted heterocyclic group;

x is selected from oxygen, sulfur and NH;

(iv)

wherein R is¹¹And R¹²And is attached to R¹¹To the nitrogen atom and bound to R¹²The > C ═ N-groups above together may form a heterocycle, substituted heterocycle, heteroaryl or substituted heteroaryl ring; and

(v)

wherein R is¹³Selected from the group consisting of hydrogen, alkyl, and substituted alkyl;

R¹⁴selected from the group consisting of hydrogen, alkyl, and substituted alkyl;

x is selected from oxygen, sulfur and NH;

and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the present invention may also be provided in the form of prodrugs that are capable of being converted (e.g., hydrolyzed, metabolized, etc.) in vivo to the compounds of formula I described above. In a preferred example of such an embodiment, the carboxylic acid in the compound of formula I is modified to a group that can be converted in vivo to a carboxylic acid (including salts thereof). In a particularly preferred embodiment, the prodrug is represented by a compound of formula IA:

wherein

R¹Selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;

R²selected from hydrogen, alkyl, substitutedAnd R is alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and¹and R²To the connection R²Nitrogen atom and SO₂The groups together may form a heterocyclic or substituted heterocyclic group;

R⁵selected from isopropyl, -CH₂-W and ═ CH-W, wherein W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acylamino, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyl-heterocycle, carboxyl-substituted heterocycle and hydroxyl, with the proviso that when R is present⁵(ii) when is ═ CH-W, then (H) is removed from formula (hi) and W is not hydroxy;

R⁶selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocycloxy, substituted heterocycloxy, -NHOY, and-NH (CH)₂)_pCOOY ', wherein Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, Y' is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, p is an integer from 1 to 8;

q is selected from:

(i)

wherein X is selected from oxygen, sulfur and NH;

(ii)

(iii)

R¹⁰selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or R⁹And R¹⁰And is attached to R⁹To the nitrogen atom of R¹⁰A carbon atom of (A) and-C (X)The groups together may form a heterocyclic or substituted heterocyclic group;

x is selected from oxygen, sulfur and NH;

(iv)

(v)

x is selected from oxygen, sulfur and NH;

and pharmaceutically acceptable salts thereof.

Preferably in the compounds of formulae I and IA described above, R¹Selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl. More preferably R¹Selected from the group consisting of methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-tert-butylphenyl, 2, 4, 6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 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-tert-butoxyphenyl, 4- (3' -dimethylamino-n-propoxy) -phenyl, methyl, ethyl, propyl, isopropyl, 4-methylphenyl, 4-tert-butylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-dichlorophenyl, 3, 4, 2-carboxyphenyl, 2- (methoxy)Carbonyl) phenyl, 4- (H)₂NC (O) -) phenyl, 4- (H₂NC (S) -) phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3, 5-bis- (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH)₃C (O) NH-phenyl, 4- (PhNHC (O) NH-) phenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- (CH)₃SC (═ NH) -) phenyl, 4-chloro-3- (H)₂NS(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-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, pyridin-3-yl, pyrimidin-2-yl, 1-dichloro-4-yl, 1-N-methyl-4-thienyl, 1-N-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-1, 3, 4-thiadiazol-2-yl.

Preferably in the compounds of formulae I and IA described above, R²Is hydrogen, methyl, phenyl, benzyl, - (CH)₂)₂-2-thienyl and- (CH)₂)₂-φ。

In one embodiment, R¹And R²And is attached to R²To the nitrogen atom and bound to R¹SO of₂The groups together form a heterocyclic group or a substituted heterocyclic group. Preferred heterocyclic and substituted heterocyclic groups include rings containing 5 to 7 ring atoms and 2 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, which may be optionally fused with another ring such as a phenyl or cyclohexyl ring to form a fused heterocyclic ring of 10 to 14 ring atoms and 2 to 4 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Particularly preferred R¹/R²The bound groups include, for example, benzisothiazolone (saccharin-2-yl), N-2, 10-camphorsultamido, and 1, 1-dioxo-2, 3-dihydro-3, 3-dimethyl-1, 2-benzisothiazol-2-yl.

In a preferred embodiment, R²And R³And is attached to R²Nitrogen atom of substituent and bound to R³Carbon atoms on the substituents together form a heterocyclic or substituted heterocyclic group of 4 to 6 ring atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, which ring may optionally be substituted by 1 to 2 heteroatoms selected from fluorine, methyl, hydroxy, oxo (═ O), amino, phenyl, phenylthio, benzylthio, (thiomorpholin-4-yl) c (O) O-, CH₃S(O)₂-and CH₃S(O)₂O-or may be fused with another ring, such as a phenyl or cycloalkyl ring, to form a fused heterocyclic ring of 10 to 14 ring atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. The heterocyclic ring includes azetidinyl (e.g., L-azetidinyl), thiazolidinyl (e.g., L-thiazolidinyl), piperidinyl (e.g., L-piperidinyl), piperazinyl (e.g., L-piperazinyl), indolinyl (e.g., L-2, 3-indolin-2-yl), tetrahydroquinolinyl (e.g., L-1, 2, 3, 4-tetrahydroquinolin-2-yl), thiomorpholinyl (e.g., L-thiomorpholine 3-yl), pyrrolidinyl (e.g., L-pyrrolidinyl), substituted pyrrolidinyl such as 4-hydroxypyrrolidinyl (e.g., 4- α - (or β -) hydroxy-L-pyrrolidinyl), 4-oxopyrrolidinyl (e.g., 4-oxo-L-pyrrolidinyl), 4-fluoropyrrolidinyl (e.g., 4- α - (or β -) fluoro-L-pyrrolidinyl), 4, 4-difluoropyrrolidinyl (e.g., 4, 4-difluoro-L-pyrrolidinyl), 4- (thiomorpholin-4-yl C (O) O-) pyrrolidinyl (e.g., 4- α - (or β -) - (thiomorpholin-4-yl C (O) O-) -L-pyrrolidinyl, 4- (CH-) - (O-)₃S(O)₂O-) pyrrolidinyl (e.g., 4-alpha- (or beta-) (CH)₃S(O)₂O-) -L-pyrrolidinyl, 3-phenylpyrrolidinyl (e.g., 3- α - (or β -) phenyl-L-pyrrolidinyl), 3-phenylthiopyrrolidinyl (e.g., 3- α - (or β -) phenylthio-L-pyrrolidinyl), 4-aminopyrrolidinyl (e.g., 4- α - (or β -) amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (e.g., 3- α - (or β -) methoxy-L-pyrrolidinyl), 4-dimethylpyrrolidinyl, substituted piperazinyl such as 4-N-Cbz-piperazinyl, and 4- (CH-pyrrolidinyl)₃S(O)₂-) piperazinyl, substituted thiazolidinyl such as 5, 5-dimethylthiazolidin-4-yl, 1-dioxo-thiazolidinyl (e.g., L-1, 1-dioxo-thiazolidin-2-yl), substituted 1, 1-dioxo-thiazolidinyl such as L-1, 1-diOxo-5, 5-dimethylthiazolidin-2-yl, 1-dioxothiomorpholinyl (e.g., L-1, 1-dioxo-thiomorpholin-3-yl), and the like.

Preferably in the compounds of formulae I and IA described above, R³Including by hydrogen, methyl, phenyl, benzyl, diphenylmethyl, -CH₂CH₂-COOH、-CH₂-COOH, 2-amidoethyl, isobutyl, tert-butyl, -CH₂O-benzyl and hydroxymethyl substituted all isomers produced. Furthermore, in another preferred embodiment, R³And R²And is attached to R²The nitrogen atoms in (a) together may form a heterocyclic group or a substituted heterocyclic group.

Preferably in the compounds of formulae I and IA described above, R⁴Selected from hydrogen, methyl, ethyl, phenyl, and wherein R³And R⁴Together with the carbon atom to which they are attached form a cycloalkyl group of 3 to 6 carbon atoms or a heterocyclic group of 3 to 8 ring atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Q is preferably-C (O) N (O) -, -CH₂NH-, -CH (OH) C (O) NH-, -NHC (O) NH-or tetrazole-1, 5-diyl.

R⁵Preferably selected from all possible isomers produced by substitution with:

4-methylbenzyl group,

4-hydroxybenzyl,

4-methoxybenzyl,

4-tert-butoxybenzyl group,

4-benzyloxy-benzyl,

4-[φ-CH(CH₃)O-]Benzyl group,

4- [ phi-CH (COOH) O- ] benzyl,

4-[BocNHCH₂C(O)NH-]Benzyl group,

4-chlorobenzyl,

4-[NH₂CH₂C(O)NH-]Benzyl group,

4-carboxybenzyl group,

4-[CbzNHCH₂CH₂NH-]Benzyl group,

3-hydroxy-4- (phi-OC (O) NH-) benzyl,

4-[HOOCCH₂CH₂C(O)NH-]Benzyl group,

Benzyl group,

4- [ 2' -carboxyphenoxy- ] benzyl,

4- [ phi-C (O) NH- ] benzyl,

3-carboxybenzyl group,

4-iodobenzyl group,

4-hydroxy-3, 5-diiodobenzyl,

4-hydroxy-3-iodobenzyl,

4- [ 2' -carboxyphenyl- ] benzyl,

φ-CH₂CH₂-、

4-nitrobenzyl,

2-carboxybenzyl group,

4- [ dibenzylamino ] -benzyl,

4- [ (1 '-cyclopropylpiperidin-4' -yl) C (O) NH- ] benzyl,

4-[-NHC(O)CH₂NHBoc]Benzyl group,

4-carboxybenzyl group,

4-hydroxy-3-nitrobenzyl,

4-[-NHC(O)CH(CH₃)NHBoc]Benzyl group,

4-[-NHC(O)CH(CH₂φ)NHBoc]Benzyl group,

Isobutyl, and,

Methyl, methyl,

4-[CH₃C(O)NH-]Benzyl group,

-CH₂- (3-indolyl),

N-butyl,

tert-butyl-OC (O) CH₂-、

tert-butyl-OC (O) CH₂CH₂-、

H₂NC(O)CH₂-、

H₂NC(O)CH₂CH₂-、

BocNH-(CH₂)₄-、

tert-butyl-OC (O) - (CH)₂)₂-、

HOOCCH₂-、

HOOC(CH₂)₂-、

H₂N(CH₂)₄-、

An isopropyl group,

(1-naphthyl) -CH₂-、

(2-naphthyl) -CH₂-、

(2-Phenylthio) -CH₂-、

(φ-CH₂-OC(O)NH-(CH₂)₄-、

cyclohexyl-CH₂-、

benzyloxy-CH₂-、

HOCH₂-、

5- (3-N-benzyl) imidazolyl-CH₂-、

2-pyridyl-CH₂-、

3-pyridyl-CH₂-、

4-pyridyl-CH₂-、

5- (3-N-methyl) imidazolyl-CH₂-、

N-benzylpiperidin-4-yl-CH₂-、

N-Boc-piperidin-4-yl-CH₂-、

N- (phenyl-carbonyl) piperidin-4-yl-CH₂-、

H₃CSCH₂CH₂-、

1-N-benzylimidazol-4-yl-CH₂-、

isopropyl-C (O) NH- (CH)₂)₄-、

isobutyl-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) -CH₂-、

4-imidazolyl group,

4-[(CH₃)₂NCH₂CH₂CH₂-O-]Benzyl group,

4- [ (benzyl)₂N-]-benzyl group,

4-aminobenzyl group,

allyloxy-C (O) NH (CH)₂)₄-、

allyloxy-C (O) NH (CH)₂)₃-、

allyloxy-C (O) NH (CH)₂)₂-、

NH₂C(O)CH₂-、

φ-CH＝、

2-pyridyl-C (O) NH- (CH)₂)₄-、

4-methylpyridin-3-yl-C (O) NH- (CH)₂)₄-、

3-methylthiophen-2-yl-C (O) NH- (CH)₂)₄-、

2-pyrrolyl-C (O) NH- (CH)₂)₄-、

2-furyl-C (O) NH- (CH)₂)₄-、

4-methylphenyl-SO₂-N(CH₃)CH₂C(O)NH(CH₂)₄-、

4- [ cyclopentylethynyl ] -benzyl,

4- [ -NHC (O) - (N-Boc) -pyrrolidin-2-yl) ] -benzyl- ] -methyl- ]

1-N-methylimidazol-4-yl-CH₂-、

1-N-methylimidazol-5-yl-CH₂-、

imidazol-5-yl-CH₂-、

6-methylpyridin-3-yl-C (O) NH- (CH)₂)₄-、

4- [ 2' -carboxymethylphenyl ] -benzyl,

4-[-NHC(O)NHCH₂CH₂CH₂-φ]-benzyl group,

4-[-NHC(O)NHCH₂CH₂-φ]-benzyl group,

-CH₂C(O)NH(CH₂)₄φ、

4-[φ(CH₂)₄O-]-benzyl group,

4- [ -C.ident.C-phi-4' phi ] -benzyl,

4-[-C≡C-CH₂-O-S(O)₂-4’-CH₃-φ]-benzyl group,

4-[-C≡C-CH₂NHC(O)NH₂]-benzyl group,

4-[-C≡C-CH₂-O-4’-COOCH₂CH₃-φ]-benzyl group,

4-[-C≡C-CH(NH₂) -cyclohexyl radical]-benzyl group,

-(CH₂)₄NHC(O)CH₂-3-indolyl group,

-(CH₂)₄NHC(O)CH₂CH₂-3-indolyl group,

-(CH₂)₄NHC (O) -3- (5-methoxyindolyl),

-(CH₂)₄NHC (O) -3- (1-methylindolyl),

-(CH₂)₄NHC(O)-4-(-SO₂(CH₃)-φ)、

-(CH₂)₄NHC(O)-4-(C(O)CH₃) -phenyl group,

-(CH₂)₄NHC (O) -4-fluorophenyl,

-(CH₂)₄NHC(O)CH₂O-4-fluorophenyl,

4- [ -C.ident.C- (2-pyridyl) ] benzyl,

4-[-C≡C-CH₂-O-phenyl]Benzyl group,

4-[-C≡C-CH₂OCH₃]Benzyl group,

4- [ -C.ident.C- (3-hydroxyphenyl) ] benzyl,

4-[-C≡C-CH₂-O-4’-(-C(O)OC₂H₅) Phenyl radical]Benzyl group,

4-[-C≡C-CH₂CH(C(O)OCH₃)₂]Benzyl group,

4-[-C≡C-CH₂NH- (4, 5-dihydro-4-oxo-5-phenyl-oxazol-2-yl),

3-aminobenzyl group,

4-[-C≡C-CH₂CH(NHC(O)CH₃)C(O)OH]-benzyl group,

-CH₂C(O)NHCH(CH₃)φ、

-CH₂C(O)NHCH₂- (4-dimethylamino) -phi,

-CH₂C(O)NHCH₂-4-nitrophenyl,

-CH₂CH₂C(O)N(CH₃)CH₂-φ、

-CH₂CH₂C(O)NHCH₂CH₂- (N-methyl) -2-pyrrolyl,

-CH₂CH₂C(O)NHCH₂CH₂CH₂CH₃、

-CH₂CH₂C(O)NHCH₂CH₂-3-indolyl group,

-CH₂C(O)N(CH₃)CH₂Phenyl, phenyl,

-CH₂C(O)NH(CH₂)₂- (N-methyl) -2-pyrrolyl,

-CH₂C(O)NHCH₂CH₂CH₂CH₃、

-CH₂C(O)NHCH₂CH₂-3-indolyl group,

-(CH₂)₂C(O)NHCH(CH₃)φ、

-(CH₂)₂C(O)NHCH₂-4-dimethylaminophenyl group,

-(CH₂)₂C(O)NHCH₂-4-nitrophenyl,

-CH₂C(O)NH-4-[-NHC(O)CH₃-phenyl radical]、

-CH₂C (O) NH-4-pyridyl,

-CH₂C (O) NH-4- [ dimethylaminophenyl group]、

-CH₂C (O) NH-3-methoxyphenyl,

-CH₂CH₂C (O) NH-4-chlorophenyl,

-CH₂CH₂C (O) NH-2-pyridyl,

-CH₂CH₂C (O) NH-4-methoxyphenyl,

-CH₂CH₂C (O) NH-3-pyridyl,

4-[(CH₃)₂NCH₂CH₂O-]Benzyl group,

-(CH₂)₃NHC(NH)NH-SO₂-4-methylphenyl,

4-[(CH₃)₂NCH₂CH₂O-]Benzyl group,

-(CH₂)₄NHC(O)NHCH₂CH₃、

-(CH₂)₄NHC (O) NH-phenyl,

-(CH₂)₄NHC (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)CH₂NHC (O) NH-3' -methylphenyl]Benzyl group,

4- [ -NHC (O) - (2 ', 3' -indolin-2-yl) ] benzyl,

4- [ -NHC (O) - (2 ', 3' -dihydro-N-Boc-indol-2-yl) ] benzyl,

p-[-OCH₂CH₂-1 '- (4' -pyrimidinyl) -piperazinyl]Benzyl group,

4-[-OCH₂CH₂- (1' -piperidinyl)]Benzyl group,

4-[-OCH₂CH₂- (1' -pyrrolidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂- (1' -piperidinyl)]Benzyl-),

-CH₂-3- (1, 2, 4-triazolyl)

4-[-OCH₂CH₂CH₂-4- (3' -chlorophenyl) -piperazin-1-yl]Benzyl group,

4-[-OCH₂CH₂N(φ)CH₂CH₃]Benzyl group,

4-[-OCH₂-3' - (N-Boc) -piperidinyl]Benzyl group,

4- [ di-n-pentylamino ] benzyl,

4- [ n-pentylamino ] benzyl,

4- [ di-isopropylamino-CH₂CH₂O-]Benzyl group,

4-[-OCH₂CH₂- (N-morpholinyl)]Benzyl group,

4- [ -O- (3' - (N-Boc) -piperidinyl ] benzyl,

4-[-OCH₂CH(NHBoc)CH₂Cyclohexyl radical]Benzyl group,

p-[OCH₂CH₂- (N-piperidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂- (4-m-chlorophenyl) -piperazin-1-yl]Benzyl group,

4-[-OCH₂CH₂- (N-homopiperidinyl)]Benzyl group,

4- [ -NHC (O) -3' - (N-Boc) -piperidinyl ] benzyl,

4-[-OCH₂CH₂N- (benzyl)₂]Benzyl group,

-CH₂-2-thiazolyl,

3-hydroxybenzyl,

4-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4-[-NHC(S)NHCH₂CH₂- (N-morpholino)]Benzyl group,

4-[-OCH₂CH₂N(C₂H₅)₂]Benzyl group,

4-[-OCH₂CH₂CH₂N(C₂H₅)₂]Benzyl group,

4-[CH₃(CH₂)₄NH-]Benzyl group,

4- [ N-N-butyl, N-N-pentylamino- ] benzyl,

4- [ -NHC (O) -4' -piperidinyl ] benzyl,

4-[-NHC(O)CH(NHBoc)(CH₂)₄NHCbz]Benzyl group,

4- [ -NHC (O) - (1 ', 2 ', 3 ', 4 ' -tetrahydro-N-Boc-isoquinolin-1 ' -yl ] benzyl,

p-[-OCH₂CH₂CH₂-1 '- (4' -methyl) -piperazinyl]Benzyl group,

-(CH₂)₄NH-Boc、

3-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

3-[-OCH₂CH₂- (1' -pyrrolidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂N(CH₃) Benzyl radical]Benzyl group,

4-[-NHC(S)NHCH₂CH₂CH₂- (N-morpholino)]Benzyl group,

4-[-OCH₂CH₂- (N-morpholino)]Benzyl group,

4-[-NHCH₂- (4' -chlorophenyl)]Benzyl group,

4- [ -NHC (O) NH- (4' -cyanophenyl) ] benzyl,

4-[-OCH₂COOH]Benzyl group,

4-[-OCH₂COO-tert-butyl]Benzyl group,

4- [ -NHC (O) -5' -fluoroindol-2-yl ] benzyl,

4-[-NHC(S)NH(CH₂)₂-1-piperidinyl group]Benzyl group,

4-[-N(SO₂CH₃)(CH₂)₃-N(CH₃)₂]Benzyl group,

4-[-NHC(O)CH₂CH(C(O)OCH₂φ)-NHCbz]Benzyl group,

4-[-NHS(O)₂CF₃]Benzyl group,

3- [ -O- (N-methylpiperidin-4' -yl) ] benzyl,

4-[-C(＝NH)NH₂]Benzyl group,

4-[-NHSO₂-CH₂Cl]Benzyl group,

4- [ -NHC (O) - (1 ', 2 ', 3 ', 4 ' -tetrahydroisoquinolin-2 ' -yl ] benzyl,

4-[-NHC(S)NH(CH₂)₃-N-morpholino]Benzyl group,

4-[-NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]Benzyl group,

4-[-C(O)NH₂]Benzyl group,

4- [ -NHC (O) NH-3' -methoxyphenyl ] benzyl,

4-[-OCH₂CH₂-indol-3' -yl]Benzyl group,

4-[-OCH₂C (O) NH-benzyl]Benzyl group,

4-[-OCH₂C (O) O-benzyl]Benzyl group,

4-[-OCH₂C(O)OH]Benzyl group,

4-[-OCH₂-2 ' - (4 ', 5 ' -dihydro) imidazolyl]Benzyl group,

-CH₂C(O)NHCH₂- (4-dimethylamino) phenyl,

4- [ -NHC (O) -L-2' -pyrrolidinyl-N-SO₂-4' -methylphenyl radical]Benzyl group,

4-[-NHC(O)NHCH₂CH₂CH₃]Benzyl group,

4-aminobenzyl group,

4-[-OCH₂CH₂-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl]Benzyl group,

4- [ -O- (N-methylpiperidin-4' -yl) ] benzyl,

3-methoxybenzyl,

4- [ -NHC (O) -piperidin-3' -yl ] benzyl,

4- [ -NHC (O) -pyridin-2' -yl ] benzyl,

4-[-NHCH₂- (4' -chlorophenyl)]Benzyl group,

4-[-NHC(O)-(N-(4’-CH₃-φ-SO₂) -L-pyrrolidin-2' -yl)]Benzyl group,

4-[-NHC(O)NHCH₂CH₂-φ]Benzyl group,

4-[-OCH₂C(O)NH₂]Benzyl group,

4-[-OCH₂C (O) NH-tert-butyl]Benzyl group,

4-[-OCH₂CH₂-1- (4-hydroxy-4-phenyl) -piperidinyl]Benzyl group,

4-[-NHSO₂-CH＝CH₂]Benzyl group,

4-[-NHSO₂-CH₂CH₂Cl]Benzyl group,

-CH₂C(O)NHCH₂CH₂N(CH₃)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’-(CH₃)₂NC (O) O-) phenyl) -C (O) NH-]Benzyl group,

4- [ -NHC (O) -1 '-methylpiperidin-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) CCH₂-O-benzyl) -NH-]Benzyl group,

[BocNHCH₂C(O)NH-]Butyl, isobutyl, or isobutyl,

4-benzyl group,

2-hydroxyethyl group,

4-[(Et)₂NCH₂CH₂CH₂NHC(S)NH-]Benzyl group,

4- [ (1 ' -Boc-4 ' -hydroxypyrrolidin-2 ' -yl) C (O) NH- ] benzyl,

4-[φCH₂CH₂CH₂NHC(S)NH-]Benzyl group,

4- [ (perhydroindol-2' -yl) C (O) NH- ] benzyl,

2- [ 4-hydroxy-4- (3-methoxythien-2-yl) piperidin-1-yl ] ethyl,

4- [ (1 '-Boc-perhydroindol-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- (φ NHC (S) NH) benzyl,

4- (EtNHC (S) NH) benzyl,

4-(φCH₂NHC (S) NH) benzyl,

3- [ (1 '-Boc-piperidin-2' -yl) C (O) NH- ] benzyl,

3- [ piperidin-2' -yl-C (O) NH- ] benzyl,

4- [ (3 '-Boc-thiazolidin-4' -yl) C (O) NH- ] benzyl,

4- (pyridin-3' -yl-NHC (S) NH) benzyl,

4-(CH₃-NHC (S) NH) benzyl,

4-(H₂NCH₂CH₂CH₂C (O) NH) benzyl,

4-(BocHNCH₂CH₂CH₂C (O) NH) benzyl,

4- (pyridin-4' -yl-CH₂NH) benzyl group,

4- [ (N, N-bis (4-N, N-dimethylamino) benzyl) amino ] benzyl,

4- [ (1-Cbz-piperidin-4-yl) C (O) NH- ] butyl,

4-[φCH₂OCH₂(BocHN)CHC(O)NH]Benzyl group,

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-[CH₃NHCH₂CH₂CH₂C(O)NH-]Benzyl group,

4-[CH₃N(Boc)CH₂CH₂CH₂C(O)NH-]Benzyl group,

4- (aminomethyl) benzyl,

4-[φCH₂OCH₂(H₂N)CHC(O)NH]Benzyl group,

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 '-indolin-2' -yl) -C (O) NH ] benzyl,

4- (pyridin-3' -yl-CH₂NH) benzyl group,

4- [ (1 '-Cbz-piperidin-4' -yl) C (O) NH- ] benzyl,

4- [ (piperidin-1' -yl) C (O) CH₂-O-]Benzyl group,

4-[(CH₃)₂CH)₂NC(O)CH₂-O-]Benzyl group,

4-[HO(O)C(Cbz-NH)CHCH₂CH₂-C(O)NH-]Benzyl group,

4-[φCH₂O(O)C(Cbz-NH)CHCH₂CH₂-C(O)NH-]Benzyl group,

4- [ -NHC (O) -2' -methoxyphenyl ] benzyl,

4- [ (pyrazin-2' -yl) C (O) NH- ] benzyl,

4-[HO(O)C(NH₂)CHCH₂CH₂-C(O)NH-]Benzyl group,

4- (2 '-formyl-1', 2 ', 3', 4 '-tetrahydroisoquinolin-3' -yl-CH₂NH-) benzyl group,

N-Cbz-NHCH₂-、

4- [ (4 '-methylpiperazin-1' -yl) C (O) O- ] benzyl,

4-[CH₃(N-Boc)NCH₂C(O)NH-]Benzyl group,

4- [ -NHC (O) - (1 ', 2 ', 3 ', 4 ' -tetrahydro-N-Boc-isoquinolin-3 ' -yl ] -benzyl,

4-[CH₃NHCH₂C(O)NH-]Benzyl group,

(CH₃)₂NC(O)CH₂-、

4- (N-methylacetamido) benzyl,

4- (1 ', 2 ', 3 ', 4 ' -tetrahydroisoquinolin-3 ' -yl-CH₂NH-) benzyl group,

4-[(CH₃)₂NHCH₂C(O)NH-]Benzyl group,

(1-tosylimidazol-4-yl) methyl,

4- [ (1 '-Boc-piperidin-4' -yl) C (O) NH- ] benzyl,

4-trifluoromethyl benzyl,

4- [ (2' -bromophenyl) C (O) NH- ] benzyl,

4-[(CH₃)₂NC(O)NH-]Benzyl group,

4-[CH₃OC(O)NH-]Benzyl group,

4-[(CH₃)₂NC(O)O-]Benzyl group,

4-[(CH₃)₂NC(O)N(CH₃)-]Benzyl group,

4-[CH₃OC(O)N(CH₃)-]Benzyl group,

4- (N-methyl trifluoroacetylamino) 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-[(CH₃)₂NC(O)O-]Benzyl group,

4- [ (4 ' -phenyl-1 ' -Boc-piperidin-4 ' -yl) -C (O) O- ] benzyl,

4- (N-toluenesulfonylamino) benzyl,

4-[(CH₃)₃CC(O)NH-]Benzyl group,

4- [ (morpholin-4' -yl) C (O) NH- ] benzyl,

4-[(CH₃CH₂)₂NC(O)NH-]Benzyl group,

4- [ -C (O) NH- (4' -piperidinyl) ] benzyl,

4- [ (2' -trifluoromethylphenyl) C (O) NH- ] benzyl,

4- [ (2' -methylphenyl) C (O) NH- ] benzyl,

4-[(CH₃)₂NS(O)₂O-]Benzyl group,

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) -C (O) NH- ] benzyl,

4- [ (morpholin-4' -yl) C (O) O- ] benzyl,

3-nitro-4- (CH)₃OC(O)CH₂O-) benzyl group,

(2-benzoxazolinon-6-yl) methyl-,

(2H-1, 4-benzoxazin-3 (4H) -on-7-yl) methyl-, (4H-methyl-phenyl),

4-[(CH₃)₂NS(O)₂NH-]Benzyl group,

4-[(CH₃)₂NS(O)₂N(CH₃)-]Benzyl group,

4- [ (thiomorpholin-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 '-methylsulfonylpiperazin-1' -yl) -benzyl,

3-nitro-4- [ (morpholin-4' -yl) -C (O) O- ] benzyl,

4-{[(CH₃)₂NC(S)]₂N- } benzyl,

N-Boc-2-aminoethyl-,

4- [ (1, 1-dioxothiomorpholin-4-yl) -C (O) O- ] benzyl,

4-[(CH₃)₂NS(O)₂-]Benzyl group,

4- (imidazolidin-2 '-one-1' -yl) benzyl,

4- [ (piperidin-1' -yl) C (O) O- ] benzyl,

1-N-benzyl-imidazol-4-yl-CH₂-、

3, 4-ethylenedioxybenzyl group,

3, 4-dioxymethylene benzyl,

4-[-N(SO₂)(CH₃)CH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4- (3 ' -formylimidazolidin-2 ' -one-1 ' -yl) benzyl,

4-[NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]Benzyl group,

[2 '- [ 4' -hydroxy-4 '- (3' -methoxythiophen-2 '-yl) piperidin-2' -yl ] ethoxy ] benzyl, and

p-[(CH₃)₂NCH₂CH₂N(CH₃)C(O)O-]a benzyl group.

In a preferred embodiment, R⁵Preferably selected from all possible isomers produced by substitution with:

3-[(CH₃)₂NC(O)O-]benzyl group,

4-[(CH₃)₂NC(O)O-]Benzyl group,

4-[(CH₃)₂NS(O)₂O-]Benzyl group,

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 '-carboxypiperidin-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' -ylethyleneketal) 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 '- (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) piperazin-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 '- (phenyl C (O) -) piperazin-1' -yl) C (O) O- ] benzyl,

4- [ (4 '- (pyridin-4-yl C (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' -yl-C (O) O-) benzyl,

4- [ (4 '-trifluoromethanesulfonylpiperazin-1' -yl-C (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,

(another name is 4- [ (1, 1-dioxothiomorpholin-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 group,

4- [ (2' - (N-methyl-N-toluene-4-sulfonylamino) ethyl) (CH)₃)N-C(O)O-]Benzyl group,

4- [ (2 '- (morpholin-4' -yl) ethyl) (CH)₃)NC(O)O-]Benzyl group,

4- [ (2' - (hydroxy) ethyl) (CH)₃)NC(O)O-]Benzyl group,

4- [ bis (2' - (hydroxy) ethyl) NC (O) O- ] benzyl,

4- [ (2' - (formyloxy) ethyl) (CH)₃)NC(O)O-]Benzyl group,

4-[(CH₃OC(O)CH₂)HNC(O)O-]Benzyl group,

4- [ 2' - (phenylNHC (O) O-) ethyl- ] HNC (O) O- ] benzyl,

3-chloro-4- [ (CH)₃)₂NC(O)O-]Benzyl group,

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- [ (thiomorpholin-4' -yl) C (O) O- ] benzyl and

3-fluoro-4- [ (CH)₃)₂NC(O)O-]A benzyl group.

In the compounds of formula IA, R⁶Preference is given to 2, 4-dioxotetrahydrofuran-3-yl (3, 4-enol), methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopentyloxy, neopentyloxy, 2-. alpha. -isopropyl-4-. beta. -methylcyclohexyloxy, 2-. beta. -isopropyl-4-. beta. -methylcyclohexyloxy, -NH₂Benzyloxy, -NHCH₂COOH、-NHCH₂CH₂COOH, -NH-adamantyl, -NHCH₂CH₂COOCH₂CH₃、-NHSO₂-p-CH₃-φ、-NHOR⁸Wherein R is⁸Is hydrogen, methyl, isopropyl or benzyl, O- (N-succinimidyl), -O-cholest-5-en-3-beta-yl, -OCH₂-OC(O)C(CH₃)₃、-O(CH₂)_zNHC (O) W wherein z is 1 or 2, W is selected from pyridin-3-yl, N-methylpyridinyl and N-methyl-1, 4-dihydro-pyridin-3-yl, -NR 'C (O) -R', wherein R 'is aryl, heteroaryl or heterocycle, R' is hydrogen or-CH₂C(O)OCH₂CH₃。

Preferred compounds within the scope of the compounds of formulae I and IA above include, for example:

n- [ N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl ] -L-phenylalanine

N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-L-phenylalanine

N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-D-phenylalanine

N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl ] -L-4- (N-benzyloxycarbonyl-isopiperidinecarboxamido) phenylalanine

N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl ] -L-4- (isopiperidinecarboxamido) phenylalanine

(2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl ] -2- (4-nitrobenzyl) propionic acid

(2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl ] -2- (4- (N-tert-butoxycarbonylisopiperidinecarboxamido) benzyl) propionic acid methyl ester

(2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl ] -2- (4- (N-tert-butoxycarbonylisopiperidinecarboxamido) benzyl) propionic acid

N- [ N- (toluene-4-sulfonyl) pyrrolidin-2-yl ] aminocarbonyl ] -L-phenylalanine

And pharmaceutically acceptable salts thereof, and any ester of any of the above compounds, wherein one ester is replaced by another ester selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl esters.

The present invention also provides a method of binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I or IA as described above under conditions wherein the compound binds to VLA-4.

Certain of the compounds of formulae I and IA described above are useful for reducing VLA-4 mediated inflammation in vivo.

The invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of formula I or IA, as described above, but wherein R is not included³And R⁵Are compounds derived from L-amino acids or other starting materials of similar configuration. Alternatively, the first and second electrodes may be,racemic mixtures may also be used.

The pharmaceutical composition is useful for treating a VLA-4 mediated disorder. Such conditions include, for 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 brain trauma, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury such as that seen in adult respiratory distress syndrome.

Accordingly, the present invention also provides a method of treating an inflammatory disease mediated by VLA-4 in a patient, which method comprises administering to the patient a pharmaceutical composition as described above.

Preferred compounds of formulae I and IA above include those listed in table I below:

R¹	R²	R³	R⁴	R⁵	R⁶	Q
R¹	R²	R³	R⁴	R⁵	R⁶	Q	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂-	-OH	-CH₂-NH-
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂the-L-isomer	-OH	-C(O)N(O)-	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂-	-OH	-CH₂-NH-
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂the-L-isomer	-OH	-C(O)N(O)-	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂The (E) -D-isomer	-OH	-C(O)N(O)-
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (1-Boc-piperidin-4-yl) C (O) NH-]Benzyl-	-OH	-CH(OH)C(O)NH-	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂The (E) -D-isomer	-OH	-C(O)N(O)-
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (1-Boc-piperidin-4-yl) C (O) NH-]Benzyl-	-OH	-CH(OH)C(O)NH-	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (piperidin-4-yl) C (O) NH-]Benzyl-	-OH	-CH(OH)C(O)NH-
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	4-NO₂-Ph-CH₂-	-OH	Tetrazole-1, 5-diyl¹	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (piperidin-4-yl) C (O) NH-]Benzyl-	-OH	-CH(OH)C(O)NH-
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	4-NO₂-Ph-CH₂-	-OH	Tetrazole-1, 5-diyl¹	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (1-Boc-piperidin-4-yl) C (O) NH-]Benzyl-	-OCH₃	Tetrazole-1, 5-diyl
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (1-Boc-piperidin-4-yl) C (O) NH-]Benzyl-	-OH	Tetrazole-1, 5-diyl¹	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (1-Boc-piperidin-4-yl) C (O) NH-]Benzyl-	-OCH₃	Tetrazole-1, 5-diyl
p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	p- [ (1-Boc-piperidin-4-yl) C (O) NH-]Benzyl-	-OH	Tetrazole-1, 5-diyl¹	p-CH₃-Ph-	R²/R³3 carbon atoms of the Ring (L-pyrrolidinyl)	--	-H	Ph-CH₂-	-OH	-NHC(O)NH-

¹Tetrazole-1, 5-diyl ═ e

Detailed Description

As described above, the present invention relates to compounds that inhibit leukocyte adhesion, particularly leukocyte adhesion mediated by VLA-4. When describing the compounds, compositions and methods of this invention, the following terms have the following meanings, unless otherwise indicated.

Definition of

As used herein, "alkyl" refers to an alkyl group preferably containing 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of this term are methyl, t-butyl, n-heptyl, octyl and the like.

"substituted alkyl" refers to an alkyl group preferably containing 1 to 10 carbon atoms and bearing 1 to 5 substituents selected from alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thiocarbamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxy, nitro, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, cycloalkyl, substituted-heteroaryl, carboxy-heterocycle, carboxy-substituted heterocycle, cycloalkyl, substituted-heterocycle, substituted-alkyl, substituted cycloalkyl, guanidino sulfone, mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cycloalkylthio, substituted cycloalkylthio, heteroarylthio, substituted heteroarylthio, heterocyclylthio, substituted heterocyclylthio, heteroaryl, substituted aryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted cycloalkoxy, substituted heteroaryloxy, heterocyclyloxy, substituted arylthio, substituted heteroarylthio, substituted heterocyclyloxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, or substituted heterocyclyloxyHeterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂Substituted heterocycles, -OSO₂-NRR (wherein R is hydrogen or alkyl), -NRS (O)₂-alkyl, -NRS (O)₂-substituted alkyl, -NRS (O)₂-aryl, -NRS (O)₂Substituted aryl, -NRS (O)₂-heteroaryl, -NRS (O)₂-substituted heteroaryl, -NRS (O)₂-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles (wherein R is hydrogen or alkyl), mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric di-substituted amines bearing different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and substituted alkyl groups having amino groups blocked by conventional blocking groups, e.g. Boc, Cbz, formyl, etc., or by-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-alkenyl, -SO₂-substituted alkenyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl, -SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocycle, -SO₂-substituted heterocycle and-SO₂NRR (where R is hydrogen or alkyl) substituted alkyl/substituted alkyl.

"alkoxy" refers to the group "alkyl-O-", which includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, 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 groups H-C (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) -, heterocycle-C (O) -, and substituted heterocycle-C (O) -, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"acylamino" refers to the group-C (O) NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and where each R is joined together with the nitrogen atom to form a heterocycle or substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Thiocarbonylamino" refers to the group-C (S) NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and where each R is joined together with the nitrogen atom to form a heterocycle or substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"acyloxy" refers to the group alkyl-C (O) O-, substituted alkyl C (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-, heterocycle-C (O) O-, and substituted heterocycle-C (O) O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, Substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"alkenyl" means an alkenyl group preferably containing 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and containing at least 1, preferably 1-2 sites of alkenyl unsaturation.

"substituted alkenyl" refers to alkenyl groups having 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thiocarbamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxy, nitro, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, cycloalkyl, substituted cycloalkyl, guanidino sulfone, substituted aryl, heteroaryl, substituted aryl, amino, acyl, acylamino, amidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted, Mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cycloalkylthio, substituted cycloalkylthio, heteroarylthio, substituted heteroarylthio, heterocyclic thio, substituted heterocyclic thio, heteroaryl, substitutedAryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocycloxy, substituted heterocycloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂Substituted heterocycles, -OSO₂-NRR (wherein R is hydrogen or alkyl), -NRS (O)₂-alkyl, -NRS (O)₂-substituted alkyl, -NRS (O)₂-aryl, -NRS (O)₂Substituted aryl, -NRS (O)₂-heteroaryl, -NRS (O)₂-substituted heteroaryl, -NRS (O)₂-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles (wherein R is hydrogen or alkyl), mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric di-substituted amines bearing different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and substituted alkenyl groups having amino groups blocked by conventional blocking groups, e.g. Boc, Cbz, formyl, etc., or by-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-alkenyl, -SO₂-substituted alkenyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl, -SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocycle, -SO₂-substituted heterocycle and-SO₂NRR (whichWherein R is hydrogen or alkyl) substituted alkenyl/substituted alkenyl.

"alkynyl" means an alkynyl group preferably containing 2 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and containing at least 1, preferably 1-2 sites of alkynyl unsaturation.

"substituted alkynyl" refers to alkynyl groups having 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thiocarbamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxy, nitro, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, cycloalkyl, substituted cycloalkyl, guanidino sulfone, guanidino, substituted aryl, or heteroaryl, Mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cycloalkylthio, substituted cycloalkylthio, heteroarylthio, substituted heteroarylthio, heterocyclylthio, substituted heterocyclylthio, heteroaryl, substituted aryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocycloxy, substituted heterocycloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂Substituted heterocycles, -OSO₂-NRR (wherein R is hydrogen or alkyl), -NRS (O)₂-alkyl, -NRS (O)₂-substituted alkyl, -NRS (O)₂-aryl, -NRS (O)₂Substituted aryl, -NRS (O)₂-heteroaryl, -NRS (O)₂-substituted heteroaryl, -NRS (O)₂-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles (wherein R is hydrogen or alkyl), mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric di-substituted amines bearing different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and substituted alkynyl groups having amino groups blocked by conventional blocking groups, e.g. Boc, Cbz, formyl, etc., or by-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-alkenyl, -SO₂-substituted alkenyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl, -SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocycle, -SO₂-substituted heterocycle and-SO₂NRR (wherein R is hydrogen or alkyl) substituted alkynyl/substituted alkynyl.

"amidino" means a group H₂NC (═ NH) -, the term "alkylamidino" refers to compounds bearing 1 to 3 alkyl groups (e.g., alkyl-HNC (═ NH) -, etc.).

"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, wherein R is hydrogen or alkyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminocarbonyloxy" refers to the 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, -NRC (O) O-heteroaryl, -NRC (O) O-substituted heteroaryl, -NRC (O) O-heterocyclic, and-NRC (O) O-substituted heterocyclic, where R is hydrogen or alkyl, where alkyl, substituted alkyl, O-substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Oxycarbonylamino" refers to the group-OC (O) NH₂OC (O) NRR, -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-heterocycle, and-OC (O) NR-substituted heterocycle, wherein R is hydrogen, alkyl, or wherein each R is joined to the nitrogen atom to form a heterocycle or substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Thiocarbonylamino" refers to the group-OC (S) NH₂-OC (S) NRR, -OC (S) NR-alkyl, -OC (S) NR-substituted alkyl, -OC (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-heterocycle, and-OC (S) NR-substituted heterocycle, wherein R is hydrogen, alkyl, or wherein each R is linked to the nitrogen atom to form a heterocycle or substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminocarbonylamino" refers to the group-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-substituted heterocyclic, where each R is independently of the other hydrogen, NRC (O) NRR-alkyl, -NRC (O) NR-alkyl, NRC (O) NR-substituted heterocyclic, where each R is independently of the other, Alkyl, or wherein each R is taken together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring, and wherein one of the amino groups is blocked with a conventional blocking group such as Boc, Cbz, formyl, and the like, 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.

"Aminothiocarbonylamino" means the group-NRC (S) NRR, -NRC (S) NR-alkyl, -NRC (S) NR-substituted alkyl, -NRC (S) NR-alkenyl, -NRC (S) NR-substituted alkenyl, -NRC (S) NR-alkynyl, -NRC (S) NR-substituted alkynyl, -NRC (S) NR-aryl, -NRC (S) NR-substituted aryl, -NRC (S) NR-cycloalkyl, -NRC (S) NR-substituted cycloalkyl, -NRC (S) NR-heteroaryl and-NRC (S) NR-substituted heteroaryl, -NRC S (NR) -heterocyclic and-NRC (S) NR-substituted heterocyclic, wherein each R is independently of the other hydrogen, or a substituted aryl, or a heteroaryl, or a substituted aryl, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable, Alkyl, or wherein each R is taken together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring, and wherein one of the amino groups is blocked with a conventional blocking group such as Boc, Cbz, formyl, and the like, 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.

"aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms containing a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl) wherein the fused rings may be aromatic or non-aromatic (e.g., 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) on-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

Substituted aryl refers to aryl substituted with 1 to 3 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, thiocarbamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, substituted alkynyl, amidino, aminothiocarbonylamino, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyloxy, heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy, carboxyalkyl, Carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, carboxyamido, cyano, mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, heteroarylthio, substituted heteroarylthio, cycloalkylthio, substituted cycloalkylthio, heterocyclylthio, substituted heterocyclylthio, cycloalkyl, substituted cycloalkyl, guanidino sulfone, halogen, nitro, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocycloxy, substituted heterocycloxy, oxycarbonylamino, oxysulfuro, thionyloxy, thioSubstituted carbonylamino, -S (O)₂-alkyl, -S (O)₂-substituted alkyl, -S (O)₂Cycloalkyl, -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-heterocycle, -S (O)₂-substituted heterocycles, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂-substituted heterocycles, -OSO₂-NRR (wherein 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-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles (where R is hydrogen or alkyl), mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric di-substituted amines with different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle and the amino group on the substituted aryl is blocked with a conventional blocking group such as Boc, Cbz, formyl etc. or by-SO₂NRR (wherein R is hydrogen or alkyl).

"aryloxy" refers to the group aryl-O-which includes, for example, phenoxy, naphthoxy, and the like.

"substituted aryloxy" refers to a substituted aryl-O-group.

"Aryloxyaryl" means the group-aryl-O-aryl.

"substituted aryloxyaryl" refers to aryloxyaryl substituted on one or both aromatic rings with 1 to 3 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, thiocarbamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocycloxy, substituted heterocycloxy, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, Carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, carboxyamido, cyano, mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, heteroarylthio, substituted heteroarylthio, cycloalkylthio, substituted cycloalkylthio, heterocyclylthio, substituted heterocyclylthio, cycloalkyl, substituted cycloalkyl, guanidino sulfone, halogen, nitro, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, oxycarbonylamino, oxythiocarbonylamino, -S (O)₂-alkyl, -S (O)₂-substituted alkyl, -S (O)₂Cycloalkyl, -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-heterocycle, -S (O)₂-substituted heterocycles, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂-substituted heterocycles, -OSO₂-NRR (wherein 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-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles (where R is hydrogen or alkyl), mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric di-substituted amines with different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle and the amino group on the substituted aryl is blocked with a conventional blocking group such as Boc, Cbz, formyl etc. or by-SO₂NRR (wherein R is hydrogen or alkyl).

"cycloalkyl" refers to a cyclic alkyl group of 3 to 8 carbon atoms containing a single ring and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Polycyclic alkyl groups such as adamantyl and the like are excluded from this definition.

"cycloalkenyl" refers to cyclic alkenyl groups of 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.

"substituted cycloalkyl" and "substituted cycloalkenyl" with 1 to 5 substituents, preferably 3 to 8 carbon atomsCycloalkyl and cycloalkenyl, the substituents being selected from oxo (═ O), thio (═ S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thiocarbamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxy, cyano, nitro, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, cycloalkyl, substituted cycloalkyl, guanidino sulfone, cyano, nitro, carboxyl, carboxyalkyl, carboxyalkylamino, substituted aryloxy, substituted aryloxyaryl, halogen, hydroxy, mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cycloalkylthio, substituted cycloalkylthio, heteroarylthio, substituted heteroarylthio, heterocyclylthio, substituted heterocyclylthio, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂-substituted heterocycles, -OSO₂-NRR (wherein 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-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles (where R is hydrogen or alkyl), mono-and di-alkylAmino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric di-substituted amines with different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and substituted alkynyls in which the amino group is blocked with a conventional blocking group such as Boc, Cbz, formyl, etc., or with-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-alkenyl, -SO₂-substituted alkenyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl, -SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocycle, -SO₂-substituted heterocycle and-SO₂NRR (wherein R is hydrogen or alkyl) substituted alkynyl/substituted alkynyl.

"Cycloalkoxy" refers to an-O-cycloalkyl group.

"substituted cycloalkoxy" refers to an-O-substituted cycloalkyl group.

"guanidino" refers to the group-NRC (═ NR) NRR, -NRC (═ NR) NR-alkyl, -NRC (═ NR) NR-substituted alkyl, -NRC (═ NR) NR-alkenyl, -NRC (═ NR) NR-substituted alkenyl, -NRC (═ NR) NR-alkynyl, -NRC (═ NR) NR-substituted alkynyl, -NRC (═ NR) NR-aryl, -NRC (═ NR) NR-substituted aryl, -NRC (═ NR) NR-cycloalkyl, -NRC (═ NR) NR-heteroaryl, -NRC (═ NR) NR-substituted heteroaryl, -NRC (═ NR) NR-heterocyclic ring, and-NRC (═ NR) NR-substituted heterocyclic ring, where each R is independently of each other hydrogen and alkyl and where one of the amino groups is blocked by a conventional blocking group such as Boc, Boc, Cbz, formyl, and the like, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"guanidinosulfone" refers to the group-NRC (═ NR) NRSO₂-alkyl, -NRC (═ NR) NRSO₂-substituted alkyl, -NRC (═ NR) NRSO₂-alkenyl, -NRC (═ NR) NRSO₂-substituted alkenyl, -NRC (═ NR) NRSO₂-alkynyl, -NRC (═ NR) NRSO₂-substituted alkynyl, -NRC (═ NR) NRSO₂-aryl, -NRC (═ NR) NRSO₂-substituted aryl, -NRC (═ NR) NRSO₂-cycloalkyl, -NRC (═ NR) NRSO₂-substituted cycloalkyl, -NRC (═ NR) NRSO₂-heteroaryl and-NRC (═ NR) NRSO₂-substituted heteroaryl, -NRC (═ NR) NRSO₂-heterocyclic ring and-NRC (═ NR) NRSO₂-substituted heterocycle, wherein each R is independently from each other hydrogen and alkyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.

"heteroaryl" refers to an aromatic carbocyclic group containing from 2 to 10 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. The heteroaryl group can contain a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl and furyl.

"substituted heteroaryl" refers to heteroaryl substituted with 1 to 3 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, thiocarbamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, andheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, carboxyamido, cyano, mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, heteroarylthio, substituted heteroarylthio, cycloalkylthio, substituted cycloalkylthio, heterocyclylthio, substituted heterocyclylthio, cycloalkyl, substituted cycloalkyl, guanidino sulfone, halogen, nitro, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy-substituted alkyl, carboxy-substituted cycloalkyl, carboxy-substituted alkylthio, arylthio, carboxyamido, cyano, mercapto, alkylthio, substituted alkylthio, arylthio, substituted heteroarylthio, cycloalkylthio, substituted cycloalkylthio, substituted cycloalkyloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -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-heterocycle, -S (O)₂-substituted heterocycles, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂-substituted heterocycles, -OSO₂-NRR (wherein 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-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-Substituted heterocycles (where R is hydrogen or alkyl), mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, asymmetric disubstituted amines with different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle and the amino group on the substituted aryl is blocked with a conventional blocking group such as Boc, Cbz, formyl etc. or by-SO₂NRR (wherein R is hydrogen or alkyl).

"heteroaryloxy" refers to the group-O-heteroaryl and "substituted heteroaryloxy" refers to the group-O-substituted heteroaryl.

"heterocycle" refers to a monocyclic or multiple fused ring saturated or unsaturated group containing 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, wherein, in the fused ring system, one or more of the rings may be aryl or heteroaryl.

"substituted heterocycle" refers to a heterocyclic group substituted with 1 to 3 substituents selected from oxo (═ O), thio (═ 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, carboxy, carboxyalkyl, carboxy-substituted alkyl, carboxy-cycloalkyl, carboxy-substituted cycloalkyl, carboxyaryl, carboxy-substituted aryl, carboxyheteroaryl, carboxy-substituted heteroaryl, carboxyheterocycle, carboxy-substituted heterocycle, and pharmaceutically acceptable salts thereof, Cycloalkyl, substituted cycloalkyl, guanidino sulfone, mercapto, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cycloalkylthio, substituted cycloalkylthio, heteroarylthio, substituted heteroarylthio, heterocyclic thioAryl, substituted heterocyclylthio, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O)₂Alkyl, -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-heterocycle, -OS (O)₂-substituted heterocycles, -OSO₂-NRR (wherein 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-heterocycle, -NRS (O)₂-substituted heterocycles, -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-heterocycle, -NRS (O)₂-NR-substituted heterocycles wherein R is hydrogen or alkyl, mono-and di-alkylamino, 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-heterocyclylamino, mono-and di-substituted heterocyclylamino, unsymmetrically disubstituted amines bearing different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; and substituted alkynyl groups having amino groups blocked by conventional blocking groups, e.g. Boc, Cbz, formyl, etc., or by-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-alkenyl, -SO₂-substituted alkenyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl, -SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocycle, -SO₂-substitutionand-SO₂NRR (wherein R is hydrogen or alkyl) substituted alkynyl/substituted alkynyl.

Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indoline, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, 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.

"heterocyclyloxy" refers to the group-O-heterocycle, and "substituted heterocyclyloxy" refers to the group-O-substituted heterocycle.

"mercapto" means the group-SH.

"alkylthio" means a radical-S-alkyl.

"substituted alkylthio" refers to the group-S-substituted alkyl.

"Cycloalkylsulfanyl" refers to the group-S-cycloalkyl.

"substituted cycloalkylthio" refers to the group-S-substituted cycloalkyl.

"arylthio" refers to the group-S-aryl and "substituted arylthio" refers to the group-S-substituted aryl.

"heteroarylthio" means a group-S-heteroaryl and "substituted heteroarylthio" means a group-S-substituted heteroaryl.

"Heterocyclylthio" means the group-S-heterocycle and "substituted heterocyclylthio" means the group-S-substituted heterocycle.

"pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of compounds of formula I derived from various organic and inorganic counterions known in the art, including, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and salts derived from organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like, when the molecule contains a basic functional group.

Preparation of the Compounds

The compounds of the present invention can be prepared from readily available starting materials by the following general methods and procedures. It is to be understood that where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Optimal reaction conditions may vary with the particular reactants or solvents used, and such conditions may be determined by one skilled in the art by routine optimization methods.

Furthermore, conventional protecting groups may be required to prevent unwanted reactions of certain functional groups, as will be apparent to those skilled in the art. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, a number of Protecting Groups are described in t.w.greene and g.m.wuts, Protecting Groups in organic synthesis, second edition, Wiley, New York, 1991 and references cited therein.

In addition, the compounds of the present invention typically contain one or more chiral centers. Thus, these compounds may be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers or diastereomers, or as stereoisomerically enriched mixtures, if desired. All such stereoisomers (including stereoisomerically enriched mixtures) are included within the scope of the present invention unless otherwise indicated. Pure stereoisomers (or stereoisomerically enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents as are well known in the art. Alternatively, racemic mixtures of the compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

In a preferred synthetic method, compounds of formulae I and IA wherein Q is a tetrazole-1, 5-diyl moiety are readily prepared by reacting the corresponding amide (i.e., wherein Q is-C (O) NH-) with an equimolar amount of phosphorus pentachloride (PCl)₅) In an anhydrous inert solvent such as benzene, and then reacting the resulting imidoyl chloride with azido acid (HN)₃) And (4) processing to prepare. Typically, the reaction is carried out by reacting the amide with PCl₅Contact time was about 90 minutes at room temperature. The imidoyl chloride formed is usually not isolated but is reacted in situ with an equimolar amount of azido acid at room temperature for about 2 hours to give the tetrazole.

The amide intermediate used in this reaction (i.e., where Q is-C (O) NH-) is readily prepared by: first the amino acid of formula II:

wherein R is²And R³As defined herein (e.g., in formulae I and IIA), with sulfonyl chlorides of formula III:

wherein R is¹As defined herein, to produce an N-sulfonyl amino acid of formula IV:

wherein R is¹-R³As defined herein.

The reaction is generally carried out by reacting the amino acid of formula II with at least 1 equivalent, preferably from about 1.1 to about 2 equivalents of sulfonyl chloride III in an inert diluent such as dichloromethane and the like. Typically, the reaction is carried out at a temperature of about-70 ℃ to about 40 ℃ for about 1 to about 24 hours. Preferably, the reaction is carried out in the presence of a suitable base to scavenge the acid formed during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. Alternatively, the reaction may be carried out under Schotten-Baumann-type conditions with an aqueous base such as sodium hydroxide or the like. After the reaction is completed, the N-sulfonylamino acid IV formed can be recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.

The amino acid of formula II used in the above reaction is a known compound or a compound that can be prepared from a known compound by a conventional synthetic method. Examples of suitable amino acids for use in this reaction include, but are not limited to, L-proline, trans-4-hydroxy-L-proline, cis-4-hydroxy-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-thiomorpholine-3-carboxylic acid, L-proline-2-proline-3-proline-3, Glycine, 2-tert-butylglycine, D, L-phenylglycine, L-alanine, alpha-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D, L-phenylsarcosine, L-aspartic acid beta-tert-butyl ester, L-glutamic acid gamma-tert-butyl ester, L- (O-benzyl) serine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid (cycloleucine), 1-aminocyclohexanecarboxylic acid, L-serine, etc. If desired, carboxylic acid esters of amino acids of formula II, e.g., methyl, ethyl, and the like, can be used with sulfonyl chloride III in the above reaction. The ester group is then hydrolyzed to the carboxylic acid using conventional reagents and conditions, i.e., treatment with an alkali metal hydroxide in an inert diluent such as methanol/water, to provide the N-sulfonylamino acid IV.

Also, the sulfonyl chloride of formula III used in the above reaction is a known compound or a compound that can be prepared from a known compound by a conventional synthetic method. Said compoundsUsually from the corresponding sulfonic acid, i.e. of the formula R¹-SO₃H (wherein R is¹As defined above) was prepared from phosphorus trichloride and phosphorus pentachloride. The reaction is generally carried out by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorus trichloride and phosphorus pentachloride, either directly or in an inert solvent such as methylene chloride, at a temperature of about 0 ℃ to about 80 ℃ for about 1 to about 48 hours, thereby obtaining the sulfonyl chloride. Alternatively, the sulfonyl chloride of formula III may be derived from the corresponding mercapto compound, i.e. formula R¹-SH compounds (wherein R¹As defined herein) by reacting mercapto groups with chlorine (Cl)₂) And water under conventional reaction conditions.

Examples of sulfonyl chlorides suitable for use in the reaction 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-bis-trifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylaminobenzenesulfonyl chloride, 4-dimethylaminobenz, 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, bromide or anhydride may be used in place of sulfonyl chloride in the above reaction to prepare the N-sulfonyl amino acid of formula IV.

The intermediate N-sulfonyl amino acid of formula IV can also be prepared by reacting a sulfonamide of formula V:

wherein R is¹And R²As defined herein, with formula L (R)³) Prepared by reacting a carboxylic acid derivative of CHCOOR, wherein L is a leaving group, e.g., chloro, bromo, iodo, mesylate, tosylate, etc., and R is³As defined herein, R is hydrogen or alkyl. The reaction is generally carried out by reacting sulfonamide V with at least 1 equivalent, preferably 1.1 to 2 equivalents, of the carboxylic acid derivative in the presence of a suitable base, such as triethylamine, in an inert diluent, such as DMF, at a temperature of about 24 ℃ to about 37 ℃ for about 0.5 to about 4 hours. This reaction is also described in Zuckermann et al, J.Am.chem.Soc., 1992, 114, 10646-. Preferred carboxylic acid derivatives for this reaction are alpha-chloro and alpha-bromoformates such as t-butyl bromoacetate and the like. When a carboxylic acid ester is used in this reaction, the ester group is subsequently hydrolyzed using conventional methods to provide the N-sulfonyl amino acid of formula IV.

Amide intermediates wherein Q is-C (O) NH-are prepared by coupling an intermediate N-sulfonyl amino acid of formula IV with an amino acid derivative of formula VI:

wherein R is⁵And R⁶As defined herein. The coupling reaction is generally carried out using a known coupling reagent such as carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate) or the like. Suitable carbodiimides include, for example, Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), and the like. Carbodiimide coupling reagents adsorbed on the polymer, such as those described in Tetrahedron Letters, 34(48), 7685(1993), may also be used if desired. In addition, the coupling reaction can be accelerated by a known coupling accelerator such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or the like.

The coupling reaction is generally carried out by contacting the N-sulfonyl amino acid IV with about 1 to about 2 equivalents of the coupling reagent and at least 1 equivalent, preferably about 1 to about 1.2 equivalents of the amino acid derivative VI in an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N-dimethylformamide and the like. Typically, the reaction is carried out at a temperature of about 0 ℃ to about 37 ℃ for about 12 to about 24 hours. After the reaction is complete, the amide is recovered by conventional means including neutralization, extraction, precipitation, chromatographic separation, filtration, and the like.

Alternatively, the N-sulfonylamino acid IV may be converted to an acid halide and the acid halide may then be coupled to the amino acid derivative VI to provide the amide. The acid halide of VI may be prepared by contacting VI with an inorganic acid halide such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or preferably oxalyl chloride under conventional conditions. Typically, the reaction is carried out with about 1 to 5 molar equivalents of an inorganic acid halide or oxalyl chloride, either directly or in an inert solvent such as methylene chloride or carbon tetrachloride, at a temperature of about 0 ℃ to about 80 ℃ for about 1 to about 48 hours. A catalyst such as N, N-dimethylformamide may also be used in the reaction.

The acid halide of the N-sulfonyl amino acid IV is then contacted with at least 1 equivalent, preferably from about 1.1 to about 1.5 equivalents, of the amino acid derivative VI in an inert diluent, such as methylene chloride, at a temperature of from about-70 ℃ to about 40 ℃ for about 1 to about 24 hours. The reaction is preferably carried out in the presence of a suitable base to scavenge the acid formed during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. Alternatively, the reaction may be carried out with an aqueous base such as sodium hydroxide or the like under Schotten-Baumann-type conditions. After the reaction is complete, the amide is recovered by conventional means including neutralization, extraction, precipitation, chromatographic separation, filtration, and the like.

Alternatively, amide intermediates wherein Q is-C (O) NH-may be prepared by first forming a diamino acid derivative of formula VII:

wherein R is²、R³、R⁵And R⁶As defined herein. Diamino acid derivatives of formula VII are readily prepared by coupling amino acids of formula II with amino acid derivatives of formula VI using conventional amino acid coupling techniques and reagents such as the carbodiimides, BOP reagents, and the like described above. The diamino acid VII can then be sulfonated with sulfonyl chlorides of formula III to form amides according to the synthetic methods described above.

The amino acid derivative of formula VI used in the above reaction is a known compound or a compound that can be prepared from a known compound by a conventional synthetic method. For example, the amino acid derivatives of formula VI can be prepared by C-alkylation of commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with an alkyl or substituted alkyl halide. The reaction is generally carried out by treating diethyl 2-acetamidomalonate with at least 1 equivalent of sodium ethoxide and at least 1 equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. The C-alkylated malonate formed is then deacetylated, hydrolyzed, and decarboxylated by heating to reflux in aqueous hydrochloric acid for about 6 to about 12 hours to give the amino acid, usually as the hydrochloride salt.

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

In another preferred embodiment, compounds of formula I/IA wherein Q is-CH (OH) C (O) NH-are readily prepared by coupling an α -hydroxy carboxylic acid of formula IVa with an amino acid derivative of formula VI:

the α -hydroxy carboxylic acid of IVa can be purchased commercially or can be prepared from readily available starting materials using conventional reagents and reaction conditions well known to those skilled in the art.

Furthermore, in another preferred embodiment, compounds of formula I/IA wherein Q is-C (O) N (O) -, are readily prepared by coupling an N-sulfonylamino acid of formula IV with an N-hydroxyamino acid of formula IVb using the coupling reagents and methods described above:

wherein R is⁵And R⁶As defined herein. The N-hydroxy amino acid of formula IVb may be derived from the formula wherein R⁶The corresponding amino acid derivative of formula IV, which is OH, is prepared by reaction with sodium nitrite and potassium bromide in dilute sulfuric acid (typically 2.5N) followed by treatment with hydroxylamine. Generally, the reaction proceeds as follows: the solution of IV and excess potassium bromide are first contacted with excess sodium nitrite in 2.5N sulfuric acid at about 0 ℃ for about 0.25 to 0.5 hours, then at room temperature for 1 hour. The product is then esterified with thionyl chloride and methanol under conventional conditions to form the methyl ester. The methyl ester is then immediately contacted with a solution of hydroxylamine in methanol and the reaction mixture is refluxed for 6 to 24 hours to yield the N-hydroxyamino acid of formula IVb.

In another preferred embodiment, compounds of formula I/IA wherein Q is-NHC (O) NH-are readily prepared by: the N-sulfonylamino acid of formula IV is contacted with an equimolar amount of diphenylphosphoryl azide in an inert solvent such as toluene, followed by treatment with a trialkylamine such as triethylamine to form the corresponding isocyanate. The intermediate isocyanate is usually not isolated but is reacted in situ with the amino acid derivative of formula VI to give the urea. The reaction is generally carried out at about 80 ℃ for about 6 to about 24 hours to form urea.

In another preferred embodiment, wherein Q is-CH (R)⁸)NR⁷The compounds of formula I/IA of (I) are readily prepared by derivatizing the amino acid of formula VIThe compound is prepared by reductive alkylation of a carbonyl compound of formula IVc using conventional reductive alkylation reagents and conditions:

generally, the reaction is carried out by contacting the amino acid derivative VI with an excess of IVc, preferably 1.1 to 2 equivalents of IVc, and an excess, preferably 1.1 to 1.5 equivalents of a reducing agent, such as sodium cyanoborohydride. Typically, the reaction is carried out in a substantially inert diluent such as methanol at about 0 ℃ to about 50 ℃, preferably at room temperature, for about 0.5 to 3 hours to give the desired product.

For ease of synthesis, the compounds of formula I are generally prepared in the form of an ester, i.e., wherein R is⁶Is alkoxy or substituted alkoxy, etc. If desired, the ester group can be hydrolyzed using conventional conditions and reagents to give the corresponding carboxylic acid. Typically, the reaction is carried out by treating the ester with at least 1 equivalent of an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, in an inert diluent, such as methanol or a mixture of methanol and water, at a temperature of from about 0 ℃ to about 24 ℃ for about 1 to about 12 hours. Alternatively, the benzyl ester can be removed by hydrogenolysis over a palladium catalyst such as palladium on carbon. If desired, the carboxylic acid formed can be coupled with amines such as beta-alanine ethyl ester, hydroxyl amines such as hydroxylamine and N-hydroxysuccinimide, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and O-benzylhydroxylamine and the like using conventional coupling reagents and conditions as described above.

It will be appreciated by those skilled in the art that other functional groups present on any of the substituents of the compounds of formula I may be modified or derivatized by known synthetic methods either before or after the above-described coupling reaction. For example, nitro groups present on substituents of compounds of formula I or intermediates thereof may be reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to form the corresponding amino groups. The reaction is typically carried out at a temperature of about 20 ℃ to about 50 ℃ for about 6 to about 24 hours in an inert diluent such as methanol. At R⁵On the substituentThe nitro group-containing compound can be produced, for example, by using a 4-nitrophenylalanine derivative or the like in the above-mentioned coupling reaction.

Likewise, the pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to form the corresponding piperidinyl analog. Typically, the reaction is carried out by treating the pyridine compound with hydrogen gas at a pressure of about 20psi to about 60psi, preferably about 40psi, in the presence of a catalyst at a temperature of about 20 ℃ to about 50 ℃ for about 2 to about 24 hours in an acidic diluent such as a mixture of methanol and aqueous hydrochloric acid. Compounds with a pyridyl group are readily prepared by using, for example, β - (2-pyridyl) -, β - (3-pyridyl) -or β - (4-pyridyl) -L-alanine derivatives in the above-described coupling reaction.

In addition, when R is a compound of formula I or an intermediate thereof⁵When the substituents contain primary or secondary amino groups, these amino groups can be further derivatized to form, for example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines, and the like, either before or after the above-described coupling reaction. At R⁵Compounds having a primary amino group on a substituent can be prepared, for example, by reducing the corresponding nitro compound as described above. Alternatively, the compound can be prepared by using an amino acid derivative derived from lysine, 4-aminophenylalanine, or the like in the above-mentioned coupling reaction.

For example, compounds of the formula I having substituents containing primary or secondary amino groups or intermediates therefor, e.g. wherein R⁵The compounds which are (4-aminophenyl) methyl groups are readily N-acylated to the corresponding amides using conventional acylating reagents and conditions. The acylation reaction is generally carried out by treating the amino compound with at least 1 equivalent, preferably from about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate), and the like, in an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N-dimethylformamide, and the like, at from about 0 ℃ to about 37 ℃ for from about 4 to about 24 hours. It is preferable to use an accelerator such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and the likeTo promote the acylation reaction. Examples of carboxylic acids suitable for this reaction include, but are not limited to, N-t-butyloxycarbonyl glycine, N-t-butyloxycarbonyl-L-phenylalanine, N-t-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-t-butyloxycarbonyl-isopiperidic acid (isonipeticoic acid), N-methylisopiperidic acid, N-t-butyloxycarbonyl-piperidinecarboxylic acid, N-t-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N- (toluene-4-sulfonyl) -L-proline and the like.

Alternatively, compounds of formula I containing primary or secondary amino groups or intermediates thereof can be N-acylated with an acid halide or carboxylic acid anhydride to form the corresponding amide. The reaction is generally carried out by treating the amino compound with at least 1 equivalent, preferably from about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent such as methylene chloride at a temperature of from about-70 ℃ to about 40 ℃ for from about 1 to about 24 hours. If desired, an acylation catalyst such as 4- (N, N-dimethylamino) pyridine may be used to facilitate the acylation reaction. The acylation reaction is preferably carried out in the presence of a suitable base to scavenge the acid formed during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. Alternatively, the reaction may be carried out under Schotten-Baumann-type conditions with an aqueous base such as sodium hydroxide or the like.

Examples of acid halides and carboxylic acid anhydrides suitable for this reaction include, but are not limited to, 2-methylpropanoyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoromethylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamoyl chlorides such as N, N-dimethylcarbamoyl chloride, N-diethylcarbamoyl chloride, and the like may also be used in this reaction to form ureas. Similarly, a dicarbonate such as di-tert-butyl dicarbonate may be used to form the carbamate.

In a similar manner, compounds of formula I containing primary or secondary amino groups or intermediates thereof can be N-sulfonylated with sulfonyl halides or sulfonic anhydrides to form sulfonamides. Suitable sulfonyl halides or anhydrides for this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chlorideP-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Likewise, sulfamoyl chlorides, such as dimethylsulfamoyl chloride, can also be used to generate sulfonamides (e.g., > N-SO₂-N＜)。

In addition, primary or secondary amino groups on substituents of compounds of formula I or intermediates thereof may be reacted with isocyanates or isothiocyanates to give ureas or thioureas, respectively. The reaction is generally carried out by contacting the amino compound with at least 1 equivalent, preferably from about 1.1 to about 1.2 equivalents, of the isocyanate or isothiocyanate in an inert diluent, such as toluene, at a temperature of from about 24 ℃ to about 37 ℃ for about 12 to about 24 hours. The isocyanates and isothiocyanates used in this reaction are commercially available or can be prepared from commercially available compounds by known synthetic methods. For example, isocyanates and isothiocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and isothiocyanates suitable for this reaction include, but are not limited to, ethyl isocyanate, N-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl isothiocyanate, ethyl isothiocyanate, 2-phenylethyl isothiocyanate, 3-phenylpropyl isothiocyanate, 3- (N, N-diethylamino) propyl isothiocyanate, phenyl isothiocyanate, benzyl isothiocyanate, 3-pyridyl isothiocyanate, fluorescein isothiocyanate (isomer I), and the like.

Furthermore, when the compounds of formula I or intermediates thereof contain primary or secondary amino groups, the amino groups can be reductively alkylated with an aldehyde or ketone to form secondary or tertiary amino groups. The reaction is generally carried out by contacting the amide with at least 1 equivalent, preferably from about 1.1 to about 1.5 equivalents, of the aldehyde or ketone and at least 1 equivalent, based on the amide, of a metal hydride reducing agent such as sodium cyanoborohydride in an inert diluent such as methanol, tetrahydrofuran, or mixtures thereof, at a temperature of from about 0 ℃ to about 50 ℃ for from about 1 to about 72 hours. Aldehydes and ketones suitable for this reaction include, for example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde, and the like.

Likewise, when the compounds of formula I or intermediates thereof bear hydroxyl-containing substituents, they may be carried out before or during the coupling reaction described aboveThe hydroxyl groups are then further modified or derivatized to yield, for example, ethers, carbamates, and the like. For example, at R⁵The compound having a hydroxyl group on the substituent may be prepared in the above reaction using an amino acid derivative of formula V derived from tyrosine or the like.

For example, compounds of formula I having a hydroxyl-containing substituent or intermediates thereof, e.g. wherein R⁵Compounds which are (4-hydroxyphenyl) methyl groups are readily O-alkylated to ethers. The O-alkylation reaction is generally carried out by contacting the hydroxy compound with a suitable alkali or alkaline earth base such as potassium carbonate in an inert diluent such as acetone, 2-butanone, or the like, to produce an alkali or alkaline earth salt of the hydroxy group. The salt generally does not need to be isolated but is reacted in situ with at least 1 equivalent of an alkyl or substituted alkyl halide or sulfonate such as alkyl chloride, bromide, iodide, mesylate or tosylate to give the ether. Typically, the reaction is carried out at a temperature of about 60 ℃ to about 150 ℃ for about 24 to about 72 hours. When an alkyl chloride or bromide is used in the reaction, it is preferred to add a catalytic amount of sodium iodide or potassium iodide to the reaction mixture.

Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, t-butyl bromoacetate, N-t-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-methylpiperazin) propyl chloride, N-tert-butylpiperazin) ethyl chloride, N-butylacetamide, 1-bromoethylbenzene, ethyl α -bromophenylacetate, 2- (N-ethyl-N-phenylamino) ethyl chloride, 2- (N, N-ethylamino) propyl chloride, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4-hydroxy-4-phenylpiperidine) ethyl chloride, N-t-butoxycarbonyl-3-piperidinemethyltosylate, and the like.

Alternatively, the hydroxy groups present on the substituents of the compounds of formula I or intermediates thereof may be O-alkylated with the Mitsunobu reaction. In this reaction, an alcohol such as 3- (N, N-dimethylamino) -1-propanol and the like is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent such as tetrahydrofuran at a temperature of about-10 ℃ to about 5 ℃ for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of a hydroxy compound such as N-tert-butyltyrosine methyl ester is then added and the reaction mixture is stirred at a temperature of about 0 ℃ to about 30 ℃ for about 2 to about 48 hours to provide an O-alkylated product.

Likewise, compounds of formula I containing an aryl hydroxyl group or intermediates thereof can be reacted with aryl iodides to provide diaryl ethers. Typically, the reaction is carried out by forming an alkali metal salt of the hydroxy group with a suitable base such as sodium hydride in an inert diluent such as xylene at a temperature of from about-25 ℃ to about 10 ℃. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous dimethyl sulfide bromide complex at a temperature of about 10 ℃ to about 30 ℃ for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide such as sodium 2-iodobenzoate and the like. The reaction solution is then heated to about 70 ℃ to about 150 ℃ for about 2 to about 24 hours to provide the diaryl ether.

Furthermore, compounds containing hydroxyl groups can also be derivatized to the carbamate form. In one method of preparing the carbamates, the hydroxy compound of formula I or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as methylene chloride, at a temperature of about-25 ℃ to about 0 ℃ for about 0.5 to about 2.0 hours. The carbonate formed is treated with an excess, preferably from about 2 to about 5 equivalents, of a trialkylamine such as triethylamine for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine to give the carbamate. Examples of amines suitable for this reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine, and the like.

Alternatively, in another method of preparing carbamates, a hydroxyl containing compound is treated with about 1.0 to about 1.5 equivalents of carbamoyl chloride in an inert diluent such as methylene chloride at a temperature of about 25 ℃ to about 70 ℃ for about 2 to about 72 hours. Typically, the reaction is carried out in the presence of a suitable base to scavenge the acid formed during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. In addition, it is preferable to add at least 1 equivalent (based on the hydroxy compound) of 4- (N, N-dimethylamino) pyridine to the reaction mixture to promote the reaction. Examples of carbamoyl chlorides suitable for this reaction include, for example, dimethylcarbamoyl chloride, diethylcarbamoyl chloride, and the like.

Likewise, when a compound of formula I or an intermediate thereof contains a primary or secondary hydroxyl group, the hydroxyl group is readily converted to a leaving group and then displaced to form, for example, amines, sulfides and fluorides. For example, derivatives of 4-hydroxy-L-proline can be converted to the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives by nucleophilic displacement of the derivatized hydroxy group. In general, when chiral compounds are used in these reactions, the stereochemistry of the carbon atom attached to the derivatized hydroxyl group is typically reversed.

These reactions generally proceed as follows: the hydroxyl compound is first converted to a leaving group such as a tosylate by treating the hydroxyl compound with at least 1 equivalent of a sulfonyl halide such as p-toluenesulfonyl chloride or the like in pyridine. The reaction is typically carried out at a temperature of about 0 ℃ to about 70 ℃ for about 1 to about 48 hours. The tosylate formed may then be displaced with sodium azide, for example, by contacting the tosylate with at least 1 equivalent of sodium azide in an inert diluent such as a mixture of N, N-dimethylformamide and water at a temperature of from about 0 ℃ to about 37 ℃ for from about 1 to about 12 hours to form the corresponding azide compound. The azido group can then be hydrogenated to an amino group (-NH), for example, using a palladium on carbon catalyst₂) A compound is provided.

Also, the tosylate group is easily displaced by the thiol group to form a sulfide. The reaction is generally carried out by contacting the tosylate with at least 1 equivalent of a thiol such as thiophenol in the presence of a suitable base such as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) in an inert diluent such as N, N-dimethylformamide at a temperature of from about 0 ℃ to about 37 ℃ for a period of from about 1 to about 12 hours to form the sulfide. In addition, treatment of the tosylate with morpholine sulfur trifluoride in an inert diluent such as methylene chloride at a temperature of from about 0 ℃ to about 37 ℃ for about 12 to about 24 hours affords the corresponding fluoride compound.

Furthermore, compounds of the formula I or intermediates thereof which bear substituents containing iodoaryl groups, e.g. when R is¹Is (4-iodophenyl) methyl, it is readily converted to the biaryl compound either before or after the above-described coupling reaction. Typically, the reaction is carried out by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an aryl zinc iodide such as 2- (methoxycarbonyl) phenyl zinc iodide in the presence of a palladium catalyst such as palladium tetrakis (triphenylphosphine) in an inert diluent such as tetrahydrofuran at a temperature of about 24 ℃ to about 30 ℃ until the end of the reaction. This reaction is also described in, for example, Rieke, j.

In some cases, the compounds of formula I or intermediates thereof may also bear substituents containing one or more sulfur atoms. For example, when the amino acid of formula II used in the above reaction is derived from L-thiazolidine-4-carboxylic acid, L- (5, 5-dimethyl) thiazolidine-4-carboxylic acid, L-thiomorpholine-3-carboxylic acid, or the like, a sulfur atom will be present. When present, the sulfur atom may be oxidized to give the sulfoxide or sulfone compound using conventional reagents and reaction conditions either before or after the above-described coupling reaction. Suitable agents for oxidizing sulfides to sulfoxides include, for example, hydrogen peroxide, 3-chloroperbenzoic acid (MCPBA), sodium periodate, and the like. The oxidation reaction is generally carried out by contacting the sulfide with about 0.95 to about 1.1 equivalents of an oxidizing agent in an inert diluent such as methylene chloride at a temperature of about-50 ℃ to about 75 ℃ for about 1 to about 24 hours. The formed sulfoxide can then be further oxidized to the corresponding sulfone by contact with an additional at least 1 equivalent of an oxidizing agent such as hydrogen peroxide, MCPBA, or sodium permanganate, and the like. Alternatively, the sulfones may be prepared directly by contacting the sulfide with at least 2 equivalents, preferably an excess, of the oxidizing agent. The reaction is further described in March, "Advanced organic chemistry", 4 th edition, pp.1201-1202, Wiley Publisher, 1992.

With other than hydrogen, as mentioned aboveR²Substituted compounds of formula I can be prepared using N-substituted amino acids of formula II, such as sarcosine, N-methyl-L-phenylalanine, and the like, in the coupling reaction described above. Alternatively, the compounds may be prepared by reacting a sulfonamide of formula I or IV (wherein R is²Is hydrogen) is prepared by conventional synthetic methods by N-alkylation. Typically, the N-alkylation reaction is carried out by contacting the sulfonamide with at least 1 equivalent, preferably 1.1 to 2 equivalents, of an alkyl or substituted alkyl halide in the presence of a suitable base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone, and the like, at a temperature of about 25 ℃ to about 70 ℃ for about 2 to about 48 hours. Alkyl or substituted alkyl halides suitable for use in this reaction include, but are not limited to, methyl iodide and the like.

Further, wherein R²Is hydrogen and R¹Sulfonamides of formula I or IV that are 2-alkoxycarbonylaryl groups may undergo intramolecular cyclization to form 1, 2-benzisothiazol-3-one derivatives or analogs thereof. The reaction is generally carried out as follows: a sulfonamide such as benzyl N- (2-methoxycarbonylphenylsulfonyl) glycine-L-phenylalanine is treated with about 1.0 to 1.5 equivalents of a suitable base such as an alkali metal hydride in an inert diluent such as tetrahydrofuran at a temperature of about 0 ℃ to about 30 ℃ for about 2 to about 48 hours to provide a cyclized 1, 2-benzisothiazol-3-one derivative.

Finally, compounds of formula I wherein Q contains a thiocarbonyl group (C ═ S) can be prepared by substituting the amino acid II with an aminothioacid derivative during the above synthesis. The aminothioacid derivatives can be prepared by Shalaky et al, j.org.chem., 61: 9045-: 3808-3809(1997) and the references cited therein.

Pharmaceutical preparation

When used as medicaments, the compounds of formulae I and IA are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective for administration in both injectable and oral compositions. The compositions are prepared according to methods well known in the pharmaceutical art and comprise at least one active compound.

The invention also includes pharmaceutical compositions comprising one or more compounds of formulae I and IA as active ingredients and a pharmaceutically acceptable carrier. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient or enclosed within a carrier which may be in the form of a capsule, sachet, cachet, filled paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material and serves as an excipient, carrier, or medium for the active ingredient. Thus, the compositions of the present invention may be in the form of tablets, pills, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In preparing the formulations, it may be necessary to pre-mill the active compound to the appropriate particle size prior to mixing with the other ingredients. If the active compound is substantially insoluble, it is usually milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, its particle size is generally adjusted by milling to provide a substantially uniform distribution in the formulation, for example, a particle size distribution of about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may further comprise: lubricants such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; sweetening agents and flavoring agents. The compositions of the present invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by methods known in the art.

Preferably, the compositions of the present invention are formulated in unit dosage forms, each unit dosage form containing from about 5 to about 100mg, more often from about 10 to about 30mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human beings and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compounds of the present invention are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the actual amount of the compound of the invention to be administered will be determined by a physician, in the light of the relevant factors including the condition being treated, the chosen route of administration, the particular compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

To prepare solid compositions, such as tablets, the active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, this is meant to indicate that the active ingredient is dispersed evenly throughout the composition, so that it is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation composition is then subdivided into unit dosage forms of the type described above containing, for example, from 0.1 to about 500mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill of the present invention may comprise an inner dosage component and an outer dosage component, the latter being coated over the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach and to maintain the inner component intact in the duodenum or to delay release. A variety of materials may be used for such enteric layers or coatings, including various polymeric acids and mixtures of polymeric acids with shellac, cetyl alcohol and cellulose acetate, among others.

Liquid dosage forms for oral or injectable administration in which the novel compositions of the present invention may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable water or organic solvents or mixtures thereof, and powders. Such liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. The composition is preferably administered by the oral or nasal respiratory route to obtain a local or systemic effect. The composition in a preferably pharmaceutically acceptable solvent may be sprayed with an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

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

Formulation example 1

Hard gelatin capsules were prepared containing the following components:

measurement of

Components (mg/capsule)

Active ingredient 30.0

Starch 305.0

Magnesium stearate 5.0

The above components were mixed and filled into hard gelatin capsules in an amount of 340 mg.

Formulation example 2

Tablets were prepared with the following ingredients:

measurement of

Components (mg/tablet)

Active ingredient 25.0

Microcrystalline cellulose 200.0

Colloidal silica 10.0

Stearic acid 5.0

The components were mixed and compressed into tablets weighing 240mg each.

Formulation example 3

A dry powder inhaler formulation was prepared containing the following components:

components By weight%

Active ingredient 5

Lactose 95

The active mixture is mixed with lactose and the mixture is added to a dry powder inhaler device.

Formulation example 4

Tablets each containing 30mg of active ingredient were prepared as follows:

measurement of

Components (mg/tablet)

Active ingredient 30.0mg

Starch 45.0mg

Microcrystalline cellulose 35.0mg

Polyvinylpyrrolidone

(in the form of a 10% aqueous solution) 4.0mg

Sodium carboxymethyl starch 4.5mg

Magnesium stearate 0.5mg

Talcum powder1.0mg

A total amount of 120mg

The active ingredient, starch and cellulose were screened through a 20 mesh U.S. sieve and mixed thoroughly. The resulting powder was mixed with a polyvinylpyrrolidone solution and then sieved through a 16 mesh U.S. sieve. The resulting granules were dried at 50 to 60 ℃ and then sieved through a 16 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc, previously sieved through a 30 mesh U.S. sieve, were then added to the above granules, mixed and then compressed on a tableting machine into tablets weighing 150mg each.

Formulation example 5

Capsules each containing 40mg of drug were prepared as follows:

measurement of

Components (mg/capsule)

Active ingredient 40.0mg

Starch 109.0mg

Magnesium stearate1.0mg

Total amount of 150.0mg

The active ingredient, cellulose, starch, and magnesium stearate were mixed, sieved through a 20 mesh U.S. sieve, and filled into hard gelatin capsules in an amount of 150 mg.

Formulation example 6

Each suppository containing 25mg of active ingredient was prepared as follows:

components Measurement of

Active ingredient 25mg

Saturated fatty acid glycerides to 2,000mg

The active ingredient is passed through a 60 mesh U.S. sieve and suspended in saturated fatty acid glycerides that have been previously melted with the least amount of heat required. The mixture was then poured into 2.0g capacity-sized suppository molds and allowed to cool.

Preparation fruitExample 7

A suspension containing 50mg of drug per 5.0ml dose was prepared as follows:

components Measurement of

Active ingredient 50.0mg

Xanthan gum 4.0mg

Sodium carboxymethylcellulose (11%)

Microcrystalline cellulose (89%) 50.0mg

Sucrose 1.75g

Sodium benzoate 10.0mg

Appropriate amount of flavoring agent and coloring agent

Purified water to 5.0ml

The drug, sucrose and xanthan gum were mixed, sieved through a 10 mesh U.S. sieve, and then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. The sodium benzoate, flavor and color are diluted with some water and added with stirring. Sufficient water was then added to produce the desired volume.

Formulation example 8

Measurement of

Components (mg/capsule)

Active ingredient 15.0mg

Starch 407.0mg

Magnesium stearate3.0mg

Total amount 425.0mg

The active ingredient, cellulose, starch and magnesium stearate are mixed, sieved through a 20 mesh U.S. sieve and filled into hard gelatin capsules in an amount of 560 mg.

Formulation example 9

An intravenous administration formulation was prepared as follows:

components Measurement of

Active ingredient 250.0mg

Isotonic saline 1000ml

Formulation example 10

The topical formulations were prepared as follows:

components Measurement of

1-10g of active ingredient

Emulsifying wax 30g

20g of liquid paraffin

White Vaseline to 100g

White petrolatum is heated to melt. Liquid paraffin and emulsifying wax were added and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture was then cooled until a solid formed.

Another preferred formulation for use in the method of the present invention is a transdermal delivery device ("patch"). The transdermal patch may be used to deliver the compounds of the present invention in controlled amounts, either continuously or discontinuously. The construction and use of transdermal patches for the delivery of drugs is well known in the art. See, for example, U.S. Pat. No. 5,023,252 issued to 1991, 6, 11, which is incorporated herein by reference. The patch may be configured to release the drug continuously, in pulses, or on demand.

Where desired or necessary, direct or indirect localization techniques can be used to introduce the pharmaceutical composition into the brain. Direct techniques typically involve placing a drug delivery catheter into the ventricular system of the host to bypass the blood brain barrier. An implantable delivery system for delivering biological factors to specific anatomical regions of the body is described in U.S. Pat. No. 5,011,472, which is incorporated herein by reference.

Indirect techniques are generally preferred, which generally involve formulating the composition to provide latency of the drug by converting the hydrophilic drug into a fat-soluble drug. Latency is generally achieved by: the hydroxyl, carbonyl, sulfate radical and primary amine radical existing on the medicine are blocked, so that the medicine has stronger lipid solubility and can pass through the blood brain barrier. Alternatively, delivery of hydrophilic drugs can be facilitated by intraarterial infusion of hypertonic solutions that transiently open the blood-brain barrier.

Applications of

The compounds of the invention are useful for binding VLA-4 (. alpha.) in biological samples₄β₁Integrins) and thus can be used to determine VLA-4 in biological samples. In such an assay, a compound of the invention may be immobilized on a solid support and a VLA-4 sample added thereto. The amount of VLA-4 can be determined by conventional methods, such as a sandwich ELISA assay. Alternatively, labeled VLA-4 can be used in a competitive assay to determine the amount of VLA-4 present in a sample. Other suitable assay methods are well known in the art.

In addition, some of the compounds of the present invention inhibit VLA-4 mediated adhesion of leukocytes to endothelial cells in vivo and are therefore useful in the treatment of VLA-4 mediated diseases. 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 brain trauma, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that seen in adult respiratory distress syndrome.

The above-described biological activities of the compounds of the invention can be identified in a variety of systems. For example, the compound may be immobilized on a solid surface and adhesion of VLA-4 expressing cells may be determined. A large number of compounds can be screened using the model. Cells suitable for use in the assay include any cell known to express VLA-4, such as T cells, B cells, monocytes, eosinophils, and basophils. A number of leukocyte cell lines can also be used, examples of which include Jurkat and U937.

The ability of a test compound to competitively inhibit binding between VLA-4 and VCAM-1 or between VLA-4 and a labeled compound known to bind VLA-4, such as a compound of the invention or an antibody to VLA-4, can also be determined. In these assays, VCAM-1 can be immobilized on a solid surface. In these assays, VCAM-1 can also be expressed as a recombinant fusion protein with an Ig tail (e.g., IgG), which allows detection of binding to VLA-4 in an immunoassay. Alternatively, cells expressing VCAM-1, such as activated endothelial cells or VCAM-1 transfected fibroblasts, may be used. The assay described in international patent application WO 91/05038 is particularly preferred for the assay to determine the ability to block adhesion to brain endothelial cells. This patent application is incorporated by reference herein in its entirety.

Many assay methods use labeled assay components. The marking system may take many forms. The label may be coupled directly or indirectly to the component to be assayed according to methods well known in the art. A wide variety of labels can be used. The components can be labeled using any of several methods. The most common detection method is to use³H、¹²⁵I、³⁵S、¹⁴C or³²Autoradiography of P-labeled compounds. Non-radioactive labels include ligands that bind to the labeled antibody, fluorophores, chemiluminescent agents, enzymes, and antibodies that can serve as members of a specific binding pair for the labeled ligand. The choice of label depends on the sensitivity desired, the ease of binding to the compound, stability requirements and the instrumentation available.

Suitable in vivo models for determining the efficacy of treatment of inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other models of inflammation that rely on α 4 integrins.

Compounds having the desired biological activity can be modified as desired to provide desired properties, such as improved pharmacological properties (e.g., in vivo stability, bioavailability) and ability to be detected in diagnostic applications. For example, the introduction of one or more D-amino acids into the sulfonamide compounds of the invention generally improves in vivo stability. Stability can be determined by a variety of methods, for example by determining the half-life of the protein during incubation with peptidases or human plasma or serum. A variety of such protein stability assays are described in the prior art (see, e.g., Verhoef et al, Eur. J. drug method. Pharmacokinet., 1990, 15 (2): 83-93).

For diagnostic applications, various labels may be attached to compounds that provide a detectable signal, either directly or indirectly. Thus, the compounds of the present invention can be modified in a variety of ways depending on the end purpose while maintaining biological activity. In addition, various reactive sites for attachment of particles, solid substrates, macromolecules, etc. can be introduced at the ends.

The labeled compounds can be used in a variety of in vivo and in vitro applications. A variety of labels can be used, such as radionuclides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-111), fluorescent substances (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like. Those skilled in the art will know of other suitable labels for binding to the complex, or will be able to determine suitable labels by routine experimentation. Binding of these labels can be achieved using standard techniques well known to those skilled in the art.

In vitro applications include diagnostic applications, such as the examination of inflammatory responses by detecting the presence of VLA-4 expressing leukocytes. The compounds of the invention may also be used to isolate or label the cells. Furthermore, as described above, the compounds of the invention can be used to identify potential inhibitors of the VLA-4/VCAM-1 interaction.

For in vivo diagnostic imaging to determine, for example, sites of inflammation, radioisotopes are generally used in accordance with well-known techniques. The radioisotope can be bound to the peptide directly or indirectly using an intermediate functional group. For example, chelators such as diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metal ion radioisotopes.

The complexes may also be labeled with paramagnetic isotopes for in vivo diagnostic purposes, such as the well-known Magnetic Resonance Imaging (MRI) or Electron Spin Resonance (ESR). In general, any conventional contrast diagnostic imaging method may be used. For photographic imaging, gamma-ray and positron emitting radioisotopes are commonly used, and for MRI, paramagnetic isotopes are commonly used. Thus, the compounds of the present invention can be used to monitor the course of an improvement in an inflammatory response in an individual. By determining an increase or decrease in lymphocytes expressing VLA-4, it can be determined whether a particular treatment regimen established to ameliorate the disease is effective.

The compositions of the present invention are useful for blocking or inhibiting cell adhesion associated with a variety of diseases and disorders. For example, there are a variety of inflammatory disorders associated with integrins or leukocytes. Conditions treatable with the compositions of the present invention include, for example, transplant rejection (e.g., allograft rejection), alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile form diabetes), retinitis, cancer metastasis, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g., adult respiratory distress syndrome), asthma, nephritis, 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 diseases such as Multiple Sclerosis (MS), viral meningitis and encephalitis.

Inflammatory bowel disease is the collective name for two similar diseases known as crohn's disease and ulcerative colitis. Crohn's disease is a spontaneous chronic ulcerative constrictive inflammatory disease characterized by well-defined and transmural phenomena in all layers of the intestinal wall due to the granulomatous inflammatory response. The disease may occur in any part of the gastrointestinal tract from the mouth to the anus, but it mainly affects the terminal ileum and/or colon. Ulcerative colitis is an inflammation that is primarily localized to the colonic mucosa and submucosa. Among the lesions of the inflammatory bowel wall are a large number of lymphocytes and macrophages, which may be responsible for inflammatory lesions.

Asthma is characterized by an enhanced responsiveness of the tracheobronchial tree to various stimuli-enhanced paroxysmal contractions of the bronchi. Stimulation causes IgE-coated mast cells to release a variety of inflammatory mediators including histamine, eosinophils and neutrophiles, leukotrienes, prostaglandins, and platelet activating factor. The release of these factors leads to the pooling of basophils, eosinophils, and neutrophils, which leads to inflammatory injury.

Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aorta, and iliac). The primary lesion, an atheroma, consists of a focal plaque with a raised intima, with a lipid core and an overlying fibrous cap. Atheromas compromise blood flow and weaken the affected arteries. Myocardial and cerebral infarctions are the major consequences of the disease. Macrophages and leukocytes collect on the atheroma and cause inflammatory damage.

Rheumatoid arthritis is a chronic, recurrent inflammatory disease that causes mainly joint damage and destruction. Rheumatoid arthritis generally affects the small joints of the hands and feet first, but may affect the wrists, elbows, ankles and knees later. The arthritis is caused by the interaction of leukocytes and synovial cells that infiltrate the inner layer of the joint synovial fluid from the circulating blood stream. See, e.g., Paul, Immunology (3 rd edition, Raven Press, 1993).

Another indication of a compound of the invention is the treatment of VLA-4 mediated organ or transplant rejection. In recent years, the efficacy of surgical techniques for transplanting tissues and organs such as skin, kidney, liver, heart, lung, pancreas, and bone marrow has improved dramatically. Perhaps the most prominent problem is the lack of satisfactory agents that induce immune tolerance in the recipient to the transplanted allograft or organ. When allogeneic cells or organs are transplanted into a host (i.e., the donor and recipient are different individuals of the same species), the host immune system may mount an immune response to foreign antigens in the transplant (host-versus-transplant disease), resulting in destruction of the transplanted tissue. CD8⁺Cells, CD4 cells and monocytes are all associated with rejection of transplanted tissue. The compounds of the invention that bind to alpha-4 integrin are particularly useful for blocking alloantigen-induced immune responses in a recipient and thereby preventing the cells from participating in the destruction of transplanted tissue or organs. See, for examplePaul et al, Transplant International 9, 420-425 (1996); georczynski et al, Immunology 87, 573-580 (1996); georcyznski et al, transplantation. Immunol. (transplantation immunology) 3, 55-61 (1995); yang et al, Transplantation 60, 71-76 (1995); anderson et al, APMIS 102, 23-27 (1994).

A related use of the compounds of the invention that bind VLA-4 is in modulating immune responses involving "graft-versus-host" disease (GVHD). See, e.g., Schlegel et al, J.Immunol.155, 3856-. GVHD is a potentially lethal disease that occurs when immunocompetent cells are transferred into allogeneic recipients. In this case, the immunocompetent cells of the donor may attack the recipient's tissue. Skin, intestinal epithelium, and liver tissue are major targets of attack and may be destroyed during GVHD. This disease is a particularly serious problem when immune tissues are transplanted, such as bone marrow transplantation; however, there are few reports of severe GVHD in other transplants, including heart and liver transplants. The therapeutic agents of the present invention can be particularly useful in blocking the activation of donor T-cells, thereby affecting their ability to lyse host target cells.

Another application of the compounds of the present invention is in the inhibition of tumor metastasis. Various tumor cells have been reported to express VLA-4, and compounds that bind VLA-4 block adhesion of such cells to endothelial cells. Steinback et al, Urol. Res. (urological study) 23, 175-83 (1995); orosz et al, int.j. cancer (journal of international cancer) 60, 867-71 (1995); freedman et al, Leuk. Lymphoma 13, 47-52 (1994); okahara et al, Cancer Res. (Cancer research) 54, 3233-6 (1994).

Another application of the compounds of the invention is the treatment of multiple sclerosis. Multiple sclerosis is a progressive, neuropathic autoimmune disease estimated to occur in 250,000-350,000 people in the united states. Multiple sclerosis is thought to be caused by a specific autoimmune response in which some white blood cells attack and cause destruction of the myelin, insulating sheath covering nerve fibers. It has been shown that murine monoclonal antibodies directed against VLA-4 block in an animal model of multiple sclerosis(ii) breaking the adhesion of leukocytes to endothelial cells and thereby preventing inflammation of the central nervous system and secondary paralysis in the animal¹⁶。

The pharmaceutical compositions of the present invention are suitable for use in a variety of delivery systems. Formulations suitable for use in the present invention are described in Remington's Pharmaceutical Sciences, MacePublizing Company, Philadelphia, Pa., 17 th edition (1985).

To increase serum half-life, the compounds of the invention may be encapsulated, placed in the liposome cavity, made into a gel, or other conventional techniques that increase serum half-life of the compounds of the invention may be used. Various methods for preparing liposomes are described, for example, in U.S. Pat. Nos. 4,235,871, 4,501,728, and 4,837,028 to Szoka et al, which are incorporated herein by reference.

The amount administered to a patient will depend on the compound being administered, the purpose of the administration, e.g., whether prophylactic or therapeutic, the physical condition of the patient, the mode of administration, and the like. For therapeutic applications, the compositions are administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications. An amount sufficient to achieve this goal is defined as a "therapeutically effective dose". For this application, an effective amount will depend on the disease being treated and the judgment of the clinician based on factors such as the severity of the inflammation, the age, weight and general condition of the patient.

The composition is administered to the patient in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or the compositions may be sterile filtered. The resulting aqueous solution may be packaged for use as is, or the resulting aqueous solution may be lyophilized and the lyophilized formulation admixed with a sterile aqueous carrier just prior to administration. The pH of the compound preparation is generally 3 to 11, more preferably 5 to 9, most preferably 7 to 8. It will be appreciated that some of the above excipients, carriers or stabilizers may result in the formation of salts of the drug.

The therapeutic dosage of the compounds of the invention will vary with, for example, the particular application being treated, the mode of administration of the compound, the health of the patient and the judgment of the prescribing physician, and the like. For example, for intravenous administration, the dose will generally be from about 20 μ g to about 500 μ g/kg body weight, preferably from about 100 μ g to about 300 μ g/kg body weight. For intranasal administration, suitable dosages will generally be from about 0.1pg to 1mg/kg body weight. Effective doses can be derived from dose-response curves obtained from in vitro or animal model test systems.

The following synthetic and biological examples are provided to illustrate the invention and are not intended to limit the scope of the invention in any way. All temperatures are in degrees Celsius unless otherwise noted.

Examples

In the examples described below, the following abbreviations have the following meanings. An abbreviation has a recognized meaning if it is not defined.

aq or aq. ═ aqueous

AcOH ═ acetic acid

broad doublet of bd

bm is broad multiplet

bs as wide singlet

Bn ═ benzyl

Boc ═ N-tert-butoxycarbonyl

Boc₂Di-tert-butyl O-dicarbonate

BOP ═ benzotriazol-1-yloxy-tris (dimethylamino) phosphonium

Hexafluorophosphates

Cbz ═ benzyloxycarbonyl

CHCl₃Chloroform ═

CH₂Cl₂Methylene chloride ═

(COCl)₂Oxalyl chloride

d is doublet

ddd-doublet

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 ═ dimethyl sulfoxide

EDC ═ 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

Amine hydrochloride

Et₃N-triethylamine

Et₂Ethyl ether (O ═ ethyl ether)

EtOAc ═ ethyl acetate

EtOH ═ ethanol

eq or eq ═ equivalent

Fmoc ═ N- (9-fluorenylmethoxycarbonyl)

FmocONSu ═ N- (9-fluorenylmethoxycarbonyl) -succinimide

g is g ═ g

h is hour

H₂O is water

HBr ═ hydrobromic acid

HCl ═ hydrochloric acid

HOBT ═ 1-hydroxybenzotriazole hydrate

hr as hour

K₂CO₃Arbutine potassium carbonate

L is liter

m is multiplet

MeOH ═ methanol

mg ═ mg

MgSO₄Magnesium sulfate ═ magnesium sulfate

mL to mL

mm-mm

mM ═ millimole

mmol ═ millimolar concentration

mp is melting point

N is equivalent concentration

NaCl sodium chloride

Na₂CO₃Sodium carbonate (sodium bicarbonate)

NaHCO₃Sodium bicarbonate

NaOEt ═ sodium ethoxide

NaOH (sodium hydroxide)

NH₄Cl ═ ammonium chloride

NMM ═ N-methylmorpholine

Phe ═ L-phenylalanine

Pro ═ L-proline

psi pounds per square inch

PtO₂Platinum oxide (II)

q is quartet

quint

rt-room temperature

s ═ singlet

sat is saturated

t is triplet

t-BuOH ═ tert-butanol

TFA ═ trifluoroacetic acid

THF ═ tetrahydrofuran

TLC or TLC ═ thin layer chromatography

Ts ═ tosyl group

TsCl ═ tosyl chloride

TsOH-tosylate

μ L ═ microliter

In the following examples, all temperatures are in degrees Celsius unless otherwise specified. The following compounds were prepared by the following method.

Method 1

N-tosylation process

N-tosylation of the appropriate amino acid is carried out by the method of Cupps, Boutin and Rapoport, J.org.chem.1985, 50, 3972.

Method 2

Methyl ester preparation method

Amino acid methyl esters were prepared using the method of Brenner and Huber, helv.

Method 3

BOP coupling method

The desired dipeptide ester is prepared by reacting the appropriate N-protected amino acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate [ BOP ] (2.0 equivalents), triethylamine (1.1 equivalents) and DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography to give the dipeptide ester.

Method 4

Hydrogenation Process I

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

Method 5

Hydrolysis method I

To the appropriate ester is added ice-cold (0 ℃ C.) THF/H₂To the O solution (2: 1, 5-10ml) was added LiOH (or NaOH) (0.95 equiv.). The temperature was maintained at 0 ℃ and the reaction was completed in 1-3 hours. The reaction mixture was extracted with ethyl acetate and the aqueous phase was freeze dried to give the desired carboxylate.

Method 6

Ester hydrolysis Process II

To the appropriate ester is added ice-cold (0 ℃ C.) THF/H₂To the O solution (2: 1, 5-10ml) was added LiOH (1.1 equiv). The temperature was maintained at 0 ℃ and the reaction was completed in 1-3 hours. The reaction mixture was concentrated, the residue was added to water and the pH was adjusted to 2-3 with hydrochloric acid. The product was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the desired acid.

Method 7

Ester hydrolysis Process III

Dissolving the appropriate ester in dioxane/H₂O (1: 1) and 0.9 eq 0.5N NaOH was added. The reaction was stirred for 3-16 hours and then concentrated. The residue obtained is dissolved in H₂O and extracted with ethyl acetate. The aqueous phase was freeze-dried to give the desired sodium carboxylate salt.

Method 8

Sulphonylation Process I

To an appropriately protected aminophenylalanine analogue (11.2mmol) dissolved in dichloromethane (25ml) and cooled to-78 ℃ was added the desired sulfonyl chloride (12mmol) followed by pyridine (2ml) dropwise. The solution was warmed to room temperature and stirred for 48 hours. The reaction solution was transferred with dichloromethane (100mL) to a 250mL separatory funnel and extracted with 1N HCl (50 mL. times.3), brine (50mL) and water (100 mL). The organic phase was dried (MgSO)₄) And the solvent is concentrated to give the desired product.

Method 9

Reductive amination process

Performing Tos-Pro-p-NH by using acetic acid, sodium triacetoxyborohydride and dichloromethane₂-reductive amination of Phe and the appropriate aldehyde, and the combined mixture is stirred at room temperature overnight. The crude product was purified by flash chromatography.

Method 10

BOC removal method

Anhydrous hydrogen chloride (HCl) gas was bubbled through a solution of the appropriate Boc-amino acid ester in methanol at 0 ℃ for 15 minutes, then the reaction mixture was stirred for 3 hours. The solution was concentrated to a syrup and then dissolved in Et₂O and concentrated again. The process was repeated and the resulting solid was placed under high vacuum overnight.

Method 11

Process for the hydrolysis of tert-butyl esters I

Dissolving tert-butyl ester in CH₂Cl₂Using in combination TAnd (5) FA processing. The reaction is completed in 1 to 3 hours, the reaction mixture is then concentrated and the residue is dissolved in H₂O, then freeze-dried to give the desired acid.

Method 12

EDC coupling method I

To N- (toluene-4-sulfonyl) -L-proline (1 equivalent) in CH₂Cl₂To the solution (5-20ml) was added the appropriate amino acid ester hydrochloride (1 eq), N-methylmorpholine (1.1-2.2 eq) and 1-hydroxybenzotriazole (2 eq), placed in an ice bath and then 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 water and the organic phase was washed with saturated sodium bicarbonate and brine, dried (MgSO)₄Or Na₂SO₄) Filtered and then concentrated. The crude product was purified by column chromatography.

Method 13

EDC coupling method II

To a solution of the appropriate N-protected amino acid (1 eq) in DMF (5-20ml) was added the appropriate amino acid ester hydrochloride (1 eq), Et₃N (1.1 equiv.) and 1-hydroxybenzotriazole (2 equiv.) were placed in an ice bath and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.1 equiv.) was added. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with 0.2N citric acid, H₂Washed with saturated sodium bicarbonate and brine, dried (MgSO 4)₄Or Na₂SO₄) Filtered and then concentrated. The crude product was purified by column chromatography or preparative TLC.

Method 14

Sulfonylation Process II

The appropriate sulfonyl chloride was dissolved in dichloromethane and placed in an ice bath. L-Pro-L-Phe-OMe HCl (1 eq.) and Et are added₃N (1.1 eq), the reaction was warmed to room temperature and stirred under nitrogen overnight. The reaction mixture was concentrated and the residue was taken up in EtOAc and H₂Partition between O, wash the organic phase with saturated sodium bicarbonate and brine, and dry (MgSO)₄Or Na₂SO₄) Filtered and then concentrated. The crude product was purified by column chromatography or preparative TLC.

Method 15

Sulfonylation Process III

To L-Pro-L-4- (3-dimethylaminopropyloxy) -Phe-OMe [ prepared by the procedure described in method 10](1 equivalent) of CH₂Cl₂Et was added to the solution₃N (5 equiv.) and then the appropriate sulfonyl chloride (1.1 equiv.) is added. The reaction was warmed to room temperature and stirred under nitrogen overnight. The mixture was concentrated, dissolved in ethyl acetate and washed with saturated sodium bicarbonate and 0.2N citric acid. The aqueous phase was made basic with solid sodium bicarbonate and the product was extracted with ethyl acetate. The organic phase was washed with brine and dried (MgSO)₄Or Na₂SO₄) Filtered and then 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 Process II

To a solution of azlactone in methanol (10-15ml) was added NaOAc (1 eq.) and 10% Pd/C. Mixing the mixture at 40psi H₂The lower part is arranged in a hydrogenator. After 8-16 hours, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give dehydrodipeptide methyl ester. Dissolving the ester in dioxane/H₂O (5-10ml), to which was added 0.5N NaOH (1.05 equiv). After 1-3 hours, the reaction mixture was concentrated and the residue was redissolved in H₂O and washed with ethyl acetate. The aqueous phase was made acidic with 0.2N HCl and the product was extracted with ethyl acetate. The combined organic layers were washed with brine (1X 5ml) and dried (MgSO)₄Or Na₂SO₄) Filtration followed by concentration gave the acid as a 1: 1 diastereomer mixture.

Method 17

Process for the hydrolysis of tert-butyl esters II

Dissolving tert-butyl ester in CH₂Cl₂(5ml) then treated with TFA (5 ml). The reaction was completed in 1-3 hours, then the reaction mixture was concentrated and the residue was dissolved in H₂O is then concentrated. The residue was redissolved in water and then freeze dried 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-prolinol (prolinol) (358mg, 1.41mmol) and Et at room temperature under nitrogen₃N (3.0 equiv., 590mL) was added together to 7mL of anhydrous DMSO. In another flask, a solution of pyridine sulfur trioxide complex (3.0 equivalents, 660mg) in 3mL of DMSO was cooled to 15 ℃ under a nitrogen atmosphere. The latter reaction mixture was injected with a prolinol solution and then warmed to room temperature. After 2 hours, the reaction was poured into ice-cold brine (10mL) and extracted with ether (2X 50 mL). The organic layer was washed with 10% citric acid (25mL), water, saturated sodium bicarbonate (25mL) and brine. After filtration and evaporation of the solvent under reduced pressure, the desired prolinal is isolated in the form of a fluffy solid. Then the L-phenylalanine benzyl ester and NaCNBH are added₃(1.0 eq.) were added together in methanol (4 mL). The pH was maintained at 6.0 with 1 drop of acetic acid. The reaction mixture was stirred at room temperatureAnd (4) at night. EtOAc was added along with water and brine. The organic layer was washed several times and then dried over magnesium sulfate. After filtration and evaporation of the solvent under reduced pressure, the crude product is eluted with EtOAc/hexane 1: 1 on silica gel column chromatography. The ester was diluted with EtOAc/EtOH/water 1: 0.5, and a catalytic amount of 10% palladium on carbon was added followed by hydrogenation. After filtration through celite, the title product is isolated as a white foam.

The physical data are as follows:

¹H NMR(300MHz，CDCl₃)：δ＝7.76(m，2H)，7.39-7.26(m，7H)，4.05(m，1H)，3.92(m，1H)，3.55-3.12(m，5H)，2.82(m，1H)，2.38(s，3H)，1.55(m，3H)，1.25(m，2H)。

mass spectrum: (FAB)403(M + H).

Example 2

Synthesis of N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-L-phenylalanine

Sodium nitrite powder (1.27g) was added portionwise to a solution of potassium bromide (4.896g) and D-phenylalanine (2g) in 2.5N sulfuric acid (24.2ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 20 minutes and then at room temperature for 1 hour. The product was extracted with ether (3 × 15ml), and the combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo. The product (2.4g) was used in the subsequent reaction without further purification. Methyl ester was prepared from thionyl chloride and methanol. The product (2g) was immediately added to a solution of hydroxylamine in methanol (10 ml). Free hydroxylamine was prepared by treating a solution of hydroxylamine HCl (1.15g) in methanol (10ml) with Na (380 mg). The reaction mixture was refluxed overnight, evaporated in vacuo and the residue partitioned between water and chloroform. The separated organic layer was dried and then evaporated. The residue was partitioned again between 2N HCl and ether. The separated aqueous layer was made alkaline with sodium hydrogencarbonate, extracted with chloroform, dried over magnesium sulfate, filtered and evaporated in vacuo to give 400mg of N-hydroxy-L-phenylalanine methyl ester. A solution of N- (toluene-4-sulfonyl) -L-proline carbonyl chloride (412mg) in THF (10ml) was added dropwise to a solution of the reaction product of the previous step (280mg) containing triethylamine (145mg) in THF (20ml) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour, at room temperature for 1 hour, then evaporated in vacuo and the residue partitioned between water and ethyl acetate. The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was subjected to flash chromatography on 30g of silica gel. Elution with chloroform gave 360mg of N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-L-phenylalanine methyl ester. The title compound was prepared from the reaction product of the previous step (1150mg) in THF (80ml) which was immediately treated with 1N NaOH (2.57 ml). The mixture was stirred at room temperature overnight. The crystalline product was filtered off, washed with diethyl ether and then dried at 0.1 torr to give 750mg of the title compound, mp 202-.

Example 3

Synthesis of N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-D-phenylalanine

The title compound was prepared according to the procedure described for example 2, substituting D-phenylalanine for L-phenylalanine.

The physical data are as follows:

MS：[(+)FAB]，[M+H]⁺433。

example 4

N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl ] -L-4- (N-

Synthesis of benzyloxycarbonyl-isopiperidinecarboxamido) phenylalanine

2- (hydroxyacetyl) pyrrolidine (J.org.chem. (1991), 56, 1624) was N-tosylated and the resulting product was coupled with an appropriately substituted phenylalanine using standard peptide synthesis methods. Basic hydrolysis of the ester gave the title compound, mp 92-95 ℃.

The physical data are as follows:

MS(+)FAB[M+H]⁺707。

example 5

N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl ] -L-4-

Synthesis of (isopiperidinecarboxamido) phenylalanine

The product of example 4 was hydrogenated with Pd/C in ethanol for 4 hours for deprotection. The catalyst was filtered off, the filtrate was added to water and then lyophilized to give 240mg of a white solid.

The physical data are as follows:

MS(+)FAB[M+H]⁺573。

calculated values: c₂₈H₃₆N₄O₇S·CF₃CO₂H·3H₂O C: 48.71, respectively; h: 5.73; n: 7.57. measured value: c: 48.88, respectively; h: 5.35; n: 7.45.

example 6

(2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl ] -2- (4-)

Synthesis of nitrobenzyl) propionic acid

N- (toluene-4-sulfonyl-L-prolyl-L- (4-nitro) phenylalanine methyl ester with an equimolar amount of PCl₅Mixed in anhydrous benzene and then stirred for 90 minutes. The yellow solution was treated with a benzene solution of azido acid and the mixture was stirred at room temperature for 2 hours, then diluted with benzene and washed with saturated sodium bicarbonate and brine. The organic layer was dried and then evaporated to give a pale yellow foam. The title compound was prepared from the reaction product of the previous step by conventional alkaline hydrolysis to give a yellow-white fluffy solid, mp 150-.

The physical data are as follows:

MS(+)FAB[M+H]⁺487。

example 7

(2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl ] -2- (4-)

Synthesis of methyl (N-tert-butoxycarbonylisopiperidinecarboxamido) benzyl) propionate

The nitro intermediate described in example 6 was reduced, dissolved in dichloromethane and combined with N-Boc-isopipecacic acid, HOBT, cooled to 5 ℃ and then treated with DCC. The reaction mixture was warmed to room temperature overnight, filtered, evaporated to dryness and the residue was taken up in ethyl acetate. The organic layer was washed according to conventional procedures, dried and evaporated to give the title compound, mp 92-102 ℃.

The physical data are as follows:

MS(+)FAB[M+H]⁺682。

example 8

(2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl ] -2- (4-)

Synthesis of (N-tert-butyloxycarbonylisiperidylaminobenzoylamino) benzyl) propionic acid

The title compound was prepared from the product of example 7 by conventional base hydrolysis procedures, mp180-189 ℃.

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 (1g, 3.71mmol) was placed under argonTo a solution of diphenylphosphoryl azide (1.13g, 3.71mmol) in 50mL of toluene was added. Triethylamine (394mg, 3.9mmol) was added, and the mixture was heated at 80 ℃ for 2 hours. L-phenylalanine benzyl ester (1.75g, 4.1mmol) and triethylamine (394mg, 3.9mmol) were added and heated at 80 ℃ overnight. Toluene was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel, hexane: EtOAc, 2: 1) to give benzyl ester (540mg, 28%) as a white solid. By hydrogenation (10% Pd/C, EtOH, 40psi H₂) The benzyl ester was removed. The catalyst was removed and the product was washed with EtOH/Et₂Recrystallization from O afforded the title compound as a white solid (75mg, 40%).

The physical data are as follows:

C₂₁H₂₅N₃O₅S·0.75 H₂o calculated value C: 56.68; h: 6.00; n: 9.44.

found value C: 56.94, respectively; h: 5.68; n: 9.05.

mass Spectrometry [ FAB][M-H]^-M/Z 430(100％)。

Example A

In vitro assay for determining binding of test compounds to VLA-4

Evaluation of test Compounds and alpha Using in vitro assays₄β₁Binding of integrins. The compounds that bind in this assay can be used to determine the level of VCAM-1 in a biological sample by conventional assays (e.g., competitive assays). The assay is in IC₅₀The sensitivity in terms of value was as low as about 1 nM.

α₄β₁Integrin activity is measured by interaction of soluble VCAM-1 with Jurkat cells (e.g., American type culture accession Nos. TIB 152, TIB 153 and CRL 8163), a cell that expresses high levels of alpha₄β₁Human T-cell lines of integrins. VCAM-1 is expressed as alpha with the cell surface₄β₁Integrin-dependent mode interactions(Yednock, et al J.biol.chem., 1995, 270: 28740).

Recombinant soluble VCAM-1 is expressed as a chimeric fusion protein comprising 7 extracellular VCAM-1 domains at the N-terminus and human IgG at the C-terminus₁A heavy chain constant region. VCAM-1 fusion proteins were prepared and purified as described for Yednock, supra.

Jurkat cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine, as per Yednock, supra.

Jurkat cells were incubated with 1.5mM MnCl₂And 5. mu.g/mL 15/7 antibody on ice for 30 minutes. Mn⁺²The receptor can be activated to enhance ligand binding, 15/7 is recognition of activated/ligand occupied alpha₄β₁Monoclonal antibodies in integrin conformation and capable of immobilizing molecules in that conformation, thereby stabilizing VCAM-1/alpha₄β₁Integrin interactions. Yednock et al, supra. Antibodies similar to the 15/7 antibody prepared by other researchers can be used in this assay (Luque et al, 1996, J.biol.chem.271: 11067).

Cells were then incubated for 30 minutes with varying concentrations of test compound between 66 μ M and 0.01 μ M diluted using standard 5-point serial dilutions. Then 15. mu.L of soluble recombinant VCAM-1 fusion protein was added to Jurkat cells and incubated on ice for 30 minutes (Yednock et al, supra).

The cells were then washed 2 times and resuspended in PE-conjugated goat F (ab')₂Anti-mouse IgG Fc (Immunotech, Westbrook, ME) and incubation for 30 min on ice in the dark. Cells were washed 2 times and analyzed using a standard fluorescence activated cell sorter ("FACS") as per Yednock et al, supra.

IC₅₀Compound pair alpha less than about 15 mu M₄β₁Has binding affinity.

When tested in this assay, theThe compounds of examples 1-9 all had IC's of 15. mu.M or less₅₀。

Example B

For determining the extent of alpha formation of a test compound₄β₁Binding in vitro saturation assay

Described below are in vitro assays for determining the plasma levels of a compound required to exhibit activity in an experimental autoimmune encephalomyelitis ("EAE") model (described in the examples below) or other in vivo models.

Jurkat cells in log phase growth were washed and suspended in standard animal plasma containing 20. mu.g/ml 15/7 antibody (described in the previous example).

Jurkat cells were diluted (2-fold dilution) into standard plasma samples containing varying concentrations of known test compounds ranging from 66 μ M to 0.01 μ M diluted using standard 12-point serial dilution (standard curve) or into plasma samples derived from peripheral blood of animals treated with test compounds.

The cells were then incubated at room temperature for 30 minutes and washed with phosphate buffered saline ("PBS") (assay medium) containing 2% fetal bovine serum and 1mM calcium chloride and 1mM magnesium chloride to remove unbound 15/7 antibody.

The cells were then exposed to phycoerythrin-conjugated goat F (ab')₂Anti-murine IgG Fc (Immunotech, Westbrook, ME) and incubated at 4 ℃ in the dark for 30 minutes, wherein the goat F (ab')₂Anti-murine igg Fc has been previously adsorbed by co-incubation with 5% serum from experimental animals (for any non-specific cross-reactions).

Cells were washed 2 times with assay medium and then resuspended in assay medium. Then the samples were taken according to Yednock et al, j.biol.chem., 1995, 270: 28740, analyzed using a standard fluorescence activated cell sorter ("FACS").

The data are then plotted in a fluorescence-versus-dose fashion, such as a standard dose-response fashion. The dose given at the top plateau of the curve represents the level required to achieve efficacy in an in vivo model.

The assay can also be used to determine other integrins, e.g., alpha₉β₁Integrin-and alpha₄β₁The binding sites for the most relevant integrins (Palmer et al, 1993, J.cell Bio., 123: 1289) saturate the required plasma levels. The binding is in vivo for alpha₉β₁The prediction of mediated inflammatory conditions including, for example, airway hyperreactivity and obstruction that occurs with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion following angioplasty, fibrosis and glomerular scarring due to kidney disease, arterial stenosis, synovial membrane hypertrophy in rheumatoid arthritis, and inflammation and scarring that occur with the progression of ulcerative colitis and crohn's disease.

Thus, the code α can be used₉The above assay was performed using SW 480(ATTC # CCL228) as a human colon cancer cell line transfected with cDNA for integrin (Yokosaki et al, 1994, J.biol.chem., 269: 26691) instead of Jurkat cells to determine alpha₉β₁Binding of integrins. Expression of other alpha and beta may be used₁Subunit SW 480 cells served as controls.

Thus, another aspect of the invention relates to the treatment of α in a mammalian patient₉β₁A method of mediating a disease, said method comprising administering to said patient a therapeutically effective amount of a compound of the present invention. The compounds of the present invention are preferably administered in the form of the pharmaceutical compositions described above. The effective daily dosage will depend upon such factors as the age, weight and physical condition of the patient as can be readily determined by a clinician. However, in a preferred embodiment, the compounds of the present invention are administered at a dosage of about 20-500 μ g/kg/day.

Example C

In vivo evaluation

The effect of a compound to be tested on reducing locomotor injury in rats or guinea pigs was determined using a standard multiple sclerosis model, experimental autoimmune (or allergic) encephalomyelitis ("EAE"). The reduction of motor impairment is based on the blocking of adhesion between leukocytes and endothelial cells and is associated with the anti-inflammatory activity of the compounds to be tested. This model has been described by Keszthelyi et al, Neurology, 1996, 47: 1053-1059, and for determining the delay in onset of disease.

The brain and spinal cord of adult Hartley guinea pigs were homogenized in equal volumes of phosphate buffered saline. To this homogenate was added an equal volume of Freund's complete adjuvant (100mg of Mycobacterium tuberculosis plus 10ml of Freund's incomplete adjuvant). The mixture was emulsified by passing it repeatedly through a 20ml syringe using a peristaltic pump for about 20 minutes.

Female Lewis rats (2-3 months old, 170-. Onset of motor injury was observed after approximately 9 days.

Treatment with the test compound was started on day 8, i.e. immediately before the onset of symptoms. The compound to be tested is administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP"). The dose is 10mg/kg-200mg/kg bid, administered for 5 days, typically 10-100mg/kg SC, 10-50mg/kg PO and 10-100mg/kg IP.

Use of anti-alpha capable of delaying onset of symptoms₄β₁The integrin antibody GG5/3(Keszthelyi et al, Neurology, 1996, 47: 1053-.

Body weight and motor injury were measured once daily. The motor injury was assessed using the following clinical scores:

0 has not changed any more

1 debilitation or paralysis of the tail

2 weakness of hind limb

3 hind limb paralysis

4 dying or dead

A test compound is considered active if it delays the onset of symptoms, e.g., produces a clinical score of no greater than 2, or slows the loss of body weight compared to a control.

Example D

Asthma model

α₄β₁Integrin-mediated inflammatory disorders include, for example, airway hyperreactivity and obstruction that occurs with chronic asthma. An asthma model useful for determining the efficacy of the compounds of the invention in treating asthma in vivo is described below.

According to Abraham et al, j.clin.invest, 93: 776-787(1994) and Abraham et al, Am J.Respir Crit Care Med, 156: 696-703(1997), both of which are incorporated herein by reference in their entirety, the compounds of the present invention are formulated as aerosols and administered to sheep sensitive to ascaris suum antigens. A compound is considered active in this model if it reduces early antigen-induced bronchial responses and/or blocks late tracheal responses, e.g., has protective effects against antigen-induced late responses and airway hyperreactivity ("AHR").

The tracheal effect of the test compounds was determined using allergic sheep that exhibited early and late bronchial reactions to inhaled ascaris suum antigens. After local anesthesia of the nostrils with 2% lidocaine, a dilating catheter was inserted through one nostril to the bottom of the esophagus. The cufflated endotracheal tube was then inserted into the trachea via the other nostril under the guidance of a flexible fiberoptic bronchoscope.

Pleural pressure was estimated according to Abraham (1994). The aerosol (see formulation below) was formed using a disposable medical nebulizer, which was capable of providing an aerosol with a mass median aerodynamic diameter of 3.2 μm (as measured by an Andersen cascade impactor). The nebulizer was connected to a dosimeter system consisting of a solenoid valve and a compressed gas source (20 psi). The output port of the nebulizer was directly connected to a plastic T-piece, one end of which was connected to the inhalation portion of the piston type respiratory mask. At the beginning of the inhalation cycle of the respirator, the solenoid valve was opened for 1 second. The aerosol was released at a VT of 500ml and a rate of 20 breaths/min. A 0.5% sodium bicarbonate solution was used as a control.

To evaluate the bronchial response, carbachol cumulative concentration-response curves were plotted according to Abraham (1994). Bronchial biopsies can be taken 24 hours after antigen challenge, before and after the start of treatment. Bronchial biopsies can be performed according to Abraham (1994).

Dust cell in vitro adhesion assays were also performed according to Abraham (1994) and the percentage of adherent cells was calculated.

Aerosol formulation

A solution of the test compound at a concentration of 30.0-100.0mg/mL in 0.5% sodium bicarbonate/saline (w/v) was prepared as follows:

A. preparation of a 0.5% sodium bicarbonate/brine stock: 100.0mL

Components	G/100.0 mL	Final concentration
Components	G/100.0 mL	Final concentration	Sodium bicarbonate	0.5g	0.5％
Salt water	Adding proper amount of the mixture to 100.0mL	Adding proper amount of the mixture to 100 percent	Sodium bicarbonate	0.5g	0.5％

The method comprises the following steps:

1. 0.5g of sodium bicarbonate was added to a 100mL volumetric flask.

2. Approximately 90.0mL of saline was added and sonicated until dissolved.

3. Add to 100.0mL with the appropriate amount of brine and mix well.

B. Preparation of 30.0mg/mL test compound: 10.0mL

Components	G/10.0 mL	Final concentration
Components	G/10.0 mL	Final concentration	Test compounds	0.300g	30.0-100.0mg/mL
0.5% sodium bicarbonate/brine stock	Adding proper amount of the mixture to 10.0mL	Adding proper amount of the mixture to 100 percent	Test compounds	0.300g	30.0-100.0mg/mL

The method comprises the following steps:

1. 0.300g of test compound was added to a 10.0mL volumetric flask.

2. Approximately 9.7mL of 0.5% sodium bicarbonate/brine stock was added.

3. Sonication was carried out until the test compound was completely dissolved.

4. Add to 10.0mL with appropriate amount of 0.5% sodium bicarbonate/brine stock and mix well.

The compounds of the invention are active in this model using conventional oral formulations.

Claims

1. A compound of formula I:

wherein

R²selected from hydrogen, alkyl, substitutedAlkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and R¹And R²To the connection R²Nitrogen atom and SO₂The groups together may form a heterocyclic or substituted heterocyclic group;

q is

R⁸selected from the group consisting of hydrogen, alkyl, and substituted alkyl; or R⁷And R⁸And is attached to R⁷To the nitrogen atom and bound to R⁸The carbon atoms on which may together form a heterocyclic or substituted heterocyclic ring.

2. A compound of formula IA:

wherein

R⁴selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroarylA group, a heterocycle, a substituted heterocycle, and, when R is³Not with R²When a heterocyclic or substituted heterocyclic group is formed, then R³And R⁴May form, together with the carbon atom to which they are attached, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic ring, or a substituted heterocyclic group;

q is

3. RightsA compound according to claim 1 or 2, wherein R is¹Selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.

4. The compound of claim 1 or 2, wherein R¹Selected from the group consisting of methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-tert-butylphenyl, 2, 4, 6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 3, 5-difluorophenyl, 2-chlorophenyl, 3-aminophenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3, 5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 4-tert-butoxyphenyl, 4- (3' -dimethylamino-n-propoxy) -phenyl, methyl, ethyl, propyl, isopropyl, 4-methylphenyl, 4-tert-butylphenyl, 2-chlorophenyl, 3-aminophenyl, 4-chlorophenyl, 4-dichlorophenyl, 3, 2-carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4- (H)₂NC (O) -) phenyl, 4- (H₂NC (S) -) phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3, 5-bis- (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH)₃C (O) NH-phenyl, 4- (PhNHC (O) NH-) phenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- (CH)₃SC (═ NH) -) phenyl, 4-chloro-3- (H)₂NS(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-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, pyridin-3-yl, pyrimidin-2-yl, 1-dichloro-4-yl, 1-N-methyl-4-thienyl, 1-N-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-1, 3, 4-thiadiazol-2-yl.

5. The compound of claim 1 or 2, wherein R²Selected from hydrogen, methyl, phenyl, benzyl, - (CH)₂)₂-2-thienyl and- (CH)₂)₂-φ。

6. The compound of claim 1 or 2, wherein R²And R³And is attached to R²Nitrogen atom of substituent and bound to R³The carbon atoms on the substituents together form a heterocyclic group or a substituted heterocyclic group.

7. The compound of claim 6, wherein R²And R³And is attached to R²Nitrogen atom of substituent and bound to R³The carbon atoms on the substituents together form a substituted heterocyclic ring.

8. The compound of claim 1 or 2, wherein R¹And R²And is attached to R²To the nitrogen atom and bound to R¹SO of₂The groups are joined together to form a heterocyclic or substituted heterocyclic ring.

9. The compound of claim 1 or 2, wherein R³Selected from the group consisting of hydrogen, methyl, phenyl, benzyl, diphenylmethyl, 2-carboxyethyl, 2-amidoethyl, isobutyl, tert-butyl, carboxymethyl, -CH₂O-benzyl and hydroxymethyl.

10. The compound of claim 1 or 2, wherein R⁴Selected from hydrogen, methyl, ethyl and phenyl.

11. The compound of claim 1 or 2, wherein Q is selected from-CH₂NH-and tetrazole-1, 5-diyl.

12. The compound of claim 1 or 2, wherein R⁵Selected from:

4-methylbenzyl group,

4-hydroxybenzyl,

4-methoxybenzyl,

4-tert-butoxybenzyl group,

4-benzyloxy-benzyl,

4-[φ-CH(CH₃)O-]Benzyl group,

4- [ phi-CH (COOH) O- ] benzyl,

4-[BocNHCH₂C(O)NH-]Benzyl group,

4-chlorobenzyl,

4-[NH₂CH₂C(O)NH-]Benzyl group,

4-carboxybenzyl group,

4-[CbzNHCH₂CH₂NH-]Benzyl group,

3-hydroxy-4- (phi-OC (O) NH-) benzyl,

4-[HOOCCH₂CH₂C(O)NH-]Benzyl group,

Benzyl group,

4- [ 2' -carboxyphenoxy- ] benzyl,

4- [ phi-C (O) NH- ] benzyl,

3-carboxybenzyl group,

4-iodobenzyl group,

4-hydroxy-3, 5-diiodobenzyl,

4-hydroxy-3-iodobenzyl,

4- [ 2' -carboxyphenyl- ] benzyl,

φ-CH₂CH₂-、

4-nitrobenzyl,

2-carboxybenzyl group,

4- [ dibenzylamino ] -benzyl,

4- [ (1 '-cyclopropylpiperidin-4' -yl) C (O) NH- ] benzyl,

4-[-NHC(O)CH₂NHBoc]Benzyl group,

4-carboxybenzyl group,

4-hydroxy-3-nitrobenzyl,

4-[-NHC(O)CH(CH₃)NHBoc]Benzyl group,

4-[-NHC(O)CH(CH₂φ)NHBoc]Benzyl group,

Isobutyl, and,

Methyl, methyl,

4-[CH₃C(O)NH-]Benzyl group,

-CH₂- (3-indolyl),

N-butyl,

tert-butyl-OC (O) CH₂-、

tert-butyl-OC (O) CH₂CH₂-、

H₂NC(O)CH₂-、

H₂NC(O)CH₂CH₂-、

BocNH-(CH₂)₄-、

tert-butyl-OC (O) - (CH)₂)₂-、

HOOCCH₂-、

HOOC(CH₂)₂-、

H₂N(CH₂)₄-、

An isopropyl group,

(1-naphthyl) -CH₂-、

(2-naphthyl) -CH₂-、

(2-thienyl) -CH₂-、

(φ-CH₂-OC(O)NH-(CH₂)₄-、

cyclohexyl-CH₂-、

benzyloxy-CH₂-、

HOCH₂-、

5- (3-N-benzyl) imidazolyl-CH₂-、

2-pyridyl-CH₂-、

3-pyridyl-CH₂-、

4-pyridyl-CH₂-、

5- (3-N-methyl) imidazolyl-CH₂-、

N-benzylpiperidin-4-yl-CH₂-、

N-Boc-piperidin-4-yl-CH₂-、

N- (phenyl-carbonyl) piperidin-4-yl-CH₂-、

H₃CSCH₂CH₂-、

1-N-benzylimidazol-4-yl-CH₂-、

isopropyl-C (O) NH- (CH)₂)₄-、

isobutyl-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) -CH₂-、

4-imidazolyl group,

4-[(CH₃)₂NCH₂CH₂CH₂-O-]Benzyl group,

4- [ (benzyl)₂N-]-benzyl group,

4-aminobenzyl group,

allyloxy-C (O) NH (CH)₂)₄-、

allyloxy-C (O) NH (CH)₂)₃-、

allyloxy-C (O) NH (CH)₂)₂-、

NH₂C(O)CH₂-、

φ-CH＝、

2-pyridyl-C (O) NH- (CH)₂)₄-、

4-methylpyridin-3-yl-C (O) NH- (CH)₂)₄-、

3-methylthiophen-2-yl-C (O) NH- (CH)₂)₄-、

2-pyrrolyl-C (O) NH- (CH)₂)₄-、

2-furyl-C (O) NH- (CH)₂)₄-、

4-methylphenyl-SO₂-N(CH₃)CH₂C(O)NH(CH₂)₄-、

4- [ cyclopentylethynyl ] -benzyl,

4- [ -NHC (O) - (N-Boc) -pyrrolidin-2-yl) ] -benzyl- ] -methyl- ]

1-N-methylimidazol-4-yl-CH₂-、

1-N-methylimidazol-5-yl-CH₂-、

imidazol-5-yl-CH₂-、

6-methylpyridin-3-yl-C (O) NH- (CH)₂)₄-、

4- [ 2' -carboxymethylphenyl ] -benzyl,

4-[-NHC(O)NHCH₂CH₂CH₂-φ]-benzyl group,

4-[-NHC(O)NHCH₂CH₂-φ]-benzyl group,

-CH₂C(O)NH(CH₂)₄φ、

4-[φ(CH₂)₄O-]-benzyl group,

4- [ -C.ident.C-phi-4' phi ] -benzyl,

4-[-C≡C-CH₂-O-S(O)₂-4′-CH₃-φ]-benzyl group,

4-[-C≡C-CH₂NHC(O)NH₂]-benzyl group,

4-[-C≡C-CH₂-O-4′-COOCH₂CH₃-φ]-benzyl group,

4-[-C≡C-CH(NH₂) -cyclohexyl radical]-benzyl group,

-(CH₂)₄NHC(O)CH₂-3-indolyl group,

-(CH₂)₄NHC(O)CH₂CH₂-3-indolyl group,

-(CH₂)₄NHC (O) -3- (5-methoxyindolyl),

-(CH₂)₄NHC (O) -3- (1-methylindolyl),

-(CH₂)₄NHC(O)-4-(-SO₂(CH₃)-φ)、

-(CH₂)₄NHC(O)-4-(C(O)CH₃) -phenyl group,

-(CH₂)₄NHC (O) -4-fluorophenyl,

-(CH₂)₄NHC(O)CH₂O-4-fluorophenyl,

4- [ -C.ident.C- (2-pyridyl) ] benzyl,

4-[-C≡C-CH₂-O-phenyl]Benzyl group,

4-[-C≡C-CH₂OCH₃]Benzyl group,

4- [ -C.ident.C- (3-hydroxyphenyl) ] benzyl,

4-[-C≡C-CH₂-O-4′-(-C(O)OC₂H₅) Phenyl radical]Benzyl group,

4-[-C≡C-CH₂CH(C(O)OCH₃)₂]Benzyl group,

4-[-C≡C-CH₂NH- (4, 5-dihydro-4-oxo-5-phenyl-oxazol-2-yl),

3-aminobenzyl group,

4-[-C≡C-CH₂CH(NHC(O)CH₃)C(O)OH]-benzyl group,

-CH₂C(O)NHCH(CH₃)φ、

-CH₂C(O)NHCH₂- (4-dimethylamino) -phi,

-CH₂C(O)NHCH₂-4-nitrophenyl,

-CH₂CH₂C(O)N(CH₃)CH₂-φ、

-CH₂CH₂C(O)NHCH₂CH₂- (N-methyl) -2-pyrrolyl,

-CH₂CH₂C(O)NHCH₂CH₂CH₂CH₃、

-CH₂CH₂C(O)NHCH₂CH₂-3-indolyl group,

-CH₂C(O)N(CH₃)CH₂Phenyl, phenyl,

-CH₂C(O)NH(CH₂)₂- (N-methyl) -2-pyrrolyl,

-CH₂C(O)NHCH₂CH₂CH₂CH₃、

-CH₂C(O)NHCH₂CH₂-3-indolyl group,

-(CH₂)₂C(O)NHCH(CH₃)φ、

-(CH₂)₂C(O)NHCH₂-4-dimethylaminophenyl group,

-(CH₂)₂C(O)NHCH₂-4-nitrophenyl,

-CH₂C(O)NH-4-[-NHC(O)CH₃-phenyl radical]、

-CH₂C (O) NH-4-pyridyl,

-CH₂C (O) NH-4- [ dimethylaminophenyl group]、

-CH₂C (O) NH-3-methoxyphenyl,

-CH₂CH₂C (O) NH-4-chlorophenyl,

-CH₂CH₂C (O) NH-2-pyridyl,

-CH₂CH₂C (O) NH-4-methoxyphenyl,

-CH₂CH₂C (O) NH-3-pyridyl,

4-[(CH₃)₂NCH₂CH₂O-]Benzyl group,

-(CH₂)₃NHC(NH)NH-SO₂-4-methylphenyl,

4-[(CH₃)₂NCH₂CH₂O-]Benzyl group,

-(CH₂)₄NHC(O)NHCH₂CH₃、

-(CH₂)₄NHC (O) NH-phenyl,

-(CH₂)₄NHC (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)CH₂NHC (O) NH-3' -methylphenyl]Benzyl group,

4- [ -NHC (O) - (2 ', 3' -indolin-2-yl) ] benzyl,

4- [ -NHC (O) - (2 ', 3' -dihydro-N-Boc-indol-2-yl) ] benzyl,

p-[-OCH₂CH₂-1 '- (4' -pyrimidinyl) -piperazinyl]Benzyl group,

4-[-OCH₂CH₂- (1' -piperidinyl)]Benzyl group,

4-[-OCH₂CH₂- (1' -pyrrolidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂- (1' -piperidinyl)]Benzyl-),

-CH₂-3- (1, 2, 4-triazolyl)

4-[-OCH₂CH₂CH₂-4- (3' -chlorophenyl) -piperazin-1-yl]Benzyl group,

4-[-OCH₂CH₂N(φ)CH₂CH₃]Benzyl group,

4-[-OCH₂-3' - (N-Boc) -piperidinyl]Benzyl group,

4- [ di-n-pentylamino ] benzyl,

4- [ n-pentylamino ] benzyl,

4- [ di-isopropylamino-CH₂CH₂O-]Benzyl group,

4-[-OCH₂CH₂- (N-morpholinyl)]Benzyl group,

4- [ -O- (3' - (N-Boc) -piperidinyl ] benzyl,

4-[-OCH₂CH(NHBoc)CH₂Cyclohexyl radical]Benzyl group,

p-[OCH₂CH₂- (N-piperidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂- (4-m-chlorophenyl) -piperazin-1-yl]Benzyl group,

4-[-OCH₂CH₂- (N-homopiperidinyl)]Benzyl group,

4- [ -NHC (O) -3' - (N-Boc) -piperidinyl ] benzyl,

4-[-OCH₂CH₂N- (benzyl)₂]Benzyl group,

-CH₂-2-thiazolyl,

3-hydroxybenzyl,

4-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4-[-NHC(S)NHCH₂CH₂- (N-morpholino)]Benzyl group,

4-[-OCH₂CH₂N(C₂H₅)₂]Benzyl group,

4-[-OCH₂CH₂CH₂N(C₂H₅)₂]Benzyl group,

4-[CH₃(CH₂)₄NH-]Benzyl group,

4- [ N-N-butyl, N-N-pentylamino- ] benzyl,

4- [ -NHC (O) -4' -piperidinyl ] benzyl,

4-[-NHC(O)CH(NHBoc)(CH₂)₄NHCbz]Benzyl group,

p-[-OCH₂CH₂CH₂-1 '- (4' -methyl) -piperazinyl]Benzyl group,

-(CH₂)₄NH-Boc、

3-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

3-[-OCH₂CH₂- (1' -pyrrolidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂N(CH₃) Benzyl radical]Benzyl group,

4-[-NHC(S)NHCH₂CH₂CH₂- (N-morpholino)]Benzyl group,

4-[-OCH₂CH₂- (N-morpholino)]Benzyl group,

4-[-NHCH₂- (4' -chlorophenyl)]Benzyl group,

4- [ -NHC (O) NH- (4' -cyanophenyl) ] benzyl,

4-[-OCH₂COOH]Benzyl group,

4-[-OCH₂COO-tert-butyl]Benzyl group,

4- [ -NHC (O) -5' -fluoroindol-2-yl ] benzyl,

4-[-NHC(S)NH(CH₂)₂-1-piperidinyl group]Benzyl group,

4-[-N(SO₂CH₃)(CH₂)₃-N(CH₃)₂]Benzyl group,

4-[-NHC(O)CH₂CH(C(O)OCH₂φ)-NHCbz]Benzyl group,

4-[-NHS(O)₂CF₃]Benzyl group,

3- [ -O- (N-methylpiperidin-4' -yl) ] benzyl,

4-[-C(＝NH)NH₂]Benzyl group,

4-[-NHSO₂-CH₂Cl]Benzyl group,

4- [ -NHC (O) - (1 ', 2 ', 3 ', 4 ' -tetrahydroisoquinolin-2 ' -yl ] benzyl,

4-[-NHC(S)NH(CH₂)₃-N-morpholino]Benzyl group,

4-[-NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]Benzyl group,

4-[-C(O)NH₂]Benzyl group,

4- [ -NHC (O) NH-3' -methoxyphenyl ] benzyl,

4-[-OCH₂CH₂-indol-3' -yl]Benzyl group,

4-[-OCH₂C (O) NH-benzyl]Benzyl group,

4-[-OCH₂C (O) O-benzyl]Benzyl group,

4-[-OCH₂C(O)OH]Benzyl group,

4-[-OCH₂-2 ' - (4 ', 5 ' -dihydro) imidazolyl]Benzyl group,

-CH₂C(O)NHCH₂- (4-dimethylamino) phenyl,

4-[-NHC(O)NHCH₂CH₂CH₃]Benzyl group,

4-aminobenzyl group,

4- [ -O- (N-methylpiperidin-4' -yl) ] benzyl,

3-methoxybenzyl,

4- [ -NHC (O) -piperidin-3' -yl ] benzyl,

4- [ -NHC (O) -pyridin-2' -yl ] benzyl,

4-[-NHCH₂- (4' -chlorophenyl)]Benzyl group,

4-[-NHC(O)-(N-(4′-CH₃-φ-SO₂) -L-pyrrolidin-2' -yl)]Benzyl group,

4-[-NHC(O)NHCH₂CH₂-φ]Benzyl group,

4-[-OCH₂C(O)NH₂]Benzyl group,

4-[-OCH₂C (O) NH-tert-butyl]Benzyl group,

4-[-OCH₂CH₂-1- (4-hydroxy-4-phenyl) -piperidinyl]Benzyl group,

4-[-NHSO₂-CH＝CH₂]Benzyl group,

4-[-NHSO₂-CH₂CH₂C]]Benzyl group,

-CH₂C(O)NHCH₂CH₂N(CH₃)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′-(CH₃)₂NC (O) O-) phenyl) -C (O) NH-]Benzyl group,

4- [ -NHC (O) -1 '-methylpiperidin-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) CCH₂-O-benzyl) -NH-]Benzyl group,

[BocNHCH₂C(O)NH-]Butyl, isobutyl, or isobutyl,

4-benzyl group,

2-hydroxyethyl group,

4-[(Et)₂NCH₂CH₂CH₂NHC(S)NH-]Benzyl group,

4- [ (1 ' -Boc-4 ' -hydroxypyrrolidin-2 ' -yl) C (O) NH- ] benzyl,

4-[φCH₂CH₂CH₂NHC(S)NH-]Benzyl group,

4- [ (perhydroindol-2' -yl) C (O) NH- ] benzyl,

2- [ 4-hydroxy-4- (3-methoxythien-2-yl) piperidin-1-yl ] ethyl,

4- [ (1 '-Boc-perhydroindol-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- (φ NHC (S) NH) benzyl,

4- (EtNHC (S) NH) benzyl,

4-(φCH₂NHC(S)NH) Benzyl group,

3- [ (1 '-Boc-piperidin-2' -yl) C (O) NH- ] benzyl,

3- [ piperidin-2' -yl-C (O) NH- ] benzyl,

4- [ (3 '-Boc-thiazolidin-4' -yl) C (O) NH- ] benzyl,

4- (pyridin-3' -yl-NHC (S) NH) benzyl,

4-(CH₃-NHC (S) NH) benzyl,

4-(H₂NCH₂CH₂CH₂C (O) NH) benzyl,

4-(BocHNCH₂CH₂CH₂C (O) NH) benzyl,

4- (pyridin-4' -yl-CH₂NH) benzyl group,

4- [ (N, N-bis (4-N, N-dimethylamino) benzyl) amino ] benzyl,

4- [ (1-Cbz-piperidin-4-yl) C (O) NH- ] butyl,

4-[φCH₂OCH₂(BocHN)CHC(O)NH]Benzyl group,

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-[CH₃NHCH₂CH₂CH₂C(O)NH-]Benzyl group,

4-[CH₃N(Boc)CH₂CH₂CH₂C(O)NH-]Benzyl group,

4- (aminomethyl) benzyl,

4-[φCH₂OCH₂(H₂N)CHC(O)NH]Benzyl group,

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 '-indolin-2' -yl) -C (O) NH ] benzyl,

4- (pyridin-3' -yl-CH₂NH) benzyl group,

4- [ (1 '-Cbz-piperidin-4' -yl) C (O) NH- ] benzyl,

4- [ (piperidin-1' -yl) C (O) CH₂-O-]Benzyl group,

4-[(CH₃)₂CH)₂NC(O)CH₂-O-]Benzyl group,

4-[HO(O)C(Cbz-NH)CHCH₂CH₂-C(O)NH-]Benzyl group,

4-[φCH₂O(O)C(Cbz-NH)CHCH₂CH₂-C(O)NH-]Benzyl group,

4- [ -NHC (O) -2' -methoxyphenyl ] benzyl,

4- [ (pyrazin-2' -yl) C (O) NH- ] benzyl,

4-[HO(O)C(NH₂)CHCH₂CH₂-C(O)NH-]Benzyl group,

N-Cbz-NHCH₂-、

4- [ (4 '-methylpiperazin-1' -yl) C (O) O- ] benzyl,

4-[CH₃(N-Boc)NCH₂C(O)NH-]Benzyl group,

4-[CH₃NHCH₂C(O)NH-]Benzyl group,

(CH₃)₂NC(O)CH₂-、

4- (N-methylacetamido) benzyl,

4- (1 ', 2 ', 3 ', 4 ' -tetrahydroisoquinolin-3 ' -yl-CH₂NH-) benzyl group,

4-[(CH₃)₂NHCH₂C(O)NH-]Benzyl group,

(1-tosylimidazol-4-yl) methyl,

4- [ (1 '-Boc-piperidin-4' -yl) C (O) NH- ] benzyl,

4-trifluoromethyl benzyl,

4- [ (2' -bromophenyl) C (O) NH- ] benzyl,

4-[(CH₃)₂NC(O)NH-]Benzyl group,

4-[CH₃OC(O)NH-]Benzyl group,

4-[(CH₃)₂NC(O)O-]Benzyl group,

4-[(CH₃)₂NC(O)N(CH₃)-]Benzyl group,

4-[CH₃OC(O)N(CH₃)-]Benzyl group,

4- (N-methyl trifluoroacetylamino) 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-[(CH₃)₂NC(O)O-]Benzyl group,

4- [ (4 ' -phenyl-1 ' -Boc-piperidin-4 ' -yl) -C (O) O- ] benzyl,

4- (N-toluenesulfonylamino) benzyl,

4-[(CH₃)₃CC(O)NH-]Benzyl group,

4- [ (morpholin-4' -yl) C (O) NH- ] benzyl,

4-[(CH₃CH₂)₂NC(O)NH-]Benzyl group,

4- [ -C (O) NH- (4' -piperidinyl) ] benzyl,

4- [ (2' -trifluoromethylphenyl) C (O) NH- ] benzyl,

4- [ (2' -methylphenyl) C (O) NH- ] benzyl,

4-[(CH₃)₂NS(O)₂O-]Benzyl group,

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) -C (O) NH- ] benzyl,

4- [ (morpholin-4' -yl) C (O) O- ] benzyl,

3-nitro-4- (CH)₃OC(O)CH₂O-) benzyl group,

(2-benzoxazolinon-6-yl) methyl-,

(2H-1, 4-benzoxazin-3 (4H) -on-7-yl) methyl-, (4H-methyl-phenyl),

4-[(CH₃)₂NS(O)₂NH-]Benzyl group,

4-[(CH₃)₂NS(O)₂N(CH₃)-]Benzyl group,

4- [ (thiomorpholin-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 '-methylsulfonylpiperazin-1' -yl) -benzyl,

3-nitro-4- [ (morpholin-4' -yl) -C (O) O- ] benzyl,

4-{[(CH₃)₂NC(S)]₂N- } benzyl,

N-Boc-2-aminoethyl-,

4- [ (1, 1-dioxothiomorpholin-4-yl) -C (O) O- ] benzyl,

4-[(CH₃)₂NS(O)₂-]Benzyl group,

4- (imidazolidin-2 '-one-1' -yl) benzyl,

4- [ (piperidin-1' -yl) C (O) O- ] benzyl,

1-N-benzyl-imidazol-4-yl-CH₂-、

3, 4-ethylenedioxybenzyl group,

3, 4-dioxymethylene benzyl,

4-[-N(SO₂)(CH₃)CH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4- (3 ' -formylimidazolidin-2 ' -one-1 ' -yl) benzyl,

4-[NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]Benzyl group,

p-[(CH₃)₂NCH₂CH₂N(CH₃)C(O)O-]a benzyl group.

13. The compound of claim 2, wherein R⁶Selected from the group consisting of 2, 4-dioxotetrahydrofuran-3-yl (3, 4-enol), methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopentyloxy, neopentyloxy, 2- α -isopropyl-4- β -methylcyclohexyloxy, 2- β -isopropyl-4- β -methylcyclohexyloxy, -NH₂Benzyloxy, -NHCH₂COOH、-NHCH₂CH₂COOH, -NH-adamantyl, -NHCH₂CH₂COOCH₂CH₃、-NHSO₂-p-CH₃-φ、-NHOR⁸Wherein R is⁸Is hydrogen, methyl, isopropyl or benzyl, O- (N-succinimidyl), -O-cholest-5-en-3-beta-yl, -OCH₂-OC(O)C(CH₃)₃、-O(CH₂)_zNHC (O) W wherein z is 1 or 2, W is selected from pyridin-3-yl, N-methylpyridinyl and N-methyl-1, 4-dihydro-pyridin-3-yl, -NR 'C (O) -R', wherein R 'is aryl, heteroaryl or heterocycle, R' is hydrogen or-CH₂C(O)OCH₂CH₃。

14. The compound of claim 1 selected from:

n- [ N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl ] -L-phenylalanine

N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-L-phenylalanine

N- [ N- (toluene-4-sulfonyl) -L-prolyl ] -N-hydroxy-D-phenylalanine

N- [ [ N- (toluene-4-sulfonyl) pyrrolidin-2-yl ] aminocarbonyl ] -L-phenylalanine

And pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I:

wherein

R²selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and R¹And R²To the connection R²Nitrogen atom and SO₂The radicals together may formA heterocyclic or substituted heterocyclic group;

q is

R⁸selected from the group consisting of hydrogen, alkyl, and substituted alkyl; orR is⁷And R⁸And is attached to R⁷To the nitrogen atom and bound to R⁸The carbon atoms on which may together form a heterocyclic or substituted heterocyclic ring.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IA:

wherein

R⁴selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and when R is³Not with R²When a heterocyclic or substituted heterocyclic group is formed, then R³And R⁴Together with the carbon atoms to which they are attached may form cycloalkanesA group, a substituted cycloalkyl, a heterocycle, or a substituted heterocyclic group;

q is

17. The pharmaceutical composition of claim 15 or 16, wherein R¹Selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.

18. The pharmaceutical composition of claim 15 or 16, wherein R¹Selected from the group consisting of methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-tert-butylphenyl, 2, 4, 6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 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-tert-butoxyphenyl, 4- (3' -dimethylamino-n-propoxy) -phenyl, methyl, ethyl, propyl, isopropyl, 4-methylphenyl, 4-tert-butylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-dichlorophenyl, 3, 4, 2-carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4- (H)₂NC (O) -) phenyl, 4- (H₂NC (S) -) phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3, 5-bis- (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH)₃C (O) NH-phenyl, 4- (PhNHC (O) NH-) phenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- (CH)₃SC (═ NH) -) phenyl, 4-chloro-3- (H)₂NS(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-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, pyridin-3-yl, pyrimidin-2-yl, 1-dichloro-4-yl, 1-N-methyl-4-thienyl, 1-N-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-1, 3, 4-thiadiazol-2-yl.

19. The pharmaceutical composition of claim 15 or 16, wherein R²Selected from hydrogen, methyl, phenyl, benzyl, - (CH)₂)₂-2-thienyl and- (CH)₂)₂-φ。

20. The pharmaceutical composition of claim 15 or 16, wherein R²And R³And is attached to R²Nitrogen atom on substituent andis connected to R³The carbon atoms on the substituents together form a heterocyclic group or a substituted heterocyclic group.

21. The pharmaceutical composition of claim 20, wherein R²And R³And is attached to R²Nitrogen atom of substituent and bound to R³The carbon atoms on the substituents together form a substituted heterocyclic ring.

22. The pharmaceutical composition of claim 15 or 16, wherein R¹And R²And is attached to R²To the nitrogen atom and bound to R¹SO of₂The groups are joined together to form a heterocyclic or substituted heterocyclic ring.

23. The pharmaceutical composition of claim 15 or 16, wherein R³Selected from the group consisting of hydrogen, methyl, phenyl, benzyl, diphenylmethyl, 2-carboxyethyl, 2-amidoethyl, isobutyl, tert-butyl, carboxymethyl, -CH₂O-benzyl and hydroxymethyl.

24. The pharmaceutical composition of claim 15 or 16, wherein R⁴Selected from hydrogen, methyl, ethyl and phenyl.

25. The pharmaceutical composition of claim 15 or 16, wherein Q is selected from-CH₂NH-and tetrazole-1, 5-diyl.

26. The pharmaceutical composition of claim 15 or 16, wherein R⁵Selected from:

4-methylbenzyl group,

4-hydroxybenzyl,

4-methoxybenzyl,

4-tert-butoxybenzyl group,

4-benzyloxy-benzyl,

4-[φ-CH(CH₃)O-]Benzyl group,

4- [ phi-CH (COOH) O- ] benzyl,

4-[BocNHCH₂C(O)NH-]Benzyl group,

4-chlorobenzyl,

4-[NH₂CH₂C(O)NH-]Benzyl group,

4-carboxybenzyl group,

4-[CbzNHCH₂CH₂NH-]Benzyl group,

3-hydroxy-4- (phi-OC (O) NH-) benzyl,

4-[HOOCCH₂CH₂C(O)NH-]Benzyl group,

Benzyl group,

4- [ 2' -carboxyphenoxy- ] benzyl,

4- [ phi-C (O) NH- ] benzyl,

3-carboxybenzyl group,

4-iodobenzyl group,

4-hydroxy-3, 5-diiodobenzyl,

4-hydroxy-3-iodobenzyl,

4- [ 2' -carboxyphenyl- ] benzyl,

φ-CH₂CH₂-、

4-nitrobenzyl,

2-carboxybenzyl group,

4- [ dibenzylamino ] -benzyl,

4- [ (1 '-cyclopropylpiperidin-4' -yl) C (O) NH- ] benzyl,

4-[-NHC(O)CH₂NHBoc]Benzyl group,

4-carboxybenzyl group,

4-hydroxy-3-nitrobenzyl,

4-[-NHC(O)CH(CH₃)NHBoc]Benzyl group,

4-[-NHC(O)CH(CH₂φ)NHBoc]Benzyl group,

Isobutyl, and,

Methyl, methyl,

4-[CH₃C(O)NH-]Benzyl group,

-CH₂- (3-indolyl),

N-butyl,

tert-butyl-OC (O) CH₂-、

tert-butyl-OC (O) CH₂CH₂-、

H₂NC(O)CH₂-、

H₂NC(O)CH₂CH₂-、

BocNH-(CH₂)₄-、

tert-butyl-OC (O) - (CH)₂)₂-、

HOOCCH₂-、

HOOC(CH₂)₂-、

H₂N(CH₂)₄-、

An isopropyl group,

(1-naphthyl) -CH₂-、

(2-naphthyl) -CH₂-、

(2-thienyl) -CH₂-、

(φ-CH₂-OC(O)NH-(CH₂)₄-、

cyclohexyl-CH₂-、

benzyloxy-CH₂-、

HOCH₂-、

5- (3-N-benzyl) imidazolyl-CH₂-、

2-pyridyl-CH₂-、

3-pyridyl-CH₂-、

4-pyridyl-CH₂-、

5- (3-N-methyl) imidazolyl-CH₂-、

N-benzylpiperidin-4-yl-CH₂-、

N-Boc-piperidin-4-yl-CH₂-、

N- (phenyl-carbonyl) piperidin-4-yl-CH₂-、

H₃CSCH₂CH₂-、

1-N-benzylimidazol-4-yl-CH₂-、

isopropyl-C (O) NH- (CH)₂)₄-、

isobutyl-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) -CH₂-、

4-imidazolyl group,

4-[(CH₃)₂NCH₂CH₂CH₂-O-]Benzyl group,

4- [ (benzyl)₂N-]-benzyl group,

4-aminobenzyl group,

allyloxy-C (O) NH (CH)₂)₄-、

allyloxy-C (O) NH (CH)₂)₃-、

allyloxy-C (O) NH (CH)₂)₂-、

NH₂C(O)CH₂-、

φ-CH＝、

2-pyridyl-C (O) NH- (CH)₂)₄-、

4-methylpyridin-3-yl-C (O) NH- (CH)₂)₄-、

3-methylthiophen-2-yl-C (O) NH- (CH)₂)₄-、

2-pyrrolyl-C (O) NH- (CH)₂)₄-、

2-furyl-C (O) NH- (CH)₂)₄-、

4-methylphenyl-SO₂-N(CH₃)CH₂C(O)NH(CH₂)₄-、

4- [ cyclopentylethynyl ] -benzyl,

4- [ -NHC (O) - (N-Boc) -pyrrolidin-2-yl) ] -benzyl- ] -methyl- ]

1-N-methylimidazol-4-yl-CH₂-、

1-N-methylimidazol-5-yl-CH₂-、

imidazol-5-yl-CH₂-、

6-methylpyridin-3-yl-C (O) NH- (CH)₂)₄-、

4- [ 2' -carboxymethylphenyl ] -benzyl,

4-[-NHC(O)NHCH₂CH₂CH₂-φ]-benzyl group,

4-[-NHC(O)NHCH₂CH₂-φ]-benzyl group,

-CH₂C(O)NH(CH₂)₄φ、

4-[φ(CH₂)₄O-]-benzyl group,

4- [ -C.ident.C-phi-4' phi ] -benzyl,

4-[-C≡C-CH₂-O-S(O)₂-4′-CH₃-φ]-benzyl group,

4-[-C≡C-CH₂NHC(O)NH₂]-benzyl group,

4-[-C≡C-CH₂-O-4′-COOCH₂CH₃-φ]-benzyl group,

4-[-C≡C-CH(NH₂) -cyclohexyl radical]-benzyl group,

-(CH₂)₄NHC(O)CH₂-3-indolyl group,

-(CH₂)₄NHC(O)CH₂CH₂-3-indolyl group,

-(CH₂)₄NHC (O) -3- (5-methoxyindolyl),

-(CH₂)₄NHC (O) -3- (1-methylindolyl),

-(CH₂)₄NHC(O)-4-(-SO₂(CH₃)-φ)、

-(CH₂)₄NHC(O)-4-(C(O)CH₃) -phenyl group,

-(CH₂)₄NHC (O) -4-fluorophenyl,

-(CH₂)₄NHC(O)CH₂O-4-fluorophenyl,

4- [ -C.ident.C- (2-pyridyl) ] benzyl,

4-[-C≡C-CH₂-O-phenyl]Benzyl group,

4-[-C≡C-CH₂OCH₃]Benzyl group,

4- [ -C.ident.C- (3-hydroxyphenyl) ] benzyl,

4-[-C≡C-CH₂-O-4′-(-C(O)OC₂H₅) Phenyl radical]Benzyl group,

4-[-C≡C-CH₂CH(C(O)OCH₃)₂]Benzyl group,

4-[-C≡C-CH₂NH- (4, 5-dihydro-4-oxo-5-phenyl-oxazol-2-yl),

3-aminobenzyl group,

4-[-C≡C-CH₂CH(NHC(O)CH₃)C(O)OH]-benzyl group,

-CH₂C(O)NHCH(CH₃)φ、

-CH₂C(O)NHCH₂- (4-dimethylamino) -phi,

-CH₂C(O)NHCH₂-4-nitrophenyl,

-CH₂CH₂C(O)N(CH₃)CH₂-φ、

-CH₂CH₂C(O)NHCH₂CH₂- (N-methyl) -2-pyrrolyl,

-CH₂CH₂C(O)NHCH₂CH₂CH₂CH₃、

-CH₂CH₂C(O)NHCH₂CH₂-3-indolyl group,

-CH₂C(O)N(CH₃)CH₂Phenyl, phenyl,

-CH₂C(O)NH(CH₂)₂- (N-methyl) -2-pyrrolyl,

-CH₂C(O)NHCH₂CH₂CH₂CH₃、

-CH₂C(O)NHCH₂CH₂-3-indolyl group,

-(CH₂)₂C(O)NHCH(CH₃)φ、

-(CH₂)₂C(O)NHCH₂-4-dimethylaminophenyl group,

-(CH₂)₂C(O)NHCH₂-4-nitrophenyl,

-CH₂C(O)NH-4-[-NHC(O)CH₃-phenyl radical]、

-CH₂C (O) NH-4-pyridyl,

-CH₂C (O) NH-4- [ dimethylaminophenyl group]、

-CH₂C (O) NH-3-methoxyphenyl,

-CH₂CH₂C (O) NH-4-chlorophenyl,

-CH₂CH₂C (O) NH-2-pyridyl,

-CH₂CH₂C (O) NH-4-methoxyphenyl,

-CH₂CH₂C (O) NH-3-pyridyl,

4-[(CH₃)₂NCH₂CH₂O-]Benzyl group,

-(CH₂)₃NHC(NH)NH-SO₂-4-methylphenyl,

4-[(CH₃)₂NCH₂CH₂O-]Benzyl group,

-(CH₂)₄NHC(O)NHCH₂CH₃、

-(CH₂)₄NHC (O) NH-phenyl,

-(CH₂)₄NHC (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)CH₂NHC (O) NH-3' -methylphenyl]Benzyl group,

4- [ -NHC (O) - (2 ', 3' -indolin-2-yl) ] benzyl,

4- [ -NHC (O) - (2 ', 3' -dihydro-N-Boc-indol-2-yl) ] benzyl,

p-[-OCH₂CH₂-1 '- (4' -pyrimidinyl) -piperazinyl]Benzyl group,

4-[-OCH₂CH₂- (1' -piperidinyl)]Benzyl group,

4-[-OCH₂CH₂- (1' -pyrrolidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂- (1' -piperidinyl)]Benzyl-),

-CH₂-3- (1, 2, 4-triazolyl)

4-[-OCH₂CH₂CH₂-4- (3' -chlorophenyl) -piperazin-1-yl]Benzyl group,

4-[-OCH₂CH₂N(φ)CH₂CH₃]Benzyl group,

4-[-OCH₂-3' - (N-Boc) -piperidinyl]Benzyl group,

4- [ di-n-pentylamino ] benzyl,

4- [ n-pentylamino ] benzyl,

4- [ di-isopropylamino-CH₂CH₂O-]Benzyl group,

4-[-OCH₂CH₂- (N-morpholinyl)]Benzyl group,

4- [ -O- (3' - (N-Boc) -piperidinyl ] benzyl,

4-[-OCH₂CH(NHBoc)CH₂Cyclohexyl radical]Benzyl group,

p-[OCH₂CH₂- (N-piperidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂- (4-m-chlorophenyl) -piperazin-1-yl]Benzyl group,

4-[-OCH₂CH₂- (N-homopiperidinyl)]Benzyl group,

4- [ -NHC (O) -3' - (N-Boc) -piperidinyl ] benzyl,

4-[-OCH₂CH₂N- (benzyl)₂]Benzyl group,

-CH₂-2-thiazolyl,

3-hydroxybenzyl,

4-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4-[-NHC(S)NHCH₂CH₂- (N-morpholino)]Benzyl group,

4-[-OCH₂CH₂N(C₂H₅)₂]Benzyl group,

4-[-OCH₂CH₂CH₂N(C₂H₅)₂]Benzyl group,

4-[CH₃(CH₂)₄NH-]Benzyl group,

4- [ N-N-butyl, N-N-pentylamino- ] benzyl,

4- [ -NHC (O) -4' -piperidinyl ] benzyl,

4-[-NHC(O)CH(NHBoc)(CH₂)₄NHCbz]Benzyl group,

p-[-OCH₂CH₂CH₂-1 '- (4' -methyl) -piperazinyl]Benzyl group,

-(CH₂)₄NH-Boc、

3-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4-[-OCH₂CH₂CH₂N(CH₃)₂]Benzyl group,

3-[-OCH₂CH₂- (1' -pyrrolidinyl)]Benzyl group,

4-[-OCH₂CH₂CH₂N(CH₃) Benzyl radical]Benzyl group,

4-[-NHC(S)NHCH₂CH₂CH₂- (N-morpholino)]Benzyl group,

4-[-OCH₂CH₂- (N-morpholino)]Benzyl group,

4-[-NHCH₂- (4' -chlorophenyl)]Benzyl group,

4- [ -NHC (O) NH- (4' -cyanophenyl) ] benzyl,

4-[-OCH₂COOH]Benzyl group,

4-[-OCH₂COO-tert-butyl]Benzyl group,

4- [ -NHC (O) -5' -fluoroindol-2-yl ] benzyl,

4-[-NHC(S)NH(CH₂)₂-1-piperidinyl group]Benzyl group,

4-[-N(SO₂CH₃)(CH₂)₃-N(CH₃)₂]Benzyl group,

4-[-NHC(O)CH₂CH(C(O)OCH₂φ)-NHCbz]Benzyl group,

4-[-NHS(O)₂CF₃]Benzyl group,

3- [ -O- (N-methylpiperidin-4' -yl) ] benzyl,

4-[-C(＝NH)NH₂]Benzyl group,

4-[-NHSO₂-CH₂Cl]Benzyl group,

4- [ -NHC (O) - (1 ', 2 ', 3 ', 4 ' -tetrahydroisoquinolin-2 ' -yl ] benzyl,

4-[-NHC(S)NH(CH₂)₃-N-morpholino]Benzyl group,

4-[-NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]Benzyl group,

4-[-C(O)NH₂]Benzyl group,

4- [ -NHC (O) NH-3' -methoxyphenyl ] benzyl,

4-[-OCH₂CH₂-indoleIndole-3' -yl]Benzyl group,

4-[-OCH₂C (O) NH-benzyl]Benzyl group,

4-[-OCH₂C (O) O-benzyl]Benzyl group,

4-[-OCH₂C(O)OH]Benzyl group,

4-[-OCH₂-2 ' - (4 ', 5 ' -dihydro) imidazolyl]Benzyl group,

-CH₂C(O)NHCH₂- (4-dimethylamino) phenyl,

4-[-NHC(O)NHCH₂CH₂CH₃]Benzyl group,

4-aminobenzyl group,

4- [ -O- (N-methylpiperidin-4' -yl) ] benzyl,

3-methoxybenzyl,

4- [ -NHC (O) -piperidin-3' -yl ] benzyl,

4- [ -NHC (O) -pyridin-2' -yl ] benzyl,

4-[-NHCH₂- (4' -chlorophenyl)]Benzyl group,

4-[-NHC(O)-(N-(4′-CH₃-φ-SO₂) -L-pyrrolidin-2' -yl)]Benzyl group,

4-[-NHC(O)NHCH₂CH₂-φ]Benzyl group,

4-[-OCH₂C(O)NH₂]Benzyl group,

4-[-OCH₂C (O) NH-tert-butyl]Benzyl group,

4-[-OCH₂CH₂-1- (4-hydroxy-4-phenyl) -piperidinyl]Benzyl group,

4-[-NHSO₂-CH＝CH₂]Benzyl group,

4-[-NHSO₂-CH₂CH₂Cl]Benzyl group,

-CH₂C(O)NHCH₂CH₂N(CH₃)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′-(CH₃)₂NC (O) O-) phenyl) -C (O) NH-]Benzyl group,

4- [ -NHC (O) -1 '-methylpiperidin-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) CCH₂-O-benzyl) -NH-]Benzyl group,

[BocNHCH₂C(O)NH-]Butyl, isobutyl, or isobutyl,

4-benzyl group,

2-hydroxyethyl group,

4-[(Et)₂NCH₂CH₂CH₂NHC(S)NH-]Benzyl group,

4- [ (1 ' -Boc-4 ' -hydroxypyrrolidin-2 ' -yl) C (O) NH- ] benzyl,

4-[φCH₂CH₂CH₂NHC(S)NH-]Benzyl group,

4- [ (perhydroindol-2' -yl) C (O) NH- ] benzyl,

2- [ 4-hydroxy-4- (3-methoxythien-2-yl) piperidin-1-yl ] ethyl,

4- [ (1 '-Boc-perhydroindol-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- (φ NHC (S) NH) benzyl,

4- (EtNHC (S) NH) benzyl,

4-(φCH₂NHC (S) NH) benzyl,

3- [ (1 '-Boc-piperidin-2' -yl) C (O) NH- ] benzyl,

3- [ piperidin-2' -yl-C (O) NH- ] benzyl,

4- [ (3 '-Boc-thiazolidin-4' -yl) C (O) NH- ] benzyl,

4- (pyridin-3' -yl-NHC (S) NH) benzyl,

4-(CH₃-NHC (S) NH) benzyl,

4-(H₂NCH₂CH₂CH₂C (O) NH) benzyl,

4-(BocHNCH₂CH₂CH₂C (O) NH) benzyl,

4- (pyridin-4' -yl-CH₂NH) benzyl group,

4- [ (N, N-bis (4-N, N-dimethylamino) benzyl) amino ] benzyl,

4- [ (1-Cbz-piperidin-4-yl) C (O) NH- ] butyl,

4-[φCH₂OCH₂(BocHN)CHC(O)NH]Benzyl group,

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-[CH₃NHCH₂CH₂CH₂C(O)NH-]Benzyl group,

4-[CH₃N(Boc)CH₂CH₂CH₂C(O)NH-]Benzyl group,

4- (aminomethyl) benzyl,

4-[φCH₂OCH₂(H₂N)CHC(O)NH]Benzyl group,

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 '-indolin-2' -yl) -C (O) NH ] benzyl,

4- (pyridin-3' -yl-CH₂NH) benzyl group,

4- [ (1 '-Cbz-piperidin-4' -yl) C (O) NH- ] benzyl,

4- [ (piperidin-1' -yl) C (O) CH₂-O-]Benzyl group,

4-[(CH₃)₂CH)₂NC(O)CH₂-O-]Benzyl group,

4-[HO(O)C(Cbz-NH)CHCH₂CH₂-C(O)NH-]Benzyl group,

4-[φCH₂O(O)C(Cbz-NH)CHCH₂CH₂-C(O)NH-]Benzyl group,

4- [ -NHC (O) -2' -methoxyphenyl ] benzyl,

4- [ (pyrazin-2' -yl) C (O) NH- ] benzyl,

4-[HO(O)C(NH₂)CHCH₂CH₂-C(O)NH-]Benzyl group,

N-Cbz-NHCH₂-、

4- [ (4 '-methylpiperazin-1' -yl) C (O) O- ] benzyl,

4-[CH₃(N-Boc)NCH₂C(O)NH-]Benzyl group,

4-[CH₃NHCH₂C(O)NH-]Benzyl group,

(CH₃)₂NC(O)CH₂-、

4- (N-methylacetamido) benzyl,

4- (1 ', 2 ', 3 ', 4 ' -tetrahydroisoquinolin-3 ' -yl-CH₂NH-) benzyl group,

4-[(CH₃)₂NHCH₂C(O)NH-]Benzyl group,

(1-tosylimidazol-4-yl) methyl,

4- [ (1 '-Boc-piperidin-4' -yl) C (O) NH- ] benzyl,

4-trifluoromethyl benzyl,

4- [ (2' -bromophenyl) C (O) NH- ] benzyl,

4-[(CH₃)₂NC(O)NH-]Benzyl group,

4-[CH₃OC(O)NH-]Benzyl group,

4-[(CH₃)₂NC(O)O-]Benzyl group,

4-[(CH₃)₂NC(O)N(CH₃)-]Benzyl group,

4-[CH₃OC(O)N(CH₃)-]Benzyl group,

4- (N-methyl trifluoroacetylamino) 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-[(CH₃)₂NC(O)O-]Benzyl group,

4- [ (4 ' -phenyl-1 ' -Boc-piperidin-4 ' -yl) -C (O) O- ] benzyl,

4- (N-toluenesulfonylamino) benzyl,

4-[(CH₃)₃CC(O)NH-]Benzyl group,

4- [ (morpholin-4' -yl) C (O) NH- ] benzyl,

4-[(CH₃CH₂)₂NC(O)NH-]Benzyl group,

4- [ -C (O) NH- (4' -piperidinyl) ] benzyl,

4- [ (2' -trifluoromethylphenyl) C (O) NH- ] benzyl,

4- [ (2' -methylphenyl) C (O) NH- ] benzyl,

4-[(CH₃)₂NS(O)₂O-]Benzyl group,

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) -C (O) NH- ] benzyl,

4- [ (morpholin-4' -yl) C (O) O- ] benzyl,

3-nitro-4- (CH)₃OC(O)CH₂O-) benzyl group,

(2-benzoxazolinon-6-yl) methyl-,

(2H-1, 4-benzoxazin-3 (4H) -on-7-yl) methyl-, (4H-methyl-phenyl),

4-[(CH₃)₂NS(O)₂NH-]Benzyl group,

4-[(CH₃)₂NS(O)₂N(CH₃)-]Benzyl group,

4- [ (thiomorpholin-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 '-methylsulfonylpiperazin-1' -yl) -benzyl,

3-nitro-4- [ (morpholin-4' -yl) -C (O) O- ] benzyl,

4-{[(CH₃)₂NC(S)]₂N- } benzyl,

N-Boc-2-aminoethyl-,

4- [ (1, 1-dioxothiomorpholin-4-yl) -C (O) O- ] benzyl,

4-[(CH₃)₂NS(O)₂-]Benzyl group,

4- (imidazolidin-2 '-one-1' -yl) benzyl,

4- [ (piperidin-1' -yl) C (O) O- ] benzyl,

1-N-benzyl-imidazol-4-yl-CH₂-、

3, 4-ethylenedioxybenzyl group,

3, 4-dioxymethylene benzyl,

4-[-N(SO₂)(CH₃)CH₂CH₂CH₂N(CH₃)₂]Benzyl group,

4- (3 ' -formylimidazolidin-2 ' -one-1 ' -yl) benzyl,

4-[NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]Benzyl group,

p-[(CH₃)₂NCH₂CH₂N(CH₃)C(O)O-]a benzyl group.

27. The pharmaceutical composition of claim 16, wherein R⁶Selected from the group consisting of 2, 4-dioxotetrahydrofuran-3-yl (3, 4-enol), methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopentyloxy, neopentyloxy, 2- α -isopropyl-4- β -methylcyclohexyloxy, 2- β -isopropyl-4- β -methylcyclohexyloxy, -NH₂Benzyloxy, -NHCH₂COOH、-NHCH₂CH₂COOH, -NH-adamantyl, -NHCH₂CH₂COOCH₂CH₃、-NHSO₂-p-CH₃-φ、-NHOR⁸Wherein R is⁸Is hydrogen, methyl, isopropyl or benzyl, O- (N-succinimidyl), -O-cholest-5-en-3-beta-yl, -OCH₂-OC(O)C(CH₃)₃、-O(CH₂)_zNHC (O) W wherein z is 1 or 2, W is selected from pyridin-3-yl, N-methylpyridinyl and N-methyl-1, 4-dihydro-pyridin-3-yl, -NR 'C (O) -R', wherein R 'is aryl, heteroaryl or heterocycle, R' is hydrogen or-CH₂C(O)OCH₂CH₃。

28. A method for binding VLA-4 in a biological sample, which method comprises contacting the biological sample with a compound of claim 1 or 2 under conditions wherein the compound binds to VLA-4.

29. Use of a compound of claim 1 or 2 for the manufacture of a medicament for treating an inflammation mediated by VLA-4 in a mammalian patient.

30. The use of claim 29, wherein said inflammation is selected from the group consisting of asthma, alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury.