JP2001512134A - Substituted phenylalanine-type compounds that inhibit VLA-4-mediated leukocyte adhesion - Google Patents

Abstract

  (57) [Summary] Disclosed are compounds that bind VLA-4. It is also believed that these compounds inhibit leukocyte adhesion, particularly VLA-4 mediated leukocyte adhesion. The compounds are useful in mammalian patients, e.g., humans, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory super-diseases, rheumatoid arthritis, tissue transplants, metastatic tumors and myocardial ischemia. It is useful in treating inflammatory diseases. The compounds are also administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

This application is related to US patent application Ser. No. 08/920, filed Jul. 31, 1997.
U.S. Provisional Patent Application Ser. Claim the benefit of the issue.

[0002] The present invention relates to compounds that inhibit leukocyte adhesion, particularly VLA-4 mediated leukocyte adhesion.

[0003]

[Prior art]

 REFERENCES The following publications, patents and patent applications are referenced in this application by superscript numbers.
To use. 1 Hemler and Takada, European Patent Application Publication No. 330,506, published August 30, 1998 2 Elices et al., Cell,60: 577-584 (1990) 3 Springer, Nature,346: 425-434 (1990) 4 Osborn, Cell,62: 3-6 (1990) 5 Vedder et al., Surgery,106: 509 (1989) 6 Pretolani et al. Exp. Med. ,180: 795 (1994) 7 Abraham et al. Clin. Invest. ,93: 776 (1 994) 8 Mulligan et al. Immunology,150: 2407 (1993) 9 Cybulsky et al., Science,251: 788 (1991) 10 Li et al., Artioslcer. Thromb. ,13197 (
1993) 11 Sasseville et al., Am. J. Path. ,144: 27 (19
94) 12 Yang et al., Proc. Nat. Acad. Science (USA), 90 : 10494 (1993) 13 Burkly et al., Diabetes,43: 529 (1994) 14 Baron et al. Clin. Invest. ,93: 1700 (19
94) 15 Hamann et al. Immunology,152: 3238 (19
94) 16 Yednock et al., Nature,356: 63 (1992) 17 Baron et al. Exp. Med. ,177: 57 (1993) 18 van Dinther-Janssen et al. Immunology
,147: 4207 (1991) 19 van Dinther-Janssen et al., Annals. Rheum
atic Dis. ,52: 672 (1993) 20 Elices et al. Clin. Invest. ,93: 405 (19
94) 21 Postigo et al. Clin. Invest. ,89: 1445 (
1991) 22 Paul et al., Transpl. Proceed. ,25: 813 (19
93) 23 Okarhara et al., Can. Res. ,54: 3233 (1994) 24 Paavonen et al. Int. J. Can. ,58: 298 (1994
) 25 Schadendorf et al. Path. ,170: 429 (199
3) 26 Bao et al., Diff. ,52: 239 (1993) 27 Lauri et al. Cancer,68: 862 (1
993) 28 Kawaguchi et al., Japanese J. Org. Cancer Res.
,831304 (1992) 29 Kogan et al., US Pat. No. 5,510,332, Apr. 23, 1996.
Issue 30 International Application Publication No. WO 96/01644 All of the above known documents, patents and patent applications
It is specifically and individually indicated that the permit application is incorporated by reference in its entirety
If so, the entire same range is hereby incorporated by reference.

Description of the Prior Art VLA-4 (also called α4β1 integrin and CD49d / CD29), first identified by Hemler and Takada ¹ , is a member of the β1 integrin family of cell surface receptors, each of which is It contains two subunits, an α-chain and a β-chain. VLA-4 contains an α4 chain and a β1 chain. There are at least nine β1 integrins, all of which have the same β1 in common, each with a different α-chain. All nine of these receptors bind to different elements of various cell matrix molecules, such as fibronectin, laminin, collagen, and the like. For example, VLA-4 binds fibronectin. VLA-4 also binds to non-matrix molecules expressed on endothelial cells and other cells. This non-matrix molecule includes VCAM-1 expressed on cytokinin-activated human umbilical vein endothelial cells in culture. VAL-
Four different epitopes have been shown to be involved in fibronectin and VCAM-1 binding activity, each of which is independently inhibited. ^Two

[0005] Cell-cell adhesion mediated by VLA-4 and other cell surface receptors occurs in connection with many inflammatory reactions. At the site of injury or other inflammatory stimuli, activated vascular endothelial cells express leukocyte adherent molecules. Part of the mechanism by which leukocytes attach to endothelial cells involves that cell surface receptors on leukocytes recognize and attach to corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes pass through the vessel wall into the site of injury and release chemical mediators to fight infection. See Springer ³ and Osborn ⁴ for a description of adhesion receptors in the immune system.

[0006] Inflammatory encephalopathies such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (
MS), and meningitis are examples of central nervous system disorders in which the endothelial / leukocyte attachment mechanism has caused the destruction of healthy brain tissue. Many leukocytes undergo these inflammatory disorders and cross the blood-brain barrier (BBB). Leukocytes release toxic transmitters that cause extensive tissue damage and impair neurotransmission and paralysis.

[0007] In other organ systems, tissue damage also occurs through attachment mechanisms that cause leukocyte migration or activation. For example, the initial stroke following myocardial ischemia on heart tissue can be further complicated by the influx of leukocytes to the site of injury, causing further stroke (Vedder et al. ⁵ ). Other inflammatory conditions caused by adhesion mechanisms include, by way of example, asthma ^6-8 , Alzheimer's disease, atherosclerosis ^9-10 , AIDS dementia ¹¹ , diabetes ^12-14 (including acute juvenile onset diabetes), Inflammatory bowel disease ¹⁵ (including ulcerative colitis and Crohn's disease), multiple sclerosis ^16-17 , rheumatoid arthritis ^18-21 , tissue transplantation ²² , tumor metastasis ^23-28 , meningitis, encephalitis, seizures, And acute leukocyte-mediated lung injury that occurs in cerebral injuries, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and adult respiratory distress syndrome and the like.

[0008]

[Problems to be solved by the invention]

In view of the above, for example, to diagnose VLA-4 mediated conditions, VLA-
Evaluation assays that measure the level of VLA-4 in biological samples containing No. 4 may be useful. Furthermore, despite the increasing understanding of leukocyte adhesion,
The technical effort to use inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions ^{29 and 30} came to be performed is from recently. The present invention addresses these and other needs.

[0009]

[Means for Solving the Problems]

DISCLOSURE OF THE INVENTION The present invention provides compounds that bind to VLA-4. Such compounds can be used, for example, to determine if VLA-4 is present in a sample, or in pharmaceutical compositions, for VLA-4 mediated cell adhesion, eg, VLA-4 of VCAM-1.
Can be used to inhibit binding to The compound of the present invention has a binding affinity for VLA-4 represented as IC ₅₀ of about 15 μM or less (Exemplified Compound 13 described below).
6) and is defined by the following equation:

Embedded image [Where R ¹ Is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, hetero
R is selected from the group consisting of aryl and substituted heteroaryl; ^Two Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted
Cyclic, aryl, substituted aryl, heteroaryl, and substituted hetero
R is selected from the group consisting of aryl ¹ And R ^Two Is R ^Two Nitrogen atom and R ¹ SO bound to _Two A heterocyclic or substituted heterocyclic group with the group; ^Three Is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl.
Selected from the group consisting of ^Two Is R ¹ And Hete
When no ring group is formed, R ^Two And R ^Three And R ^Two Nitrogen atom and R ^Three Tied to
A heterocyclic or substituted heterocyclic group with the combined carbon atoms; ^Five Is-(CH _Two ) _x -Ar-R ^Five' And R ^Five' Is selected from the group consisting of the following (a) to (u): (a) a substituted alkylcarbonylamino (provided that at least
Another substituent is alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, alkenyl, amino, amidino, alkylamido
Dino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocar
Bonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy
, Cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxy-substituted heterocyclic, cycloal
Killed, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thio
Alkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloa
Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl
Thioheterocyclic, substituted thioheterocyclic, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O) _Two -Alkyl, -OS (O) _Two -Substituted alkyl, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O) _Two -Heteroaryl,
-OS (O) _Two -Substituted heteroaryl, -OS (O) _Two -Heterocyclic,-
OS (O) _Two -Substituted heterocyclic, -OSO _Two -NRR (where R is hydrogen or
Or alkyl), -NRS (O) _Two -Alkyl, -NRS (O) _Two -Substituted alkyl
, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O
) _Two -Heteroaryl, -NRS (O) _Two -Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substituted heterocyclic, -NRS
(O) _Two -NR-alkyl, -NRS (O) _Two -NR-substituted alkyl, -NRS (
O) _Two -NR-aryl, -NRS (O) _Two -NR-substituted aryl, -NRS (O
) _Two -NR-heteroaryl, -NRS (O) _Two -NR-substituted heteroaryl,-
NRS (O) _Two -NR-heterocyclic, -NRS (O) _Two -NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, and
And an asymmetric di-substituted amine, wherein the alkyl, substituted alkyl, aryl, substituted
Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitution
Asymmetric di-substituents having different substituents selected from the group consisting of substituted heterocyclics and amino groups protected by common protecting groups such as Boc, Cbz, formyl,
-Substituted amine) or -SO _Two -Alkyl, -SO _Two −substitution
Alkyl, -SO _Two -Alkenyl, -SO _Two -Substituted alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, -SO _Two -Heterocyclic, -SO _Two -Substituted heterocyclic, and -SO _Two NR
Alkyl / substituted alkyl substituted by R (where R is hydrogen or alkyl)
(B) carboxyl and COOR (R is an alkyl group)
, Substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetero
Alkoxy) substituted with a substituent selected from the group consisting of
(C) aryl and heteroaryl; (d) —NR′R ′ (wherein, R ′ is each independently an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloaryl
Alkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic
(Where at least one R ′ is a substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic).
When R ′ is cyclic alkyl and R ′ is substituted alkyl, at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O) _Two -Alkyl, -OS (O) _Two -Substitution
Lucil, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O
) _Two -Heteroaryl, -OS (O) _Two -Substituted heteroaryl, -OS (O) _Two -Heterocyclic, -OS (O) _Two -Substituted heterocyclic, -OSO _Two -N
RR (where R is hydrogen or alkyl), -NRS (O) _Two -Alkyl, -NR S (O) _Two -Substituted alkyl, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O) _Two -Substituted hetero
Aryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substitution
Cyclic, -NRS (O) _Two -NR-alkyl, -NRS (O) _Two -NR-
Substituted alkyl, -NRS (O) _Two -NR-aryl, -NRS (O) _Two -NR-
Substituted aryl, -NRS (O) _Two -NR-heteroaryl, -NRS (O) _Two -NR
-Substituted heteroaryl, -NRS (O) _Two -NR-heterocyclic, -NR S (O) _Two -NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.) or -S
O _Two -Alkyl, -SO _Two -Substituted alkyl, -SO _Two -Alkenyl, -SO _Two −substitution
Alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two −
Substituted heteroaryl, -SO _Two -Heterocyclic, -SO _Two -Substitution heterocycle
Rick, and -SO _Two (E) -alkoxy-NR "R", wherein R "is independently alkyl, Substitution
Alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete
Aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
Selected from the group consisting of clicks (provided that each R ″ is a substituted alkyl
Wherein at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
Si, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl,
Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl
Sil-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl ant
, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxy
-Substituted heteroaryl, carboxyl heterocyclic, carboxy-substituted
Heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, gua
Nidino sulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl,
Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohetero
Aryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohetero
Cyclic, heterocyclic, substituted heterocyclic, cycloalkoxy
Si, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy
, Heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl
Mino, oxythiocarbonylamino, -OS (O) _Two -Alkyl, -OS (O) _Two -Substituted alkyl, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl,-
OS (O) _Two -Heteroaryl, -OS (O) _Two -Substituted heteroaryl, -OS (
O) _Two -Heterocyclic, -OS (O) _Two -Substituted heterocyclic, -OS
O _Two -NRR (where R is hydrogen or alkyl), -NRS (O) _Two -Alkyl,
-NRS (O) _Two -Substituted alkyl, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O) _Two -Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two −
Heterocyclic, -NRS (O) _Two -NR-alkyl, -NRS (O) _Two −
NR-substituted alkyl, -NRS (O) _Two -NR-aryl, -NRS (O) _Two -N
R-substituted aryl, -NRS (O) _Two -NR-heteroaryl, -NRS (O) _Two -NR-substituted heteroaryl, -NRS (O) _Two -NR-heterocyclic, -NRS (O) _Two -NR-substituted heterocyclic (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 heteroaryls
Amino, mono- and di-heterocyclic amino, mono- and di-configuration
Substituted heterocyclic amino and unsymmetrical di-substituted amines,
, Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of
Selected from the group consisting of asymmetric di-substituted amines having different substituents and amino groups protected by conventional protecting groups such as Boc, Cbz, formyl, etc.)
Or -SO _Two -Alkyl, -SO _Two -Substituted alkyl, -SO _Two -Alkenyl, -SO _Two -Substituted alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, -SO _Two -Heterocyclic, -S
O _Two -Substituted heterocyclic, and -SO _Two NRR wherein R is hydrogen or
(F) substituted alkenyl or substituted alkynyl (provided that the substituted alkenyl / alkyl is
At least one substituent on the nyl moiety is alkyl, substituted alkyl, aryl,
Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Group consisting of teloaryl, heterocyclic, and substituted heterocyclic
But is substituted by a substituted alkyl,
At least one substituent on the moiety on the aryl is an alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O) _Two -Alkyl, -OS (O) _Two -Substitution
Lucil, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O
) _Two -Heteroaryl, -OS (O) _Two -Substituted heteroaryl, -OS (O) _Two -Heterocyclic, -OS (O) _Two -Substituted heterocyclic, -OSO _Two -N
RR (where R is hydrogen or alkyl), -NRS (O) _Two -Alkyl, -NR S (O) _Two -Substituted alkyl, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O) _Two -Substituted hetero
Aryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substitution
Cyclic, -NRS (O) _Two -NR-alkyl, -NRS (O) _Two -NR-
Substituted alkyl, -NRS (O) _Two -NR-aryl, -NRS (O) _Two -NR-
Substituted aryl, -NRS (O) _Two -NR-heteroaryl, -NRS (O) _Two -NR
-Substituted heteroaryl, -NRS (O) _Two -NR-heterocyclic, -NR S (O) _Two -NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
Is -SO _Two -Alkyl, -SO _Two -Substituted alkyl, -SO _Two -Alkenyl, -SO _Two -Substituted alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, -SO _Two -Heterocyclic, -SO _Two -Substitution heterocyclic, and -SO _Two An alkyl / substituted alkyl group substituted by NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided that substituted aryl
At least one substituent on the alkoxy / heteroaryloxy is halogen, arsenic
Droxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxy
Ethylene, alkoxy, alkeneoxy, alkyneoxy, alkylamino,
Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylua
Other than mino, N-alkyl or N, N-dialkylurea); (h) -alkoxy saturated heterocyclic, -alkoxy saturated substituted heterosa
Click, -substituted alkoxy-heterocyclic, and -substituted alkoxy
(I) -O-heterocyclic and -O-substituted heterocyclic; (j) tetrazolyl; (k) -NR-SO _Two -Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least the alkyl moiety of the substituted alkylsulfonylamino
Another substituent is halogen, hydroxyl, amino, nitro, trifluoromethyl.
Tyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-di
Oxymethylene, 1,2-dioxyethylene, alkoxy, alkeneoxy, a
Ruquinoxy, alkylamino, alkenylamino, alkynylamino, alk
Carbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonyl
Ruamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl
(L) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino,
(M) substituted alkoxy (provided that a substituent on the alkyl portion of the substituted alkoxy is not substituted with alkenylsulfonylamino and alkynylsulfonylamino)
Is alkoxy-NR''R '', unsaturated heterocyclyl, alkyloxy,
Oxy, heteroaryloxy, aryl, heteroaryl, and halo
Gen, hydroxyl, amino, nitro, trifluoromethyl, trifluorometh
Xy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2
-Dioxyethylene, alkoxy, alkeneoxy, alkyneoxy, alkyl
Amino, alkenylamino, alkynylamino, alkylcarbonyloxy,
Sil, alkylcarbonylamino, alkoxycarbonylamino, alkylsul
Substituted by honylamino, N-alkyl or N, N-dialkylurea
(N) amidines and amidines substituted with 1 to 3 substituents, wherein
Substituents are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
Independent of substituted alkynyl, aryl, heteroaryl and heterocyclic
(O) -C (O) NR "" R "", wherein R "" is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkenyl, substituted alk
Nil, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl
From substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of: Provided that one R ′ ″ is an unsaturated heterocyclylalkyl, aryl, heteroaryl, or halogen, hydroxyl, amino, nitro
B, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, al
Quinyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy,
Alkeneoxy, alkyneoxy, alkylamino, alkenylamino, alk
Nylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
Aryl / heteroaryl substituted by N, N-dialkylurea
In other cases, the other R ′ ″ is alkyl, substituted alkyl (other than unsaturated heterocyclyl-substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted
Alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted
(P) -NR ¹² C (O) -R ⁸ (Where R ⁸ Is alkyl, substituted alkyl, cyclo
Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group ¹² Is alkyl, substituted alkyl, aryl, substituted aryl,
Chloroalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, f
(Q) -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, or -SO _Two -Alkyl; (r) -NR'C (O) NR ⁹ R ⁹ (Wherein R ′ is alkyl, substituted alkyl, ant
, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Substituted heteroaryl, heterocyclic and substituted heterocyclic
Each R ⁹ Is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group): (s) -NR'C (O) OR ⁹ (Wherein R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group ⁹ Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of heterocyclic, heterocyclic and substituted heterocyclic.
(T) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O)
NH-substituted heterocyclyl; Ar is aryl, heteroaryl, substituted aryl, or substituted heteroaryl
X is an integer from 1 to 4; Q is -C (X) NR ⁷ Where R is ⁷ Is a group consisting of hydrogen and alkyl
X is selected from the group consisting of oxygen and sulfur)] and pharmaceutically acceptable salts thereof.

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

Embedded image [Where R ¹ Is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, hetero
R is selected from the group consisting of aryl and substituted heteroaryl; ^Two Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted
Cyclic, aryl, substituted aryl, heteroaryl, and substituted hetero
R is selected from the group consisting of aryl ¹ And R ^Two Is R ^Two Nitrogen atom and R ¹ SO bound to _Two Group together with a heterocyclic or substituted heterocyclic group.
And R ^Three Is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl.
Selected from the group consisting of ^Two Is R ¹ And Hete
When no ring group is formed, R ^Two And R ^Three And R ^Two Nitrogen atom and R ^Three Tied to
A heterocyclic or substituted heterocyclic group with the combined carbon atoms; ^Five Is-(CH _Two ) _x -Ar-R ^Five' And R ^Five' Is selected from the group consisting of: (a) a substituted alkylcarbonylamino (provided that at least
Another substituent is alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, alkenyl, amino, amidino, alkylamido
Dino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocar
Bonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy
, Cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxy-substituted heterocyclic, cycloal
Killed, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thio
Alkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloa
Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl
Thioheterocyclic, substituted thioheterocyclic, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O) _Two -Alkyl, -OS (O) _Two -Substituted alkyl, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O) _Two -Heteroaryl,
-OS (O) _Two -Substituted heteroaryl, -OS (O) _Two -Heterocyclic,-
OS (O) _Two -Substituted heterocyclic, -OSO _Two -NRR (where R is hydrogen or
Or alkyl), -NRS (O) _Two -Alkyl, -NRS (O) _Two -Substituted alkyl
, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O
) _Two -Heteroaryl, -NRS (O) _Two -Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substituted heterocyclic, -NRS
(O) _Two -NR-alkyl, -NRS (O) _Two -NR-substituted alkyl, -NRS (
O) _Two -NR-aryl, -NRS (O) _Two -NR-substituted aryl, -NRS (O
) _Two -NR-heteroaryl, -NRS (O) _Two -NR-substituted heteroaryl,-
NRS (O) _Two -NR-heterocyclic, -NRS (O) _Two -NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, and
And an asymmetric di-substituted amine, wherein the alkyl, substituted alkyl, aryl, substituted
Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitution
Asymmetric di-substituents having different substituents selected from the group consisting of substituted heterocyclics and amino groups protected by common protecting groups such as Boc, Cbz, formyl,
-Substituted amine) or -SO _Two -Alkyl, -SO _Two −substitution
Alkyl, -SO _Two -Alkenyl, -SO _Two -Substituted alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, -SO _Two -Heterocyclic, -SO _Two -Substituted heterocyclic, and -SO _Two NR
Alkyl / substituted alkyl substituted by R (where R is hydrogen or alkyl)
(B) carboxyl and COOR (R is an alkyl group)
, Substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetero
Alkoxy) substituted with a substituent selected from the group consisting of
(C) aryl and heteroaryl; (d) —NR′R ′ (wherein, R ′ is each independently an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloaryl
Alkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic
(Where at least one R ′ is a substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic).
When R ′ is cyclic alkyl and R ′ is substituted alkyl, at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O) _Two -Alkyl, -OS (O) _Two -Substitution
Lucil, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O
) _Two -Heteroaryl, -OS (O) _Two -Substituted heteroaryl, -OS (O) _Two -Heterocyclic, -OS (O) _Two -Substituted heterocyclic, -OSO _Two -N
RR (where R is hydrogen or alkyl), -NRS (O) _Two -Alkyl, -NR S (O) _Two -Substituted alkyl, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O) _Two -Substituted hetero
Aryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substitution
Cyclic, -NRS (O) _Two -NR-alkyl, -NRS (O) _Two -NR-
Substituted alkyl, -NRS (O) _Two -NR-aryl, -NRS (O) _Two -NR-
Substituted aryl, -NRS (O) _Two -NR-heteroaryl, -NRS (O) _Two -NR
-Substituted heteroaryl, -NRS (O) _Two -NR-heterocyclic, -NR S (O) _Two -NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.) or -S
O _Two -Alkyl, -SO _Two -Substituted alkyl, -SO _Two -Alkenyl, -SO _Two −substitution
Alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two −
Substituted heteroaryl, -SO _Two -Heterocyclic, -SO _Two -Substitution heterocycle
Rick, and -SO _Two (E) -alkoxy-NR "R", wherein R "is independently alkyl, Substitution
Alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete
Aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
Selected from the group consisting of clicks (provided that each R ″ is a substituted alkyl
Wherein at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
Si, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl,
Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl
Sil-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl ant
, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxy
-Substituted heteroaryl, carboxyl heterocyclic, carboxyl-position
Substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,
Anidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl
, Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohete
Loaryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohete
Cyclic, heterocyclic, substituted heterocyclic, cycloalco
Xy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy
Si, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl
Amino, oxythiocarbonylamino, -OS (O) _Two -Alkyl, -OS (O 2) _Two -Substituted alkyl, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O) _Two -Heteroaryl, -OS (O) _Two -Substituted heteroaryl, -O
S (O) _Two -Heterocyclic, -OS (O) _Two -Substituted heterocyclic,-
OSO _Two -NRR (where R is hydrogen or alkyl), -NRS (O) _Two -Archi
, -NRS (O) _Two -Substituted alkyl, -NRS (O) _Two -Aryl, -NRS (
O) _Two -Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O) _Two -Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substituted heterocyclic, -NRS (O) _Two —NR-alkyl, —NRS (O 2) _Two -NR-substituted alkyl, -NRS (O) _Two -NR-aryl, -NRS (O) _Two -NR-substituted aryl, -NRS (O) _Two -NR-heteroaryl, -NRS (
O) _Two -NR-substituted heteroaryl, -NRS (O) _Two -NR-heterocyclic
H, -NRS (O) _Two -NR-substituted heterocyclic (where R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di- (substituted alkyl
L) amino, mono- and di-arylamino, mono- and di-substituted aryl
Amino, mono- and di-heteroarylamino, mono- and di-substituted hetero
Arylamino, mono- and di-heterocyclic amino, mono- and di-
-Substituted heterocyclic amino and unsymmetrical di-substituted amines,
Alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted hetero
Selected from the group consisting of aryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of asymmetric di-substituted amines having different substituents selected and an amino group protected by a conventional protecting group such as Boc, Cbz, formyl and the like.
Or -SO _Two -Alkyl, -SO _Two -Substituted alkyl, -SO _Two -Alkenyl, -SO _Two -Substituted alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, -SO _Two -Heterocyclic,
-SO _Two -Substituted heterocyclic, and -SO _Two NRR wherein R is hydrogen or
Is an alkyl / substituted alkyl group substituted by alkyl); (f) substituted alkenyl or substituted alkynyl, provided that
At least one substituent on the nyl moiety is alkyl, substituted alkyl, aryl,
Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Group consisting of teloaryl, heterocyclic, and substituted heterocyclic
But is substituted by a substituted alkyl,
At least one substituent on the moiety on the aryl is an alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O) _Two -Alkyl, -OS (O) _Two -Substitution
Lucil, -OS (O) _Two -Aryl, -OS (O) _Two -Substituted aryl, -OS (O
) _Two -Heteroaryl, -OS (O) _Two -Substituted heteroaryl, -OS (O) _Two -Heterocyclic, -OS (O) _Two -Substituted heterocyclic, -OSO _Two -N
RR (where R is hydrogen or alkyl), -NRS (O) _Two -Alkyl, -NR S (O) _Two -Substituted alkyl, -NRS (O) _Two -Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O) _Two -Substituted hetero
Aryl, -NRS (O) _Two -Heterocyclic, -NRS (O) _Two -Substitution
Cyclic, -NRS (O) _Two -NR-alkyl, -NRS (O) _Two -NR-
Substituted alkyl, -NRS (O) _Two -NR-aryl, -NRS (O) _Two -NR-
Substituted aryl, -NRS (O) _Two -NR-heteroaryl, -NRS (O) _Two -NR
-Substituted heteroaryl, -NRS (O) _Two -NR-heterocyclic, -NR S (O) _Two -NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
Is -SO _Two -Alkyl, -SO _Two -Substituted alkyl, -SO _Two -Alkenyl, -SO _Two -Substituted alkenyl, -SO _Two -Cycloalkyl, -SO _Two -Substituted cycloalkyl, -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, -SO _Two -Heterocyclic, -SO _Two -Substitution heterocyclic, and -SO _Two An alkyl / substituted alkyl group substituted by NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided that substituted aryl
At least one substituent on the alkoxy / heteroaryloxy is halogen, arsenic
Droxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxy
Ethylene, alkoxy, alkeneoxy, alkyneoxy, alkylamino,
Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylua
Other than mino, N-alkyl or N, N-dialkylurea); (h) -alkoxy saturated heterocyclic, -alkoxy saturated substituted heterosa
Click, -substituted alkoxy-heterocyclic, and -substituted alkoxy
(I) -O-heterocyclic and -O-substituted heterocyclic; (j) tetrazolyl; (k) -NR-SO _Two -Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least the alkyl moiety of the substituted alkylsulfonylamino
Another substituent is halogen, hydroxyl, amino, nitro, trifluoromethyl.
Tyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-di
Oxymethylene, 1,2-dioxyethylene, alkoxy, alkeneoxy, a
Ruquinoxy, alkylamino, alkenylamino, alkynylamino, alk
Carbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonyl
Ruamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl
(L) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino,
(M) substituted alkoxy (provided that a substituent on the alkyl portion of the substituted alkoxy is not substituted with alkenylsulfonylamino and alkynylsulfonylamino)
Is alkoxy-NR''R '', unsaturated heterocyclyl, alkyloxy,
Oxy, heteroaryloxy, aryl, heteroaryl, and halo
Gen, hydroxyl, amino, nitro, trifluoromethyl, trifluorometh
Xy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2
-Dioxyethylene, alkoxy, alkeneoxy, alkyneoxy, alkyl
Amino, alkenylamino, alkynylamino, alkylcarbonyloxy,
Sil, alkylcarbonylamino, alkoxycarbonylamino, alkylsul
Substituted by honylamino, N-alkyl or N, N-dialkylurea
(N) amidines and amidines substituted with 1 to 3 substituents, wherein
Substituents are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
Independent of substituted alkynyl, aryl, heteroaryl and heterocyclic
(O) -C (O) NR "" R "", wherein R "" is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkenyl, substituted alk
Nil, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl
From substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of: Provided that one R ′ ″ is an unsaturated heterocyclylalkyl, aryl, heteroaryl, or halogen, hydroxyl, amino, nitro
B, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, al
Quinyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy,
Alkeneoxy, alkyneoxy, alkylamino, alkenylamino, alk
Nylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
Aryl / heteroaryl substituted by N, N-dialkylurea
In other cases, the other R ′ ″ is alkyl, substituted alkyl (other than unsaturated heterocyclyl-substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted
Alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted
(P) -NR ¹² C (O) -R ⁸ (Where R ⁸ Is alkyl, substituted alkyl, cyclo
Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group ¹² Is alkyl, substituted alkyl, aryl, substituted aryl,
Chloroalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, f
(Q) -SO _Two -Aryl, -SO _Two -Substituted aryl, -SO _Two -Heteroaryl, -SO _Two -Substituted heteroaryl, or -SO _Two -Alkyl; (r) -NR'C (O) NR ⁹ R ⁹ (Wherein R ′ is alkyl, substituted alkyl, ant
, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Substituted heteroaryl, heterocyclic and substituted heterocyclic
Each R ⁹ Is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group): (s) -NR'C (O) OR ⁹ (Wherein R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group ⁹ Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of heterocyclic, heterocyclic and substituted heterocyclic.
(T) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O)
NH-substituted heterocyclyl; Ar is aryl, heteroaryl, substituted aryl, or substituted heteroaryl
X is an integer from 1 to 4; R ⁶ Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloa
Lucoxy, -O- (N-succinimidyl), -NH-adamantyl, -O-co
Rest-5-en-3-β-yl, —NHOY (where Y is hydrogen, alkyl,
Substituted alkyl, aryl, and substituted aryl), -NH (CH _Two ) _p COOY (expression
Wherein p is an integer from 1 to 8 and Y is as defined above), -OCH _Two NR ⁹ R ^Ten (Where R ⁹ Is selected from the group consisting of -C (O) -aryl and -C (O) -substituted aryl; ^Ten Is hydrogen and -CH _Two COOR ¹¹ (Where R ¹¹ Is selected from the group consisting of alkyl)), and -NHSO _Two Z (where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl)
, Heteroaryl, substituted heteroaryl, heterocyclic and substituted
Q is -C (X) NR ⁷ -(Where R ⁷ Is selected from the group consisting of hydrogen and alkyl
X is selected from the group consisting of oxygen and sulfur) and pharmaceutically acceptable salts thereof, provided that R ¹ Is p-CH _Three -Φ-, R ⁶ Is methoxy, Q is -C (O) NH-, and R is ^Two And R ^Three Is bonded to form a pyrrolidinyl group
If formed, R ^Five Is p-[-OCH _Two CH _Two N (C _Two H _Five ) _Two ] -Benzyl-,
p-[-OCH _Two CH _Two N (isopropyl) _Two ] -Benzyl-, p-[-OCH _Two C
H _Two -1-pyrrolidinyl] -benzyl-, p-[-OCH _Two CH _Two -1- (4-pyrrolidinyl) piperazinyl] -benzyl-, p-[-OCH _Two CH _Two -N-morpho
Linyl] -benzyl- or p-[-OCH _Two CH _Two -N-piperidinyl] -b
On condition that it is not an enzyme).

Preferably, in the compounds of formulas I and IA above, R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl. You. More preferably, R ¹ is 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2- (Methoxycarbonyl) phenyl,
2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (C
H ₃ C (O) NH-) phenyl, 4-trifluoromethoxyphenyl, 4-shear Nofeniru, isopropyl, 3,5-di - (trifluoromethyl) phenyl, 4
-T-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-
Thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-bromophenyl
Amidinophenyl, _{4-methyl-amidinophenyl, 4- [CH 3 SC (=} NH)] phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1
-N- methyl-4-pyrazolyl, 2-thiazolyl, _{5-methyl-1,3,4-thiadiazol-2-yl, 4- [H 2 NC (S} )] phenyl, 4-Aminofeni Le, 4-fluorophenyl , 2-fluorophenyl, 3-fluorophenyl, 3
, 5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4-
It is selected from the group consisting of (3′-dimethylamino-n-propoxy) -phenyl, and 1-methylpyrazol-4-yl.

Preferably, in the compounds of formulas I and IA above, R ² is hydrogen, methyl, phenyl, benzyl,-(CH ₂ ) ₂ -2-thienyl, and-(CH ₂ ) ₂ -Φ.

In one embodiment, R ¹ and R ² are combined with a nitrogen atom attached to R ² and a SO ₂ group attached to R ¹ to form a heterocyclic or substituted heterocyclic group. . Preferred heterocyclic and substituted heterocyclic groups include those having 5 to 7 ring atoms and having 2 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur in the ring. The ring optionally fused to another ring, such as a phenyl or cyclohexyl ring, having 10-14 ring atoms and having 2-4 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. This gives a fused heterocycle having atoms. Particularly preferred examples of R ¹ / R ² bonded groups include benzisothiazolone sulfonyl (saccharin-2-yl) are.

In one preferred embodiment, R ² and R ³ have from 4 to 6 ring atoms, with the nitrogen atom attached to the R ² substituent and the carbon atom attached to the R ³ substituent, Forming a heterocyclic or substituted heterocyclic group having 1-2 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, wherein said ring is optionally
Substituted with one or two substituents selected from fluoro, methyl, hydroxy, amino, phenyl, thiophenyl, thiobenzyl, or fused with another ring such as a phenyl or cycloalkyl ring to form 10-14 It is also possible to provide a fused heterocycle having one ring atom and one or two heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Such heterocyclic rings include azetidinyl (eg, L-azetidinyl), thiazolidinyl (eg, L-azetidinyl).
Thiazolidinyl), piperidinyl (eg, L-piperidinyl), piperazinyl (eg, L-piperazinyl), dihydroindolyl (eg, L-2,3-dihydroindol-2-yl), tetrahydroquinolinyl (eg, L-1,2)
, 3,4-tetrahydroquinolin-2-yl), thiomorpholinyl (e.g. L
-Thiomorpholin-3-yl), pyrrolidinyl (eg L-pyrrolidinyl),
Substituted pyrrolidinyl, for example, 4-hydroxypyrrolidinyl (eg, 4-α-
(Or β-) hydroxy-L-pyrrolidinyl), 4-fluoropyrrolidinyl (
For example, 4-α- (or β-) fluoro-L-pyrrolidinyl), 3-phenylpyrrolidinyl (eg, 3-α- (or β-) phenyl-L-pyrrolidinyl)
, 3-thiophenylpyrrolidinyl (eg, 3-α- (or β-) thiophenyl-L-pyrrolidinyl), 4-aminopyrrolidinyl (eg, 4-α- (or β-) amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (for example 3-
substituted piperidinyls such as α- (or β-) methoxy-L-pyrrolidinyl), 4,4-di-methylpyrrolidinyl, such as 4-N-Cbz-piperidinyl,
Substituted thiazolidinyls such as 5,5-dimethylthiazolindin-4-yl, 1
, 1-dioxo-thiazolidinyl (eg, L-1,1-dioxo-thiazolidine-2-yl), substituted 1,1-dioxo-thiazolidinyl, eg, L-1,1
1,1-dioxothiomorpholinyl (e.g., L-1,1-dioxo-thiomorpholin-3-yl) such as -dioxo-5,5-dimethylthiazolidine-2-yl;

Preferably, in the compounds of formulas I and IA above, R ³ is methyl, phenyl, benzyl, diphenylmethyl, —CH ₂ CH ₂ —COOH, —CH ₂ —COOH, ₂ -amidoethyl, isobutyl include t- butyl, -CH ₂ O-benzyl, all isomers arising by substitution with you and hydroxymethyl. Further, in another preferred embodiment, R ³ and R ² form a heterocyclic group or a substituted heterocyclic group with the nitrogen atom bonded to R ² .

Q is preferably —C (O) NH— or —C (S) NH—.

R ⁵ is preferably selected from all possible isomers resulting from substitution by the following groups:

4- [NH_TwoCH_TwoC (O) NH-] benzyl, 4- [HOOCCH_TwoCH_TwoC (
O) NH-] benzyl, 4-[-NHC (O) CH_TwoNHBoc] benzyl, 4-[— NHC (O) CH (CH_Three) NHBoc] benzyl, 4-[— NHC (O) CH (CH_TwoΦ) NHBoc] benzyl, 4-[— NHC (O) CH_TwoNHC (
O) NH-3'-methylphenyl] benzyl, 4-[-NHC (O) CH (NH Boc) (CH_Two)_FourNHCbz] benzyl, 4-[-NHC (O) CH_TwoCH (C (O) OCH_TwoΦ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH_TwoCH_TwoCH_TwoCH_TwoNH_Two) NHBoc] benzyl, 4- [H_TwoNCH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- (BocHNCH_TwoCH_Two CH_TwoC (O) NH-) benzyl, 4- [ΦCH_TwoOCH_Two(BocHN) CHC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoCH_TwoCH_TwoC (O) NH-] B
Benzyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH_Three N (Boc) CH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoOCH _Two (H_TwoN) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH
) CHCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoO (O) C (Cbz-NH) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [HO (O) C (
NH_Two) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [CH_Three(N-Boc
) NCH_TwoC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoC (O) NH-] benzyl, 4-[(CH_Three)_TwoNCH_TwoC (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxyphenyl-]-benzyl
, 4- [2-carboxymethylphenyl-]-benzyl, 4- [ΦCH_TwoOC (O) NHCH_TwoCH_TwoNH-] benzyl, 4-N [-(SO_Two) CH_Three] -CH_TwoCH_TwoCH_TwoN (CH_Three)_TwoBenzyl, 4-t-butyl-O (O) CCH_Two-O-benzyl NH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzene
Zyl) amino] benzyl, 4- (2-formyl-1,2,3,4-tetrahydro
Isoquinolin-3-yl-CH_TwoNH) benzyl, 4-[-OCH_TwoCH_Two-1'-
(4′-pyrimidinyl) -piperazinyl] -benzyl, 4-[— OCH_TwoCH_Two-(1'-piperidinyl) -benzyl, 4-[-OCH_TwoCH_Two-(1'-Pyrrolidini
Ru)] benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1'-piperidinyl)]-ben
Jill, 4-[(CH_Three)_TwoNCH_TwoCH_TwoCH_Two-O-] benzyl, 4-[(CH_Three) _Two NCH_TwoCH_TwoO-]-benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1 '-(4'-
Methylpiperazinyl))]-benzyl, 4-[— OCH_TwoCH_TwoCH_Two-4- (3 '
-Chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_TwoN (Φ) CH_TwoCH_Three] -Benzyl, 4-[-OCH_Two-3 '-(N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidini
Benzyl], 3-[-O- (N-methylpiperidin-4-yl] benzyl, 4
-[-O- (N-methylpiperidin-4-yl] benzyl, 4- [di-isoprop]
Ropyramino-CH_TwoCH_TwoO-]-benzyl, 4- [N-3-methylbutyl-N
-Trifluoromethanesulfonyl) amino] benzyl, 4-[-OCH_TwoCH_Two−
(N-morpholinyl)]-benzyl, 4-[— OCH_TwoCH (NHBoc) CH_Two Cyclohexyl] -benzyl, 4- [OCH_TwoCH_Two-(N-piperidinyl) -b
Undil, 4-[-OCH_TwoCH_TwoCH_Two-(4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_Two-(N-homopiperidinyl)
-Benzyl, 4-[-OCH_TwoCH_TwoN (benzyl)_Two] -Benzyl, 3-[— O CH_TwoCH_TwoCH_TwoN (CH_Three)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five )_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN
(CH_Three) Benzyl) -benzyl, 4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl, [cyclopentylacetyleni
] -Benzyl, 4-[-C≡C-Φ-4′Φ] -benzyl, 4-[-C≡C-CH_Two-OS (O)_Two-4'-CH_Three-Φ] -benzyl, 4-[-C≡C-CH_Two NHC (O) NH_Two] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-COO CH_TwoCH_Three) Φ] -benzyl, 4-[— C≡C—CH (NH_Two) -Cyclohexyl] -benzyl, 4-[— C≡C—CH_Two—O-phenyl] -benzyl, 4-[— C≡C—CH_TwoOCH_Three] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-C
(O) OC_TwoH_Five) Phenyl] -benzyl, 4-[— C≡C—CH_TwoCH (C (O) OCH_Three)_Two] -Benzyl, 4-[— C≡C—CH_TwoCH (NHC (O) CH_Three)
C (O) OH] -benzyl, 4-[-C≡C-CH_TwoNH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-
OCH_TwoCH_TwoCH_Two-(N-morpholino)]-benzyl, 4-[-OCH_TwoCOO
H] -benzyl, 4-[-OCH_TwoCOO-t-butyl] -benzyl, 4-[-N (SO_TwoCH_Three) (CH_Two)_Three-N (CH_Three)_Two] -Benzyl, 4-[-NHS (O
)_TwoCF_Three] -Benzyl, 4-[— C (＝ NH) NH_Two] -Benzyl, 4-[-N HSO_Two-CH_TwoCl] -benzyl, 4-[-OCH_TwoC (O) NH-benzyl] -benzyl, 4-[-OCH_TwoC (O) O-benzyl] -benzyl, 4-[-O CH_TwoC (O) OH] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] -benzyl,
-[-OCH_TwoC (O) NH_Two] -Benzyl, 4-[-OCH_TwoC (O) NH-t-butyl] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4-f
Enyl) -piperidinyl] -benzyl, 4-[-NHSO_Two-CH = CH_Two] -B
Nyl, 4-[-NHSO_Two-CH_TwoCH_TwoCl] -benzyl, 4-benzyl-benzyl, 4-[— OCH_TwoC (O) piperidin-1-yl] benzyl, 4-[-OCH_TwoC (O) N (CH (CH_Three)_Two)_TwoBenzyl, 4-amidinobenzyl, 4
-Acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4 (-N
HC (O) CH_TwoNHC (O) NH-fluorescein) benzyl, 4- (NHC (O) CH_TwoCH (NH_Two) COOH, (1-toluenesulfonylimidizole)
4-yl) -methyl-, [(1-N, N-dimethylaminosulfonyl) -imidi
Zol-4-yl] methyl-, 4- (N-toluenesulfonylamino) benzyl
, And 4- [N-methyltrifluoroacetamido] phenyl.

In the compound of formula IA, R ⁶ is preferably 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, isopropoxy, n-butoxy, t-butoxy, Cyclopentoxy, neopentoxy, 2-α
-Iso-propyl-4-β-methylcyclohexoxy, 2-β-isopropyl-
4-β-methylcyclohexoxy, —NH ₂ , benzyloxy, —NHCH ₂ CO
_{OH, -NHCH 2 CH 2 COOH,} -NH- adamantyl, -NHCH ₂ CH ₂ C
_{OOCH 2 CH 3, -NHSO 2 -p} -CH 3 -Φ, -NHOR 8 ( wherein, R ⁸ is hydrogen, methyl, isopropyl or benzyl), O-(N-succinimidyl), -
O-cholest-5-en-3-β-yl, —OCH ₂ —OC (O) C (CH ₃ ) ₃ , —O (CH ₂ ) _Z NHC (O) W (where z is 1 or 2 And W is pyrido-
3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl), -NR "C (O) -R ', where R 'is aryl, heteroaryl or heterocyclic, R''is hydrogen or -CH ₂ C (O) is a OCH ₂ CH _3).

Preferred compounds falling within the scope of Formulas I and IA above include those exemplified below.

N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4- [3- (carboxy) propionamide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-L-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-phenylalanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (fluorescein) thiouried] acetamido} -L-phenylalanine N -(Toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-
Methylphenyl) uried] acetamide {-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-Nε-carbobenzyloxy-L-lysyl) amino]
-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbobenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-L-lysyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (L-aspartyl) amino] -L-phenylalanine N- (toluene- 4-sulfonyl) -L-prolyl-4- (4-aminobutylamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxyl-carbonylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramide] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxylcarbonyl-N-methylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(O-benzyl)
-L-seryl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [δ- (D, L-glutamyl) amino] -L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylsarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxyl-carbonylsarcosyl) amino]- L-
Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino ] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(sarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(N, N-dimethylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N, N-dimethyl Glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxy Benzyloxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenyl] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 -[2- (methoxycarbonyl) phenyl] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [3- (
N, N-dimethylamino) propyl] -N- [trifluoromethanesulfonyl]
Amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [4- [
(Tert-butoxycarbonyl) methoxy] benzyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N, N-di [
4- (N, N-dimethylamino) benzyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N-[(2-
Formyl-1,2,3,4-tetrahydroisoquinolin-3-yl) methyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [2- (N, N-dimethylamino) Ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L -Prolyl-4- [2- (N-ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N- Diisopropylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3-cyclohexyl 2- (N-ter- butoxycarbonylamino) propoxy] -L- phenylalanine methyl ester N- (thiophene-2-sulfonyl) -L- prolyl -4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (5-chlorothiophen-2-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- ( 2,5-dichlorothiophen-3-sulfonyl) -L-prolyl-4-
[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (1-methylpyrazole-4-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine methyl ester N- (Toluene-4-sulfonyl) -L-prolyl-3- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (thiazol-2-sulfonyl) -L-prolyl-4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl- N-benzylamino) propoxy] -L-phenylalanine methyl ester N- (1-methylimidazole-4-sulfonyl) -L-prolyl-4- [3
-(N, N-dimethylamino) propoxy] -L-phenylalanine N- (2-methylthiadiazole-5-sulfonyl) -L-prolyl-4- [
3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-thiaprolyl-4- [3- (N, N
-Dimethylamino) propoxy] -L-phenylalanine N- (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (3,3-dimethyl) prolyl-4
-[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L -Phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (thiamorpholine-3-carbonyl) -4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-propyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L-phenylalani N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(Cyclopentyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- {2-
[4- (phenyl) phenyl] ethynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Toluene-4-sulfonyloxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Ureido) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(1-aminocyclohex-1-yl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (methoxy)
Prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (methoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4- [3- (4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (4- Ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl] -D , L-Phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (4-acetamido-4-carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) ) Sarkosyl-4- (4-acetamido-4)
-Carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {3-[(4,5-
Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5 -Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1
-Inyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L -Prolyl-4- {2- [4- (pyrimidin-2-yl) piperazin-1-yl] ethoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- ( Piperidin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (piperidin-1-yl) propoxy] -L-phenylalanine methyl ester N- Toluene-4-sulfonyl) -L- prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (piperidin-1-yl) ethoxy] -L-phenylalanine N- (toluene -4-sulfonyl) -L-prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine methyl ester N -(Toluene-4-sulfonyl) -L-prolyl-3- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-Methylpiperazin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-3- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4- {2- [4- (3-
Methoxythien-2-yl) -4-hydroxypiperidin-1-yl] ethoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-3- (1-methylpiperidin-4-oxy ) -D, L-Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (1-methylpiperidine-4-oxy) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L -(5,5-Dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L- (1,1-dioxothiomorpholine- 3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene) 4-Sulfonyl) -L- (1,1-dioxothiomorpholine-3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (toluene-4-sulfonyl)- L- (5,5-dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (α-toluenesulfonyl) -L-prolyl-4- (1-methylpiperidine-4- Oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- Prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine N- (toluene-4- Ruphonyl) -L-prolyl-4-N- (chloromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (vinylsulfonyl) amino-L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (N-trifluoromethanesulfonyl-N-isobutyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl- 4-N- (vinylsulfonyl) amino-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-benzylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene- 4-sulfonyl) -L-prolyl-4-[(ben Carbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(carboxy) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(carboxy) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) ) -L-Prolyl-4-[(aminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butylaminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (4-phenyl-4-hydroxypiperidin-1-yl) ethoxy] -L-phenylalaninemethyl Ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidine-1
-Ylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4 -Sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (amidino) phenylalanine N -(Toluene-4-sulfonyl) sarcosyl-D, L-4- (aminocarbonyl) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methylacetamido) -L-phenylalanine isopropyl ester N -(Toluene-4-sulfonyl) L-prolyl-4- (N-methylacetamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methyltrifluoroacetamido) -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl)- L-prolyl-L-4- (N-methylpiperidineoxy) -phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiapropyl-L- (4-methylpiperidineoxy ) Phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- ( 4-phenyl) -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-
Phenylalanine and pharmaceutically acceptable salts thereof, and any of the ester compounds listed above, wherein one ester is a methyl ester, an ethyl ester, an n-
An ester compound substituted by another ester selected from the group consisting of propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester.

The present invention also provides a method for binding to VLA-4 in a biological sample, the method comprising the steps of: Contacting with a compound of IA.

Some of the compounds of formulas I and IA described above have VLA in vivo.
-Useful for reducing mediated inflammation.

The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of formula I or IA as described above, wherein R ³ and R ⁵ are L-amino acids or other Pharmaceutical compositions comprising compounds excluding those derived from similarly constituted starting materials are also provided.

[0025] The pharmaceutical composition may be used to treat a VLA-4-mediated disease state. Examples of such disease states 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, seizures and cerebral injury, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury that occurs in adult respiratory distress syndrome, etc. Is included. Therefore, the present invention provides VLA-4
Also provided is a method of treating a patient for a mediated inflammatory disease, the method comprising administering to the patient a pharmaceutical composition as described above.

Preferred compounds of Formulas I and IA above include those listed in Tables 1-18 below.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

In each case, Q is —C (O) NH—.

[0028]

DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention relates to compounds that inhibit leukocyte adhesion, particularly those that are mediated by VLA-4. Before describing the present invention in further detail, the following terms will first be defined.

Definitions As used herein, the term “alkyl” refers to an alkyl group, preferably 1 to
Refers to an alkyl group having 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of this term include groups such as methyl, t-butyl, n-heptyl, octyl, and the like.

The term “substituted alkyl” preferably refers to an atom consisting of 1 to 10 carbon atoms.
A alkyl group, including alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, amino, amidino, alkylamidino, thioa
Midino, alkylthioamidino, aminoacyl, aminocarbonylamino, amino
Nothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,
Aryloxy, substituted aryloxy, aryloxyaryl, substituted aryl
Oxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,
Ruboxyl alkyl, carboxyl-substituted alkyl, carboxyl-cycloal
Kill, carboxyl-substituted cycloalkyl, carboxylaryl, carboxy
-Substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl
Reel, carboxyl heterocyclic, carboxyl-substituted heterocyclic
, Cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone
, Thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl
Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted
Thioheteroaryl, thioheterocyclic, substituted thioheterocyclic,
Heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted
Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryl
Oxy, substituted heteroaryloxy, heterocyclyloxy, substituted hetero
Cyclyloxy, oxycarbonylamino, oxythiocarbonylamino,-
OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two-Allyl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl, -OS
(O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (
O)_Two-Substituted heterocyclic, -OS (O)_Two-NRR wherein R is hydrogen or
Is alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl,
-NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O)_Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, unpaired
Di-substituted amines, alkyl, substituted alkyl, aryl, substituted aryl
, Heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic
Asymmetric di-substituted amines having different substituents selected from the group consisting of clicks
And amino groups protected by common protecting groups such as Boc, Cbz, formyl, and the like.
Having 1 to 5 substituents selected from the group consisting of substituted alkyl groups having
Alkyl group or -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -S
O_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO_Two-NRR (wherein, R
Represents an alkyl / substituted alkyl group substituted by hydrogen or alkyl).
Point.

“Alkoxy” refers to an “alkyl-O—” group, 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 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 cyclo Alkyl-C (O)-, aryl-C (O)-, substituted aryl-C (O
)-, Heteroaryl-C (O)-, substituted heteroaryl-C (O), heterocyclic-C (O)-, and substituted heterocyclic-C (O)- Where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,
Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Acylamino” refers to a —C (O) NRR group, 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, heterocyclic, substituted heterocyclic Each R together with the nitrogen atom 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, heterocyclic, and substituted heterocyclic are as defined herein.

“Thiocarbonylamino” refers to the group —C (S) NRR where each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein each R is bonded together with a 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, heterocyclic, and substituted heterocyclic are described herein. Also defined in the book It is.

“Acyloxy” refers to alkyl-C (O) O—, substituted alkyl-C (O) O—
, Alkenyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl-C
(O) O-, substituted alkynyl-C (O) O-, aryl-C (O) O-, substituted aryl-C (O) O-, cycloalkyl-C (O) O-, substituted cycloalkyl-
C (O) O-, heteroaryl-C (O) O-, substituted heteroaryl-C (O)
O-, heterocyclic-C (O) O-, and substituted heterocyclic-C
(O) refers to each group of O-, wherein alkyl, substituted alkyl, alkenyl,
Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Alkenyl” preferably refers to 2 to 10 carbon atoms, more preferably 2 to 10 carbon atoms.
An alkenyl group having 6 carbon atoms and having alkenyl unsaturation at at least one position, more preferably at one or two positions.

“Substituted alkenyl” refers to alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl , Substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl Aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl Telocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thio Heteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonyl amino, -OS (O) ₂ - alkyl, -O S (O) ₂ - substituted alkyl, -OS (O) ₂ - aryl, -OS (O) ₂ - substituted the aryl, -OS (O) ₂ - heteroaryl, -OS (O) ₂ - substituted heteroaryl, -OS (O) ₂ - Heterosai click, -OS (O) ₂ - substituted heterocyclic, -OS (O) ₂ -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, -NR
S (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -N
RS (O) ₂ -substituted heterocyclic, -NRS (O) _2- NR-alkyl,-
NRS (O) _2- NR-substituted alkyl, -NRS (O) _2- NR-aryl, -N
RS (O) _2- NR-substituted aryl, -NRS (O) _2- NR-heteroaryl,
-NRS (O) _2- NR-substituted heteroaryl, -NRS (O) _2- NR-heterocyclic, -NRS (O) _2- NR-substituted heterocyclic (where R is hydrogen or alkyl), 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-heterocyclic amino, mono- and di-substituted heterocyclic amino, asymmetric di-substituted amine,
Asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and Boc, Cb
z, an alkenyl group having 1 to 5 substituents selected from the group consisting of a substituted alkenyl group having an amino group protected by a usual protecting group such as formyl,
Alternatively, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl, -SO ₂ - cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ - aryl, - SO ₂ - substituted aryl, -SO ₂ - heteroaryl Lumpur, -SO ₂ - substituted heteroaryl, -SO ₂ - heterocyclic, -SO ₂ - in the substituted heterocyclic, and -SO ₂ -NRR (wherein, R Refers to an alkenyl / substituted alkenyl group substituted by hydrogen or alkyl).

“Alkynyl” means an alkynyl group preferably having 2 to 10, more preferably 3 to 6, carbon atoms and having alkynyl unsaturation at at least one, more preferably at one or two, positions. Refers to.

“Substituted alkynyl” refers to alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl , Substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl Aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl Telocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thio Heteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonyl amino, -OS (O) ₂ - alkyl, -O S (O) ₂ - substituted alkyl, -OS (O) ₂ - aryl, -OS (O) ₂ - substituted the aryl, -OS (O) ₂ - heteroaryl, -OS (O) ₂ - substituted heteroaryl, -OS (O) ₂ - Heterosai click, -OS (O) ₂ - substituted heterocyclic, -OS (O) ₂ -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, -NR
S (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -N
RS (O) ₂ -substituted heterocyclic, -NRS (O) _2- NR-alkyl,-
NRS (O) _2- NR-substituted alkyl, -NRS (O) _2- NR-aryl, -N
RS (O) _2- NR-substituted aryl, -NRS (O) _2- NR-heteroaryl,
-NRS (O) _2- NR-substituted heteroaryl, -NRS (O) _2- NR-heterocyclic, -NRS (O) _2- NR-substituted heterocyclic (where R is hydrogen or alkyl), 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-heterocyclic amino, mono- and di-substituted heterocyclic amino, asymmetric di-substituted amine,
Asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and Boc, Cb
z, an alkynyl group having 1 to 5 substituents selected from the group consisting of a substituted alkynyl group having an amino group protected by a usual protecting group such as formyl,
Alternatively, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl, -SO ₂ - cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ - aryl, - SO ₂ - substituted aryl, -SO ₂ - heteroaryl Lumpur, -SO ₂ - substituted heteroaryl, -SO ₂ - heterocyclic, -SO ₂ - in the substituted heterocyclic, and -SO ₂ -NRR (wherein, R Refers to an alkynyl / substituted alkynyl group substituted by hydrogen or alkyl).

“Amidino” is

Embedded image The term "alkylamidino" refers to compounds having one to three alkyl groups (e.g., alkyl

Embedded image ).

“Thioamidino” is

Embedded image Wherein R is hydrogen or alkyl.

“Aminoacyl” refers to —NRC (O) alkyl, —NRC (O) substituted alkyl, —NRC (O) cycloalkyl, —NRC (O) substituted cycloalkyl, —N
RC (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. R is hydrogen or alkyl; alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic Is as defined herein.

“Aminocarbonyloxy” refers to —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, -NR
C (O) O-heteroaryl, -NRC (O) O-substituted heteroaryl, -NR
C (O) O-heterocyclic and -NRC (O) O-substituted heterocyclic, where R is hydrogen or alkyl, alkyl,
Substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are
It is as defined herein.

“Oxycarbonylamino” refers to —OC (O) NH ₂ , —OC (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, -O
C (O) NR-substituted heteroaryl, -OC (O) NR-heterocyclic,
And -OC (O) NR-substituted heterocyclic groups, wherein R is hydrogen, alkyl, or each R is combined with a nitrogen atom to form a heterocycle or substituted heterocycle, and 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. It is.

“Oxythiocarbonylamino” refers to —OC (S) NH ₂ , —OC (S) N RR, —OC (S) NR-alkyl, —OC (S) NR-substituted alkyl, —OC
(S) NR-alkenyl, -OC (S) NR-substituted alkenyl, -OC (S) N
R-alkynyl, -OC (S) NR-substituted alkynyl, -OC (S) NR-cycloalkyl, -OC (S) NR-substituted cycloalkyl, -OC (S) NR-aryl, -OC (S) NR -Substituted aryl, -OC (S) NR-heteroaryl,
-OC (S) NR-substituted heteroaryl, -OC (S) NR-heterocyclic, and -OC (S) NR-substituted heterocyclic, wherein R is hydrogen, alkyl, Alternatively, each R is joined with a nitrogen atom to form a heterocycle or substituted heterocycle, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, Substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to —NRC (O) NRR, —NRC (O) N
R-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, -N
RC (O) NR-substituted cycloalkyl, -NRC (O) NR-heteroaryl,
-NRC (O) NR-substituted heteroaryl, -NRC (O) NR-heterocyclic, and -NRC (O) NR-substituted heterocyclic, wherein each R is independently , Hydrogen, alkyl, or each R is bonded together with a nitrogen atom to form a heterocyclic ring or a substituted heterocyclic ring, or when one of the amino groups is protected by a usual protecting group such as Boc, Cbz, formyl, etc. There is an 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” refers to —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, -NRC (S) NR-substituted heteroaryl, -NRC (S) NR-heterocyclic, and -NRC (S) NR -Refers to each group of substituted heterocyclic, wherein each R is independently hydrogen, alkyl, or each R is combined with a nitrogen atom to form a heterocycle or substituted heterocycle, or an amino group May be protected by conventional protecting groups such as Boc, Cbz, formyl and the like, and include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic Are those defined herein.

“Aryl” or “Ar” is an unsaturated aromatic carbocyclic group consisting of 6 to 14 carbon atoms, which is a monocyclic (eg, phenyl) or fused polycyclic (eg, naphthyl or anthryl) The fused ring may or may not be aromatic (eg, 2-benzoxazolinone, 2H
-1,4-benzoxazin-3 (4H) -1-7yl and the like). Preferred aryls include phenyl and naphthyl.

“Substituted aryl” refers to hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,
Aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, Carboxylalkyl,
Carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-
Substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, carboxamide, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl , Thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl , Substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy Substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonyl amino, -S (O) ₂ - alkyl, -S (O) ₂ - substituted alkyl, -S (O) ₂ -Cycloalkyl, -S (O) ₂ -substituted cycloalkyl, -S (O) ₂ -alkenyl,
-S (O) ₂ - substituted alkenyl, -S (O) ₂ - aryl, -S (O) ₂ - substituted the aryl, -S (O) ₂ - heteroaryl, -S (O) ₂ - substituted heteroaryl , −
S (O) ₂ -heterocyclic, -S (O) ₂ -substituted heterocyclic, -O
S (O) ₂ - alkyl, -OS (O) ₂ - substituted alkyl, -OS (O) ₂ - aryl Le, -OS (O) ₂ - substituted aryl, -OS (O) ₂ - heteroaryl, -OS (
O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O
) ₂ - substituted heterocyclic, -OSO ₂ -NRR (wherein, R is hydrogen or alkyl), - NRS (O) ₂ - alkyl, -NRS (O) ₂ - substituted alkyl, -NR
S (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) _2- heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) _2- NR-alkyl, -NRS (O) _2- NR-substituted alkyl, -NRS (O) _2-
NR-aryl, -NRS (O) _2- NR-substituted aryl, -NRS (O) _2- N
R-heteroaryl, -NRS (O) _2- NR-substituted heteroaryl (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-heterocyclic amino, mono- and di-substituted heterocyclic amino, asymmetric di-substituted amine An asymmetric di-substituted amine having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and Boc; C
bz, an aryl group substituted by 1 to 3 substituents selected from the group consisting of an amino group on a substituted aryl protected by a usual protecting group such as formyl, or -SO ₂ Refers to an aryl group substituted by -NRR, wherein R is hydrogen or alkyl.

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

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

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

“Substituted aryloxyaryl” refers to hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl on one or both aryl rings. , Alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-
Substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, carboxamide, cyano,
Thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, Guanidino, guanidino sulfone, halo,
Nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxy Thiocarbonylamino, -S (O
) ₂ -alkyl, -S (O) ₂ -substituted alkyl, -S (O) ₂ -cycloalkyl, -S (O) ₂ -substituted cycloalkyl, -S (O) ₂ -alkenyl, -S (O) ₂ -substituted alkenyl, -S (O) ₂ -aryl, -S (O) ₂ -substituted aryl, -S (
O) ₂ -heteroaryl, -S (O) ₂ -substituted heteroaryl, -S (O) _2- heterocyclic, -S (O) ₂ -substituted heterocyclic, -OS (O) ₂ -alkyl , -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O
) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR (wherein, R is hydrogen or alkyl), - N RS (O) 2 - alkyl, -NRS (O) ₂ - substituted alkyl, -NRS (O) ₂ - aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic,- NRS (O) _2- NR-alkyl, -NRS (O) _2- NR-substituted alkyl, -NRS (O) _2- NR-aryl, -NRS (O) _2- NR-substituted aryl, -NRS (O) ₂ -NR- heteroar- Lumpur, -NRS (O) ₂ -NR- substituted heteroaryl (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-heterocyclic amino, mono- and di-substituted heterocyclic Amino, an asymmetric di-substituted amine which is alkyl,
Unsymmetrical di-substituted amines having different substituents selected from the group consisting of substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and Boc, Cbz, formyl, and the like. or it refers to an aryloxy aryl group substituted by one to three substituents selected from the group consisting of amino groups on the protected substituted aryl by conventional protecting groups, or, -SO ₂ -NRR ( Wherein R refers to an aryloxyaryl group substituted by hydrogen or alkyl.

“Cycloalkyl” refers to a cyclic alkyl group having a single ring of 3 to 8 carbon atoms, including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Multicyclic alkyl groups such as adamantanyl are excluded from this definition.

“Cycloalkenyl” refers to cyclic alkynyl groups of 3 to 8 carbon atoms having one or more unsaturations but no aromaticity.

“Substituted cycloalkyl” and “substituted cycloalkenyl” are preferably 3
Consisting of ~ 8 carbon atoms, oxo (= O), thioxo (= S), alkoxy,
Substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
, Substituted aryl, aryloxy, substituted aryloxy, aryloxy
Reel, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro
B, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, cal
Boxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl
Aryl, carboxyl-substituted aryl, carboxyl heteroaryl, carbo
Xyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl
-Substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino
, Guanidino sulfone, thiol, thioalkyl, substituted thioalkyl, thioali
, Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thio
Heteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thio
Heterocyclic, heteroaryl, substituted heteroaryl, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two -Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl,
-OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic,-
OS (O)_Two-Substituted heterocyclic, -OSO_Two-NRR (where R is hydrogen or
Or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl
, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O
)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS
(O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, unpaired
Di-substituted amines, alkyl, substituted alkyl, aryl, substituted aryl
, Heteroaryl, substituted heteroaryl, heterocyclic, and substituted hetero
Asymmetric di-substitution with different substituents selected from the group consisting of cyclic
Protected by amines and common protecting groups such as Boc, Cbz, formyl, etc.
1 to 5 substitutions selected from the group consisting of substituted alkynyl groups having an amino group
A cycloalkyl or cycloalkenyl group having a group, or -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substituted heterocyclyl
And -SO_TwoRefers to an alkynyl / substituted alkynyl group substituted by -NRR, wherein R is hydrogen or alkyl.

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

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

“Guanidino” refers to -NRC (= NR) NRR, -NRC (= NR) NR-
Alkyl, -NRC (= NR) NR-substituted alkyl, -NRC (= NR) NR-
Alkenyl, -NRC (= NR) NR-substituted alkenyl, -NRC (= NR) N
R-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, and -NRC (= NR) NR-substituted heterocyclic, wherein each R is independently And one of the hydrogen, alkyl, or amino groups may be protected by conventional protecting groups such as Boc, Cbz, formyl, and the like. , Substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0061] A "guanidino _{sulfone", -NRC (= NR) NRSO 2} - alkyl, - NRC (= NR) NRSO 2 - substituted _{alkyl, -NRC (= NR) NRSO 2} - alkenyl, -NRC (= NR) NRSO ₂ - substituted _{alkenyl, -NRC (= NR) NRSO 2} - _{alkynyl, -NRC (= NR) NRSO 2} - substituted alkynyl, -
NRC (= NR) NRSO ₂ - _{aryl, -NRC (= NR) NRSO 2} - substituted _{aryl, -NRC (= NR) NRSO 2} - _{cycloalkyl, -NRC (= NR) NRSO 2} - substituted cycloalkyl, -NRC ( = NR) NRSO ₂ - heteroaryl, -NRC (= NR) NRSO ₂ - substituted heteroaryl, -NRC (= NR) NRSO ₂ - heterocyclic, and -NRC (= NR) NRSO ₂ - substituted heterocyclic Each group, wherein each R is independently hydrogen and alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, Aryl, substituted heteroaryl, heterocyclic and substituted heterocyclic Rick are those defined herein.

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

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

“Substituted heteroaryl” refers to hydroxy, acyl, acylamino, thiocar
Bonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alcohol
Xy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino,
Alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyl
Xy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted
Aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cyclo
Alkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyl
Kuryloxy, substituted heterocyclyloxy, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxyl-substituted heterocyclic, carboxyl
Silamide, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl
, Substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocy
Chloroalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thio
Telocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guani
Dinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterosa
Cyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy
Si, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy
Si, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbo
Nilamino, -S (O)_Two-Alkyl, -S (O)_Two-Substituted alkyl, -S (O) _Two -Cycloalkyl, -S (O)_Two-Substituted cycloalkyl, -S (O)_Two-Alkenyl, -S (O)_Two-Substituted alkenyl, -S (O)_Two-Aryl, -S (O)_Two-Substituted aryl, -S (O)_Two-Heteroaryl, -S (O)_Two-Substituted heteroaryl
, -S (O)_Two-Heterocyclic, -S (O)_Two-Substitution heterocyclic
, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl,-
OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -O
S (O)_Two-Substituted heterocyclic, -OSO_Two-NRR wherein R is hydrogen or
Is alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl,
-NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O) _Two -Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O)_Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O_Two) -NR-heterocyclic, -NRS (O_Two) -NR-substituted hete
Cyclic, wherein R is hydrogen or alkyl, mono- and di-alkyl
Ruamino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Ruamino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-
Telocyclic amino, mono- and di-substituted heterocyclic amino, non-
Symmetric di-substituted amines, alkyl, substituted alkyl, aryl, substituted aryl
, Heteroaryl, substituted heteroaryl, heterocyclic, and substituted
Asymmetric di-positions having different substituents selected from the group consisting of telocyclic
Protected by substituted amines and common protecting groups such as Boc, Cbz, formyl, etc.
From 1 to 3 substituents selected from the group consisting of amino groups on substituted aryl
Refers to a heteroaryl group substituted by_Two-NRR (wherein R is hydrogen or alkyl) a heteroaryl group
Point to.

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

“Heterocycle” and “heterocyclic” refer to 1-10 carbon atoms,
Consisting of 1 to 4 ring heteroatoms selected from nitrogen, sulfur, or oxygen;
Refers to a saturated or unsaturated group having a single ring or a condensed polycyclic ring. In the condensed ring system, one or more rings may be aryl or heteroaryl.

“Saturated heterocyclic” refers to an unsaturated bond (eg, a carbon-carbon unsaturated bond, a carbon-nitrogen unsaturated bond, a nitrogen-nitrogen unsaturated bond, etc.) in any ring. Refers to a monocyclic or condensed polycyclic heterocycle having no ring.

“Unsaturated heterocyclic” refers to an unsaturated bond in any ring (eg, a carbon-carbon unsaturated bond, a carbon-nitrogen unsaturated bond, a nitrogen-nitrogen unsaturated bond, etc.). ) Having a non-aromatic heterocyclic ring composed of a single ring or a condensed polycyclic ring.

“Substituted heterocyclic” refers to oxo (＝ O), thioxo (＝ S),
Coxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyl
Roxy, amino, amidino, alkylamidino, thioamidino, aminoacyl,
Aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloki
Si, aryl, substituted aryl, aryloxy, substituted aryloxy, aryl
Oxyaryl, substituted aryloxyaryl, halogen, hydroxyl, shea
No, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl
, Carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl,
Boxyl aryl, carboxyl-substituted aryl, carboxyl heteroaryl
, Carboxyl-substituted heteroaryl, carboxyl heterocyclic, cal
Boxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,
Anidino, guanidino sulfone, thiol, thioalkyl, substituted thioalkyl,
Thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl
Thioheteroaryl, substituted thioheteroaryl, thioheterocyclic,
Substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterosa
Cyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy
Si, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy
Si, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbo
Nilamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS
(O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocycle
Tick, -OS (O)_Two-Substituted heterocyclic, -OS (O)_Two-NRR (wherein
, R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two−
Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl,
-NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl,-
NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substituted heterocyclic
H, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl
, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl,
-NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted hetero
Aryl, -NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-N
R-substituted heterocyclic (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
And di-heterocyclic amino, mono- and di-substituted heterocyclic
Amino, an asymmetric di-substituted amine, wherein alkyl, substituted alkyl, aryl,
Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,
Having different substituents selected from the group consisting of
With symmetric di-substituted amines and common protecting groups such as Boc, Cbz, formyl, etc.
Selected from the group consisting of substituted alkynyl groups having an amino group protected by
A heterocyclic group having from 3 to 3 substituents, or -SO_Two-Alkyl, -SO_Two -Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two -Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl,-
SO_Two-Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO _Two Refers to an alkynyl / substituted alkynyl group substituted by -NRR, wherein R is hydrogen or alkyl.

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

The term “saturated heterocyclic” means that any ring has an unsaturated bond (eg, a carbon-carbon unsaturated bond, a carbon-nitrogen unsaturated bond, a nitrogen-nitrogen unsaturated bond, etc.). No. refers to a substituted heterocyclic ring consisting of a single ring or a condensed polycyclic ring.

The term “unsaturated substituted heterocyclic” refers to an unsaturated bond in any ring (eg, a carbon-carbon unsaturated bond, a carbon-nitrogen unsaturated bond, a nitrogen-nitrogen unsaturated bond). And the like, and a non-aromatic substituted heterocycle composed of a single ring or a condensed polycycle.

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

“Substituted alkylcarbonylamino” refers to the group —NHC (O) -substituted alkyl.

“Thiol” refers to the group —SH.

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

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

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

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

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

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

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

“Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound of Formula I, which may be derived from various organic or inorganic counterions known in the art. And examples thereof include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functional group, a salt of an organic or inorganic acid, for example, Includes hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of Compounds The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Even when typical or preferred process conditions (ie, reaction temperatures, times, reactant mole ratios, solvents, pressures, etc.) are given, other process conditions may be used unless otherwise specified. You will see what can be done. Optimum reaction conditions may vary with the particular reactants and solvents used, but such conditions can be determined by one skilled in the art by routine optimization methods.

As is well known to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting or deprotecting a particular functional group, are well known to those skilled in the art. For example, a number of protecting groups are described in T.W. W. G
reene and G.C. M. Wuts “Protecting Groups
in Organic Synthesis Second Edition, Wiley, New Y
ork, 1991 and references therein.

In addition, the compounds of the invention typically contain one or more chiral centers. Thus, if desired, the compounds can be prepared or separated as pure stereoisomers, ie, enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the invention unless otherwise indicated. Pure stereoisomer (
Or concentrated mixtures) can be produced, for example, by using optically active substances or stereoselective agents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

In a preferred synthetic method, compounds of formulas I and IA, where Q is —C (O) NR ⁷ , are first substituted with an amino acid of formula II:

Embedded image Wherein R ² , R ³ and R ⁴ are as previously defined; coupled with a sulfonyl chloride of formula III

Embedded image Wherein R ¹ is as defined above. Prepared by providing an N-sulfonyl amino acid of formula IV below.

Embedded image (Wherein R ¹ -R ³ are as defined above)

The reaction is typically carried out by contacting an amino acid of formula II with at least one equivalent, preferably 1.1 to 2 equivalents of sulfonyl chloride III in an inert diluent such as dichloromethane. Done. Generally, the reaction is conducted at a temperature in the range of about -70 ° C to 40 ° C for about 1 hour to about 24 hours. Preferably, the reaction is performed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, for example, triethylamine, diisopropylethylamine,
Tertiary amines such as N-methylmorpholine are included. Alternatively, the reaction can be carried out under Schotten-Baumer type conditions using an aqueous alkali such as sodium hydroxide as the base. After completion of the reaction, the resulting N-sulfonyl amino acid IV is recovered by a conventional method including neutralization, extraction, precipitation, chromatography, filtration and the like.

The amino acids of formula II used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. Examples of suitable amino acids used in this reaction include L-proline, trans-4-hydroxyl-L-proline, cis-4-hydroxyl-L-proline, trans-3-phenyl-L-proline, cis-3- Phenyl-L-proline, L- (2-methyl) proline, L-pipecolic acid, L-azetidine-2-carboxylic acid, L-indoline-2-carboxylic acid, L-1,2,3,4-tetrahydroisoquinoline -3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L- (
5,5-dimethyl) thiazolidine-4-carboxylic acid, L-thiamorpholine-3-
Carboxylic acid, glycine, 2-tert-butylglycine, D, L-phenylglycine, L-alanine, α-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D, L-phenylsarcosine, L-aspartic acid β-tert-butyl ester, L-glutamic acid γ-tert-
Butyl ester, L- (O-benzyl) serine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid (cycloleucine), 1-aminocyclohexanecarboxylic acid, L-serine, etc. But are not limited to these. If desired, the corresponding carboxylic acid esters of amino acids of formula II, such as methyl esters, ethyl esters, etc., can be used in the reaction with sulfone chloride III described above. Thereafter, the ester group is hydrolyzed to a carboxylic acid by performing a treatment with an alkali metal hydroxide in an inert diluent such as methanol / water or the like under the usual reagents and conditions, whereby the N-sulfonyl amino acid IV is converted. obtain.

Similarly, the sulfonyl chlorides of formula III used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. Such compounds typically include the corresponding sulfonic acid,
That is, it is prepared from a compound of the formula R ¹ —SO ₃ H, wherein R ¹ is as previously defined, using phosphorus trichloride or phosphorus pentachloride. This reaction is generally carried out by reacting the sulfonic acid with 2 to 5 molar equivalents of phosphorus trichloride and phosphorus pentachloride directly or in an inert solvent such as dichloromethane in a temperature range of about 0 ° C to about 80 ° C.
This is done by contacting for 48 hours, resulting in the sulfonyl chloride.
Alternatively, the sulfonyl chloride of formula III can be converted from the corresponding thio compound, ie, a compound of formula R ¹ -SH, where R ¹ is as defined above, under conventional reaction conditions with chlorine (Cl ₂ ) And water treatment.

Examples of sulfonyl chlorides suitable for use in the present invention include 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-te
rt-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, chloride 2
-Carboxybenzenesulfonyl, 4-cyanobenzenesulfonyl chloride, chloride 3
4,4-dichlorobenzenesulfonyl, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride,
4-thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,4-chloride
6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-thiazolesulfonyl chloride 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, chloride Examples include, but are not limited to, 2-pyrimidinesulfonyl and the like. If desired, an N-sulfonyl amino acid of Formula IV may be prepared using sulfonyl fluoride, sulfonyl bromide, or sulfonic acid in the above reaction instead of sulfonyl chloride.

An intermediate N-sulfonyl amino acid of Formula IV is a sulfonamide of Formula V:

Embedded image Wherein R ¹ and R ² are as previously defined. Formula L (R ³ ) CHCOOR wherein L is a leaving group such as chloro, bromo, iodo, mesylate, tosylate, and R ³ Is as defined above, and R is hydrogen or an alkyl group). The reaction is typically carried out in an inert diluent, such as DMF, in the presence of a suitable base, such as triethylamine, in a temperature range from about 24 ° C. to about 37 ° C.
Approximately 0.5 to 4 hours, at least 1 equivalent of sulfonamide V, preferably 1.1 to
It is carried out by contacting with 2 equivalents of a carboxylic acid derivative. This reaction is described in Zuckermann et al. Am. Chem. Soc. , 1992, 1
14, 10646-10647, are described in further detail. Preferred carboxylic acid derivatives used in this reaction are α-chloro and α-bromocarboxylic acid esters such as tert-bromoacetic acid ester. If a carboxylic acid ester is used in this reaction, the ester group is subsequently hydrolyzed using conventional methods to give the N-sulfonyl amino acid of formula IV.

The compound of formula I is then obtained by coupling the intermediate N-sulfonyl amino acid of formula IV with an amino acid derivative of formula VI below.

Embedded image Wherein R ⁵ -R ⁷ are as previously defined. The coupling reaction is typically carried out using well-known coupling reagents such as carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris (dimethyl Amino) phosphonium hexafluorophosphonate) and the like.
Suitable carbodiimides include, for example, dicyclohexylcarbodiimide (
DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (
EDC) and the like. If desired, carbodiimide coupling reagents can be used, for example, in Tetrahedron Letters, 34 (48), 7685 (1
As described in 993), it may be used in a form supported by a polymer. Further, a coupling accelerator such as N-hydroxysuccinimide or 1-hydroxybenzotriazole may be used to facilitate the coupling reaction.

The coupling reaction typically involves the addition of about 1-2 equivalents of N-sulfonyl amino acid IV in an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide. Ring reagent and at least one equivalent, preferably about 1-1.2 equivalents of amino acid derivative V
This is done by contacting I. Generally, the reaction is carried out at about 0 ° C to about 37 ° C.
In the temperature range of about 12 to 24 hours. After completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like.

As an alternative, the N-sulfonyl amino acid IV can be converted to an acid halide and the acid halide coupled with an amino acid derivative VI to give a compound of formula I. The acid halide of VI, under conventional conditions,
It can be prepared by contacting VI with an inorganic acid halide such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or preferably with oxyallyl chloride. Generally, the reaction employs 1 to 5 molar equivalents of an inorganic acid halide or oxyallyl chloride, either directly or in an inert solvent such as dichloromethane or carbon tetrachloride, at a temperature of about 0 ° C to about 80 ° C. About 1 in range
It takes from about 48 hours to about 48 hours. A catalyst such as N, N-dimethylformamide may be used in this reaction.

Next, the acid halide of N-sulfonyl amino acid IV is treated with an inert diluent such as dichloromethane in a temperature range of about -70 ° C to about 40 ° C for about 1 hour to about 2 hours.
Over a period of 4 hours, contact with at least 1 equivalent, preferably from about 1.1 equivalents to about 1.5 equivalents of amino acid derivative VI. This reaction is preferably performed in the presence of a suitable base for capturing the acid generated during the reaction. Suitable bases include, for example,
Tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine are included. Alternatively, the reaction can be carried out under Schotten-Baumer type conditions using an aqueous alkali such as sodium hydroxide as the base. After completion of the reaction, the compound of formula I is recovered by a usual method including neutralization, extraction, precipitation, chromatography, filtration and the like.

As an alternative, the compounds of formula I can also be prepared by first forming a diamino acid derivative of formula VII:

Embedded image Wherein R ² , R ³ and R ⁵ -R ⁷ are as previously defined. The diamino acid derivatives of formula VII can be prepared using conventional amino acid coupling techniques and reagents such as carbodiimides, as described above. It can be easily prepared by coupling an amino acid of the formula II with an amino acid derivative of the formula VI using a BOP reagent or the like. The diamino acid VII is then sulfonated using the sulfonyl chloride of formula III and the synthetic method described above to give a compound of formula I.

The amino acid derivative of Formula VI used in the above reaction is either a known compound or a compound that can be produced from a known compound by a conventional synthetic method. For example, amino acid derivatives of formula VI can be obtained from commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA)
) Can be prepared by C-alkylation with an alkyl or a substituted alkyl halide. The reaction typically involves treating diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 hours to about 12 hours. It is done by doing. The resulting C-alkylated malonic acid is then deacetylated, hydrolyzed, and decarboxylated by heating in aqueous hydrochloric acid under reflux for about 6 hours to about 12 hours, yielding the typical amino acid Is obtained as a hydrochloride.

Examples of amino acid derivatives of formula VI suitably used in the above reaction include L-4
-Nitrophenylalanine methyl ester, L-tyrosine methyl ester, D,
L-homo-4-nitrophenylalanine methyl ester, L- (O-benzyl)
Tyrosine methyl ester, L-3,5-diiodotyrosine methyl ester, L-
Examples include, but are not limited to, 3-indotyrosine methyl ester. Of course, other esters or amides of the above compounds may be used if desired.

For ease of synthesis, compounds of Formula I are typically ester (ie, R ⁶ Is an alkoxy or substituted alkoxy group). If desired, the ester group is hydrolyzed using normal conditions and reagents to give the corresponding
Rubonic acid can also be obtained. Typically, the reaction is methanol or methanol
At least 1 equivalent of ester in an inert diluent, such as a mixture of water and water.
Alkali metal hydroxides, such as lithium, sodium, or potassium
Treated with hydroxide in a temperature range of about 0 ° C to about 24 ° C for about 1 hour to about 12 hours
It is done by doing. Alternatively, the benzyl ester was supported on carbon
It can also be removed by hydrogenolysis using a palladium catalyst such as palladium.
Wear. The obtained carboxylic acid may optionally be an amine such as β-amine ethyl ester.
Hydroxy, such as amine, hydroxylamine and N-hydroxysuccinimide
Min, and O-methylhydroxylamine and O-benzylhydroxylamine
And other substituted alkoxyamines, as described above,
Coupling can also be performed using conditions and conditions.

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

Similarly, for the pyridyl group, to give the corresponding piperidinyl analogs,
Hydrogenation can be carried out in an acidic diluent in the presence of a platinum catalyst such as platinum oxide. Generally, the reaction is conducted in a pressure range of about 20 psi to about 60 psi, preferably about 4 psi.
At a pressure of 0 psi, the pyridine compound is hydrogenated in an acidic diluent such as a mixture of methanol and aqueous hydrochloric acid over a period of about 2 hours to about 24 hours at a temperature of about 20 ° C. to about 50 ° C. in the presence of a catalyst. This is done by processing. The compound having a pyridyl group can be obtained by, for example, using a β- (2-pyridyl)-, β- (3-pyridyl)-, or β- (4-pyridyl) -L-alanine derivative in the above coupling reaction. It can be easily manufactured.

Further, when the R ⁵ substituent of the compound of formula I or an intermediate thereof comprises a primary amino group or a secondary amino group, such an amino group may be, for example, an amide, sulfonamide, urea, thiourea, It can be further derivatized before or after the above coupling reaction to provide carbamates, secondary and tertiary amines, and the like.
Compounds having a primary amino group on the R ⁵ substituent, for example, may be prepared by reduction of the nitro compound that corresponds as described above. Alternatively, such compounds can be prepared using an amino acid derivative of Formula VI derived from lysine, 4-aminophenylalanine, and the like in the above coupling reaction.

By way of example, a compound of formula I having a substituent containing a primary or secondary amino group or an intermediate thereof, such as when R ⁵ is a (4-aminophenyl) methyl group, is N-acylation can be readily accomplished using conventional acylating reagents and conditions to provide the desired amide. This acylation reaction is typically carried out in the presence of carbodiimide, a BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate), dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N 2
In an inert diluent, such as N, N-dimethylformamide, at a temperature in the range of about 0 ° C. to about 37 ° C. for about 4 hours to about 24 hours, at least one equivalent of the amino compound;
It is preferably carried out by treating with about 1.1 equivalent to about 1.2 equivalent of carboxylic acid. Preferably, an accelerator such as N-hydroxysuccinimide, 1-hydroxybenzotriazole may be used to facilitate the acylation reaction.
Examples of suitable carboxylic acids used in this reaction include N-tert-butyroxycarbonylglycine, N-tert-butyroxycarbonyl-L-phenylalanine, N-tert-butyroxycarbonyl-L-aspartic acid benzyl ester, benzoic acid Acid, N-tert-butyroxycarbonyl isonipecotic acid,
N-methylisonipecotic acid, N-tert-butyroxycarbonyl nipecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3
-Carboxylic acid, N- (toluene-4-sulfonyl) -L-proline and the like, but are not limited thereto.

Alternatively, the compound of formula I or an intermediate thereof containing a primary or secondary amino group may be converted to an N-acyl with an acyl halide or carboxylic anhydride to form the corresponding amide. Can be The reaction is typically carried out in an inert diluent such as dichloromethane at a temperature in the range of about -70 ° C to about 40 ° C for about 1 hour.
Over a period of time to about 24 hours, at least one equivalent, preferably about 1.
It is carried out by contacting 1 equivalent to about 1.2 equivalents of an acyl halide or carboxylic anhydride. If desired, to facilitate the acylation reaction, 4- (N
, N-dimethylamino) pyridine and the like. The acylation reaction is preferably performed in the presence of a suitable base for capturing the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine. Alternatively, the reaction can be performed under Schotten-Baumer type conditions using an aqueous alkali such as sodium hydroxide.

Examples of suitable acyl halides and carboxylic anhydrides used in this reaction include 2-methylpropynyl chloride, trimethylacetyl chloride, phenylacetyl, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride , 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like, but are not limited thereto. To give urea in this reaction, N, N chloride
Carbamyl chlorides such as -dimethylcarbamyl and N, N-diethylcarbamyl chloride can also be used. Similarly, to give carbamates, di-te
A dicarbonate such as rt-butyl may be used.

Similarly, compounds of formula I containing a primary or secondary amino group or intermediates thereof may be N-sulfonated with a sulfonyl halide or sulfonic anhydride to form a sulfonamide. Is also good. Suitable sulfonyl halides and sulfonic anhydrides for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Absent. Similarly, sulfamoyl chlorides such as dimethylsulfamoyl chloride can be used to provide sulfamides (eg,> N—SO ₂ —N <).

Furthermore, the primary and secondary amino groups present on the substituents of the compound of formula I or its intermediates are reacted with isocyanates or thioisocyanates to give ureas and thioureas, respectively. be able to. The reaction is typically carried out in an inert diluent such as toluene in a temperature range of about 24 ° C. to about 37 ° C. for about 12 hours to about 24 hours, with at least one equivalent, preferably about 1 equivalent, of the amino compound. .1
It is carried out by contacting with from equivalent to about 1.2 equivalents of isocyanate or thioisocyanate. Suitable isocyanates and thioisocyanates used in this reaction are either commercially available or can be prepared from commercially available compounds by well known synthetic methods. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of suitable isocyanates and thioisocyanates used in this reaction include ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, Methyl thiocyanate, ethyl thiocyanate, 2-phenylethyl thiocyanate, 3-phenylpropyl thiocyanate, 3- (N, N-diethylamino) propyl thiocyanate, phenyl thiocyanate, benzyl thiocyanate, Examples include, but are not limited to, 3-pyridyl thioisocyanate, fluorescein thioisocyanate (isomer I), and the like.

Furthermore, if the compound of formula I or an intermediate thereof contains a primary or secondary amino group, the amino group is reduced with an aldehyde or ketone to form a secondary or tertiary amino group. Alkylation. This reaction typically involves the conversion of the amino compound in an inert diluent, such as methanol, tetrahydrofuran, and mixtures thereof, at a temperature range of about 0 ° C. to about 50 ° C. for about 1 hour to about 72 hours. It is carried out by contacting at least 1 equivalent, preferably from about 1.1 equivalents to about 1.5 equivalents of the aldehyde or ketone, and at least 1 equivalent of the metal hydroxide reducing agent based on the amino compound. Suitable aldehydes and ketones for use in this reaction include, by way of example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde, and the like.

Similarly, when the compound of formula I or an intermediate thereof has a substituent containing a hydroxyl group, this hydroxyl group may be added before or after the above coupling reaction to give, for example, ethers, carbamates and the like. Can be further modified or derivatized. For example a compound having a hydroxyl group on R ⁵ substituents can be prepared using an amino acid derivative of formula VI derived from such tyrosine Te reaction smell above.

By way of example, when a compound of formula I having a substituent containing a hydroxyl group or an intermediate thereof, such as when R ⁵ is a (4-hydroxyphenyl) methyl group, the compound or intermediate is readily converted to an O It can be alkylated to form an ether; This O-alkylation typically involves contacting the hydroxy compound with a suitable alkali or alkaline earth metal base such as potassium carbonate in an inert diluent such as acetone, 2-butanone, etc. Alternatively, an alkaline earth metal salt is formed. This salt is generally not separated and reacted in situ with at least one equivalent of an alkyl or substituted alkyl halide or sulfonate, such as a chloride, bromide, iodide, mesylate, or tosylate alkyl to form an ether give. Generally, the reaction is performed at about 60 ° C. to about 150 ° C. for about 24 hours to about 72 hours. When an alkyl chloride or iodide is used in the reaction, it is preferable to add a catalytic amount of sodium iodide or potassium iodide.

Examples of suitable alkyl or substituted alkyl halides and sulfonates used in this reaction include tert-butyl bromoacetate and N-chloroacetate.
tert-butyl, 1-bromoethylbenzene, α-bromophenylacetate ethyl, 2- (N-ethyl-N-phenylamino) ethyl chloride, 2- (N, N-ethylamino) ethyl chloride, 2- (N, N-diisopropylamino) ethyl, 2- (N, N-dibenzylamino) ethyl chloride, 3- (N, N-ethylamino) chloride
Propyl, 3- (N-benzyl-N-methylamino) propyl chloride, N- (2-
Chloroethyl) morpholine, 2- (hexamethyleneimino) ethyl chloride, chloride 3
-(N-methylpiperazine) propyl, 1- (3-chlorophenyl) -4- (3
-Chlorophenyl) piperazine, 2- (4-hydroxy-4-phenylpiperidine) ethyl chloride, tosylated N-tert-butyroxycarbonyl-3-piperidinemethyl and the like, but are not limited thereto.

Alternatively, the hydroxyl groups on the substituents of the compounds of formula I or intermediates thereof may be O-alkylated using a Mitsunobu reaction.
In this reaction, an alcohol such as 3- (N, N-dimethylamino) -1-propanol and about 1.0 equivalent to about 1.3 equivalent of diethyl azodicarboxylate are combined with an inert diluent such as tetrahydrofuran. The reaction is performed in a temperature range of about -10 ° C to about 5 ° C for about 0.25 hours to about 1 hour. Next, from about 1.0 equivalent to about 1.3 equivalents.
O-alkylated by adding an equivalent amount of a hydroxy compound such as N-tert-butyl tyrosine methyl ester and stirring the reaction mixture at a temperature of about 0 ° C. to about 30 ° C. for about 2 hours to about 48 hours. Obtain the product.

Similarly, compounds of formula I containing an aryl hydroxyl group or intermediates thereof can be reacted with aryl iodides to give diaryl ethers. Generally, this reaction is carried out by forming an alkali metal salt of a hydroxyl group in a diluent such as xylene with a suitable base such as sodium hydroxide at a temperature of about -25 ° C to about 10 ° C. Will be The salt is then treated with about 1.1 equivalents to about 1.5 equivalents of the copper bromide dimethyl sulfide complex in a temperature range of about 10 ° C. to about 30 ° C. for about 0.5 hours to about 2.0 hours. And from about 1.1 equivalents to about 1.5 equivalents of an arylimide, e.g.
-Treatment with sodium iodobenzoate or the like. Thereafter, the reaction system is heated to about 70 ° C to about 1 ° C.
Heat at 50 ° C. for about 2 hours to about 24 hours to obtain the diaryl ether.

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

[0116] In another alternative carbamate production method, the hydroxy-containing compound is
Contacting about 1.0 equivalent to about 1.5 equivalents of carbamyl chloride in an inert diluent such as dichloromethane at a temperature range of about 25 ° C. to about 70 ° C. for about 2 hours to about 72 hours. Typically, the reaction is performed in the presence of a suitable base to capture the acid generated during the reaction. Suitable bases include, by way of example, triethylamine,
Tertiary amines such as diisopropylamine, N-methylmorpholine are included. Further, it is preferable to add at least one equivalent (based on the hydroxy compound) of 4- (N, N-dimethylamino) pyridine to the reaction mixture to facilitate the reaction. Examples of suitable carbamyl chlorides for use in this reaction include:
Examples include dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.

Similarly, if the compound of formula I or an intermediate thereof contains a primary or secondary hydroxyl group, such a hydroxyl group can be readily converted to a leaving group and removed, for example, an amine, sulfide , Fluoride and the like. For example, a derivative of 4-hydroxy-L-proline can be converted to the corresponding derivative of 4-amino, 4-thio, or 4-fluoro-L-proline via nucleophilic substitution of the derivatized hydroxyl group. it can. Generally, when using a chiral compound in this reaction, the stereochemistry is typically reversed at the carbon atom attached to the derivatized hydroxyl group.

These reactions are typically carried out by first treating the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride, in pyridine to remove the hydroxyl group from the leaving group. , For example, by converting to tosylate. This reaction is generally performed by reacting at a temperature of about 0 ° C to about 70 ° C for about 1 hour to about 48 hours. The resulting tosylate can be treated with at least one hour in an inert diluent, such as a mixture of N, N-dimethylformamide and water, at a temperature in the range of about 0 ° C. to about 37 ° C. for about 1 hour to about 12 hours. By contacting with an equivalent amount of sodium azide, it can be easily displaced and the corresponding azide can be obtained. Then, an azido group is reduced by hydrogenation using a palladium on carbon catalyst to give the amino (-NH _2).

Similarly, the tosylate group can be replaced by a thiol to give a sulfide. This reaction is typically carried out in an inert diluent, such as N, N-dimethylformamide, in the presence of a suitable base, such as 1,8-diazabicyclo [5.4.0] undecene-7 (DBU). This is done by contacting the tosylate with at least one equivalent of a thiol, such as a thiol, at a temperature of about 0 ° C. to about 37 ° C. for about 1 hour to about 12 hours, resulting in a sulfide. Still further, treatment of the tosylate with morpholinosulfur trifluoride in an inert diluent such as dichloromethane at a temperature in the range of about 0 ° C. to about 37 ° C. for about 12 hours to about 24 hours yields the corresponding fluoride. can get.

Further, when a compound of the formula I having a substituent containing an iodoaryl group or an intermediate thereof, for example, when R ⁵ is a (4-iodophenyl) methyl group or the like, the compound or the intermediate is formed by the above-mentioned cup. Before or after the ring reaction, it can be easily converted to a biaryl compound. Typically, the reaction is carried out in an inert diluent, such as tetrahydrofuran, in the presence of a palladium catalyst, such as palladium tetra (triphenylphosphine), in a temperature range from about 24 ° C. to about 30 ° C. until the reaction is complete. , An iodoaryl compound is treated with about 1.1 equivalents to about 2 equivalents of an arylzinc iodide, such as 2- (methylcarbonyl) phenylzinc iodide. This reaction is described, for example, in Rieke, J .; Org. Che
m. 1991, 56, 1445.

In some cases, compounds of Formula I or intermediates thereof may include substituents having one or more sulfur atoms. Such a sulfur atom may for example be such that the amino acid of formula II used in the above reaction is L-thiazolidine-4-carboxylic acid, L- (5,5-dimethyl) thiazolidine-4-carboxylic acid, L-thiamorpholine- It is present when it is derived from 3-carboxylic acid or the like. When such a sulfur atom is present, the sulfur atom can be added before or after the coupling reaction to give a sulfoxide or sulfone compound.
It can be oxidized using conventional reagents and reaction conditions. Reagents suitable for oxidizing sulfide compounds to sulfoxides include, by way of example, hydrogen peroxide,
3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is typically carried out in an inert diluent, such as dichloromethane, at a temperature in the range of about -50 ° C to about 75 ° C for about 1 hour to about 24 hours for about 0.95 equivalent to about 0.95 equivalent of the sulfide compound. It is performed by contacting with 1.1 equivalents of an oxidizing agent. The resulting sulfoxide is further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing agent, such as hydrogen peroxide, MCPBA, potassium permanganate, and the like. Alternatively, the sulfone can be made directly by contacting the sulfide with at least two equivalents, preferably an excess of the oxide. Such a reaction is described in March, "Advanced Organic Chemistry," 4th edition, pp. 147-64. 1201-1202, Wiley Publisher, 1992.

As mentioned above, compounds of formula I having an R ² substituent other than hydrogen can be used in the above coupling reactions to obtain compounds of formula I such as sarcosine, N-methyl-L-phenylalanine, etc.
It can be produced using an N-substituted amino acid of I. Alternatively, such compounds, using conventional synthetic methods, (wherein, R ² is hydrogen) the formula I or IV can also be prepared by N- alkylation of Sul Hon'amido of. Typically, this N-alkylation reaction is carried out in an inert diluent such as acetone, 2-butanone, about 2 hours.
C. by contacting the sulfonamide with at least one equivalent, preferably 1.1 to 2 equivalents of an alkyl halide or substituted alkyl halide at a temperature ranging from 5 DEG C. to about 70 DEG C. for about 2 hours to about 48 hours. Will be Examples of suitable alkyl halides or substituted alkyl halides used in this reaction include:
Examples include, but are not limited to, methyl iodide.

In addition, the sulfonamides of Formula I or IV, wherein R ² is hydrogen and R ¹ is a 2-alkoxycarbonylaryl group, are intramolecularly cyclized to 1,1
A 2-benzisothiazol-3-one derivative or analog thereof can be formed. This reaction is typically carried out in an inert diluent such as tetrahydrofuran,
In a temperature range of about 0 ° C. to about 30 ° C., a sulfonamide such as N- (2-methoxycarbonylphenylsulfonyl) glycine-L-phenylalanine benzyl ester can be used at a temperature of about 1.0 equivalent to about 1.5 equivalents of a suitable base,
For example, it is carried out by treating with a hydride of an alkali metal. By this reaction, a cyclized 1,2-benzisothiazol-3-one derivative is obtained.

Finally, compounds of formula I (where Q is —C (S) NR ⁷ ) can also be synthesized by using aminothionoic acid derivatives in place of amino acid II in the above synthesis method. it can. Such aminothionoic acid derivatives are described in Shalaky et al. Org. Chem. , 61 : 9045-9048 (1996), Bra.
in et al. Org. Chem. , 62 : 3803-3809 (1997).
), And their references.

Preparation of Pharmaceuticals When used as medicaments, the compounds of formulas I and IA are usually administered in the form of a pharmaceutical composition. These compounds are administered orally, rectally, transdermally, subcutaneously, intravenously,
Administration can be by various routes, including intramuscularly, intranasally, and the like. These compounds are prepared by methods well-known in the pharmaceutical art and comprise at least one active compound.

The present invention also includes pharmaceutical compositions comprising as active ingredients one or more compounds of formulas I and IA above and an associated pharmaceutically acceptable carrier. In preparing the compositions of the present invention, the active ingredient is usually mixed with excipients,
Diluted with an excipient, or packaged in a carrier that can take the form of capsules, bags, paper, or other containers. If the excipient functions as a diluent,
The excipient serves as a solvent, carrier or medium for the active ingredient, solid, semi-solid,
Alternatively, it may be a liquid substance. Thus, the composition may be used as tablets, pills, powders, drops, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid solvents), ointments Preparations, for example, ointments, soft and hard gelatin capsules, suppositories, injectable solutions, injectable powders and the like, containing up to about 10% by weight of the active ingredient.

Before preparing the preparation and mixing the active ingredient with the other ingredients, it may be necessary to mill the active ingredient to a suitable particle size. If the active ingredient is substantially insoluble, it is usually ground to a particle size of 200 mesh. If the active ingredient is substantially water-soluble, the particle size is usually adjusted by grinding to a particle size that is substantially uniformly dispersed in the preparation, eg, about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl Includes pyrrolidone, cellulose, water, syrup, and methylcellulose. Preparations include lubricants such as talc, magnesium stearate, mineral oil, wetting agents, emulsifying and suspending agents, methyl- and propylhydroxy-
It may further contain a preservative such as benzoate, a sweetener, a flavoring agent and the like. The compositions of the present invention can also be prepared by using methods well known in the art to enable immediate, sustained, delayed release of the active ingredient after administration to the patient.

The compositions are preferably prepared in unit dosage form, each dosage being from about 5 to about 100 m
g, usually from about 10 to about 30 mg of active ingredient. The term "unit dose form" refers to physically discrete units that are optimal as unit doses for human subjects and other animals, with a fixed amount calculated within each unit to produce the desired therapeutic effect. An amount of the active substance is included with a suitable pharmaceutical excipient.

The active compounds are effective over a wide range of dosages and are generally administered in a pharmaceutically effective amount. However, the actual amount of compound administered will depend on the condition being treated, the route of administration chosen, the compound administered, the age, weight, individual response of the patient, the severity of the patient's condition, and other relevant circumstances. And will be determined by the doctor.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to make a solid preparatory composition comprising a homogeneous mixture of the compound of the invention. When we refer to these pre-prepared compositions as homogeneous, they mean that the active ingredient is dispersed homogeneously throughout the composition and the composition is easily converted into equally effective unit dose forms, such as tablets,
It means that it can be divided into pills and capsules. This solid preparatory composition is subdivided, for example, into unit doses of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or compounded to give a dosage form that provides a lasting effect. For example, a tablet or pill may include an inner dosage portion and an outer dosage portion, the latter wrapping around the former. These two
The two parts can be separated by an enteric layer, which resists disintegration in the abdominal cavity and serves to either feed the inner part directly into the duodenum or delay its release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and polymeric acids and materials such as shellac, cetyl alcohol, and cellulose acetate. And the like.

For oral administration or for administration by injection, the novel compositions of the present invention may be incorporated with liquid forms such as aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, Emulsions suitably flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil and the like, as well as elixirs and similar pharmaceutical solvents.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route to achieve a partial or systemic effect. Compositions in suitably pharmaceutically acceptable solvents can also be nebulized using an inert gas. The nebulized solution may be drawn directly from the nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure respirator. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the preparation in an appropriate manner.

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

Formulation Example 1 Hard capsules containing the following ingredients were prepared: Ingredient Amount (mg / capsule) Active Ingredient 30.0 Starch 305.0 Magnesium Stearate 5.0 Mix the above ingredients and harden in 340 mg amount Filled into gelatin capsules.

Formulation Example 2 A tablet formulation was prepared using the following ingredients: Ingredient Amount (mg / tablet) Active Ingredient 25.0 Cellulose, Microcrystalline 200.0 Colloidal Silicon Dioxide 10.0 Stearic Acid 5. 0 The ingredients were mixed and compressed to form tablets each weighing 240 mg.

Formulation Example 3 A dry powder inhalation formulation was prepared containing the following ingredients: Ingredient% by Weight Active Ingredient 5 Lactose 95 The active mixture was mixed with lactose and the mixture was added to a dry powder inhalation device.

Formulation Example 4 Tablets each containing 30 mg of active ingredient were prepared as follows: Ingredient amount (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (in water) 4.0 mg sodium carboxymethyl starch 4.5 mg magnesium stearate 0.5 mg talc 1.0 mg total 120 mg The active ingredients, starch and cellulose are no. 20 mesh U.S. S. Pass through sieve and mix thoroughly. The solution of polyvinylpyrrolidone was mixed with the resulting powder and mixed with a 16 mesh U.S.A. S. Passed through a sieve. The granules thus prepared are dried at 50 to 60 ° C. and dried at 16 mesh U.S.A. S. Passed through a sieve. No. 30 mesh U.S. S
. After passing through a sieve, sodium carboxymethyl starch, magnesium stearate and talc were added to the granules, mixed and then compressed on a tablet machine to obtain tablets weighing 150 mg each.

Formulation Example 5 Capsules each containing 40 mg of the drug were prepared as follows: Ingredient Amount (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg Active ingredient, Mix cellulose, starch, magnesium stearate and mix
. 20 mesh U.S. S. The mixture was passed through a sieve and filled into hard gelatin capsules in a fixed amount of 150 mg.

Formulation Example 6 Suppositories each containing 25 mg of the active ingredient were prepared as follows: Ingredient Amount Active ingredient 25 mg Saturated fatty acid glyceride Until 2000 mg The active ingredient was no. 60 mesh U.S. S. The mixture was passed through a sieve and suspended in the pre-dissolved saturated fatty acid glyceride using the minimum required heating. The mixture is nominally 2.
It was poured into a 0 g capacity suppository mold and allowed to cool.

Formulation Example 7 A suspension containing 50 mg each of the drug per 5.0 ml dose was made as follows: Ingredient Amount 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethylcellulose (11%) Microcrystalline cellulose (89%) 50.0 mg sucrose 1.75 g sodium benzoate 10.0 mg fragrance and coloring appropriate amount Purified water 5.0 ml Mix medicine, sucrose, and xanthan gum until 5.0 ml. 10 mesh U.S. S. The mixture was passed through a sieve and mixed with a microcrystalline cellulose prepared in advance and an aqueous solution of sodium carboxymethylcellulose. The sodium benzoate, flavor, and color were diluted with some of the water and mixed with stirring. Sufficient water was added to the required dose.

Pharmaceutical Example 8 Ingredient Amount (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg Mix active ingredient, cellulose, starch, and magnesium stearate,
No. 20 mesh U.S. S. The mixture was passed through a sieve and filled into hard gelatin capsules at a fixed amount of 560 mg.

Formulation Example 9 An intravenous formulation was made as follows: Ingredient Amount Active Ingredient 250.0 mg Saline 1000 ml

Formulation Example 10 A topical formulation was prepared as follows. Component Amount Active ingredient 1-10 g Emulsified wax 30 g Liquid paraffin 20 g White soft paraffin Up to 100 g White soft paraffin was heated until dissolved. The liquid paraffin and the emulsified wax were mixed and stirred until dissolved. The active ingredient was added and stirring continued until dispersed.
The mixture was cooled until it solidified.

Another preferred formulation for use in the methods of the present invention utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous leaching of a controlled amount of a compound of the present invention. 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. 5,023,2525, issued Jun. 11, 1991, incorporated herein by reference.
Such patches may be configured for continuous, pulsatile, or on demand delivery of the drug.

When it is desired or needed to introduce the drug into the brain, either directly or indirectly. Direct techniques typically involve placing a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system for use in transferring biological agents to a unique anatomical region of the body is described in US Pat. No. 5,011,472, which is incorporated herein by reference. You.

Indirect techniques, which are generally preferred, typically involve formulating a composition to provide drug potential by converting a hydrophilic drug into a lipophilic drug. Latent (latentiat
ion) is generally achieved via blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present in the drug to make it more lipophilic and to cross the blood-brain barrier. Alternatively, delivery of the hydrophilic drug can be increased by intra-arterial infusion of a hypertonic solution that can temporarily open the blood-brain barrier.

[0149] Utility The compounds of the present invention can be used to couple the VLA-4 in a biological sample (alpha ₄ beta ₁ integrin), and therefore in such measurement samples for VLA-4 Has utility. In such a measurement, the compound can bind to the solid support and the VLA-4 sample added to it. VL in the sample
The amount of A-4 can be measured by conventional methods, such as using a sandwich ELISA assay. Alternatively, labeled VLA-4 may be labeled with VL in the sample.
It can be used in competition assays to determine the presence of A-4. Other suitable assays are well-known in the art.

In addition, certain compounds of the invention inhibit in vivo leukocyte adhesion to endothelial cells mediated by VLA-4, and are therefore of use in the treatment of diseases mediated by VLA-4. Can be. 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 Occurs in rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral injuries, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and adult respiratory distress syndrome Includes acute leukocyte-mediated lung injury.

The biological activity of a compound as defined above may be measured in a change in the system. For example,
The compound can be immobilized on a solid surface and the attachment of cells expressing VLA-4 can be measured. A number of compounds can be screened using such a format. Suitable cells for this assay include any leukocytes known to express VLA-4, such as T cells, B cells, monocytes, eosinophils, and basophils. Numerous white blood cell lines can also be used, examples include Jurkat and U937.

The test compound may also be a labeled compound known to bind to VLA-4, such as between VLA-4 and VCAM-1, or VLA-4, and a compound of the invention or an antibody against VLA-4. Can also be tested for the ability to competitively inhibit binding to In these assays, VCAM-1 can be immobilized on a solid surface. VCAM-1 can also be expressed as a recombinant fusion protein with an Ig tail (eg, IgG) such that binding to VLA-4 can be detected in an immunoassay. Alternatively, VCAM-1 transformed fibroblasts can be used. Assays for measuring the ability to block adhesion to brain endothelial cells are described in International Patent Application Publication No. The assay described in WO 91/05038 is particularly preferred. This application is incorporated by reference in its entirety.

Many assay formats use labeled assay components. The labeling system can be used in various forms. The label can be attached directly or indirectly to the desired components of the assay according to methods well known in the art. A wide variety of labels can be used. The component can be labeled by any one of several methods. The most common method of detection is the use of autoradiography, such as with ³ H, ¹²⁵ I, ³⁵ S, ¹⁴ C, or ³² P labeled compounds. Non-radioactive labels include labeled antibodies, fluorophores, chemiluminescent agents, ligands that bind to enzymes, and antibodies that can serve as specific binding pairing members of the labeled ligand. The choice of label is based on the sensitivity required, ease of binding to the compound, stability requirements, and availability of the device.

A suitable in vivo model to demonstrate efficacy in treating an inflammatory response is
EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other α4 integrin dependent inflammation models.

Compounds having the desired biological activity provide desired properties, such as improved pharmacological properties (eg, stability in vivo, bioavailability) or the ability to be detected in diagnostic applications. May be modified as needed.
For example, the inclusion of one or more D-amino acids in the sulfonamides of the present invention is:
Typically increases in vivo stability. Stability can be measured in various ways, such as by measuring the half-life of the protein during incubation with peptidase or human plasma or serum. Many such protein stability assays have been described (eg, Verhoef et al., Eur. J. Drug).
Metab. Pharmacokinet. , 1990, 15 (2) : 83-
93).

For diagnostic purposes, a wide variety of labels can be attached, either directly or indirectly, to compounds that can provide a detectable signal. Thus, the compounds of the present subject matter can be modified in various ways for various end goals, while maintaining biological activity.
In addition, various reaction sites can be introduced at their ends to bind to particles, solid substrates, macromolecules, and the like.

The labeled compounds can be used in a variety of in vivo or in vitro.
Radionuclides (eg, gamma-emitting radioisotopes such as technetium-99 or iodine-111), fluorophores (eg, fluorescein), enzymes, enzyme substrates,
A wide variety of labels can be utilized, such as enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like. One skilled in the art will know other suitable labels for binding to the complex, or will be able to ascertain using such routine experimentation. Attachment of these labels is accomplished using standard techniques routine to those skilled in the art.

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

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

The complex can also be labeled with a paramagnetic isotope for in vivo diagnostic purposes, such as in magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known. . Generally, any conventional method for visualizing diagnostic imaging can be used. Useful gamma and positron emitting isotopes are used for camera imaging, and paramagnetic isotopes are used for MRI. Thus, the compounds can be used to monitor the direction of improvement of an individual's inflammatory response. By measuring the increase or decrease in VLA-4 expression in lymphocytes, it is possible to determine whether a specific therapeutic regimen to ameliorate the disease is effective.

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

[0162] Inflammatory bowel disease is a term that summarizes two similar diseases related to Crohn's disease and ulcerative colitis. Crohn's disease is an idiopathic, chronic ulcerative stenotic inflammatory disease characterized by a sharp demarcation of all layers of the intestinal wall and a typical transmural inclusion by a granulomatous inflammatory response. Even though the disease most commonly affects the obstruction of the lower small intestine and / or the colon, any part of the gastrointestinal tract from the mouth to the anus may
Included. Ulcerative colitis is an inflammatory response restricted to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in the intestinal site of inflammation and can contribute to inflammation damage.

Asthma is a disease characterized by an increased response of the organ bronchial system to various stimuli that increase paroxysmal stenosis of the bronchial passages. The stimulation results in the release of various mediators of inflammation from IgE-coated mast cells, including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrienes, prostaglandins and platelet activating factors. Release of these factors recruits basophils, eosinophils and neutrophils, which lead to inflammatory damage.

[0164] Atherosclerosis is a disease of the arteries (coronary, carotid, aortic and intestinal). The basic site of the atheroma consists of the innermost focal plaque with a lipid nucleus and covered by a fiber cap. Atheromas compromise the flow of arteries and weaken the affected arteries. Myocardial and cerebral infarction is a major consequence of the disease.
Macrophages and leukocytes are collected in the atheroma, resulting in inflammatory damage.

[0165] Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily results in joint damage and destruction. Rheumatoid arthritis usually affects small joints of the hands and feet, but can involve the wrists, elbows, ankles, and knees. The arthritis results from the interaction of leukocytes and synovial cells that infiltrate the synovial lining of the joint from the circulation. For example, Paul, Im
Munology (3rd edition, Raven Press, 1993).

Another indication with the compounds of the present invention is in the treatment of organ or graft rejection mediated by VLA-4. Over the years, skin, kidneys, liver, heart, lungs,
Significant improvements have been made in increasing the effectiveness of surgical techniques for transplanting tissues or organs such as the pancreas and bone marrow. Perhaps the main outstanding problem is the lack of a satisfactory agent for inducing immune tolerance in recipients to transplanted allografts or organs. When an allogeneic cell or tissue is transplanted into a host (i.e., the donor and recipient are different individuals of the same species), the host immune system will An immune response to the antigen (host-versus-graft disease) can occur. CD8 ⁺ cells, CD4 cells and monocytes are all involved in transplant rejection. Compounds of the invention that bind to alpha-4 integrin are, inter alia,
It is useful for inhibiting an allogeneic antigen-induced immune response in a recipient, thereby preventing destruction from such cells that have participated in the destruction of the transplanted tissue or organ. For example, Paul et al., Transplant International 9,
420-425 (1996); Georczynski et al., Immunolog.
y 87, 573-580 (1996); Geocyznski et al., Tran.
plant. Immunol. 3, 55-61 (1995); Yang et al., T.
transplantation 60, 71-76 (1995); Anders
on, et al., APMIS 102, 23-27 (1994).

A related use of compounds of the present invention that bind to VLA-4 is to modulate the immune response involved in “graft versus host” disease (GVHD). For example, Schle
gel et al. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal disease that occurs when immunologically competing cells are transferred to allogeneic recipients. In this context, the donor's immune competitor cells can be attacked by the tissue in the recipient. Skin, intestinal epithelium and liver tissue
Often targeted and destroyed during the course of GVHD. The disease presents a particularly dangerous problem when the immune system is being transplanted, such as in bone marrow transplants; however, less severe GVHD is also present in other similar, including heart and liver transplants. Reported in the case. Therapeutic agents of the invention are used, inter alia, to block the activation of donor T cells, thereby preventing their ability to lyse target cells in the host.

A further use of the compounds of the invention is for inhibiting tumor metastasis. Some tumor cells have been reported to express VLA-4 and that compounds that bind to VLA-4 block the attachment of such cells to endothelial cells. Steinbac
k et al., Urol. Res. 23, 175-83 (1995); Orosz et al., I.
nt. J. Cancer 60, 867-71 (1995); Freedman.
Et al., Leuk. Lymphoma 13, 47-52 (1994); Okaha
ra et al., Cancer Res. 54, 3233-6 (1994).

A further use of the compounds of the invention is for treating multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that affects approximately 250,000 to 350,000 people in the United States. Multiple sclerosis appears to be the result of specific autoimmune reactions that initiate the attack of certain leukocytes and the destruction of myelin, which separates the sheath surrounding nerve fibers. In an animal model of multiple sclerosis, a murine monoclonal antibody directed against VLA-4 has been shown to inhibit leukocyte adherence to the endothelium and prevent central nervous system inflammation and subsequent paralysis in animals. ¹⁶ has been.

The pharmaceutical compositions of the present invention are suitable for use in various drug delivery systems. Formulations suitable for use in the present invention are Remington's Pha
rmaceutical Sciences, Mace Publishing
Company, Philadelphia, PA, 17th ed. (19
85).

To increase serum half-life, the compound can be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be used to extend the serum half-life of the compound. Can be used to provide a period. Various methods are described, for example, in US Pat. No. 4,235,87 to Szoka et al., Each of which is incorporated herein by reference.
No. 1, 4,501,728 and 4,837,028 are available for making liposomes.

The dosage administered to the patient will vary based on how it is to be administered, the purpose of the administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the composition is administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An appropriate amount to accomplish this is defined as "therapeutically effective dose." The effective amount for this use will depend on the condition of the disease to be treated and will also be determined by the attending physician based on such factors as severity of inflammation, age, weight and overall condition of the patient. Will be made by judgment.

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

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

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

[0176]

EXAMPLES In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. aq or aq. = Aqueous AcOH = acetic acid bd = global doublet bm = global multiplet bs = global singlet Bn = benzyl Boc = N-tert-butylcarbonyl Boc ₂ O = di-tert-butyl dicarbonate BOP = benzotriazole-1-yloxy- Tris (dimethylamino) phosphonium hexafluorophosphate Cbz = carbobenzyloxy CHCl ₃ = chloroform CH ₂ Cl ₂ = dichloromethane (COCl) ₂ = oxalyl chloride d = doublet dd = doublet doublet dt = doublet doublet DBU = 1.8- Diazabicyclo [5.4.0] undec-7-ene DCC = 1.3-dicyclohexylcarbodiimide DMAP = 4-N, N-dimethylaminopyridine DME = ethylene glycol dimethyl ether DM = N, N-dimethylformamide DMSO = dimethylsulfoxide EDC = 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et ₃ N = Triethylamine Et ₂ O = diethyl ether EtOAc = ethyl acetate EtOH = ethanol eq or eq. = Equivalent Fmoc = N-(9-fluorenyl methoxy carbonyl) FmocONSu = N- (9- fluorenyl methoxy carbonyl) - succinimide g = grams h = hours H ₂ O = water HBr = hydrobromic acid HCl = hydrochloric acid HOBT = 1-hydroxybenzotriazole hydrate hr = time K ₂ CO ₃ = potassium carbonate L = liter m = multiplet MeOH = methanol mg = milligram MgSO ₄ = magnesium sulfate mL = milliliter mm = millimeter mM = millimol mmol = mmol mp = melting point N = normal concentration NaCl = sodium chloride Na ₂ CO ₃ = sodium NaHCO ₃ = sodium hydrogen carbonate NaOEt = sodium ethoxide NaOH = sodium hydroxide NH ₄ Cl = ammonium chloride NM = N- methylmorpholine Phe = L-phenylalanine Pro = L-proline psi = pounds per square inch PtO ₂ = platinum oxide q = quartet quint. = Quintet rt = room temperature s = singlet sat = saturated t = triplet t-BuOH = tert-butanol TFA = trifluoroacetic acid THF = tetrahydrofuran TLC or tlc = thin layer chromatography Ts = tosyl Tsyl chloride Microliter

In the following examples, all temperatures are in degrees Celsius (unless otherwise indicated). The following method was used to make the compounds described below as indicated.

Method 1 N-Tosylation Method N-tosylation of the appropriate amino acids was performed according to Cupps, Boutin and Rapopo.
rt J.R. Org. Chem. 1985, 50, 3972.

Method 2 Method for Preparing Methyl Ester Amino acid methyl esters were prepared as described in Brenner and Huber Helv. Chi
m. It was prepared using the method of Acta 1953, 36, 1109.

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

Method 4 Hydrogenation Method I Hydrogenation was carried out using 10% palladium on carbon (10% by weight) at 30 psi overnight.
Ran with 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 LiOH (or NaOH) was added to a cooled (0 ° C.) solution of the appropriate ester in THF / H ₂ O (2: 1, 5-10 mL) (0.95 equivalents). . The temperature was kept at 0 ° C. and the reaction was completed in 1-3 hours. The reaction mixture was extracted with ethyl acetate and the aqueous phase was lyophilized to give the desired carboxylate.

Method 6 Ester Hydrolysis Method II LiOH (or NaOH) was added to a cooled (0 ° C.) solution of the appropriate ester in THF / H ₂ O (2: 1, 5-10 mL) (1.1 equivalents). ). The temperature was kept at 0 ° C. and the reaction was completed in 1-3 hours. The reaction mixture was concentrated, water was added to the residue and the pH was adjusted to 2-3 with aqueous HCl. As the reaction mixture was extracted with ethyl acetate, the combined organic phases washed with brine, dried over MgSO _4, and concentrated to obtain the filtered and the acid is desired.

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

Method 8 Sulfonylation Procedure I To a suitably protected aminophenylalanine analog (11.2 mmol) dissolved in methylene chloride (25 ml) and cooled to -78 ° C., followed by dropwise addition of pyridine (2 mL) To the sulfonyl chloride (12 mmol). The solution was warmed to room temperature and stirred for 48 hours. The reaction solution is mixed with methylene chloride for 250 minutes.
Transfer to a mL separatory funnel and extract with 1N HCl (50 mL × 3), brine (50 mL), and water (100 mL). The organic phase was dried (MgSO4) and evaporated to give the desired product.

Method 9 Reductive Amination Method The reductive amination of Tos-Pro-p-NH2-Phe with the appropriate aldehyde is treated with acetic acid, triacetoborohydride, methylene chloride and the combined mixture is treated at room temperature at room temperature. Stirred 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 ° C. for 15 minutes, and the reaction mixture was stirred for 3 hours. The solution was concentrated to syrup, dissolved in Et ₂ O, and reconcentrated. This procedure was repeated and the resulting solid was placed under high vacuum overnight.

Method 11 Tert-butyl ester hydrolysis method I Tert-butyl ester was dissolved in CH ₂ Cl ₂ and treated with TFA. The reaction was complete in 1-3 hours until the reaction mixture was concentrated, the residue was dissolved in water to give the desired acid and lyophilized.

Method 12 EDC Coupling Method I To a solution of N- (toluene-4-sulfonyl) -L-proline (1 equivalent) in CH ₂ Cl ₂ was added the appropriate amino acid ester hydrochloric acid (1 equivalent), N-methylmorpholine ( 1.1
-2.2 eq) and 1-hydroxybenzotriazole (2 eq) were mixed, placed on an ice bath, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.1 eq) was added. The reaction was warmed to room temperature and stirred overnight. Pour the mixture reaction into H ₂ O, the organic phase was washed with saturated NaHCO _3, brine, dried (MgSO ₄ or Na ₂ SO _4), filtered, and and 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 (5-20 mL) was added the appropriate amino acid ester hydrochloride (1 eq), Et ₃ N (1.1 eq) And 1-hydroxybenzotriazole (2 eq) were mixed, placed on an ice bath, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.1 eq) was added. The reaction was warmed to room temperature and stirred overnight. The mixture reaction was partitioned between EtOAc and H ₂ O, the organic phase 0.2N citric acid, H ₂ O, saturated NaHCO _3, washed with brine, dried (MgSO ₄ or Na ₂ SO _4), filtered And concentrated. The crude product was purified by column chromatography or pre-TLC.

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

Method 15 Sulfonylation Method III L-Pro-L-4- (3-dimethylaminopropyloxy) in CH ₂ Cl ₂
-Phe-OMe [prepared using the method described in Method 10] (1 equivalent)
Adding suitable sulfonyl chloride Following (1.1 eq) Et ₃ N (5 eq). The reaction was warmed to room temperature and stirred overnight under nitrogen at atmospheric pressure. The combined reaction was concentrated, dissolved in EtOAc and washed with saturated NaHCO ₃ , 0.2N citric acid. The aqueous phase was made basic with solid NaHCO ₃ and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO ₄ or Na ₂ SO _4), and filtered and concentrated. The crude methyl ester was purified by preparative TLC. The corresponding acid was prepared using the method described in Method 7.

Method 16 Hydrogenation Method II To a solution of azlactone in methanol (10-15 mL) was added NaOAc (1 equivalent).
And 10% Pd / C. The mixture was placed in a hydrogenation vessel at 40psiH _2. After 8-16 hours, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to yield dehydrodipeptide methyl ester. Esters thereof 0.5 N NaOH (1.05 equivalents) was added dioxane / H ₂ O (5-1
0 mL). After stirring for 1-3 hours, the reaction mixture was concentrated, redissolved the residue to H ₂ O, washed with EtOAc. The aqueous phase was acidified with 0.2N HCl and the product was extracted with EtOAc. Wash the organic phase with brine (1 × 5 mL),
Dried (MgSO ₄ or Na ₂ SO _4), almost filtered and the acid of diastereomers 1: concentrated to obtain 1 mixture.

Method 17 Tert-Butyl Ester Hydrolysis Method II Dissolve tert-butyl ester in CH ₂ Cl ₂ (5 mL) and add TFA (5 mL).
). The reaction is complete in 1-3 hours to the point where the reaction mixture is concentrated and concentrated by dissolving the residue in H ₂ O. The residue was redissolved to H ₂ O, lyophilized to obtain the desired product.

Example 1 (2) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylglycyl) amino] -L-phenylalanine N- (toluene- 4-Sulfonyl) -L-prolyl-4-aminophenylalanine methyl ester (2.00 g, 4.67 mmol) was added to Boc-glycine (
1.1 _{eq, 0.9g), Et 3 N (} 2.2 eq, 1.43 mL), and BOP reagent (1.1 eq, 2.27 g) with, was dissolved in 50mL of dry DMF.
The reaction mixture was stirred at room temperature for 12 hours. EtOAc (100 mL) was added. The organic phase was washed with saturated NaHCO ₃ (50 mL), 10% citric acid (20 mL), and brine (5 × 50 mL). The organic phase was dried over MgSO _4. Following evaporation of the solvent under reduced pressure, the crude material was eluted by column chromatography (silica gel; CHCl ₃ / MeOH 9: 1). The desired ester (1.90 g, 3.1 mmol) was isolated in 66% yield. Its ester is _{then, MeOH: H 2 O [1} : 1] (40mL) NaOH (1.1 eq, 1 76 mg) in was treated with 4 hours at room temperature. EtOAc was added as well as water. The aqueous phase was collected, acidified to pH 2.5 with 1N HCl and re-extracted with EtOAc. The organic phase of their was dried over MgSO _4. The title compound was isolated as an oil in 73% yield by filtration and evaporation of the solvent under reduced pressure (1.33 g, 2.26).
mmol).

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.65 (bs, 1H), 7
. 70 (d, 2H, J = 7.98 Hz), 7.50 (d, 1H, J = 7.14H)
z), 7.45 (d, 2H, J = 8.10 Hz), 7.32 (d, 2H, J = 7)
. 80 Hz), 7.11 (d, 2H, J = 8.00 Hz), 5.75 (bs, 1
H), 4.82 (m, 1H), 4.11 (m, 1H), 3.90 (bs, 2H)
, 3.38 (m, 1H), 3.21 3.10 (m, 3H), 2.41 (s, 3
H), 1.99 (m, 1H), 1.55 (m, 3H), 1.43 (s, 9H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 174.03, 172.19, 169.02, 157.28, 145.03, 137.17, 133.34,
132.58, 130.59, 128.44, 120.65, 81.16, 62
. 85, 54.05, 50.31, 37.34, 30.69, 28.87, 24
. 89, 22.14, 14.77.

Mass Spec: (FAB) 589 (M + H).

Example 2 (7) N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino]-
Synthesis of L-phenylalanine The product from Example 1 (1.33 g, 2.26 mmol) was treated with trifluoroacetic acid (1.00 mL) in dry dichloromethane (20 mL) and the reaction mixture was allowed to stand at room temperature for 12 hours. Stirred. The solvent was distilled off under reduced pressure. The crude material was left under vacuum overnight with a vacuum pump, then dissolved in methanol and cooled to 0 ° C. Ethyl ether was added and the product was collected as trifluoroacetate in 50% yield (660 mg, 1.09 mmol).

The NMR data were as follows: ¹ H NMR (300 MHz, CD ₃ OD): δ = 7.51 (d, 2H, J = 8).
. 25 Hz), 7.31 (d, 2H, J = 8.25 Hz), 7.19 (d, 2H)
, J = 7.92 Hz), 7.03 (d, 2H, J = 8.25 Hz), 4.43 (
m, 1H), 3.87 (m, 1H), 3.63 (s, 2H), 3.13-2.8.
2 (m, 4H), 2.21 (s, 3H), 1.56-1.26 (m, 4H).

¹³ C NMR (75 MHz, CD ₃ OD): δ = 174.39, 165.97, 146.34, 139.50, 135.38, 135.21, 131.28,
129.57, 121.47, 67.47, 63.86, 51.16, 42.7
2, 38.39, 32.20, 25.87, 22.09, 16.02.

Mass Spec: (FAB) 489 (M +).

Example 3 (23) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (carboxy) propionamido] -L-phenylalanine N- (toluene-4-sulfonyl) -L-Prolyl-4-aminophenylalanine methyl ester (455 mg, 1 mmol) was added to dry DMF with Et ₃ N (1.1 eq, 153 μL) and succinic anhydride (1.1 eq, 110 mg).
(10 mL). The desired monoester is obtained as a foam in a 53% yield (2%).
88 mg, 0.52 mmol). The monoester (80 mg, 0
. (15 mmol) was then hydrolyzed with NaOH (2.2 eq, 15 mg) in MeOH: H ₂ O 1: 1 (5 mL) at room temperature for 4 hours. EtOAc and water were added. The aqueous phase was collected, acidified to pH 2.5 with 1N HCl and re-extracted with EtOAc. The organic phase was dried over MgSO _4. The diacid was isolated as a foam by filtration and evaporation of the solvent under reduced pressure.

The NMR data were as follows: ¹ H NMR (300 MHz, CD ₃ OD): δ = 7.51 (d, 2H, J = 8).
. 31 Hz), 7.28 (d, 2H, J = 8.34 Hz), 7.19 (d, 2H)
, J = 8.10 Hz), 6.99 (d, 2H, J = 8.43 Hz), 4.48 (
m, 1H), 3.91 (m, 1H), 3.17-2.83 (m, 4H), 2.4
3 (s, 4H), 2.21 (s, 3H), 1.44-1.29 (m, 4H).

¹³ C NMR (75 MHz, CD ₃ OD): δ = 176.87, 174.68, 174.53, 173.30, 149.74, 146.31, 139.33,
135.50, 134.24, 131.61, 131.44, 129.53, 1
21.66, 80.05, 63.81, 55.37, 51.17, 38.25,
32.87, 32.24, 30.55, 25.89, 22.11.

Mass spec: (FAB) 532 (M + H).

Example 4 (27) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonyl-L-alanyl) amino] -L-phenylalanine Example 1 ( Following the experimental method described for 2), N- (toluene-4-sulfonyl) -L-prolyl-4-aminophenylalanine methyl ester (0.1
5 g, 0.337 mmol) were added to Et ₃ N (2.0 eq, 95 μL), Boc-L-alanine (1.1 eq, 70 mg), and BOP (1.1 eq, 163 mg)
) Together with 5 mL of dry DMF. The desired methyl ester was isolated as an oil in 49% yield (102 mg, 0.16 mmol). The ester was then hydrolyzed with NaOH (1.1 eq, 8 mg) in a 1: 1 MeOH: H ₂ O solution (4 mL). The monoacid was isolated in quantitative yield as an amorphous solid.

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 9.00 (broad s,
1H), 7.70 (d, 2H, J = 8.25 Hz), 7.45 (d, 2H, J =
8.37 Hz), 7.32 (d, 2H, J = 8.25 Hz), 7.09 (d, 2
H, J = 8.25 Hz), 5.65 (bs, 1H), 4.82 (m, 1H), 4
. 35 (bs, 1H), 4.11 (m, 1H), 3.38-3.12 (m, 4H
), 2.40 (s, 3H), 1.95 (m, 1H), 1.53 (m, 3H), 1
. 40 (s, 12H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 174.71, 172.40, 172.09, 156.72, 144.98, 137.62, 133.43,
132.21, 130.58, 128.48, 120.47, 80.98, 62
. 87, 54.05, 51.10, 50.31, 37.23, 30.73, 28
. 88, 24.92, 22.16, 18.89.

Mass spec: (FAB) 603 (M + H).

Example 5 (28) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonyl-D-alanyl) amino] -L-phenylalanine Example 1 ( Following the experimental method described in 2), N- (toluene-4-sulfonyl) -L-prolyl-L-4-aminophenylalanine methyl ester (0.15
g, the 0.337mmol), Et ₃ N (2.0 eq, 95μL), Boc-D - alanine (1.1 eq, 70 mg), and BOP (1.1 eq, 163 mg)
With 5 mL of DMF. The desired methyl ester was isolated as an oil in 33% yield (68 mg, 0.11 mmol). The ester is then:
Hydrolysis with NaOH (1.1 eq, 5 mg) in 1 MeOH: H ₂ O solution (4 mL). The monoacid was isolated as a film in a quantifiable yield.

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.90 (broad s,
1H), 7.70 (d, 2H, J = 8.25 Hz), 7.45 (d, 2H, J =
8.37 Hz), 7.32 (d, 2H, J = 8.25 Hz), 7.09 (d, 2
H, J = 8.25 Hz), 5.65 (bs, 1H), 4.82 (m, 1H), 4
. 35 (bs, 1H), 4.11 (m, 1H), 3.38-3.12 (m, 4H
), 2.40 (s, 3H), 1.95 (m, 1H), 1.53 (m, 3H), 1
. 40 (s, 12H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 174.71, 172.40, 172.09, 156.72, 144.98, 137.62, 133.43,
132.21, 130.58, 128.48, 120.47, 80.98, 62
. 87, 54.05, 51.10, 50.31, 37.23, 30.73, 28
. 88, 24.92, 22.16, 18.89.

Mass spec: (FAB) 603 (M + H).

Example 6 (29) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonyl-D-phenylalanyl) amino] -L-phenylalanine Following the experimental method described in 1 (2), N- (toluene-4-sulfonyl) -L-prolyl-4-aminophenylalanine methyl ester (0.15 g,
0.337 mmol) was added to Et ₃ N (2.0 eq, 95 μL), Boc-D-phenylalanine (1.1 eq, 99 mg), and BOP (1.1 eq, 163 m).
g) and treated with 5 mL of DMF. The desired methyl ester was isolated as an oil in 16% yield (37 mg, 0.05 mmol). The ester was then hydrolyzed with NaOH (1.1 eq, 3 mg) in a 1: 1 MeOH: H ₂ O solution (2 mL). The monoacid was isolated as an amorphous solid in a quantifiable yield.

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.56 (broad s,
1H), 7.73 (d, 2H, J = 8.13 Hz), 7.43-7.22 (m,
10H), 7.09 (d, 2H, J = 7.95 Hz), 5.78 (m, 1H),
4.87 (m, 1H), 4.65 (m, 1H), 4.11 (m, 1H), 3.4
4 (m, 1H), 3.29-3.01 (m, 4H), 2.43 (s, 3H), 2
. 08 (m, 1H), 1.60 (m, 3H), 1.33 (s, 9H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 171.88, 171.44, 170.02, 156.56, 144.96, 137.23, 136.83,
133.46, 132.78, 130.53, 130.33, 129.92, 1
29.36, 128.44, 127.64, 120.63, 81.16, 62.
84, 53.96, 50.26, 38.91, 37.90, 30.35, 28.
81, 24.96, 22.11.

Mass spec: (FAB) 679 (M + H).

Example 7 (67) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (fluorescein) thiouried] acetamido} -L-phenylalanine Example 2 (7) Of NaHCO ₃ and fluorescein isothiocyanate (isomer I-Aldrich Chemical) in EtOH and H ₂ O.
l company). Acidification of the mixture and separation of the resulting precipitate gave the title compound as an amorphous orange solid.

Mass spec: (+ FAB, 3-nitrobenzyl alcohol) 878 (MH +).

Example 8 (175) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonylglycyl) amino] -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L-prolyl-L- (4-nitro) phenylalanine methyl ester (2.00 g, 4.48 mmol) was added in a catalytic amount of 1
Dissolved in MeOH (10 mL) with 0% Pd on C. The hydrogenation reaction is 4
Performed at room temperature at 0 psi for 12 hours. Shortly after filtration of the reaction mixture through celite, the solvent was distilled off under reduced pressure to give a quantitative yield as a pink foam. The title compound was prepared therefrom using the method described in Method 12 and with N-Boc glycine.

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.72 (d, 2H, J = 8).
. 13 Hz), 7.45 (d, 2H, J = 8.49 Hz), 7.35 (d, 2H)
, J = 8.30 Hz), 7.10 (d, 2H, J = 8.37 Hz), 5.40 (
m, 1H), 4.82 (m, 1H), 4.07 (m, 1H), 3.91 (s, 2
H), 3.76 (s, 3H), 3.40 (m, 1H), 3.23 (m, 1H),
3.05 (m, 2H), 2.43 (s, 3H), 2.43 (m, 1H), 1.4
6 (m, 12H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 177.61, 171.97, 171.58, 168.52, 144.93, 137.25, 133.43,
132.55, 131.36, 130.54, 130.33, 128.39, 1
20.53, 80.50, 62.81, 54.00, 53.08, 50.25
37.83, 30.42, 28.93, 28.87, 24.81, 2.14.

Mass spec: (FAB) 603 (M + H).

Example 9 (306) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-methylphenyl) uried] acetamido} -L-phenylalanine methyl ester The methyl ester was made by the reaction of 2- (3-m-tolyl-ureido) acetic acid with N- (toluene-4-sulfonyl) -L-propyl-L- (4-amino) phenylalanine (BOP, trimethylamine, DMF, stirred overnight at room temperature). The crude product was purified by flash chromatography (silica, 9: 1 EtOAc: hexane) to give the methyl ester. The methyl ester was hydrolyzed with 1M LiOH in THF. The title compound was isolated as a white solid following acid / base treatment.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.8 (br s, 1 H); 9.96 (s, 1 H); 8.70 (S, 1H); 8.04 (d, 1H, J
= 7.9 Hz); 7.68 (d, 2H, J = 8 Hz); 7.48 (d, 2H, J
= 8.3 Hz); 7.39 (d, 2H, J = 8.3 Hz); 7.21 (s, 1H).
); 7.16 (d, 3H, J = 8.56 Hz); 7.08 (t, 1H, J = 7.
6.7 (d, 1H, J = 7.68 Hz); 6.38 (t, 1H, J
= 5.6 Hz); 4.43 (m, 1H); 4.1 (dd, 1H, J = 3.18,
3.89 (d, 2H, J = 5.49 Hz); 3.3 (m, 1H)
); 3.05 (m, 2H); 2.92 (dd, 1H, J = 8.34, 13.63).
Hz); 2.38 (s, 3H); 2.22 (s, 3H); 1.38-1.62 (
m, 4H).

IR (KBr, cm ⁻¹ ): 3380, 2990, 1650, 1605, 154
0, 1230, 1155, 660, 580, 545.

Mass Spec: ((+) FAB, m / e (%) 644 (100 [M + Na] +);
22 (25 [M + H] +).

Example 10 (380) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (L-aspartyl) amino] -L-phenylalanine Boc-L- of Boc-glycine Substitution of aspartic acid benzyl ester and method for preparation of Examples 1 (2) and 2 (7) resulted in mp = 163-170 ° C.
To give the title compound as a white solid.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ ): δ = 8.05 (d, 1H), 7.70 (d, 1H), 7.45 (dd, 4H). ), 7.18 (d, 2H), 4.40 (m, 1H)
), 4.10 (m, 1H), 2.40 (s, 3H), 1.60 (m, 6H) Mass spec: (FAB) (M + H) ^<+> 547.

Example 11 (14) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxybenzyloxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-L-tyrosine methyl ester (1.32 g, 2.95 mmol) was dissolved in DMF (50 mL) at room temperature. To this was added K ₂ CO ₃ (1.1 eq, 440 mg) and ethyl α-bromophenylacetate (1.1 eq, 750 mg). The reaction was stirred at room temperature for 12 hours.
Ethyl acetate was added and the organic phase was washed several times with brine. The organic phase was dried over MgSO ₄ . After filtration and evaporation of the solvent under reduced pressure, the residue is treated with NaOH (1
. (1 equivalent, 427 mg) and isolated in MeOH: H ₂ O 1: 1 (30 mL). The desired diacid is obtained in 88% yield (754 mg, 1.33 mmol)
Isolated.

The NMR data were as follows: ¹ H NMR (300 MHz, CD ₃ OD): δ = 7.50 (d, 2H, J = 8).
. 25 Hz), 7.35 (d, 2H, J = 7.14 Hz), 7.15 (m, 5H
), 6.95 (d, 2H, J = 8.13 Hz), 6.71 (d, 2H, J = 8.
37Hz), 5.48 (s, 1H), 4.51 (m, 1H), 3.87 (m, 1
H), 3.10-2.79 (m, 4H), 2.15 (s, 3H), 1.45-1.
. 01 (m, 4H).

¹³ C NMR (75 MHz, CD ₃ OD): δ = 174.71, 174.49, 173.98, 158.25, 146.39, 138.08, 135.37,
132.28, 131.74, 130.53, 130.36, 129.60, 1
29.00, 117.18, 79.95, 63.94, 55.31, 38.00
, 32.23, 25.88, 22.32, 15.22.

Mass spec: (FAB) 567 (M + H).

Example 12 (15) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenyl] -L-phenylalanine The product of Example 13 (178) was Treated with NaOH in dioxane and water,
After acidification, extraction, drying over MgSO ₄ , filtration and concentration, the title compound was obtained as a clear oil.

The NMR data were as follows: ¹ H NMR (CD ₃ ODw / CD ₃ ONa, 300 MHz): δ = 7.75 (d, J = 8.2, 2H), 7.44- 7.40 (m, 5H), 7.29-7.2
1 (m, 5H), 4.47 (t, J = 5.8, 1H), 4.03 (dd, J = 8
. 5, J = 3.4, 1H), 3.37-3.25 (m, 2H), 3.17-3.
06 (m, 2H), 1.89-1.80 (m, 1H), 1.64-1.47 (m
, 3H).

¹³ C NMR (CD ₃ ODw / CD ₃ ONa, 75 MHz): δ = 179.1,
177.5, 173.1, 145.8, 142.4, 141.3, 139.6,
137.8, 134.7, 131.0, 130.6, 130.5, 129.4,
129.1, 128.7, 128.1, 127.6, 63.6, 57.0, 50
. 7, 38.7, 31.7, 25.2, 21.5.

Mass spec: (+ FAB, glycerin) 537 (MH +).

Example 13 (178) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (methoxycarbonyl) phenyl] -L-phenylalanine benzyl ester L-4-Indophenylalanine [Phe (4-I) -OH] is replaced with MeOH and H
After treatment with Cl gas and concentration, HCloPhe (4-I) -OMe was obtained. This product was dissolved in DMF in N- (toluene-4-sulfonyl) -L-Pro-OH,
EDAC, give HOBT, and treated with Et ₃ N, after aqueous work N- (toluene-4-sulfonyl) -L-Pro-L-Phe and (4-I) -OMe. This product is treated in THF with Pd (PPh ₃ ) ₄ and 2- (methoxycarbonyl) phenyl zinc iodide prepared by the method of Rieke (J. Org. Chem. 199 1, 56, 1445), After aqueous work-up and flash chromatography, the title compound was obtained as a clear oil.

The NMR data were as follows: ¹ H NMR (CDCl ₃ , 300 MHz): δ = 7.81 (d, J = 7.7,
1H), 7.72 (d, J = 8.2, 2H), 7.54-7.49 (m, 1H).
, 7.42-7.16 (m, 9H), 4.93-4.86 (m, 1H), 4.1
1-4.07 (m, 1H), 3.80 (s, 3H), 3.64 (s, 3H), 3
. 42-3.28 (m, 2H), 3.15-3.08 (m, 2H), 2.43 (
s, 3H), 2.09 to 2.04 (m, 1H), 1.58 to 1.45 (m, 3H
).

¹³ C NMR (CDCl ₃ , 75 MHz): δ = 171.3, 170.8, 169.1, 144.3, 141.9, 140.1, 135.0, 132.9, 1
31.2, 130.8, 130.6, 129.9, 129.7, 129.0, 1
28.4, 127.8, 127.1, 62.2, 53.3, 52.5, 52.0
, 49.7, 37.6, 29.7, 24.2, 21.5.

Mass spec: (+ FAB, 3-nitrobenzyl alcohol) 565 (MH +).

Example 14 (35) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbobenzyloxyamino) ethyl] amino} -L-phenylalanine Following the experimental method described for the synthesis of Example 3 (23), Example 15 (17
The product from 2) (32 mg, 0.051 mmol) was added to MeOH: H ₂ O 1:
Hydrolysis with NaOH (1.1 eq, 3 mg) in 1 (1 mL). The title compound was isolated in quantitative material as a foam.

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.68 (m, 2H), 7.
30 (m, 5H), 7.20 (m, 2H), 4.77 (m, 1H), 4.46 (
m, 1H), 4.18 (m, 2H), 3.65 (m, 1H), 3.47 (m, 1
H), 3.12 (m, 2H), 2.78 (s, 1.5H), 2.54 (s, 1.H).
5H), 2.42 (s, 3H), 1.26 (m, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 171.47, 170.31, 144.78, 136.42, 135.77, 130.67, 129.88,
129.33, 127.80, 62.44, 60.99, 60.81, 54.0
0, 53.77, 38.32, 32.19, 31.96, 22.24, 14.7
6.

Mass spec: (FAB) 449 (M + H).

Example 15 (172) N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbobenzyloxyamino) ethyl] amino} -L-phenylalanine methyl ester ester synthesis N- (toluene-4-sulfonyl) -L- prolyl -L-p-amino - phenylalanine methyl ester (316 mg, 0.7 mmol) and, NaCNBH ₃ (10.0 eq, 446 mg), and carbobenzyloxy Glycinal (1.1
KOAc-HOAc solution (10 mL) [pH 6.5] in dry methanol. The reaction mixture was stirred overnight at room temperature, then the solvent was distilled off under reduced pressure. EtOAc was added and the organic phase was washed with brine, dried through a MgSO _4. After filtration and evaporation of the solvent, the crude material was eluted on a conditioning plate (silica gel, EtOAc / hexane 1: 1). The desired title compound was isolated as a film in 5% yield (40 mg, 0.06 mmol).

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.71 (d, 2H, J = 6).
. 90Hz), 7.38 (m, 5H), 7.26 (m, 2H), 6.93 (d,
2H, J = 7.20 Hz), 6.54 (d, 2H, J = 7.50 Hz), 5.1
2 (m, 1H), 5.10 (s, 2H), 4.73 (m, 1H), 4.06 (m
, 1H), 3.75 (s, 3H), 3.41 (m, 4H), 3.26 (m, 1H).
), 3.14 (m, 2H), 2.99 (m, 1H), 2.43 (s, 3H), 2
. 04 (m, 1H), 1.53 (m, 3H).

Mass spec: (FAB) 623 (M + H).

Example 16 (368) N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [3- (N, N-dimethylamino) propyl] -N- [trifluoromethanesulfonyl] amino Synthesis of -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) phenylalanine methyl ester was prepared in pyridine to form the corresponding trifluoromethanesulfonamide. Reacted with trifluoromethanesulfonyl anhydride. This compound was alkylated on the nitrogen of the trifluoromethanesulfonamide group under Mitsunobu conditions with 3-dimethylamino-1-propanol in THF. After evaporation of the solvent and aqueous washing, the mixture was purified by filtration, mp = 45-
The product was obtained as a solid at 55 ° C.

The NMR data were as follows: ¹ H NMR (CDCl ₃ , 400 Mhz): δ = 7.70 (d, 2H);
34 (d, 3H); 7.25 (m, 3H); 4.88 (m, 1H); 4.10 (
m, 1H); 3.85 (brd s, 2H); 3.79 (s, 3H); 3.32
(M, 2H), 3.08 (m, 2H); 2.43 (s, 3H); 2.18 (br
ds, 5H); 1.98 (brd s, 1H); 1.75-1.30 (brd
m, 9H).

IR (KBr, cm-1): 3400; 2970; 2800; 1750; 16
75; 1525; 1450; 1400; 1350; 1225; 1200; 116
5; 1150; 1100; 1075; 1000; 950; 825; 675; 60
0; 550.

Mass spec: (+ FAB) 663 ([M + H] +); 603; 507; 438;
06; 191; 155; 91.

Example 17 (510) N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N, N-di [4- (N, N-dimethylamino) benzyl] amino} -L Synthesis of -Phenylalanine The methyl ester is 4-N, N-dimethylaminobenzaldehyde and N-
(Toluene-4-sulfonyl) -L-prolyl-L-4-aminobenzyl-L-
Phenylalanine was stirred overnight at room temperature (acetic acid, sodium triacetoxyborohydride, methylene chloride) and prepared by reductive amination. The crude product was purified by flash chromatography and the methyl ester was hydrolyzed in the manner of Method 6 to provide the title compound.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.7 (d, 2H, J = 8.34 Hz); 7.54 (d, 1H, J = 5.71 Hz); 7.40 (d, 1
H, 8.34 Hz); 7.02 (d, 4H, J = 8.78 Hz); 6.75 (d
, 2H, J = 8.78 Hz); 6.62 (d, 4H, J = 8.78 Hz);
48 (d, 2H, J = 8.78 Hz); 4.39 (s, 4H); 3.92 (dd
, 1H, J = 2.85, 9.0 Hz); 3.78 (m, 1H); 3.33 (s,
12H); 2.86 (m, 4H); 2.39 (s, 3H); 1.62 (m, 1H).
); 1.30 (m, 1H); 1.09 (m, 2H).

IR (KBr, cm ⁻¹ ) 3380, 1610, 1520, 1400, 1350
, 1160, 800, 670.

[0257] Elemental analysis _{C 39 H 46 N 5 O 5} Li3H 2 O Calculated: C, 61.76; H, 6.9 1; N, 9.23. Found: C, 61.73; H, 6.91; N, 9.15.

Example 18 (138) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Triphenylphosphine (24. 4 g, 92.9 mmol) and 3-dimethylamino-1-propanol (8.72 g, 84.5 mmol) were added to THF (200
mL) and chilled in an ice bath. Diethyl azodicarboxylate (16.2
g, 14.6 mL, 92.9 mmol) was added dropwise via syringe over 5 minutes and prior to addition of N-Boc-tyrosine methyl ester (24.95 g, 94.5 mmol) as a solution in 100 mL THF via cannula. And further stirred for 10 minutes. The mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 19 hours. The mixture was concentrated on a rotary evaporator and placed in Et ₂ O (500mL). The mixture was extracted with 0.2N HCl (3 × 350 mL) and the combined acidic extracts were basified with NaHCO ₃ . The mixture was extracted with EtOAc (3 × 300 mL) and the combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give N-Boc-L-4- (3-dimethylaminopropyloxy). )
Phenylalanine methyl ester (26.5 g, 82%) was obtained.

N-Boc-L-4- (3-N, N-dimethylaminopropyloxy) phenylalanine methyl ester (26.5 g, 69.5 mmol) was added to MeOH (30
0 mL) and saturated with HCl gas. The mixture was stirred for 3 hours until the volatile components were distilled off, and L-4- (3-N, N-dimethylaminopropyloxy) -L-
Phenylalanine methyl ester dihydrochloride (23.6 g, 90%) was obtained.

N- (Toluene-4-sulfonyl) -L-proline hydrate was converted to L-4- (3-N, N-dimethylaminopropyloxy) -L using the procedure described in Method 13.
-Phenylalanine methyl ester bound to dihydrochloride, and N- (toluene-4-sulfonyl) -L-prolyl-L-4- (3-N, N-dimethylaminopropoxy) phenylalanine methyl ester (16.3 g, 89% ) Got. The title compound was prepared via hydrolysis of the methyl ester with 0.5N NaOH in THF / water (14.71 g, 99%).

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ ): δ = 7.75 (d, 2H, J = 8.2 Hz), 7.67 (d, 1H, J = 5.6 Hz), 7.42 (d, 2H, J = 8.2H)
z), 7.00 (d, 2H, J = 8.5 Hz), 6.71 (d, 2H, J = 8.
5 Hz), 3.98 (m, 2H), 3.90 (t, 2H, J = 6.5 Hz), 3
. 14-2.97 (4H), 2.40 (s, 3H), 2.32 (t, 2H, J =
7.0 Hz), 2.13 (s, 6H), 1.83-1.75 (3H), 1.45
-1.36 (3H).

¹³ C NMR (DMSO-d ₆ ): δ = 173.5, 169.7, 157.2,
144.1, 133.7, 130.9, 130.3, 128.1, 113.9,
65.9, 62.4, 56.0, 55.4, 49.4, 45.5, 36.1, 3
0.5, 27.3, 23.9, 21.4.

Mass spec: FABm / e562 (M + 2Na-H).

Example 19 (282) Synthesis of N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3- (N, N-dimethylaminopropoxy] -L-phenylalanine methyl ester N -Methyl-N- (toluene-p-sulfonyl) -L-serine (655 mg,
2.4 mmol) was converted to L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester hydrochloride [see Example 18 (138) for preparation]
(1.0g, 2.4mmol), HOBT ( 1.1 _{eq, 356mg), Et 3 N (} 3.2 eq, 1.1 mL), and EDC (1.1 eq, 500 mg) and in the process 13 together Treated in DMF (100 mL) according to the procedure described. The title compound was isolated as an oil in 70% yield (900 mg, 1.7 mmol).

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.68 (d, 2H, J = 8).
. 40 Hz), 7.29 (d, 2H, J = 8.10 Hz), 7.08 (d, 1H)
, J = 7.80 Hz), 7.04 (d, 2H, J = 8.70 Hz), 6.82 (
d, 2H, J = 8.70 Hz), 4.71 (m, 1H), 4.43 (m, 1H)
, 3.94 (t, 2H, J = 6.60 Hz), 3.75 (s, 3H), 3.69
(M, 1H), 3.51 (m, 1H), 3.14 (m, 1H), 2.91 (m, 1H)
1H), 2.59 (s, 3H), 2.45 (m, 2H), 2.42 (s, 3H)
, 2.20 (s, 6H), 1.87 (m, 2H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 172.04, 170.15, 158.66, 144.56, 136.02, 130.72, 130.46
128.19, 127.87, 115.31, 66.70, 60.86, 60.
65, 56.87, 54.01, 53.08, 45.95, 37.39, 31.
85, 27.91, 2.13.

Mass spec: (FAB) 536 (M + H).

Example 20 (284) N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-
Synthesis of 4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine Triphenylphosphine (1.1 equivalents) and 3-dimethylamino-1-propanol (1 equivalent) were dissolved in THF, and ice bath was applied. Chilled inside. Diethyl azodicarboxylate (1 equivalent) was added dropwise via syringe over 5 minutes and N-Boc-tyrosine methyl ester (1.0 eq.) As a solution in 100 mL THF via cannula.
(2 eq) before stirring for an additional 10 minutes. The mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 19 hours. The mixture was concentrated on a rotary evaporator and placed in Et ₂ O (500mL). The mixture was added to 0.2N HCl (3 ×
Extracted with 350 mL), the NaHCO ₃ The combined acidic extract was made basic. The mixture was extracted with EtOAc (3 × 300 mL) and the combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give N-Boc-L-4- (3-dimethylaminopropyloxy). Phenylalanine methyl ester was obtained.

N-Boc-L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester (26.5 g, 69.5 mmol) was added to MeOH (300 mL).
And saturated with HCl gas. The mixture was stirred for 3 hours until the volatile components were distilled off to obtain L-4- (3-dimethylaminopropyloxy) -L-phenylalanine methyl ester dihydrochloride (23.6 g, 90%).

N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaproline was converted to L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester using the procedure described in Method 13. Binds to dihydrochloric acid and reacts with N- (toluene-4
-Sulfonyl) -L- (5,5-dimethyl) -L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester (16.3 g, 89%) was obtained. The title compound was prepared via hydrolysis of the methyl ester with 0.5 N NaOH in THF / water and was obtained as a solid, mp => 200 ° C (dec.).

The NMR data were as follows: ¹ H NMR (CD ₃ OD, 300 MHz): δ =. 85 (s, 3H),. 94
(S, 3H), 1.78 (m, 2H), 2.23 (s, 3H), 2.28 (s,
6H), 2.57 (m, 2H), 2.83 (m, 2H), 3.71-3.74 (
m, 2H), 4.22-4.27 (m, 2H), 4.41 (d, 1H, J = 9.
1 Hz), 6.58 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J =
8.6 Hz), 7.20 (d, 2H, J = 8.3 Hz), 7.54 (d, 2H,
J = 8.3 Hz).

¹³ C NMR (CD ₃ OD, 75 MHz): δ = 22.2, 25.3, 27. 8, 30.5, 39.4, 45.2, 51.9, 56.0, 57.6, 58.2
, 67.2, 75.1, 115.8, 129.8, 131.6, 132.1, 1
32.5, 135.41, 46.7, 159.5, 170.9, 178.2.

Mass spec: (FAB +) 586 (M + H).

HPLC Analysis: (Microsorb-MVC18 Rev. Phase, 4.
Run # 1: 2. 6 × 150 mm; 1: 1 CH ₃ CN / H ₂ O with a concentration gradient of 0.05% TFA; flow rate = 1.0 ml / min; l = 254 nm; sample volume = 20 mL).
988 minutes retention time (100.0% purity) Run # 2: 3.098 minutes retention time (1
00.0% purity).

Example 21 (287) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine -Dimethylaminoethanol to 3-dimethylamino-1-
Prepared as in Example 20 (138), except substituting for propanol.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ ): δ = 7.74 (d, 2H, J = 7.4 Hz), 7.67 (d, 1H, J = 7.9 Hz), 7.42 (d, 2H, 8.0 Hz)
, 7.01 (d, 2H, J = 7.9 Hz), 6.71 (d, 2H, J = 7.8 H)
z), 3.95 (m, 4H), 3.14-2.98 (4H), 2.57 (t, 2
H, J = 5.6 Hz), 2.40 (s, 3H), 2.18 (s, 6H), 1.7
4 (m, 1H), 1.40 (m, 3H).

¹³ C NMR (DMSO-d ₆ ): δ = 173.5, 169.7, 157.0,
144.1, 133.8, 131.0, 130.9, 130.3, 128.1,
113.9, 66.0, 62.4, 58.0, 55.4, 49.4, 45.9,
36.2, 30.5, 23.9, 21.4.

Mass spec: FABm / e504 (M + H).

Example 22 (317) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N-ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester The ester is reacted with 2- (N-ethyl, N-phenyl) aminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.
Prepared via O-alkylation of (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester. The title compound was prepared using the method described in Method 7.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 1.08 (3H, t, J = 8,8 Hz); 1.39 (1H, m) 1.55 (3H, m); 2.19 (3
H, s); 2.85-3.0 (2H, m); 3.12 (1H, dd, J = 6.1)
0,6 Hz); 3.41 (2H, q, J = 6, 8, 6 Hz); 3.6 (3H, s
); 3.62 (2H, t, J = 5.5 Hz); 4.01 (2H, t, J = 5.5).
Hz); 4.04 (1H, t, J = 8, 8 Hz); 4.43 (1H, dd, J =
6.56 (1H, t, J = 8.8 Hz); 6.65 (2H,
d, J = 10 Hz); 6.8 (2H, d, J = 10 Hz); 7.1 (4H, m)
7.38 (2H, d, J = 10 Hz); 7.64 (2H, d, J = 10 Hz)
8.1 (1H, d, J = 10 Hz).

MS: + FAB, m / z 594 ([MH] +, 45%), 157 (100%).

Example 23 (321) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-diisopropylamino) ethoxy] -L-phenylalanine N- (toluene-4) with 2-diisopropylaminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide
-Sulfonyl) -L-prolyl-L-tyrosine methyl ester prepared via O-alkylation. The title compound was prepared using the method described in Method 7, mp = 121-
Prepared as a solid at 124 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 0.9 (12H, d, J = 8 Hz); 1.25-1.6 (3H, m); 1.78 (1H, m); 2.38
(3H, s); 2.7 (2H, t, J = 8.8 Hz); 2.9 (2H, m);
. 0 (2H, q, J = 5, 5, 5 Hz); 3.1 (1H, dd, J = 3, 4, 3)
Hz); 3.35 (1H, s); 3.78 (1H, t, J = 7, 7 Hz);
8. (2H, t, J = 5.5 Hz); 3.95 (1H, d, J = 10 Hz);
5 (1H, d, J = 10 Hz); 6.65 (1H; d, J = 10 Hz); 6.8
5 (1H, d, J = 10 Hz); 6.9 (1H, d, J = 10 Hz); 7.4 (
7.62 (1H, m); 7.75 (2H, d, J = 2H, d, J = 10 Hz);
10 Hz).

MS: + FAB, m / z 560 ([MH] +, 70%), 154 (100%).

Example 24 (333) Synthesis of N- (thiophen-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine And white, hygroscopic solid, mp => 20
Isolated at 0 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 300 Mhz): δ = 8.03 (br s, 1 H); 7.74 (m, 2H); 7.26 (Br s, 1H); 7.04 (d, 2
H, J = 7.0 Hz); 6.75 (d, 2H, J = 6.0 Hz); 4.16 (m
4.06 (m, 1H); 3.85 (m, 2H); 3.33 (m, 1H).
); 3.13-3.00 (br m, 3H); 2.62 (m, 2H); 2.35
(S, 3H); 1.90 (m, 2H); 1.75 (m, 1H); 1.90-1.
50 (br m, 3H), ¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 173.4, 169.9,
157.3, 136.1, 134.3, 133.5, 130.8, 130.3,
128.7, 128.7, 114.1, 65.7, 62.5, 55.1, 54.
9, 49.7, 43.9, 36.1, 30.6, 25.9, 24.1, 21.6
.

Mass spec: (PI-FAB) 532, (M) ⁺ .

Example 25 (334) Synthesis of N- (chlorothiophen-2-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine White, hygroscopic solid, mp => 200 ° C
As isolated.

The NMR data are as follows: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 7.62 (m, 2H); 7.44 (m, 2H); 6.99 (m, 2H) 6.71 (m, 2H); 4.0
5 (m, 1H); 3.92 (m, 3H); 3.26 (m, 1H); 3.09-2
. 97 (br m, 3H); 2.31 (m, 2H); 2.13 (s, 6H); 1
. 82 (m, 2H); 1.79-1.51 (br m, 4H).

¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 173.3, 169.3
157.2, 137.3, 134.3, 132.5, 130.9, 130.9,
119.8, 113.9, 65.9, 62.8, 56.0, 55.5, 49.7
, 45.5, 36.1, 30.6, 27.2, 24.0, 22.8.

Mass spec: (PI-FAB) 588, (M + Na) ⁺ .

Example 26 (336) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-diethylamino) ethoxy] -L-phenylalanine Prepared via O-alkylation of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2-diethylaminoethyl chloride in refluxing 2-butanone in the presence of potassium and sodium iodide did. The title compound was prepared using the method described in Method 7, mp = 105-10
Prepared as a 9 ° C. solid.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 1.0 (6H, t, J = 8,8 Hz); 1.25-1.45 ( 4H, m); 1.65 (2H, m);
18 (3H, s); 2.26 (2H, t, J = 2, 2 Hz); 2.65 (4H,
q, J = 5, 4, 5 Hz); 2.8-3.1 (4H, M); 3.84 (1H, d)
d, J = 5, 4, 5 Hz); 3.9 (2H, t, J = 3.3 Hz); 4.1 (1
H, d, J = 8 Hz); 6.68 (2H; d, J = 10 Hz); 6.95 (2H
, D, J = 10 Hz); 7.05 (2H, d, J = 10 Hz); 7.4 (2H,
7.63 (1H, d, J = 4 Hz); 7.73 (2H, t)
, J = 4.4 Hz).

MS: + ESI, m / z 532.4 ([MH] +, 100%).

Example 27 (340) Synthesis of N- (2,5-dichlorothiophen-3-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Compounds were prepared using Method 15 and were white, hygroscopic solids, mp => 200 ° C.
As isolated.

The NMR data are as follows: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 7.77 (d, 1H, J = 6.6 Hz); 7.43 (s, 1H); 07 (d, 2H, J = 7.4 Hz
); 6.76 (d, 2H, J = 7.4 Hz); 4.33 (m, 1H); 4.15
(M, 1H); 3.89 (t, 2H, J = 6.1 Hz); 3.29 (m, 2H)
2.97 (m, 2H); 2.57 (t, 2H, J = 7.1); 2.31 (s,
6H); 1.85 (m, 4H); 1.65 (m, 2H).

¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 173.4, 172.5,
170.0, 157.3, 134.2, 130.8, 130.5, 130.3,
127.7, 126.9, 114.1, 65.8, 61.9, 55.3, 54.
9,49.2,44.2,36.2,30.9,26.1,24.3,21.6
.

Mass spec: (PI-FAB) 600, (M) ⁺ .

Example 28 (341) Synthesis of N- (1-methylpyrazole-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Its chloride N -Methylpyrazolesulfonyl was prepared by adding N-methylpyrazole to cold (0 ° C) chlorosulfonic acid. The reaction mixture was warmed to room temperature and then heated to 100 ° C. under a stream of N ₂ overnight. The reaction mixture was then cooled to room temperature and then to 0 ° C. To this solution is added thionyl chloride (
2.5 eq.) And the reaction stirred at room temperature for 30 minutes, then at 70 ° C. for 2 hours
Heated. The reaction was cooled to room temperature and further in an ice bath. Water and ice were slowly added to the reaction and a white solid was collected by filtration. The desired sulfonyl chloride was washed with cold water and hexane. The title compound was prepared using Method 15 and isolated a white, hygroscopic solid, mp => 200 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 8.44 (s, 1H); 7.89 (s, 1H); 7.66 (d , 1H, J = 5.6 Hz); 7.00 (d
, 2H, J = 8.5 Hz); 6.70 (d, 2H, J = 8.6 Hz); 3.89
(M, 4H); 3.87 (s, 3H); 3.14-2.98 (br m, 4H)
2.34 (t, 2H, J = 7.2 Hz); 2.30 (s, 6H); 1.86 (
m, 3H); 1.81-1.75 (br m, 3H).

¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 172.3, 169.8,
157.2, 138.9, 133.7, 130.9, 130.8, 117.4,
113.9, 65.9, 62.5, 55.9, 55.3, 49.5, 36.0,
30.6, 27.2, 23.9.

Mass spec: (PI-FAB) 530, (M) ⁺ .

Example 29 (346) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine methyl ester N- (toluene-4-) with 3-diethylaminopropyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide
Prepared via O-alkylation of (sulfonyl) -L-prolyl-L-tyrosine methyl ester.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 1.0 (6H, bs); 1.4-1.6 (4H, m); 1 .85 (2H, m); 2.18 (3H, s);
2.5 (2H, bs); 2.5-2.8 (4H, bs); 2.9 (2H, m);
3.1 (1H, dd, J = 8, 10, 8 Hz); 3.35 (1H, dd, J = 8)
3.6 (3H, s); 3.94 (2H, t, J = 6.6 Hz).
4.1 (1H, m); 4.48 (1H, dd, J = 8, 6, 8 Hz); 6.8
(2H, d, J = 10 Hz); 7.1 (2H, d, J = 10 Hz); 7.4 (2
H, d, J = 10 Hz); 7.7 (2H, d, J = 10 Hz); 8.2 (1H,
d, J = 10 Hz).

MS: + ESI, m / z 560.5 ([MH] +, 100%).

Example 30 Synthesis of N- (thiazol-2-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine The sulfonyl chloride was obtained from Roblin and Clapp, JACS, 72, 489
Prepared from thiols as taught in U.S. Pat. The title compound was prepared using Method 15 and isolated as a white, hygroscopic solid, mp => 200 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 8.24 (d, 1H, J = 3.1 Hz); 8.15 (d, 1H; 3.13); 7.63 (d, 1H, J
= 5.0 Hz); 6.98 (d, 2H, J = 8.6 Hz); 6.70 (d, 2H)
, J = 8.6 Hz); 4.24 (m, 1H); 3.88 (m, 3H); 3.36
(M, 2H); 3.28-2.98 (m, 2H); 2.31 (t, 2H, J = 7)
. 0 Hz); 2.12 (s, 6H); 1.83-1.79 (br m, 4H);
1.79 (m, 1H); 1.45 (m, 1H).

¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 172.3, 168.9,
162.5, 157.2, 145.5, 131.0, 130.9, 127.5,
113.8, 65.9, 63.3, 56.1, 55.5, 50.1, 45.6,
38.8, 38.5, 35.9, 30.7, 27.3, 24.0.

Mass spec: (PI-FAB) 555, (MH + Na) ⁺ .

Example 31 (353) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine From the product of Example 33 (356) using Method 7.
mp = 87-90 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 7.75 (d, 2H, J = 10 Hz); 7.65 (d, 1H, J = 7.4 (d, 2H, J = 1)
0 Hz); 7.18-7.3 (m, 5H); 6.96 (d, 2H, J = 10 Hz)
); 6.65 (d, 2H, J = 10 Hz); 3.97 (d, 1H, J = 4 Hz)
3.91 (t, 2H, J = 4, 4 Hz); 3.8 (q, 1H, J = 2, 2, 2)
Hz); 3.42 (s, 2H); 2.95-3.1 (m, 4H); 2.42 (t
, 2H, J = 8.8 Hz); 2.38 (s, 3H); 2.08 (s, 3H);
. 85 (t, 2H, 6, 6 Hz); 1.7 (m, 1H); 1.3 (bs, 4H)
.

Example 32 (354) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine Method described in Method 7 From the product of Example 29 (346) using a solid
It was prepared as p = 76-82 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 1.0 (6H, t, J = 8, 8 Hz); 1.38 (2H, m) 1.4-1.8 (4H, m); 2.38
(3H, s); 2.45 (2H, t, J = 7, 7 Hz); 2.6 (4H, q, J
= 6, 5, 6 Hz); 2.95 (2H, m); 3.05 (1H, dd, J = 5,
3.15 (1H, dd, J = 4, 5, 4 Hz); 3.9 (2H,
4.1 (1H, t, J = 6.6 Hz); 4.1 (1H, t, J = 5.5 Hz);
m); 6.7 (2H, d, J = 10 Hz); 6.95 (2H, d, J = 10 Hz)
); 7.4 (2H, d, J = 10 Hz); 7.7 (1H, d, J = 4 Hz);
. 75 (2H, d, J = 10 Hz).

Example 33 (356) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine methyl ester The compound was prepared by N- (toluene-4-sulfonyl) -L-prolyl-L with 3- (N-benzyl, N-methyl) aminopropyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. Prepared via O-alkylation of -tyrosine methyl ester to give a solid, mp = 60-70 ° C.

Example 34 (372) Synthesis of N- (1-methylimidazole-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Prepared using Method 15, and isolated as white, hygroscopic, mp => 200 ° C.

¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 7.86 (s, 1H); 7.82 (s, 1H); 7.63 (d, 1H, J = 5.6 Hz); 6.96 (d
, 2H, J = 8.2 Hz); 6.97 (d, 2H, J = 8.6 hz); 4.12
-4.09 (br m, 1H); 3.89 (t, 2H, J = 6.5 Hz);
70 (s, 3H); 3.13 (m, 2H); 3.00 (m, 2H); 2.33 (
t, 2H, 7.2 Hz); 2.13 (s, 6H); 1.82-1.75 (m, 3
H); 1.60-1.40 (br m, 3H).

¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 172.8, 169.9,
157.2, 140.7, 136.1, 130.9, 126.6, 113.9,
65.9, 62.9, 56.0, 55.3, 49.7, 45.5, 35.9, 3
33.9, 30.6, 27.3, 24.0, 21.9.

Mass Spec: (PI-FAB) 552, (MH + Na) ⁺ .

Example 35 (373) Synthesis of N- (2-methylthiadiazole-5-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Sulfonyl chloride The products were Roblin and Clapp, JACS, 72, 48
Prepared from thiols as taught in US Pat. The title compound was prepared using Method 15 and isolated as a white, hygroscopic solid, mp => 200 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 7.66 (d, 1H, J = 3.2 Hz); 7.02 (d, 2H, J = 8.5 Hz); 6.72 (d, 2H)
, J = 8.2 Hz); 4.28 (t, 1H; 5.8 Hz); 3.96-3.89.
(Br m, 3H); 3.37-3.23 (br m, 2H); 3.02 (m,
1H); 2.95 (m, 1H); 2.82 (s, 3H); 2.39 (t, 2H,
J = 7.0 Hz); 2.13 (s, 6H); 1.83 (m, 3H); 1.80 −
1.40 (m, 3H).

¹³ C NMR (DMSO-d ₆ , 75 MHz): δ = 173.2, 170.9,
169.0, 165.9, 157.2, 130.9, 130.8, 113.9,
65.9, 63.1, 56.0, 55.6, 50.1, 45.4, 32.2, 3
0.9, 27.2, 24.1, 22.3, 15.9.

Mass Spec: (PI-FAB) 548, (M) ⁺ .

Example 36 (393) Synthesis of N- (toluene-4-sulfonyl) -L-thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine The title compound was L- Prepared as in Example 18 (138), except that thiaproline was used instead of L-proline.

The NMR data were as follows: ¹ H NMR (300 MHz, CD ₃ OD): δ = 7.57 (d, 2H, J = 8).
. 40 Hz), 7.20 (d, 2H, J = 8.10 Hz), 6.92 (d, 2H)
, J = 8.40 Hz), 6.58 (d, 2H, J = 8.40 Hz), 4.50 (
dd, 1H, J = 4.20, 7.50 Hz), 4.45 (d, 1H, J = 10.
50 Hz), 4.17 (m, 1H), 3.87 (d, 1H, J = 10.50 Hz)
), 3.76 (t, 2H, J = 6.00 Hz), 3.10 (m, 1H), 2.9
9 (m, 2H), 2.80 (m, 1H), 2.55 (m, 2H), 2.35 (m
, 1H), 2.25 (s, 6H), 2.22 (s, 3H), 1.79 (m, 2H)
).

¹³ C NMR (75 MHz, CD ₃ OD): δ = 177.75, 170.46, 159.43, 146.91, 135.93, 132.42, 131.73,
129.80, 115.75, 67.25, 57.90, 57.70, 52.9
2,45.30,38.33,34.73,27.94,24.74,22.1
6.

Mass Spec: (FAB) 546 (M + H).

Example 37 (472) N- (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine methyl Synthesis of Ester The title compound was prepared according to the method outlined for the preparation of Example 20 (284).

The NMR data are as follows: ¹ H NMR (CDCl ₃ ): δ 7.98-7.95 (d, 2H), 7.83
-7.80 (d, 2H), 7.06-7.03 (d, 2H), 6.80-6.7
7 (d, 2H), 4.80 (m, 1H), 4.48 (m, 1H), 3.95 (m
, 3H), 3.73 (s, 3H), 3.02 (m, 2H), 2.45 (m, 2H)
), 2.26 (s, 6H), 1.94 (m, 2H), 1.21 (s, 3H), 1
. 17 (s, 3H).

¹³ C NMR (CDCl ₃ ): δ 179.9, 168.2, 158.8, 141.1, 133.7, 130.9, 128.1, 117.9, 115.2, 7
4.2, 66.7, 56.9, 55.3, 53.9, 53.0, 51.1, 46
. 0, 38.0, 29.9, 28.8, 24.4.

Example 38 (514) N- (toluene-4-sulfonyl) -L- (thiamorpholine-3-carbonyl)
Synthesis of -4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine L-thiamorpholine-5-carboxylic acid was synthesized from Larsson and Carlson (
Acta Chemica Scan. 1994, 48, 517-527). N- (Toluene-4-sulfonyl) -L-thiamorpholine-5-carboxylic acid was used in the procedure described in Method 1. The title compound was prepared according to the method outlined for the preparation of Example 20 (284).

The NMR data were as follows: ¹ H NMR (CD ₃ OD): δ 7.53-7.47 (m, 2H), 7.20.
-7.14 (m, 2H), 7.00-6.85 (m, 2H), 6.58-6.5
4 (m, 2H), 4.70-4.57 (m, 1H), 4.22-4.14 (m,
1H), 3.77-3.71 (m, 3H), 3.25-3.09 (m, 1H),
2.93-2.69 (m, 4H), 2.44 (m, 3H), 2.22 (s, 3H)
), 2.18 (s, 6H), 1.92 (m, 1H), 1.68 (m, 2H).

¹³ C NMR (CD ₃ OD): δ 177.9, 177.8, 169.6, 169.6, 159.6, 159.5, 146.3, 146.1, 138.9, 1
38.9, 132.8, 132.4, 131.8, 130.5, 129.8, 1
29.2, 126.9, 115.8, 115.7, 67.4, 58.1, 57.
8, 57.1, 45.6, 44.9, 38.8, 37.9, 28.2, 28.2
, 27.9, 26.6, 26.3, 24.7, 22.1.

Example 39 (169) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-Prolyl-L-tyrosine methyl ester (2.14 g, 5.16 mmol) in a suspension of sodium hydride (60% in oil, 1.1 eq, 228 mg) in xylene (50 mL) at 0 ° C. Added. The reaction mixture was stirred for 5 minutes and cuprous bromide dimethyl sulfide complex (1.4 eq, 1.48 g) was added. The reaction mixture was stirred at 23 ° C. for 0.5 hours. 2
-Sodium benzoate iodide (1.5 eq, 8.06 mmol) was added and the reaction mixture was refluxed for 12 hours. EtOAc (100 mL) was added and the organic phase was washed with NH ₄ Cl, 10% HCl, and brine, and dried over MgSO ₄ .
The crude material was eluted on a column chromatography (silica gel) with CHCl ₃ : MeOH 9: 1 and the title compound was isolated as an oil.

The NMR data were as follows: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.16 (broad d,
1H), 7.73 (m, 2H), 7.47 (m, 2H), 7.35 (m, 2H)
, 7.21 (m, 2H), 7.03 (m, 2H), 6.76 (m, 1H), 4.
85 (m, 1H), 4.07 (m, 1H), 3.77 (s, 3H), 3.41 (
m, 1H), 3.28 (m, 1H), 3.09 (m, 2H), 2.44 (s, 3
H), 2.05 (m, 1H), 1.55 (m, 3H).

Mass spec: (FAB) 567 (M + H).

Example 40 (309) N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [4- (pyrimidin-2-yl) piperazin-2-yl] ethoxy} -L- Synthesis of Phenylalanine The methyl ester was prepared by the Mitsunobu reaction of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester according to the procedure described for the preparation of Example 20 (284). The title compound was prepared using the method described in Method 7 as a solid, mp = 102-105 ° C.

The NMR data are as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 1.35 (4H, s); 1.4 (1H, m); 1.76 (1H, m) 2.38 (3H, s); 2.5 (
2.66 (2H, t, J = 8.8 Hz); 2.9-3.1 (4H, m);
m); 3.68 (4H, t, J = 5.5 Hz); 3.8 (1H, q, J = 4, 6)
, 4 Hz); 3.95 (1H, dd, J = 2, 10, 2 Hz); 4.05 (2H
, T, 6, 6 Hz); 6.6 (1H, t, J = 5.5 Hz); 6.7 (2H, d
, J = 10 Hz); 6.96 (2H, d, J = 10 Hz); 7.4 (2H, d,
7.65 (1H, d, J = 4 Hz); 7.74 (2H, d, J)
= 10 Hz); 8.35 (2H, d, J = 5 Hz).

Example 41 (310) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (piperidin-1-yl) propoxy] -L-phenylalanine The methyl ester of which is potassium carbonate And N- (toluene-) with 1- (2-chloropropyl) piperidine in refluxing 2-butanone in the presence of sodium iodide.
Prepared via O-alkylation of 4-sulfonyl) -L-prolyl-L-tyrosine methyl ester. The title compound was prepared as a solid, mp = 122-125 ° C., using the procedure described in Method 7.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 7.74 (d, 2H, J = 10 Hz); 7.65 (d, 1H, J = 7.4 (d, 2H, J = 1)
6.96 (d, 2H, J = 1 Hz); 6.65 (d, 2H, J = 1)
0 Hz); 3.96 (dd, 1H, J = 2, 6, 2 Hz); 3.9 (t, 3H,
J = 7.7 Hz); 2.95-3.1 (m, 4H); 2.46 (t, 1H, J =
2.38 (s, 3H); 2.33 (t, 2H, J = 8.8 Hz)
2.24 (m, 2H); 1.78 (m, 3H); 1.45 (t, 4H, J = 5)
, 5 Hz); 1.38 (m, 4H).

Example 42 (311) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine The methyl ester of which is potassium carbonate And N- (toluene-4) with 1- (2-chloroethyl) pyrrolidine in the presence of sodium iodide and 2-butanone reflux.
-Sulfonyl) -L-prolyl-L-tyrosine methyl ester prepared via O-alkylation. The title compound was obtained as a solid using the procedure described in Method 7.
mp = 127-130 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 7.73 (d, 2H, J = 10 Hz); 7.65 (d, 1H, J = 7.4 (d, 2H, J = 1)
6.95 (d, 2H, J = 10 Hz); 6.65 (d, 2H, J = 1)
3.95 (t, 3H, J = 4.6 Hz); 3.7 (q, 1H, J = 2)
, 4.2 Hz); 2.95-3.1 (m, 4H); 2.72 (t, 2H, J = 6).
, 6 Hz); 2.48 (m, 3H); 2.38 (s, 3H); 1.74 (m, 1
H); 1.64 (t, 4H, J = 4, 4 Hz); 1.42 (m, 1H); 1.3
7 (s, 3H).

Example 43 (316) of N- (toluene-4-sulfonyl) -L-prolyl-4- {3- [4- (3-chlorophenyl) piperazin-l-yl] propoxy} -L-phenylalanine Synthesis The methyl ester is N- (toluene-4-sulfonyl) with 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine in 2-butanone reflux in the presence of potassium carbonate and sodium iodide. Prepared via O-alkylation of -L-prolyl-L-tyrosine methyl ester. The title compound was prepared as a solid, mp = 116-8 ° C., using the procedure described in Method 7.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 7.74 (d, 2H, J = 10 Hz); 7.65 (d, 1H, J = 7.4 (d, 2H, J = 1)
0 Hz); 7.2 (t, 1H, J = 8.8 Hz); 6.96 (d, 2H, J = 1)
6.9 (s, 1H); 6.85 (d, 1H, J = 10 Hz); 6.7
5 (d, 1H, J = 10 Hz); 6.7 (d, 2H, J = 10 Hz); 3.95
(D, 2H, J = 8 Hz); 3.92 (t, 1H, J = 8.8 Hz); 3.83
(Q, 1H, J = 5, 4, 5 Hz); 3.6 (t, 1H, 5.5 Hz); 3.1
5 (t, 4H, J = 4, 4 Hz); 2.95-3.1 (m, 4H); 2.5 (m
, 3H); 2.45 (t, 2H, J = 8.8 Hz); 2.38 (s, 3H); 1
. 84 (t, 2H, J = 7.7 Hz); 1.75 (m, 1H); 1.4 (q, 1
H, J = 8, 10, 8 Hz) 1.35 (s, 2H).

Example 44 (318) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-O-[(1-tert-butoxycarbonyl) -piperidin-3-yl) methyl] -L-tyrosine methyl ester is present in the presence of potassium carbonate and sodium iodide. Prepared via O-alkylation of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with N-Boc-3-piperidine methyl tosylate in refluxing 2-butanone. Mp = 60-62 ° C.

The title compound was solid using the procedure described in Method 7, solid, mp = 82-8.
Prepared as 4 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.77 (br s, 1H), 8.00 (d, 1H, J = 7.9 Hz). ); 7.68 (d, 2H, J = 8)
. 7.39 (d, 2H, J = 7.9 Hz); 7.13 (d, 2H, J
= 8.6 Hz); 6.81 (d, 2H, 8.6 Hz); 4.42 (m, 1H),
4.10 (m, 1H), 3.78 (m, 3H); 3.07 (dd, 1H, J = 9)
. 2.95 (dd, 1H, J = 19 Hz, 5.1 Hz); 2
. 90 (dd, 1H, J = 19 Hz); 2.8 (m, 2H); 1.80 (m, 2
H); 1.58 (m, 4H); 1.34 (brs 14H).

IR (KBr, cm ⁻¹ ): 3400, 2900, 1745, 1700, 152
5,1450,1350,1250,1160,850,800,700,65
0,600.

Mass spec: (FAB, m / e (%)) 652 (75, (M + Na ⁺ )); 53 0.2 (75); 224 (100).

Example 45 (322) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine The methyl ester is N-(-chloromethyl) morpholine
Prepared by alkylation (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester (cesium carbonate, DMF at 60 ° C. under argon for 72 h). The product was purified by flash column chromatography (silica, EtOAc) to give the methyl ester as an off-white, foam. The title compound was solid, mp = 99-, using the procedure described in Method 6.
Prepared as 101 ° C.

The NMR data were as follows: NB: ¹ H NMR with trace Tos-Pro-Phe (NMR) (DMSO-d ₆ , 400 MHz): δ = 7.73 (d, 2H, J) = 8.6 Hz); 7.62 (d, 1H, J = 5.5 Hz); 7.40 (d, 2H)
, J = 8.2 Hz); 6.69 (d, 2H); 3.95 (m, 3H), 3.8 (
m, 1H); 3.55 (m, 4H); 3.1 (m, 3H); 2.62 (t, 2H).
, J = 4 Hz); 2.4 (m, 4H); 2.38 (s, 3H); 1.7 (m, 2
H); 1.4 (m, 3H).

IR (KBr, cm ⁻¹ ): 3400, 2950, 2850, 1610, 151
0,1425,1340,1245,1150,1125,825,800,6
75,575,525.

Mass spec: (FAB, m / e (%)) 552 (100, (M + H ⁺ )).

Example 46 (325) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (piperidin-l-yl) ethoxy] -L-phenylalanine 20 (284) according to the procedure described for the preparation of piperidine ethanol and N- (toluene-4-sulfonyl) -L-prolyl-
Prepared by Mitsunobu reaction of L-tyrosine methyl ester. The title compound is
Prepared using the procedure described in Method 7 as a solid, mP = 102-106 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.73 (d, 2H, J = 8 Hz); 7.60 (d, 1H, J = 5.5 Hz); 7.39 (d, 2H, J
= 8 Hz); 6.96 (d, 2H, J = 8.6 Hz); 6.68 (d, 2H, J
= 8.6 Hz); 3.96 (m, 3H), 3.84 (dd, 1H J = 5.2
4.8 Hz); 2.97-3.10 (m, 4H); 2.56 (t, 2H, J = 5)
. 9 Hz); 2.38 (brs, 6H); 1.72 (m, 1H); 1.34-
1.48 (m, 10H).

IR (KBr, cm ⁻¹ ): 3400, 2900, 1660, 1610, 151
0, 1450, 1350, 1150, 875, 675, 600, 500. Mass spectrometry: (FAB, m / e ( %)) 542 (100, (M-H -)); 19 6 (10); 155 (75).

Example 47 (326) N- (toluene-4-sulfonyl) -L-propyl-4- {3- [4- (3-chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine Synthesis of the tyl ester The methyl ester was synthesized with N- (toluene-4-l) by 1- (2-chlorophenyl) -4- (3-chloropropyl) piperazine in the presence of potassium carbonate and sodium iodide and refluxing 2-butanone. Prepared via O-alkylation of (sulfonyl) -L-prolyl-L-tyrosine methyl ester.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 8.2 (d, 1H, J = 10 Hz); 7.68 (d, 2H, J = 7.4 (d, 2H, J = 1)
0 Hz); 7.19 (t, 1H, J = 8, 8 Hz); 7.13 (d, 2H, J =
6.9 (s, 1H); 6.85 (d, 1H, J = 10 Hz);
82 (d, 2H, J = 10 Hz); 6.75 (d, 1H, J = 10 Hz);
45 (q, 1H, J = 8, 5, 8 Hz); 4.08 (t, 1H, J = 4, 4 Hz)
); 3.94 (t, 2H, J = 5.5 Hz); 3.3 (s, 3H); 3.12 (
bs, 4H); 3.1 (t, 1H, J = 8.8 Hz); 2.96 (m, 2H);
2.47 (m, 3H); 2.38 (s, 3H); 1.85 (t, 2H, J = 6)
6 Hz); 1.57 (m, 3H); 1.4 (m, 1H).

MS: EI, m / z 682/684 ([MH] +, 18%), 209 (26%).

Example 48 (327) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepan-1-yl) ethoxy] -L-phenylalanine The title compound was prepared in Method 7. Prepared from the product of Example 49 (328) using the procedure described as a solid, mp: 105-107 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 7.75 (t, 2 H, J = 8, 8 Hz); 7.45 (d, 1 H, J = 8 Hz); 7.4 (t, 2H, J =
8.05 (d, 1H, J = 10 Hz); 6.96 (d, 1H, J)
6.7 (d, 1H, J = 10 Hz); 4.1 (t, 1H, J = 5).
, 5 Hz); 3.92 (t, 3H, J = 8.8 Hz); 3.82 (m, 1H);
3.6 (t, 1H); 2.8 (t, 2H, J = 6.6 Hz); 2.66 (d, 4)
H, J = 5 Hz); 2.5 (d, 3H, J = 10 Hz); 1.76 (t, 1H,
1.65 (m, 1H); 1.5 (bs, 6H); 1.43 (t,
1.36 (m, 2H); 1.28 (s, 1H);
15 (s, 1H).

Example 49 (328) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepan-1-yl) ethoxy] -L-phenylalanine methyl ester The title compound was carbonate N- (toluene-4) with 2- (hexamethylene-imino) ethyl chloride in refluxing 2-butanone in the presence of potassium and sodium iodide
Prepared via O-alkylation of -sulfonyl) -L-prolyl-L-tyrosine methyl ester to give a solid, mp = 60-65 ° C.

Example 50 (347) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine methyl ester The methyl ester is N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl with 3- (N-methylpiperazine) propyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide Prepared via O-alkylation of an ester.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 8.2 (t, 1 H, J = 10, 10 Hz); 7.7 (t, 2 H, J = 10,12 Hz); 7.4 (d, 2
H, J = 10 Hz); 7.1 (t, 2H, J = 10, 10 Hz); 6.8 (d,
2H, J = 10 Hz); 4.44 (q, 1H, J = 4, 6, 6 Hz); 4.1 (
dd, 1H, J = 14, 8, 8 Hz); 3.93 (t, 2H, J = 6.6 Hz)
3.6 (s, 3H); 3.08 (q, 1H, J = 6, 4, 4 Hz); 3.0 (
dd, 1H, J = 12, 4, 4 Hz); 2.9 (m, 2H); 2.38 (s, 3
H); 2.2-2.35 (m, 10H); 2.12 (s, 3H); 1.8 (t,
2H, J = 6.6 Hz); 1.55 (m, 3H); 1.41 (m, 1H).

MS: + ESI, m / z 587 ([MH] +, 100%).

Example 51 (355) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine Prepared from the product of Example 50 (347) using the procedure described in Method 7 as a solid, mp = 80-83 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 Mhz): δ = 7.75 (d, 2H, J = 10 Hz); 7.63 (d, 1H, J = 7.4 (d, 2H, J = 1)
0 Hz); 7.05 (d, 2H, J = 10 Hz); 6.95 (d, 2H, J = 1)
0 Hz); 6.67 (d, 2H, J = 10 Hz); 4.1 (d, 1H, J = 8H)
z); 3.94 (d, 1H, J = 8 Hz); 3.9 (t, 2H, J = 5.5 Hz)
); 3.8 (bs, 1H); 3.08 (m, 1H); 2.91 (d, 1H, J =
2.85 (dd, 2H, J = 6, 18, 6 Hz); 2.38 (s,
3H); 2.15 to 2.35 (m, 8H); 2.14 (s, 3H); 1.78 (
q, 2H, J = 6, 8, 6 Hz); 1.7 (m, 1H); 1.4 (m, 1H);
1.37 (m, 2H).

Example 52 (345) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester The title compound is trifluoromethane in pyridine. Prepared by reaction of sulfonic anhydride with N- (toluene-4-sulfonyl) -L-prolyl- (4-amino) phenylalanine methyl ester to give a solid, mp = 75-78 ° C.

Example 53 (370) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine The title compound was prepared by the procedure described in Method 6. And prepared from the product of Example 52 (345).

The NMR data were as follows: ¹ H NMR (CDCl ₃ , 400 MHz): δ = 8.08 (s, 1H);
7 (d, 2H) 7.56 (d, 1H); 7.34 (d, 2H); 7.22 (s,
2H); 4.85 (m, 1H); 4.16 (m, 1H) 3.40 (m, 3H);
3.09 (m, 2H); 2.44 (s, 3H) 1.86 (m, 1H); 1.50
(M, 3H).

IR (KBr, cm-1): 3390; 2950; 1750; 1650; 152
5; 1425; 1375; 1340; 1200; 1150; 950; 825;
25; 590; 550.

Mass Spec: (+ ESI) 564 ([M + H] +); 530; 462; 406;
62; 342; 335; 157.

Example 54 (387) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-benzylaminocarbonyl) -L-phenylalanine methyl ester The title compound was N-benzyl-2. -Chloroacetamide and N- (toluene-4
-Sulfonyl) -L-prolyl-L-tyrosine methyl ester prepared by alkylation (potassium carbonate, sodium iodide, reflux under argon overnight). The product was purified by flash column chromatography (silica, 1: 1 hexane: E
tOAc) to give the methyl ester as a white solid, mp = 57-59 ° C.

Example 55 (389) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzyloxycarbonyl) methoxy] -L-phenylalanine The title compound was described in Method 6. Prepared from the product of Example 4 (387) using the procedure as a solid, mp = 79-81 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.2 (br s, 1 H); 8.60 (t, 1 H); 8.03 (D, 1H, J = 7.9 Hz); 7.7
0 (d, 2H, J = 6.6 Hz); 7.39 (d, 2H, J = 8.4 Hz); 7
. 15 (d, 2H, J = 8.6 Hz); 6.87 (d, 2H, J = 8.6 Hz)
4.48 (s, 2H); 4.42 (m, 1H); 4.31 (d, 2H, J = 6)
. 3.10 (m, 1H); 3.0-3.2 (m, 2H); 2.8-2
. 9 (m, 2H); 2.38 (s, 3H); 1.2-1.6 (m, 4H).

IR (KBr, cm ⁻¹ ): 3400, 2950, 1725, 1660, 152
5,1510,1450,1350,1240,1150,1080,670,
575,550.

Mass spectrometry: (FAB, m / e (%)) 602 (10, (M + Na ⁺ )); 580 (10, (M + H ⁺ )); 131 (100).

Example 56 (390) Synthesis of N- (toluene-4-sulfonyl) -L-propyl-4-[(carboxy) methoxy] -L-phenylalanine N- (Toluene-4) with t-butyl bromoacetate -Sulfonyl) -L-propyl-L-tyrosine methyl ester alkylation (potassium carbonate, DMF, 72 hours under argon under N- (toluene-4-sulfonyl) -L-prolyl-L-
O- (tert-butoxycarbonylmethyl) -tyrosine methyl ester was obtained and flash column chromatography (silica, 1: 1 hexane: EtOA)
After c), a white solid, mp = 55 ° C., was obtained.

N- (toluene-4-sulfonyl) -L-prolyl-LO- (tert-butoxycarbonylmethyl) tyrosine was prepared using the procedure described in Method 6 to give N- (
Prepared from toluene-4-sulfonyl) -L-prolyl-LO- (tert-butoxycarbonylmethyl) -tyrosine methyl ester as a solid, mp = 69-70 ° C.

The title compound is N- (toluene-4-sulfonyl) -L by reaction with formic acid.
Prepared from -prolyl-LO- (tert-butoxycarbonylmethyl) -tyrosine. Removal of formic acid and titration with ether gave the desired compound as a white solid, mp = 70-73 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.85 (brs, 2H); 8.01 (d, 1H, J = 7.9 Hz). ); 7.69 (d, 2H, J = 8)
. 7.39 (d, 2H, J = 8.3 Hz); 7.13 (d, 2H, J
= 8.8 Hz); 6.79 (d, 2H, J = 8.6 Hz); 4.6 (s, 2H).
4.42 (m, 1H); 4.10 (m, 1H); 3.08 (m, 1H);
95 (m, 2H); 2.38 (s, 3H); 1.5 (m, 4H).

IR (KBr, cm ⁻¹ ): 3350, 2950, 1730, 1625, 151
0,1425,1340,1175,1160,1075,825,675,5
75,550.

[0382] Mass spectrometry: (FAB, m / e ( %)) 513 (100, (M + Na -)); 4 91 (75, (M + H +)).

Example 57 (407) N- (toluene-4-sulfonyl) -L-prolyl-4-[(aminocarbonyl)
Synthesis of -L-phenylalanine methyl ester The title compound was alkylation of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2-chloroacetamide (potassium carbonate, sodium iodide, 48 h argon) Under reflux of butanone). The product was purified by flash column chromatography (silica, EtOAc, then 5% MeOH in EtOAc) to give the title compound as a white solid, mp = 60-64 ° C.

Example 58 (408) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(aminocarbonyl) methoxy] -L-phenylalanine The title compound was prepared using the procedure described in Method 6. Prepared from the product of Example 57 (407) as a solid, mp = 195-196 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.2 (br s, 1 H); 8.02 (d, 1 H, J = 8. 7.69 (d, 2H, J = 8.
7.47 (br s, 1H); 7.40 (d, 2H, J = 7.9 Hz)
); 7.35 (br s, 1H); 7.14 (d, 2H, J = 8.6 Hz);
. 84 (d, 2H, J = 8.6 Hz); 4.40 (m, 1H); 4.35 (s,
2H); 4.11 (dd, 1H); 3.09 (m, 1H); 2.91 (dd, 1
H); 2.39 (s, 3H); 1.45-1.55 (m, 3H); 1.40 (m
, 1H).

IR (KBr, cm ⁻¹ ): 3500, 3350, 3250, 2950, 172
5,1675,1660,1560,1510,1450,1400,1350
, 1225, 1200, 1150, 1050, 825, 660, 575, 550
.

Mass spectrometry: (FAB, m / e (%)) 488 (100, (M−H ⁻ )).

Example 59 (409) Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butylaminocarbonyl) methoxy] -L-phenylalanine Prepared by alkylation of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with -chloro-N-tert-butylacetamide (potassium carbonate, sodium iodide, butanone reflux under argon for 48 hours). did. The product was purified by flash column chromatography (silica, 1: 1 hexane: EtOAc) to give the methyl ester as a white solid. The title compound was obtained as a solid, m, using the procedure described in Method 6.
It was prepared as p = 88-89 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.2 (br s, 1 H); 8.02 (d, 1 H, J = 8 Hz). 7.68 (d, 2H, J = 8.3H)
7.39 (d, 3H, J = 8 Hz); 7.14 (d, 2H, J = 8.8H)
z); 6.82 (dd, 2H, J = 8.4, 2 Hz); 4.40 (m, 1H);
4.32 (s, 2H); 4.10 (dd, 1H, J = 2.9, 8 Hz); 3.0
7 (m, 1H); 3.0 (dd, 1H, J = 18.7, 27.5 Hz); 2.9
4 (dd, 1H, J = 17.8, 26 Hz); 2.39 (s, 3H); 1.5 (
m, 3H); 1.4 (m, 1H); 1.29 (s, 9H).

IR (KBr, cm ⁻¹ ): 3400, 2950, 1745, 1675, 152
5,1450,1350,1225,1160,1075,825,675,5
75,540.

Mass spec: (FAB, m / e (%)) 544 (100, (M−H ⁻ )).

Example 60 (410) N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (4-phenyl-4-hydroxypiperidin-1-yl) ethoxy] -L-phenylalanine methyl ester The methyl ester is converted to N- by 4-hydroxy-4-phenylpiperidine.
Alkylation of (toluene-4-sulfonyl) -L-prolyl) -LO- (2-chloroethyl) tyrosine methyl ester (potassium carbonate, sodium iodide, 4
(Butanone reflux under argon for 8 hours). The product was purified by flash column chromatography (silica, 5% methanol in chloroform) to give the methyl ester as a white foam. The title compound was prepared using the procedure described in Method 6 as a solid, mp = 122-123 ° C.

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.72 (m, 2H); 7.61 (d, 1H, J = 5.5 Hz). 7.39 (d, 2H, J = 7.2 Hz)
); 7.28 (m, 2H); 7.17 (m, 1H); 7.04 (d, 1H, J =
6.96 (d, 1H, J = 8.6 Hz); 6.71 (dd, 2H)
, J = 2.4, 8.8 Hz); 4.75 (s, 1H); 4.1 (m, 1H);
. 0 (m, 2H); 3.9 (q, 1H); 3.8 (q, 1H); 2.8-3.1
(M, 4H, duplicate signal); 2.7 (m, 4H, duplicate signal); 2.38 (
s, 3H); 1.65 (m, 2H); 1.55 (m, 2H); 1.4 (m, 2H)
).

IR (KBr, cm ⁻¹ ): 3375, 2890, 1660, 1610, 151
0, 1390, 1325, 1250, 1160, 1075, 1040, 700,
675,575,530.

Mass spectrometry: (FAB, m / e (%)) 648 (100, (M + 2Li-H) ⁺ ), 642 (90 (M + Li) ⁺ ).

Example 61 (375) Synthesis of N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (amidino) phenylalanine N- (toluene-4-sulfonyl) sarcosyl-D, L-4-cyano Phenylalanine ethyl ester (see Example 61 (381) (167 mg, 0.388)
mmol) was dissolved in pyridine (6 mL) and then aerated until the H ₂ S gas was saturated. The mixture was stirred for 19 h, the volatiles were removed under a stream of N _2. Transfer the residue in EtOAc (50 ml), it was washed with 5% KHSO ₄ solution (2 x 25 mL). The organic solution was dried (Na ₂ SO _4), and concentrated in filtered and vacuum to give N- (toluene-4-sulfonyl) sarcosyl -D, the L-4- thiocarboxamide amidophenyl Al Amin methyl ester Was. The thioamide is converted to acetone (
10 mL). Methane iodide (1 mL) was added and the mixture was heated at reflux for 1 hour. The volatiles were removed in vacuo to give N- (toluene-4-sulfonyl) sarcosyl-D, L-4-methylthioimidate phenylalanine methyl ester hydroiodide (256 mg, 100%). The thioimidate was dissolved in MeOH (5 mL). Ammonium acetate (52mg, 0.67mm
ol) and the mixture was heated to reflux for 1.5 hours. The solvent was distilled off in vacuo and the residue was adjusted with TLC (90: 10: 1 CH ₂ Cl ₂ / MeOH /
NH ₄ OH) to give N- (toluene-4-sulfonyl) sarcosyl-D, L-4-amidinophenylalanine methyl ester (75 mg, 38%). The title compound was prepared via hydrolysis of the methyl ester using 0.5N NaOH in THF / water (66 mg, 87%).

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ ): δ = 7.66 (m, 4H), 7.43 (d, 2H, J = 7.7 Hz), 7 .29 (d, 2H, J = 8.0 Hz), 4.10 (
m, 1H), 3.57 (s, 2H), 3.20-3.06 (m, 2H), 2.5
4 (s, 3H), 2.40 (s, 3H).

Mass spec: FABm / e433 (M + H).

Example 62 (381) Synthesis of N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (aminocarbonyl) phenylalanine N- (toluene-4-sulfonyl) sarcosine was converted to 4-cyanophenylalanine methyl Ester hydrochloride (Wagner, Voight, and Viewweg Ph)
armazie 1984, 39, 226-230) to give N- (toluene-4-sulfonyl) sarcosyl-D, L-cyanophenylalanine methyl ester. The compound is 0.5N NaOH in THF / water
Prepared via hydrolysis of the methyl ester using

N- (toluene-4-sulfonyl) sarcosyl-D, L-4-cyanophenylalanine methyl ester (300 mg, 0.699 mmol) was added to EtOH (3 m
A slurry was prepared in L). NaOH (10 N, 98 μL) and H ₂ O ₂ (475 μL)
, 5.51 mmol). The mixture was heated to 50 ° C. for 16 hours and a white precipitate precipitated. The mixture was cooled to room temperature and acidified with HCl (6N). The mixture was diluted with water (20mL) and extracted with chloroform (4x25mL). The organic extract was dried (Na ₂ SO ₄ ), filtered and recrystallized from methanol to give the compound as a white solid (135mg, 45%).

The NMR data were as follows: ¹ H NMR (DMSO-d ₆ ): δ = 8, 31 (br d, 1 H, J = 3.6 Hz), 7.92 (br s, 1 H). ), 7.72 (d, 2H, J = 7.8 Hz)
, 7.62 (d, 2H, J = 7.9 Hz), 7.41-7.21 (5H), 4.
47 (m, 1H), 3.59 (m, 2H), 3.15 (m, 1H), 2.94 (
m, 1H), 2.53 (s, 3H), 2.39 (s, 3H).

¹³ C NMR (DMSO-d ₆ ): δ = 172.9, 168.0, 167.3,
143.7, 141.3, 134.2, 132.8, 130.1, 129.4,
127.8, 127.7, 53.4, 52.4, 36.7, 36.0, 21.3
.

Mass spec: FABm / e434 (M + H).

Other compounds prepared by the methods described above include those described in Tables 19-28 below as Examples 63-135:

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

In addition to the above, the following supplementary compounds were prepared as Examples 136-140:

Example 136 N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-
4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine t
Synthesis of -butyl ester The title compound was prepared as in Example 20, except that N-Boc-tyrosine t-butyl ester was used in place of N-Boc-tyrosine methyl ester.

MS: [(+) ESI], [M + H] ⁺ 620.

Example 137 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4- (N-methylpiperidinoxy) phenylalanine) tertbutyl ester The title compound was Tyr-O-1 Prepared by BOP coupling of Tos-Pro-OH with -methylpiperidine t-butyl ester (prepared by Mitsunobu reaction). The crude product was purified by flash chromatography (silica, 95: 5
(EtoAc: Et ₃ N) to give a white solid (0.615 g, 60%).

MS: ((+) ESI, m / z (%)) 586 (100 [M + H] ⁺ ).

Elemental Analysis Calculated for C ₃₁ H ₄₃ N ₃ O ₆ S: C, 63.57; H, 7.40; N,
7.17. Analytical values: C, 63.11; H, 7.37; N, 6.96.

Example 138 N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-
Synthesis of L- (4- (N-methyl (piperidinoxy) phenylalanine t-butyl ester) The title compound was prepared according to the procedure described in Example 137, substituting the appropriate starting materials.

[0412] Elemental analysis _{C 32 H 45 N 3 O 6} S 2 · 0.25CH 2 Cl 2 Calculated: C, 58.8 5; H, 7.02; N, 6.43. Analytical values: C, 58.75; H, 6.92; N
, 6.48.

MS (+ ESI): 632 [M + H] ⁺

Example 139 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine tert-butyl ester
s, J. et al. Org. Chem. (N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine tert-) as taught by J., 55, 906, 1990.
Prepared from butyl ester). The dipeptide (505 mg, 0
. 8 mmol. ), Catalytic amount of tetrakis (triphenylphosphorin) palladium (0), potassium carbonate (201 mg, 1.5 equivalents), phenylboric acid (199 m
g, 2.0 equivalents) and 15 mL of toluene were refluxed for 10 hours with stirring.
Ethyl acetate was added and the organic phase was washed with water, 1N NaOH, brine and dried over magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The crude material was purified on a preparation plate (1: 1 ethyl acetate: hexane). The silica gel was washed several times with acetonitrile and ethyl acetate. The combined fractions were concentrated and the residue was dried under reduced pressure.

The NMR data were as follows: ¹ H NMR (CDCl ₃ , 300 MHz): δ = 7.70 (m, 1H);
57 (m, 3.5H); 7.45 (m, 3.5H); 7.28 (m, 5H);
. 78 (m, 1H); 4.06 (m, 1H); 3.30 (m, 2H); 3.06
(M, 2H); 2.40 (s, 3H); 2.05 (m, 1H); 1.42 (s,
9H).

¹³ C NMR (CDCl ₃ ): δ = 171.02, 169.98, 144.4, 140.78, 139.82, 135.53, 132.82, 129.97,
129.9, 129.41, 128.78, 127.86, 127.04, 12
6.98, 82.65, 62.15, 53.74, 49.49, 37.43, 2
9.67, 27.78, 23.92, 21.37.

Example 140 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine Prepared from

The NMR data were as follows: ¹ H NMR (CD ₃ OD, 300 MHz): δ = 8.05 (m, 1H);
71 (d, 2H, J = 8.24 Hz); 7.55 (m, 4H); 7.30 (m,
8H); 4.71 (m, 1H); 4.09 (m, 1H); 3.30 (m, 3.3).
0); 3.15 (m, 3H); 2.37 (s, 3H); 1.78 (m, 1H);
1.62 (m, 4H).

¹³ C NMR (CD ₃ OD): δ = 174, 27, 145.88, 142.2, 141.23, 137.44, 135.12, 131.19, 131.15
, 129.98, 129.09, 128.4, 128.17, 128.0, 63
. 25, 54.69, 50.52, 37.85, 31.52, 25.21, 21
. 43.

[0420] In vitro assays In vitro assay for measuring the binding of a candidate compound for Example 141 VLA-4 was used to assess the binding of a candidate compound to the alpha ₄ beta ₁ integrin. Compounds that bind in this assay will be
(E.g., competition assays) can be used to assess VCAM-1 levels in biological samples. This assay can sense IC ₅₀ values as low as about 1 nM.

[0421] alpha ₄ beta ₁ integrin activity, Jurkat cells (e.g., American Type Cult
ure Collection Nos. TIB 152, TIB 153, and CRL 8163), was determined by interaction with the human T cell line and soluble VCAM-1 expressing alpha ₄ beta ₁ integrin at high levels. VCAM-1 interacts with the cell surface in an α ₄ β ₁ integrin-dependent form (Yednock et al., Bio. Chem., 1995, 270 : 2874).
0).

[0422] Recombinant soluble VCAM-1 has an extracellular domain of 7 of VCAM-1 on the N-terminus, it was expressed originating as a chimeric fusion protein containing the human IgG ₁ heavy chain constant region on the C-terminus. The VCAM-1 fusion protein was made and purified by the procedure described by Yednock, supra.

Jurkat cells were RPMI supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra.
Cultured in 11640.

Jurkat cells were incubated with 1.5 mM MnCl ₂ and 5 μg / mL for 30 minutes on ice.
Incubated with the 15/7 antibody. Mn ⁺² is a receptor that increases ligand binding activates, and 15/7 recognizes the alpha ₄ beta ₁ integrin activation / ligand occupied structures, and the molecules fixed to this structure, it by a monoclonal antibody to stabilize the VCAM- ₁ / α ₄ β 1 integrin interaction. Ye
dnock et al., supra. Antibodies similar to the 15/7 antibody have been described in other studies (Luque et al.,
1996, J.A. Bio. Chem. 271: 11067) and can be used in this assay.

Cells were incubated with candidate compounds at various concentrations ranging from 66 μM to 0.01 μM using standard 5-point serial dilutions for 30 minutes at room temperature. Then 15
μL 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 twice, resuspended at 1: 200 in PE-conjugated goat F (ab ′) ₂ anti-mouse IgG Fc (Immunotech, Westbrook, ME) for 30 minutes in the dark. And incubated on ice. Cells were washed twice and analyzed by standard fluorescence activated cell sorter ("FACS") analysis as described by Yednock et al., Supra.

[0427] Compounds having an IC ₅₀ less than about 15μM has binding affinity to α ₄ β _1.

When tested in this assay, each of the compounds in Examples 1-135 had 1
It has an IC ₅₀ of 5 μM or less.

[0429] In vitro assays for measuring plasma levels described below in vitro saturation assay for measuring the binding of a candidate compound for Example 142 alpha ₄ beta ₁ is described in the following examples, experimental autoimmune brain The compound is required to be active in a myelitis ("EAE") model, or other in vivo model.

The logarithmically grown Jurkat cells were washed and the 15/7 antibody (described in the Examples above).
Was resuspended in normal animal plasma containing 20 μg / ml.

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

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

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

The cells are washed twice with the assay medium and resuspended in the same. They are then described in Yednock et al. Bio. Chem. , 1995, 270: 287.
Analyzed by a standard fluorescence activated cell sorter ("FACS") as described in 40.

The data is then graphed as fluorescence versus dose, eg, in a normal dose-response form. The dose level leading to the upper plateau of the curve represents the level required to obtain efficacy in an in vivo model.

[0436] This assay is also closest integrin released α ₄ β ₁ (Palmer
Et al., 1993, J. Am. Cell Bio. , 123: 1289) is, the alpha ₄ beta ₁ integrin, such as, may also be used to determine the required plasma level to saturate the binding sites of other integrins. Such a bond is, for example,
In high airway hyperresponsiveness and obstruction caused by chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular obstruction following angioplasty, fibrosis and glomerular injury as a result of renal disease, aortic stenosis, rheumatoid arthritis hypertrophy of synovial, and inflammation and scarring caused by the progression of ulcerative colitis and Crohn's disease, to predict the usefulness of in vivo inflammatory conditions mediated by α ₄ β _1.

[0437] Thus, the assay described above, for determining the binding of alpha ₄ beta ₁ integrin, in place of the Jurkat cells, cDNA encoding the alpha ₉ integrin (Yok osaki etc., 1994, J.Bio.Chem , 269: 26691), a human colon sarcoma cell line, SW480 (ATTC # CCL228).
). As a control, SW480 cells expressing other α and β ₁ subunits can be used.

[0438] Accordingly, another aspect of the present invention, the disease is mediated by alpha ₄ beta _1, directed to a method for treating a disease in a mammal patient, and the method, the treatment of compounds of the present invention Administering to said patient an effective amount. Such compounds are preferably administered in a pharmaceutical composition as described above. Effective daily doses will be based on the age, weight, and condition of the patient, whose factors can be readily ascertained by the attending physician. However, in a preferred embodiment, the compound is administered from about 20 to 500 μg / kg per day.

Example 143 In Vivo Evaluation A standard multiple sclerosis model, experimental autoimmune (or allergic) encephalomyelitis ("E
AE ") was used to determine the effect of a candidate compound on reducing movement impairment in rats or guinea pigs. The reduction in movement impairment was based on blocking adhesion between leukocytes and endothelium The model correlates with the anti-inflammatory activity of the compound, as described by Keszthelyi et al.
6, 47: 1053-1059, and measures the delay in onset of disease.

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

Female Lewis rats (2-3 months, 170-220 g) or Hartle
y guinea pigs (20 days old, 180-200 g) were anesthetized with isoflurane,
Three injections of the emulsion, 0.1 ml each, were made in each thigh.
Onset of movement disorders is seen at approximately 9 days.

The candidate compound treatment began on day 8, just before the onset of symptoms. Compounds were administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP"). Doses are typically 10 to 100 mg / kg SC, 10 to 50 mg / kg PO, and 10 to 100 mg / kg IP for 5 days, 10 mg / kg to 200 m
g / kg.

[0443] delay the onset of symptoms, α ₄ β ₁ integrin antibody against GG5 / 3 (Kes
Zthelyi et al., Neurology, 1996, 47: 1053-1059.
) Was used as a positive control and injected subcutaneously at 3 mg / kg on days 8 and 11.

[0444] Body weight and movement disorders were measured daily. Motor impairment was assessed with the following clinical score: 0 No change 1 Weak or numb tail 2 Weak hind paw 3 Hind paw paralysis 4 Morbid or dead

A candidate compound is considered active if it delays the onset of signs, for example, if it produces a clinical score of no more than 2 or slows weight loss compared to controls. did.

The compounds of Examples 5, 12, 18, and 20 were active when tested in this in vivo assay.

[0447] Inflammatory conditions mediated by Example 144 Asthma Model Example alpha ₄ beta ₁ integrin include, for example airway highly sensitive and occlusion caused by chronic asthma. The following describes an asthma model that can be used to study the in vivo effects of the compounds of the present invention for use in treating asthma.

Abraham et al., J. Am. Cl
in. Invest, 93: 776-787 (1994) and Abraham et al., Am J. Am. Respir Crit Care Med, 156: 696-7.
03 (1997), the compounds of the present invention are formulated into aerosols and administered to sheep that are sensitive to Ascaris suum antibodies. Reduce early antigen-induced bronchial response and / or block late airway response;
For example, compounds that have a protective effect on antigen-induced late response and airway hypersensitivity ("AHR") are considered active in this model.

Allergic sheep, which have been shown to express both early and late bronchial responses to inhaled Ascaris suum antigen, are used to study the airway effects of candidate compounds. Following local anesthesia of the nasal passages with 2% lidocaine, the balloon catheter is advanced down the esophagus through one nostril. The animal then
A cuffed endotracheal tube is intubated through the other nostril by a flexible fiber optic bronchoscope as a guide.

Pleural pressure is assessed according to Abraham (1994). The aerosol (see formulation below) was 3.2 μm as measured on an Andersen cascade impactor.
Produced using a disposable medical nebulizer, which provides an aerosol with a mass median aerodynamic diameter of m. The nebulizer is connected to a dosimeter consisting of a solenoid valve and a source of compressed air (20 psi). The output of the nebulizer is connected to one end connected to the intake of the piston respirator,
Pointed at the piece. The solenoid valve is activated for one second at the beginning of the respirator inspiration cycle. The aerosol is delivered at 500 ml VT and 20 breaths / min. Only 0.5% sodium bicarbonate solution is used as a control.

To assess bronchial response, the cumulative concentration-response curve for carbachol was
It can be created according to Braham (1994). Bronchial biopsies can be performed around the beginning of treatment and 24 hours after antigen challenge. Bronchial biopsy can be performed according to Abraham (1994).

In vitro adhesion experiments of alveolar macrophages were performed by Abraham (1994).
And the percentage of adherent cells is calculated.

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

A. Preparation of 0.5% sodium bicarbonate / saline storage solution: 100.0 mL

[Table 29]

Method: Add 0.5 g sodium bicarbonate into a 100 mL flask. 2. Add approximately 90.0 mL saline and sonicate until dissolved. 3. Add the appropriate amount of saline up to 100 mL and mix thoroughly.

B. 30.0 mg / mL candidate compound: 10 mL preparation

[Table 30]

Method: Add 0.300 g of the candidate compound into a 10.0 mL volumetric flask. 2. Add about 9.7 mL of 0.5% sodium bicarbonate / saline stock solution. 3. Sonicate until the candidate compound is completely dissolved. 4. Add appropriate volume of 0.5% sodium bicarbonate / saline to 10.0 mL and mix thoroughly.

Using a conventional oral formulation, the compounds of the invention will be active in this model.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 A61P 35/00 35/00 43/00 111 43/00 111 C07K 5/065 C07K 5/065 5/078 5/078 A61K 37/02 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW) , SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, B , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK , SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Eugene di Sausset 94038 Mos Beach Buena Vista, California, United States 94038・ 571 (72) Inventor Christopher M. Semco USA, California ・ 94539 ・ Fremont Carpenter Coat ・ 2361 (72) Inventor Dimitrios Salantakis United States of America, Pennsylvania 18940 Newtown Sentinel Avenue 262 (72) Inventor Michael A. Place California, United States 94087 Sunnyvale Stellar Court 848 (72) Inventor Louis John Lombard, United States of America New Jersey 08502 Bell Mead South Woods Road 412 (72) Inventor Antony Cleft United States of America Pennsylvania 19047 Langhorn Barely Coat 43 (72) Inventor Andrey W. Conrady United States of America California 94123 San Francisco Cervantes # 105.95 (72) Inventor Francine S. Grant United States of America, California 94118 San Francisco Sacramento Street 3735 (72) Inventor Darren Bee Dressen America United States, California, 94403 San Mateo Casa de Campo # 2, 3110 (72) Inventor Michael S. Dappen United States, California, 94061 Redwood City Topaz Street, 640 ( 72) Inventor Reinhard Bernhard-Baudy, USA 18901 Doylestown Harrington Court 5281 (72) Inventor Susan Ashwell United States of America New Jersey 08536 Plainsboro Aspen Dry Drive 1015 F-term (reference) 4C084 AA01 AA02 AA07 BA01 BA08 BA14 BA32 CA59 MA13 MA17 MA22 MA23 MA28 MA35 MA37 MA52 MA59 MA60 MA66 ZA022 ZA162 ZA332 ZA362 ZA452 ZA592 ZA662 ZA812 ZA892 ZB112 ZB132 ZB152 ZB262 A110A HA02

Claims (37)

[Claims] 1. Formula I: ## STR1 ## [Where R¹Is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, hetero
R is selected from the group consisting of aryl and substituted heteroaryl;^TwoIs hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted
Cyclic, aryl, substituted aryl, heteroaryl, and substituted hetero
R is selected from the group consisting of aryl¹And R^TwoIs R^TwoNitrogen atom and R¹SO bound to_TwoA heterocyclic or substituted heterocyclic group with the group;^ThreeIs alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl.
Selected from the group consisting of^TwoIs R¹And Hete
When no ring group is formed, R^TwoAnd R^ThreeAnd R^TwoNitrogen atom and R^ThreeTied to
A heterocyclic or substituted heterocyclic group with the combined carbon atoms;^FiveIs-(CH_Two)_x-Ar-R^Five'And R^Five'Is selected from the group consisting of the following (a) to (u): (a) a substituted alkylcarbonylamino (provided that at least
Another substituent is alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, alkenyl, amino, amidino, alkylamido
Dino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocar
Bonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy
, Cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxy-substituted heterocyclic, cycloal
Killed, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thio
Alkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloa
Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl
Thioheterocyclic, substituted thioheterocyclic, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two -Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl,
-OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic,-
OS (O)_Two-Substituted heterocyclic, -OSO_Two-NRR (where R is hydrogen or
Or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl
, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O
)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS
(O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, and
And an asymmetric di-substituted amine, wherein the alkyl, substituted alkyl, aryl, substituted
Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitution
Asymmetric di-substituents having different substituents selected from the group consisting of substituted heterocyclics and amino groups protected by common protecting groups such as Boc, Cbz, formyl,
-Substituted amine) or -SO_Two-Alkyl, -SO_Two−substitution
Alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two -Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO_TwoNR
Alkyl / substituted alkyl substituted by R (where R is hydrogen or alkyl)
(B) carboxyl and COOR (R is an alkyl group)
, Substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetero
Alkoxy) substituted with a substituent selected from the group consisting of
(C) aryl and heteroaryl; (d) —NR′R ′ (wherein, R ′ is each independently an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloaryl
Alkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic
(Wherein at least one R ′ is a substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic).
When R ′ is cyclic alkyl and R ′ is substituted alkyl, at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
O_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two−substitution
Alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO _Two -Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two−
Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocycle
Rick, and -SO_Two(E) -alkoxy-NR "R", wherein R "is independently alkyl, Substitution
Alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete
Aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
Selected from the group consisting of clicks (provided that each R ″ is a substituted alkyl
Wherein at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
Si, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl,
Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl
Sil-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl ant
, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxy
-Substituted heteroaryl, carboxyl heterocyclic, carboxy-substituted
Heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, gua
Nidino sulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl,
Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohetero
Aryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohetero
Cyclic, heterocyclic, substituted heterocyclic, cycloalkoxy
Si, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy
, Heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl
Mino, oxythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two -Substituted alkyl, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl,-
OS (O)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (
O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OS
O_Two-NRR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl,
-NRS (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O) _Two -Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two−
Heterocyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two−
NR-substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-N
R-substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two -NR-substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted heterocyclic (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 heteroaryls
Amino, mono- and di-heterocyclic amino, mono- and di-configuration
Substituted heterocyclic amino and unsymmetrical di-substituted amines,
, Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of
Selected from the group consisting of asymmetric di-substituted amines having different substituents and amino groups protected by conventional protecting groups such as Boc, Cbz, formyl, etc.)
Or -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -S
O_Two-Substituted heterocyclic, and -SO_TwoNRR wherein R is hydrogen or
(F) substituted alkenyl or substituted alkynyl (provided that the substituted alkenyl / alkyl is
At least one substituent on the nyl moiety is alkyl, substituted alkyl, aryl,
Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Group consisting of teloaryl, heterocyclic, and substituted heterocyclic
Selected, but when substituted by substituted alkyl, substituted alkyl
At least one substituent on the moiety on the aryl is an alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
Is -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocyclic, and -SO_TwoAlkyl / substituted alkyl groups substituted by NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided that substituted aryl
At least one substituent on the oxy / heteroaryloxy is halogen,
Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-di
Xylene, alkoxy, alkeneoxy, alkyneoxy, alkylamino
, Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl
(H) other than amino, N-alkyl or N, N-dialkylurea); (h) -alkoxy saturated heterocyclic, -alkoxy saturated substituted heterosa
Click, -substituted alkoxy-heterocyclic, and -substituted alkoxy
(I) -O-heterocyclic and -O-substituted heterocyclic; (j) tetrazolyl; (k) -NR-SO_Two-Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least the alkyl moiety of the substituted alkylsulfonylamino
Another substituent is halogen, hydroxyl, amino, nitro, trifluoromethyl.
Tyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-di
Oxymethylene, 1,2-dioxyethylene, alkoxy, alkeneoxy, a
Ruquinoxy, alkylamino, alkenylamino, alkynylamino, alk
Carbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonyl
Ruamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl
(L) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino
(M) substituted alkoxy (provided that a substituent on the alkyl portion of the substituted alkoxy is not substituted with alkenylsulfonylamino and alkynylsulfonylamino)
Is alkoxy-NR''R '', unsaturated heterocyclyl, alkyloxy,
Oxy, heteroaryloxy, aryl, heteroaryl, and halo
Gen, hydroxyl, amino, nitro, trifluoromethyl, trifluorometh
Xy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2
-Dioxyethylene, alkoxy, alkeneoxy, alkyneoxy, alkyl
Amino, alkenylamino, alkynylamino, alkylcarbonyloxy,
Sil, alkylcarbonylamino, alkoxycarbonylamino, alkylsul
Substituted by honylamino, N-alkyl or N, N-dialkylurea
(N) amidines and amidines substituted with 1 to 3 substituents, wherein
Substituents are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
Independent of substituted alkynyl, aryl, heteroaryl and heterocyclic
(O) -C (O) NR "" R "", wherein R "" is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkenyl, substituted alk
Nil, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl
From substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of: Provided that one R ′ ″ is an unsaturated heterocyclylalkyl, aryl, heteroaryl, or halogen, hydroxyl, amino, nitro
B, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, al
Quinyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy,
Alkeneoxy, alkyneoxy, alkylamino, alkenylamino, alk
Nylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
Aryl / heteroaryl substituted by N, N-dialkylurea
In other cases, the other R ′ ″ is alkyl, substituted alkyl (other than unsaturated heterocyclyl-substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted
Alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted
(P) -NR¹²C (O) -R⁸(Where R⁸Is alkyl, substituted alkyl, cyclo
Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group¹²Is alkyl, substituted alkyl, aryl, substituted aryl,
Chloroalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, f
(Q) -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, or -SO_Two-Alkyl; (r) -NR'C (O) NR⁹R⁹(Wherein R ′ is alkyl, substituted alkyl, ant
, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Substituted heteroaryl, heterocyclic and substituted heterocyclic
Each R⁹Is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group): (s) -NR'C (O) OR⁹(Wherein R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group⁹Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of heterocyclic, heterocyclic and substituted heterocyclic.
(T) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O)
NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl, or substituted heteroaryl
X is an integer from 1 to 4, Q is -C (X) NR⁷Where R is⁷Is a group consisting of hydrogen and alkyl
Wherein X is selected from the group consisting of oxygen and sulfur.)] And pharmaceutically acceptable salts thereof. 2. A compound of the formula IA: [Where R¹Is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, hetero
R is selected from the group consisting of aryl and substituted heteroaryl;^TwoIs hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted
Cyclic, aryl, substituted aryl, heteroaryl, and substituted hetero
R is selected from the group consisting of aryl¹And R^TwoIs R^TwoNitrogen atom and R¹SO bound to_TwoGroup together with a heterocyclic or substituted heterocyclic group.
And R^ThreeIs alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl.
Selected from the group consisting of^TwoIs R¹And Hete
When no ring group is formed, R^TwoAnd R^ThreeAnd R^TwoNitrogen atom and R^ThreeTied to
A heterocyclic or substituted heterocyclic group with the combined carbon atoms;^FiveIs-(CH_Two)_x-Ar-R^Five'And R^Five'Is selected from the group consisting of the following (a) to (u): (a) a substituted alkylcarbonylamino (provided that at least
Another substituent is alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, alkenyl, amino, amidino, alkylamido
Dino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocar
Bonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy
, Cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxy-substituted heterocyclic, cycloal
Killed, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thio
Alkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloa
Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl
Thioheterocyclic, substituted thioheterocyclic, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two -Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl,
-OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic,-
OS (O)_Two-Substituted heterocyclic, -OSO_Two-NRR (where R is hydrogen or
Or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl
, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O
)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS
(O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, and
And an asymmetric di-substituted amine, wherein the alkyl, substituted alkyl, aryl, substituted
Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitution
Asymmetric di-substituents having different substituents selected from the group consisting of substituted heterocyclics and amino groups protected by common protecting groups such as Boc, Cbz, formyl,
-Substituted amine) or -SO_Two-Alkyl, -SO_Two−substitution
Alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two -Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO_TwoNR
Alkyl / substituted alkyl substituted by R (where R is hydrogen or alkyl)
(B) carboxyl and COOR (R is an alkyl group)
, Substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetero
Alkoxy) substituted with a substituent selected from the group consisting of
(C) aryl and heteroaryl; (d) —NR′R ′ (wherein, R ′ is each independently an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloaryl
Alkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic
(Wherein at least one R ′ is a substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic).
When R ′ is cyclic alkyl and R ′ is substituted alkyl, at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
O_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two−substitution
Alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO _Two -Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two−
Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocycle
Rick, and -SO_Two(E) -alkoxy-NR "R", wherein R "is independently alkyl, Substitution
Alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete
Aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
Selected from the group consisting of clicks (provided that each R ″ is a substituted alkyl
Wherein at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
Si, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl,
Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl
Sil-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl ant
, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxy
-Substituted heteroaryl, carboxyl heterocyclic, carboxyl-position
Substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,
Anidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl
, Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohete
Loaryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohete
Cyclic, heterocyclic, substituted heterocyclic, cycloalco
Xy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy
Si, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl
Amino, oxythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O 2)_Two-Substituted alkyl, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -O
S (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic,-
OSO_Two-NRR (where R is hydrogen or alkyl), -NRS (O)_Two-Archi
, -NRS (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (
O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two -Substituted heterocyclic, -NRS (O)_Two—NR-alkyl, —NRS (O 2)_Two-NR-substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O) _Two -NR-substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (
O)_Two-NR-substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic
H, -NRS (O)_Two-NR-substituted heterocyclic (where R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di- (substituted alkyl
L) amino, mono- and di-arylamino, mono- and di-substituted aryl
Amino, mono- and di-heteroarylamino, mono- and di-substituted hetero
Arylamino, mono- and di-heterocyclic amino, mono- and di-
-Substituted heterocyclic amino and unsymmetrical di-substituted amines,
Alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted hetero
Selected from the group consisting of aryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of asymmetric di-substituted amines having different substituents selected and an amino group protected by a conventional protecting group such as Boc, Cbz, formyl and the like.
Or -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic,
-SO_Two-Substituted heterocyclic, and -SO_TwoNRR wherein R is hydrogen or
Is an alkyl / substituted alkyl group substituted by alkyl); (f) substituted alkenyl or substituted alkynyl, provided that
At least one substituent on the nyl moiety is alkyl, substituted alkyl, aryl,
Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Group consisting of teloaryl, heterocyclic, and substituted heterocyclic
Selected, but when substituted by substituted alkyl, substituted alkyl
At least one substituent on the moiety on the aryl is an alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
Is -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocyclic, and -SO_TwoAlkyl / substituted alkyl groups substituted by NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided that substituted aryl
At least one substituent on the oxy / heteroaryloxy is halogen,
Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-di
Xylene, alkoxy, alkeneoxy, alkyneoxy, alkylamino
, Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl
(H) other than amino, N-alkyl or N, N-dialkylurea); (h) -alkoxy saturated heterocyclic, -alkoxy saturated substituted heterosa
Click, -substituted alkoxy-heterocyclic, and -substituted alkoxy
(I) -O-heterocyclic and -O-substituted heterocyclic; (j) tetrazolyl; (k) -NR-SO_Two-Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least the alkyl moiety of the substituted alkylsulfonylamino
Another substituent is halogen, hydroxyl, amino, nitro, trifluoromethyl.
Tyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-di
Oxymethylene, 1,2-dioxyethylene, alkoxy, alkeneoxy, a
Ruquinoxy, alkylamino, alkenylamino, alkynylamino, alk
Carbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonyl
Ruamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl
(L) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino
(M) substituted alkoxy (provided that a substituent on the alkyl portion of the substituted alkoxy is not substituted with alkenylsulfonylamino and alkynylsulfonylamino)
Is alkoxy-NR''R '', unsaturated heterocyclyl, alkyloxy,
Oxy, heteroaryloxy, aryl, heteroaryl, and halo
Gen, hydroxyl, amino, nitro, trifluoromethyl, trifluorometh
Xy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2
-Dioxyethylene, alkoxy, alkeneoxy, alkyneoxy, alkyl
Amino, alkenylamino, alkynylamino, alkylcarbonyloxy,
Sil, alkylcarbonylamino, alkoxycarbonylamino, alkylsul
Substituted by honylamino, N-alkyl or N, N-dialkylurea
(N) amidines and amidines substituted with 1 to 3 substituents, wherein
Substituents are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
Independent of substituted alkynyl, aryl, heteroaryl and heterocyclic
(O) -C (O) NR "" R "", wherein R "" is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkenyl, substituted alk
Nil, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl
From substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of: Provided that one R ′ ″ is an unsaturated heterocyclylalkyl, aryl, heteroaryl, or halogen, hydroxyl, amino, nitro
B, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, al
Quinyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy,
Alkeneoxy, alkyneoxy, alkylamino, alkenylamino, alk
Nylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
Aryl / heteroaryl substituted by N, N-dialkylurea
In other cases, the other R ′ ″ is alkyl, substituted alkyl (other than unsaturated heterocyclyl-substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted
Alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted
(P) -NR¹²C (O) -R⁸(Where R⁸Is alkyl, substituted alkyl, cyclo
Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group¹²Is alkyl, substituted alkyl, aryl, substituted aryl,
Chloroalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, f
(Q) -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, or -SO_Two-Alkyl; (r) -NR'C (O) NR⁹R⁹(Wherein R ′ is alkyl, substituted alkyl, ant
, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Substituted heteroaryl, heterocyclic and substituted heterocyclic
Each R⁹Is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group): (s) -NR'C (O) OR⁹(Wherein R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group⁹Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of heterocyclic, heterocyclic and substituted heterocyclic.
(T) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O)
NH-substituted heterocyclyl; Ar is aryl, heteroaryl, substituted aryl, or substituted heteroaryl
X is an integer from 1 to 4, R⁶Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloa
Lucoxy, -O- (N-succinimidyl), -NH-adamantyl, -O-co
Rest-5-en-3-β-yl, —NHOY (where Y is hydrogen, alkyl,
Substituted alkyl, aryl, and substituted aryl), -NH (CH_Two)_pCOOY (expression
Wherein p is an integer from 1 to 8 and Y is as defined above), -OCH_TwoNR⁹ R^Ten(Where R⁹Is selected from the group consisting of -C (O) -aryl and -C (O) -substituted aryl;^TenIs hydrogen and -CH_TwoCOOR¹¹(Where R¹¹Is selected from the group consisting of alkyl)), and -NHSO_TwoZ (where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl)
, Heteroaryl, substituted heteroaryl, heterocyclic and substituted
Q is -C (X) NR⁷-(Wherein, R⁷Is selected from the group consisting of hydrogen and alkyl
X is selected from the group consisting of oxygen and sulfur)¹Is p-CH_Three-Φ-, R⁶Is methoxy, Q is -C (O) NH-,^TwoAnd R^ThreeAre linked to form a pyrrolidinyl group,^FiveIs p-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl-, p-[-OCH_TwoCH_TwoN (isopropyl)_Two] -Benzyl-, p-[-OCH_TwoCH_Two-1-pyrrolidinyl] -benzyl-, p-[-OCH_TwoCH_Two-1- (4-pyrrolidinyl) piperazinyl]-
Benzyl-, p-[-OCH_TwoCH_Two-N-morpholinyl] -benzyl-, or p
-[-OCH_TwoCH_Two-N-piperidinyl] -benzyl-)
And a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl. 4. R ¹ is 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl , 2- (methoxycarbonyl) phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl,
4- (CH ₃ C (O) NH-) phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di - (trifluoromethyl) phenyl, 4-t-butylphenyl, 4- t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazole-4-
Yl, phenethyl, 1-N-methyl-imidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, _{4-methyl-amidinophenyl, 4- [CH 3 SC (=} NH)] phenyl, 5-chloro-2- Thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3
, _{4-thiadiazol-2-yl, 4- [H 2 NC (S} )] phenyl, 4-amino Nofeniru, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin - 4. The compound of claim 3, wherein the compound is selected from the group consisting of 3-yl, pyrimidin-2-yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, and 1-methylpyrazol-4-yl. Wherein R ² is hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2-2-thienyl,} and - (CH ₂₎ according to claim 1 or 2 wherein is selected from the group consisting of ₂ - [Phi] Compound. 6. R ¹ and R ² are a nitrogen atom bonded to R ² and a S atom bonded to R ^1.
_3. The compound according to claim 1 or 2, wherein the compound is combined with an O2 group to form a heterocyclic group or a substituted heterocyclic group. 7. The method according to claim 1, wherein R ² and R ³ together with the nitrogen atom bonded to the R ² substituent and the carbon bonded to the R ³ substituent form a heterocyclic group or a substituted heterocyclic group. Compound. It is 8. R ^3, methyl, phenyl, benzyl, _{diphenylmethyl, -CH 2 CH 2 -COOH, -CH} 2 -COOH, 2- amidoethyl, isobutyl, t- butyl, -CH ₂ O-benzyl, and 3. The compound according to claim 1, wherein the compound is selected from the group consisting of hydroxymethyl. 9. The compound according to claim 1, wherein Q is —C (O) NH— or —C (S) NH—. 10. R^FiveIs: 4- [NH_TwoCH_TwoC (O) NH-] benzyl, 4- [HOOCCH_TwoCH_TwoC (O
) NH-] benzyl, 4-[-NHC (O) CH_TwoNHBoc] benzyl, 4-[— NHC (O) CH (CH_Three) NHBoc] benzyl, 4-[— NHC (O) CH (CH_TwoΦ) NHBoc] benzyl, 4-[— NHC (O) CH_TwoNHC (O
) NH-3′-Methylphenyl] benzyl, 4-[— NHC (O) CH (NHB oc) (CH_Two)_FourNHCbz] benzyl, 4-[-NHC (O) CH_TwoCH (C (O) OCH_TwoΦ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH_TwoCH_TwoCH_TwoCH_TwoNH_Two) NHBoc] benzyl, 4- [H_Two NCH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- (BocHNCH_TwoCH_TwoCH_TwoC (O) NH-) benzyl, 4- [ΦCH_TwoOCH_Two(BocHN) CHC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoCH_TwoCH_TwoC (O) NH-] ben
Zyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH_ThreeN (Boc) CH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoOCH_Two (H_TwoN) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoO (O) C (Cbz-NH) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [HO (O) C (
NH_Two) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [CH_Three(N-Boc
) NCH_TwoC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoC (O) NH-] benzyl, 4-[(CH_Three)_TwoNCH_TwoC (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxyphenyl-]-benzyl
, 4- [2-carboxymethylphenyl-]-benzyl, 4- [ΦCH_TwoOC (O) NHCH_TwoCH_TwoNH-] benzyl, 4-N [-(SO_Two) CH_Three] -CH_TwoCH_TwoCH_TwoN (CH_Three)_TwoBenzyl, 4-t-butyl-O (O) CCH_Two-O-benzyl NH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzene
Zyl) amino] benzyl, 4- (2-formyl-1,2,3,4-tetrahydro
Isoquinolin-3-yl-CH_TwoNH) benzyl, 4-[-OCH_TwoCH_Two-1'-
(4′-pyrimidinyl) -piperazinyl] -benzyl, 4-[— OCH_TwoCH_Two-(1'-piperidinyl) -benzyl, 4-[-OCH_TwoCH_Two-(1'-Pyrrolidini
Ru)] benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1'-piperidinyl)]-ben
Jill, 4-[(CH_Three)_TwoNCH_TwoCH_TwoCH_Two-O-] benzyl, 4-[(CH_Three) _Two NCH_TwoCH_TwoO-]-benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1 '-(4'-
Methylpiperazinyl))]-benzyl, 4-[— OCH_TwoCH_TwoCH_Two-4- (3 '
-Chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_TwoN (Φ) CH_TwoCH_Three] -Benzyl, 4-[-OCH_Two-3 '-(N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidini
Benzyl], 3-[-O- (N-methylpiperidin-4-yl] benzyl, 4
-[-O- (N-methylpiperidin-4-yl] benzyl, 4- [di-isoprop]
Ropyramino-CH_TwoCH_TwoO-]-benzyl, 4- [N-3-methylbutyl-N
-Trifluoromethanesulfonyl) amino] benzyl, 4-[-OCH_TwoCH_Two−
(N-morpholinyl)]-benzyl, 4-[— OCH_TwoCH (NHBoc) CH_Two Cyclohexyl] -benzyl, 4- [OCH_TwoCH_Two-(N-piperidinyl) -b
Undil, 4-[-OCH_TwoCH_TwoCH_Two-(4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_Two-(N-homopiperidinyl)
-Benzyl, 4-[-OCH_TwoCH_TwoN (benzyl)_Two] -Benzyl, 3-[— O CH_TwoCH_TwoCH_TwoN (CH_Three)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five )_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN
(CH_Three) Benzyl) -benzyl, 4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl, [cyclopentylacetyleni
] -Benzyl, 4-[-C≡C-Φ-4′Φ] -benzyl, 4-[-C≡C-CH_Two-OS (O)_Two-4'-CH_Three-Φ] -benzyl, 4-[-C≡C-CH_Two NHC (O) NH_Two] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-COO CH_TwoCH_Three) Φ] -benzyl, 4-[— C≡C—CH (NH_Two) -Cyclohexyl] -benzyl, 4-[— C≡C—CH_Two—O-phenyl] -benzyl, 4-[— C≡C—CH_TwoOCH_Three] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-C
(O) OC_TwoH_Five) Phenyl] -benzyl, 4-[— C≡C—CH_TwoCH (C (O) OCH_Three)_Two] -Benzyl, 4-[— C≡C—CH_TwoCH (NHC (O) CH_Three)
C (O) OH] -benzyl, 4-[-C≡C-CH_TwoNH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-
OCH_TwoCH_TwoCH_Two-(N-morpholino)]-benzyl, 4-[-OCH_TwoCOO
H] -benzyl, 4-[-OCH_TwoCOO-t-butyl] -benzyl, 4-[-N (SO_TwoCH_Three) (CH_Two)_Three-N (CH_Three)_Two] -Benzyl, 4-[-NHS (O
)_TwoCF_Three] -Benzyl, 4-[— C (＝ NH) NH_Two] -Benzyl, 4-[-N HSO_Two-CH_TwoCl] -benzyl, 4-[-OCH_TwoC (O) NH-benzyl] -benzyl, 4-[-OCH_TwoC (O) O-benzyl] -benzyl, 4-[-O CH_TwoC (O) OH] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] -benzyl,
-[-OCH_TwoC (O) NH_Two] -Benzyl, 4-[-OCH_TwoC (O) NH-t-butyl] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4-f
Enyl) -piperidinyl] -benzyl, 4-[-NHSO_Two-CH = CH_Two] -B
Nyl, 4-[-NHSO_Two-CH_TwoCH_TwoCl] -benzyl, 4-benzyl-benzyl, 4-[— OCH_TwoC (O) piperidin-1-yl] benzyl, 4-[-OCH_TwoC (O) N (CH (CH_Three)_Two)_TwoBenzyl, 4-amidinobenzyl, 4
-Acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4 (-N
HC (O) CH_TwoNHC (O) NH-fluorescein) benzyl, 4- (NHC (O) CH_TwoCH (NH_Two) COOH, (1-toluenesulfonylimidizole)
4-yl) -methyl-, [(1-N, N-dimethylaminosulfonyl) -imidi
Zol-4-yl] methyl-, 4- (N-toluenesulfonylamino) benzyl
The compound according to claim 1, which is selected from the group consisting of, and 4- [N-methyltrifluoroacetamido] phenyl. 11. R⁶Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, isopropoxy, n-butoxy
, T-butoxy, cyclopentoxy, neopentoxy, 2-α-iso-propyl
-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylc
Clohexoxy, -NH_Two, Benzyloxy, -NHCH_TwoCOOH, -NHCH _Two CH_TwoCOOH, -NH-adamantyl, -NHCH_TwoCH_TwoCOOCH_TwoCH_Three,
-NHSO_Two-P-CH_Three-Φ, -NHOR⁸(Where R⁸Is hydrogen, methyl, isop
Ropyl or benzyl), O- (N-succinimidyl), -O-cholest-5
-En-3-β-yl, -OCH_Two-OC (O) C (CH_Three)_Three, -O (CH_Two)_Z NHC (O) W (wherein z is 1 or 2, W is pyrid-3-yl, N-meth
From tylpyridyl and N-methyl-1,4-dihydro-pyrid-3-yl
-NR "C (O) -R '(where R' is aryl, hetero
Aryl or heterocyclic, R '' is hydrogen or --CH_TwoC (O) OCH_TwoCH_ThreeThe compound according to claim 2, which is selected from the group consisting of: 12. N- (toluene-4-sulfonyl) -L-prolyl-4-
[(N-tert-butoxyl-carbonylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (carboxy) propionamide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-L-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-phenylalanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (fluorescein) thiouried] acetamido} -L-phenylalanine N -(Toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-
Methylphenyl) uried] acetamide {-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-Nε-carbobenzyloxy-L-lysyl) amino]
-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbobenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-L-lysyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (L-aspartyl) amino] -L-phenylalanine N- (toluene- 4-sulfonyl) -L-prolyl-4- (4-aminobutylamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxyl-carbonylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramide] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxylcarbonyl-N-methylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(O-benzyl)
-L-seryl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [δ- (D, L-glutamyl) amino] -L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylsarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxyl-carbonylsarcosyl) amino]- L-
Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino ] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(sarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(N, N-dimethylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N, N-dimethyl Glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxy Benzyloxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenyl] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 -[2- (methoxycarbonyl) phenyl] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [3- (
N, N-dimethylamino) propyl] -N- [trifluoromethanesulfonyl]
Amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [4- [
(Tert-butoxycarbonyl) methoxy] benzyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N, N-di [
4- (N, N-dimethylamino) benzyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N-[(2-
Formyl-1,2,3,4-tetrahydroisoquinolin-3-yl) methyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [2- (N, N-dimethylamino) Ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L -Prolyl-4- [2- (N-ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N- Diisopropylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3-cyclohexyl 2- (N-ter- butoxycarbonylamino) propoxy] -L- phenylalanine methyl ester N- (thiophene-2-sulfonyl) -L- prolyl -4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (5-chlorothiophen-2-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- ( 2,5-dichlorothiophen-3-sulfonyl) -L-prolyl-4-
[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (1-methylpyrazole-4-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine methyl ester N- (Toluene-4-sulfonyl) -L-prolyl-3- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (thiazol-2-sulfonyl) -L-prolyl-4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl- N-benzylamino) propoxy] -L-phenylalanine methyl ester N- (1-methylimidazole-4-sulfonyl) -L-prolyl-4- [3
-(N, N-dimethylamino) propoxy] -L-phenylalanine N- (2-methylthiadiazole-5-sulfonyl) -L-prolyl-4- [
3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-thiaprolyl-4- [3- (N, N
-Dimethylamino) propoxy] -L-phenylalanine N- (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (3,3-dimethyl) prolyl-4
-[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L -Phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (thiamorpholine-3-carbonyl) -4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L-phenylalani N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(Cyclopentyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- {2-
[4- (phenyl) phenyl] ethynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Toluene-4-sulfonyloxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Ureido) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(1-aminocyclohex-1-yl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (methoxy)
Prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (methoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4- [3- (4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (4- Ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl] -D , L-Phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (4-acetamido-4-carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) ) Sarkosyl-4- (4-acetamido-4)
-Carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {3-[(4,5-
Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5 -Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1
-Inyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L -Prolyl-4- {2- [4- (pyrimidin-2-yl) piperazin-1-yl] ethoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- ( Piperidin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (piperidin-1-yl) propoxy] -L-phenylalanine methyl ester N- Toluene-4-sulfonyl) -L- prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (piperidin-1-yl) ethoxy] -L-phenylalanine N- (toluene -4-sulfonyl) -L-prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine methyl ester N -(Toluene-4-sulfonyl) -L-prolyl-3- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-Methylpiperazin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-3- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4- {2- [4- (3-
Methoxythien-2-yl) -4-hydroxypiperidin-1-yl] ethoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-3- (1-methylpiperidin-4-oxy ) -D, L-Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (1-methylpiperidine-4-oxy) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L -(5,5-Dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L- (1,1-dioxothiomorpholine- 3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene) 4-Sulfonyl) -L- (1,1-dioxothiomorpholine-3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (toluene-4-sulfonyl)- L- (5,5-dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (α-toluenesulfonyl) -L-prolyl-4- (1-methylpiperidine-4- Oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- Prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine N- (toluene-4- Ruphonyl) -L-prolyl-4-N- (chloromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (vinylsulfonyl) amino-L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (N-trifluoromethanesulfonyl-N-isobutyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl- 4-N- (vinylsulfonyl) amino-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-benzylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene- 4-sulfonyl) -L-prolyl-4-[(ben Carbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(carboxy) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(carboxy) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) ) -L-Prolyl-4-[(aminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butylaminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (4-phenyl-4-hydroxypiperidin-1-yl) ethoxy] -L-phenylalaninemethyl Ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidine-1
-Ylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4 -Sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (amidino) phenylalanine N -(Toluene-4-sulfonyl) sarcosyl-D, L-4- (aminocarbonyl) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methylacetamido) -L-phenylalanine isopropyl ester N -(Toluene-4-sulfonyl) L-prolyl-4- (N-methylacetamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methyltrifluoroacetamido) -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl)- L-prolyl-L-4- (N-methylpiperidineoxy) -phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L- (4-methylpiperidineoxy ) Phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- ( 4-phenyl) -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-
A compound selected from the group consisting of phenylalanine, and pharmaceutically acceptable salts thereof, and any of the ester compounds listed above, wherein one ester is a methyl ester, an ethyl ester, an n-
An ester compound substituted by another ester selected from the group consisting of propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester. 13. A biological sample and a compound: [Where R¹Is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, hetero
R is selected from the group consisting of aryl and substituted heteroaryl;^TwoIs hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted
Cyclic, aryl, substituted aryl, heteroaryl, and substituted hetero
R is selected from the group consisting of aryl¹And R^TwoIs R^TwoNitrogen atom and R¹SO bound to_TwoGroup together with a heterocyclic or substituted heterocyclic group.
And R^ThreeIs alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl.
Selected from the group consisting of^TwoIs R¹And Hete
When no ring group is formed, R^TwoAnd R^ThreeAnd R^TwoNitrogen atom and R^ThreeTied to
A heterocyclic or substituted heterocyclic group with the combined carbon atoms;^FiveIs-(CH_Two)_x-Ar-R^Five'And R^Five'Is selected from the group consisting of the following (a) to (u): (a) a substituted alkylcarbonylamino (provided that at least
Another substituent is alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, alkenyl, amino, amidino, alkylamido
Dino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocar
Bonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy
, Cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxy-substituted heterocyclic, cycloal
Killed, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thio
Alkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloa
Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl
Thioheterocyclic, substituted thioheterocyclic, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two -Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl,
-OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic,-
OS (O)_Two-Substituted heterocyclic, -OSO_Two-NRR (where R is hydrogen or
Or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl
, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O
)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS
(O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, and
And an asymmetric di-substituted amine, wherein the alkyl, substituted alkyl, aryl, substituted
Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitution
Asymmetric di-substituents having different substituents selected from the group consisting of substituted heterocyclics and amino groups protected by common protecting groups such as Boc, Cbz, formyl,
-Substituted amine) or -SO_Two-Alkyl, -SO_Two−substitution
Alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two -Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO_TwoNR
Alkyl / substituted alkyl substituted by R (where R is hydrogen or alkyl)
(B) carboxyl and COOR (R is an alkyl group)
, Substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetero
Alkoxy) substituted with a substituent selected from the group consisting of
(C) aryl and heteroaryl; (d) —NR′R ′ (wherein, R ′ is each independently an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloaryl
Alkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic
(Wherein at least one R ′ is a substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic).
When R ′ is cyclic alkyl and R ′ is substituted alkyl, at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
O_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two−substitution
Alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO _Two -Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two−
Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocycle
Rick, and -SO_Two(E) -alkoxy-NR "R", wherein R "is independently alkyl, Substitution
Alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete
Aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
Selected from the group consisting of clicks (provided that each R ″ is a substituted alkyl
Wherein at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
Si, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl,
Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl
Sil-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl ant
, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxy
-Substituted heteroaryl, carboxyl heterocyclic, carboxyl-position
Substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,
Anidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl
, Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohete
Loaryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohete
Cyclic, heterocyclic, substituted heterocyclic, cycloalco
Xy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy
Si, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl
Amino, oxythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O 2)_Two-Substituted alkyl, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -O
S (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic,-
OSO_Two-NRR (where R is hydrogen or alkyl), -NRS (O)_Two-Archi
, -NRS (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (
O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two -Substituted heterocyclic, -NRS (O)_Two—NR-alkyl, —NRS (O 2)_Two-NR-substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O) _Two -NR-substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (
O)_Two-NR-substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic
H, -NRS (O)_Two-NR-substituted heterocyclic (where R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di- (substituted alkyl
L) amino, mono- and di-arylamino, mono- and di-substituted aryl
Amino, mono- and di-heteroarylamino, mono- and di-substituted hetero
Arylamino, mono- and di-heterocyclic amino, mono- and di-
-Substituted heterocyclic amino and unsymmetrical di-substituted amines,
Alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted hetero
Selected from the group consisting of aryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of asymmetric di-substituted amines having different substituents selected and an amino group protected by a conventional protecting group such as Boc, Cbz, formyl and the like.
Or -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic,
-SO_Two-Substituted heterocyclic, and -SO_TwoNRR wherein R is hydrogen or
Is an alkyl / substituted alkyl group substituted by alkyl); (f) substituted alkenyl or substituted alkynyl, provided that
At least one substituent on the nyl moiety is alkyl, substituted alkyl, aryl,
Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Group consisting of teloaryl, heterocyclic, and substituted heterocyclic
Selected, but when substituted by substituted alkyl, substituted alkyl
At least one substituent on the moiety on the aryl is an alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
Is -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocyclic, and -SO_TwoAlkyl / substituted alkyl groups substituted by NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided that substituted aryl
At least one substituent on the oxy / heteroaryloxy is halogen,
Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-di
Xylene, alkoxy, alkeneoxy, alkyneoxy, alkylamino
, Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl
(H) other than amino, N-alkyl or N, N-dialkylurea); (h) -alkoxy saturated heterocyclic, -alkoxy saturated substituted heterosa
Click, -substituted alkoxy-heterocyclic, and -substituted alkoxy
(I) -O-heterocyclic and -O-substituted heterocyclic; (j) tetrazolyl; (k) -NR-SO_Two-Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least the alkyl moiety of the substituted alkylsulfonylamino
Another substituent is halogen, hydroxyl, amino, nitro, trifluoromethyl.
Tyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-di
Oxymethylene, 1,2-dioxyethylene, alkoxy, alkeneoxy, a
Ruquinoxy, alkylamino, alkenylamino, alkynylamino, alk
Carbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonyl
Ruamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl
(L) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino
(M) substituted alkoxy (provided that a substituent on the alkyl portion of the substituted alkoxy is not substituted with alkenylsulfonylamino and alkynylsulfonylamino)
Is alkoxy-NR''R '', unsaturated heterocyclyl, alkyloxy,
Oxy, heteroaryloxy, aryl, heteroaryl, and halo
Gen, hydroxyl, amino, nitro, trifluoromethyl, trifluorometh
Xy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2
-Dioxyethylene, alkoxy, alkeneoxy, alkyneoxy, alkyl
Amino, alkenylamino, alkynylamino, alkylcarbonyloxy,
Sil, alkylcarbonylamino, alkoxycarbonylamino, alkylsul
Substituted by honylamino, N-alkyl or N, N-dialkylurea
(N) amidines and amidines substituted with 1 to 3 substituents, wherein
Substituents are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
Independent of substituted alkynyl, aryl, heteroaryl and heterocyclic
(O) -C (O) NR "" R "", wherein R "" is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkenyl, substituted alk
Nil, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl
From substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of: Provided that one R ′ ″ is an unsaturated heterocyclylalkyl, aryl, heteroaryl, or halogen, hydroxyl, amino, nitro
B, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, al
Quinyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy,
Alkeneoxy, alkyneoxy, alkylamino, alkenylamino, alk
Nylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
Aryl / heteroaryl substituted by N, N-dialkylurea
In other cases, the other R ′ ″ is alkyl, substituted alkyl (other than unsaturated heterocyclyl-substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted
Alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted
(P) -NR¹²C (O) -R⁸(Where R⁸Is alkyl, substituted alkyl, cyclo
Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group¹²Is alkyl, substituted alkyl, aryl, substituted aryl,
Chloroalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, f
(Q) -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, or -SO_Two-Alkyl; (r) -NR'C (O) NR⁹R⁹(Wherein R ′ is alkyl, substituted alkyl, ant
, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Substituted heteroaryl, heterocyclic and substituted heterocyclic
Each R⁹Is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group): (s) -NR'C (O) OR⁹(Wherein R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group⁹Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of heterocyclic, heterocyclic and substituted heterocyclic.
(T) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O)
NH-substituted heterocyclyl; Ar is aryl, heteroaryl, substituted aryl, or substituted heteroaryl
X is an integer from 1 to 4; R⁶Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloa
Lucoxy, -O- (N-succinimidyl), -NH-adamantyl, -O-co
Rest-5-en-3-β-yl, —NHOY (where Y is hydrogen, alkyl,
Substituted alkyl, aryl, and substituted aryl), -NH (CH_Two)_pCOOY (expression
Wherein p is an integer from 1 to 8 and Y is as defined above), -OCH_TwoNR⁹ R^Ten(Where R⁹Is selected from the group consisting of -C (O) -aryl and -C (O) -substituted aryl;^TenIs hydrogen and -CH_TwoCOOR¹¹(Where R¹¹Is selected from the group consisting of alkyl)), and -NHSO_TwoZ (where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl)
, Heteroaryl, substituted heteroaryl, heterocyclic and substituted
Q is -C (X) NR⁷-(Wherein, R⁷Is selected from the group consisting of hydrogen and alkyl
X is selected from the group consisting of oxygen and sulfur)¹Is p-CH_Three-Φ-, R⁶Is methoxy, Q is -C (O) NH-,^TwoAnd R^ThreeAre linked to form a pyrrolidinyl group,^FiveIs p-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl-, p-[-OCH_TwoCH_TwoN (isopropyl)_Two] -Benzyl-, p-[-OCH_TwoCH_Two-1-pyrrolidinyl] -benzyl-, p-[-OCH_TwoCH_Two-1- (4-pyrrolidinyl) piperazinyl]-
Benzyl-, p-[-OCH_TwoCH_Two-N-morpholinyl] -benzyl-, or p
-[-OCH_TwoCH_Two-N-piperidinyl] -benzyl-)
And a pharmaceutically acceptable salt thereof, when the above compound binds to VLA-4.
Method of binding VLA-4 in a biological sample, comprising contacting under combined conditions
. 14. The method of claim 13, wherein R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl. 15. R ¹ is 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl , 2- (methoxycarbonyl)
Phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH ₃ C (O) NH—) phenyl, 4-tri Fluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N -Methyl-3-methyl-5-chloropyrazole-4
- yl, phenethyl, 1-N-methyl-imidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, _{4-methyl-amidinophenyl, 4- [CH 3 SC (=} NH)] phenyl, 5-chloro-2 -Thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,
_{3,4-thiadiazol-2-yl, 4- [H 2 NC (S} )] phenyl, 4-A Minofeniru, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin -3-yl, pyrimidine-2-
The method of claim 14, wherein the method is selected from the group consisting of yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, and 1-methylpyrazol-4-yl. 16. R^TwoIs hydrogen, methyl, phenyl, benzyl,-(CH_Two) _Two -2-thienyl, and-(CH_Two)_Two14. The method of claim 13, wherein the method is selected from the group consisting of-[Phi]. 17. The method of claim 13, wherein R ¹ and R ² are combined with a nitrogen atom bonded to R ² and a SO ₂ group bonded to R ¹ to form a heterocyclic group or a substituted heterocyclic group. The described method. 18. The method of claim 13, wherein R ² and R ³ together with the nitrogen atom bonded to the R ² substituent and the carbon bonded to the R ³ substituent form a heterocyclic or substituted heterocyclic group. . Is 19. R ^3, methyl, phenyl, benzyl, _{diphenylmethyl, -CH 2 CH 2 -COOH, -CH} 2 -COOH, 2- amidoethyl, Isobuchi Le, t- butyl, -CH ₂ O-benzyl, 14. The method of claim 13, wherein the method is selected from the group consisting of: and hydroxymethyl. 20. The method according to claim 13, wherein Q is -C (O) NH- or -C (S) NH-. 21. R^FiveIs: 4- [NH_TwoCH_TwoC (O) NH-] benzyl, 4- [HOOCCH_TwoCH_TwoC (O
) NH-] benzyl, 4-[-NHC (O) CH_TwoNHBoc] benzyl, 4-[— NHC (O) CH (CH_Three) NHBoc] benzyl, 4-[— NHC (O) CH (CH_TwoΦ) NHBoc] benzyl, 4-[— NHC (O) CH_TwoNHC (O
) NH-3′-Methylphenyl] benzyl, 4-[— NHC (O) CH (NHB oc) (CH_Two)_FourNHCbz] benzyl, 4-[-NHC (O) CH_TwoCH (C (O) OCH_TwoΦ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH_TwoCH_TwoCH_TwoCH_TwoNH_Two) NHBoc] benzyl, 4- [H_Two NCH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- (BocHNCH_TwoCH_TwoCH_TwoC (O) NH-) benzyl, 4- [ΦCH_TwoOCH_Two(BocHN) CHC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoCH_TwoCH_TwoC (O) NH-] ben
Zyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH_ThreeN (Boc) CH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoOCH_Two (H_TwoN) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoO (O) C (Cbz-NH) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [HO (O) C (
NH_Two) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [CH_Three(N-Boc
) NCH_TwoC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoC (O) NH-] benzyl, 4-[(CH_Three)_TwoNCH_TwoC (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxyphenyl-]-benzyl
, 4- [2-carboxymethylphenyl-]-benzyl, 4- [ΦCH_TwoOC (O) NHCH_TwoCH_TwoNH-] benzyl, 4-N [-(SO_Two) CH_Three] -CH_TwoCH_TwoCH_TwoN (CH_Three)_TwoBenzyl, 4-t-butyl-O (O) CCH_Two-O-benzyl NH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzene
Zyl) amino] benzyl, 4- (2-formyl-1,2,3,4-tetrahydro
Isoquinolin-3-yl-CH_TwoNH) benzyl, 4-[-OCH_TwoCH_Two-1'-
(4′-pyrimidinyl) -piperazinyl] -benzyl, 4-[— OCH_TwoCH_Two-(1'-piperidinyl) -benzyl, 4-[-OCH_TwoCH_Two-(1'-Pyrrolidini
Ru)] benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1'-piperidinyl)]-ben
Jill, 4-[(CH_Three)_TwoNCH_TwoCH_TwoCH_Two-O-] benzyl, 4-[(CH_Three) _Two NCH_TwoCH_TwoO-]-benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1 '-(4'-
Methylpiperazinyl))]-benzyl, 4-[— OCH_TwoCH_TwoCH_Two-4- (3 '
-Chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_TwoN (Φ) CH_TwoCH_Three] -Benzyl, 4-[-OCH_Two-3 '-(N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidini
Benzyl], 3-[-O- (N-methylpiperidin-4-yl] benzyl, 4
-[-O- (N-methylpiperidin-4-yl] benzyl, 4- [di-isoprop]
Ropyramino-CH_TwoCH_TwoO-]-benzyl, 4- [N-3-methylbutyl-N
-Trifluoromethanesulfonyl) amino] benzyl, 4-[-OCH_TwoCH_Two−
(N-morpholinyl)]-benzyl, 4-[— OCH_TwoCH (NHBoc) CH_Two Cyclohexyl] -benzyl, 4- [OCH_TwoCH_Two-(N-piperidinyl) -b
Undil, 4-[-OCH_TwoCH_TwoCH_Two-(4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_Two-(N-homopiperidinyl)
-Benzyl, 4-[-OCH_TwoCH_TwoN (benzyl)_Two] -Benzyl, 3-[— O CH_TwoCH_TwoCH_TwoN (CH_Three)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five )_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN
(CH_Three) Benzyl) -benzyl, 4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl, [cyclopentylacetyleni
] -Benzyl, 4-[-C≡C-Φ-4′Φ] -benzyl, 4-[-C≡C-CH_Two-OS (O)_Two-4'-CH_Three-Φ] -benzyl, 4-[-C≡C-CH_Two NHC (O) NH_Two] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-COO CH_TwoCH_Three) Φ] -benzyl, 4-[— C≡C—CH (NH_Two) -Cyclohexyl] -benzyl, 4-[— C≡C—CH_Two—O-phenyl] -benzyl, 4-[— C≡C—CH_TwoOCH_Three] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-C
(O) OC_TwoH_Five) Phenyl] -benzyl, 4-[— C≡C—CH_TwoCH (C (O) OCH_Three)_Two] -Benzyl, 4-[— C≡C—CH_TwoCH (NHC (O) CH_Three)
C (O) OH] -benzyl, 4-[-C≡C-CH_TwoNH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-
OCH_TwoCH_TwoCH_Two-(N-morpholino)]-benzyl, 4-[-OCH_TwoCOO
H] -benzyl, 4-[-OCH_TwoCOO-t-butyl] -benzyl, 4-[-N (SO_TwoCH_Three) (CH_Two)_Three-N (CH_Three)_Two] -Benzyl, 4-[-NHS (O
)_TwoCF_Three] -Benzyl, 4-[— C (＝ NH) NH_Two] -Benzyl, 4-[-N HSO_Two-CH_TwoCl] -benzyl, 4-[-OCH_TwoC (O) NH-benzyl] -benzyl, 4-[-OCH_TwoC (O) O-benzyl] -benzyl, 4-[-O CH_TwoC (O) OH] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] -benzyl,
-[-OCH_TwoC (O) NH_Two] -Benzyl, 4-[-OCH_TwoC (O) NH-t-butyl] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4-f
Enyl) -piperidinyl] -benzyl, 4-[-NHSO_Two-CH = CH_Two] -B
Nyl, 4-[-NHSO_Two-CH_TwoCH_TwoCl] -benzyl, 4-benzyl-benzyl, 4-[— OCH_TwoC (O) piperidin-1-yl] benzyl, 4-[-OCH_TwoC (O) N (CH (CH_Three)_Two)_TwoBenzyl, 4-amidinobenzyl, 4
-Acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4 (-N
HC (O) CH_TwoNHC (O) NH-fluorescein) benzyl, 4- (NHC (O) CH_TwoCH (NH_Two) COOH, (1-toluenesulfonylimidizole)
4-yl) -methyl-, [(1-N, N-dimethylaminosulfonyl) -imidi
Zol-4-yl] methyl-, 4- (N-toluenesulfonylamino) benzyl
14. The method of claim 13, wherein the method is selected from the group consisting of, and 4- [N-methyltrifluoroacetamido] phenyl. 22. R⁶Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, isopropoxy, n-butoxy
, T-butoxy, cyclopentoxy, neopentoxy, 2-α-iso-propyl
-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylc
Clohexoxy, -NH_Two, Benzyloxy, -NHCH_TwoCOOH, -NHCH _Two CH_TwoCOOH, -NH-adamantyl, -NHCH_TwoCH_TwoCOOCH_TwoCH_Three,
-NHSO_Two-P-CH_Three-Φ, -NHOR⁸(Where R⁸Is hydrogen, methyl, isop
Ropyl or benzyl), O- (N-succinimidyl), -O-cholest-5
-En-3-β-yl, -OCH_Two-OC (O) C (CH_Three)_Three, -O (CH_Two)_Z NHC (O) W (wherein z is 1 or 2, W is pyrid-3-yl, N-meth
From tylpyridyl and N-methyl-1,4-dihydro-pyrid-3-yl
-NR "C (O) -R '(where R' is aryl, hetero
Aryl or heterocyclic, R '' is hydrogen or --CH_TwoC (O) OCH_TwoCH_Three14. The method of claim 13, wherein the method is selected from the group consisting of: 23. The compound as described above, comprising: N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4- [3- (carboxy) propionamide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-L-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-phenylalanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (fluorescein) thiouried] acetamido} -L-phenylalanine N -(Toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-
Methylphenyl) uried] acetamide {-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-Nε-carbobenzyloxy-L-lysyl) amino]
-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbobenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-L-lysyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (L-aspartyl) amino] -L-phenylalanine N- (toluene- 4-sulfonyl) -L-prolyl-4- (4-aminobutylamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxyl-carbonylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramide] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxylcarbonyl-N-methylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(O-benzyl)
-L-seryl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [δ- (D, L-glutamyl) amino] -L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylsarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxyl-carbonylsarcosyl) amino]- L-
Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino ] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(sarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(N, N-dimethylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N, N-dimethyl Glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxy Benzyloxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenyl] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 -[2- (methoxycarbonyl) phenyl] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [3- (
N, N-dimethylamino) propyl] -N- [trifluoromethanesulfonyl]
Amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [4- [
(Tert-butoxycarbonyl) methoxy] benzyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N, N-di [
4- (N, N-dimethylamino) benzyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N-[(2-
Formyl-1,2,3,4-tetrahydroisoquinolin-3-yl) methyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [2- (N, N-dimethylamino) Ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L -Prolyl-4- [2- (N-ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N- Diisopropylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3-cyclohexyl 2- (N-ter- butoxycarbonylamino) propoxy] -L- phenylalanine methyl ester N- (thiophene-2-sulfonyl) -L- prolyl -4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (5-chlorothiophen-2-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- ( 2,5-dichlorothiophen-3-sulfonyl) -L-prolyl-4-
[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (1-methylpyrazole-4-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine methyl ester N- (Toluene-4-sulfonyl) -L-prolyl-3- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (thiazol-2-sulfonyl) -L-prolyl-4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl- N-benzylamino) propoxy] -L-phenylalanine methyl ester N- (1-methylimidazole-4-sulfonyl) -L-prolyl-4- [3
-(N, N-dimethylamino) propoxy] -L-phenylalanine N- (2-methylthiadiazole-5-sulfonyl) -L-prolyl-4- [
3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-thiaprolyl-4- [3- (N, N
-Dimethylamino) propoxy] -L-phenylalanine N- (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (3,3-dimethyl) prolyl-4
-[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L -Phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (thiamorpholine-3-carbonyl) -4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L-phenylalani N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(Cyclopentyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- {2-
[4- (phenyl) phenyl] ethynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Toluene-4-sulfonyloxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Ureido) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(1-aminocyclohex-1-yl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (methoxy)
Prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (methoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4- [3- (4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (4- Ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl] -D , L-Phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (4-acetamido-4-carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) ) Sarkosyl-4- (4-acetamido-4)
-Carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {3-[(4,5-
Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5 -Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1
-Inyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L -Prolyl-4- {2- [4- (pyrimidin-2-yl) piperazin-1-yl] ethoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- ( Piperidin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (piperidin-1-yl) propoxy] -L-phenylalanine methyl ester N- Toluene-4-sulfonyl) -L- prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (piperidin-1-yl) ethoxy] -L-phenylalanine N- (toluene -4-sulfonyl) -L-prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine methyl ester N -(Toluene-4-sulfonyl) -L-prolyl-3- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-Methylpiperazin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-3- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4- {2- [4- (3-
Methoxythien-2-yl) -4-hydroxypiperidin-1-yl] ethoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-3- (1-methylpiperidin-4-oxy ) -D, L-Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (1-methylpiperidine-4-oxy) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L -(5,5-Dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L- (1,1-dioxothiomorpholine- 3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene) 4-Sulfonyl) -L- (1,1-dioxothiomorpholine-3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (toluene-4-sulfonyl)- L- (5,5-dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (α-toluenesulfonyl) -L-prolyl-4- (1-methylpiperidine-4- Oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- Prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine N- (toluene-4- Ruphonyl) -L-prolyl-4-N- (chloromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (vinylsulfonyl) amino-L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (N-trifluoromethanesulfonyl-N-isobutyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl- 4-N- (vinylsulfonyl) amino-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-benzylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene- 4-sulfonyl) -L-prolyl-4-[(ben Carbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(carboxy) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(carboxy) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) ) -L-Prolyl-4-[(aminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butylaminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (4-phenyl-4-hydroxypiperidin-1-yl) ethoxy] -L-phenylalaninemethyl Ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidine-1
-Ylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4 -Sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (amidino) phenylalanine N -(Toluene-4-sulfonyl) sarcosyl-D, L-4- (aminocarbonyl) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methylacetamido) -L-phenylalanine isopropyl ester N -(Toluene-4-sulfonyl) L-prolyl-4- (N-methylacetamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methyltrifluoroacetamido) -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl)- L-prolyl-L-4- (N-methylpiperidineoxy) -phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L- (4-methylpiperidineoxy ) Phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- ( 4-phenyl) -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-
A compound selected from the group consisting of phenylalanine, and pharmaceutically acceptable salts thereof, and any of the ester compounds listed above, wherein one ester is a methyl ester, an ethyl ester, an n-
An ester compound substituted by another ester selected from the group consisting of propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester. Item 14. The method according to Item 13. 24. The above compound is represented by the following formula: N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
24. The method according to claim 23, which is butoxylcarbonylglycyl) amino] -L-phenylalanine. 25. A pharmaceutically acceptable carrier, having the formula: [Where R¹Is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, hetero
R is selected from the group consisting of aryl and substituted heteroaryl;^TwoIs hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted
Cyclic, aryl, substituted aryl, heteroaryl, and substituted hetero
R is selected from the group consisting of aryl¹And R^TwoIs R^TwoNitrogen atom and R¹SO bound to_TwoGroup together with a heterocyclic or substituted heterocyclic group.
And R^ThreeIs alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl.
Selected from the group consisting of^TwoIs R¹And Hete
When no ring group is formed, R^TwoAnd R^ThreeAnd R^TwoNitrogen atom and R^ThreeTied to
A heterocyclic or substituted heterocyclic group with the combined carbon atoms;^FiveIs-(CH_Two)_x-Ar-R^Five'And R^Five'Is selected from the group consisting of the following (a) to (u): (a) a substituted alkylcarbonylamino (provided that at least
Another substituent is alkoxy, substituted alkoxy, acyl, acylamino, thio
Carbonylamino, acyloxy, alkenyl, amino, amidino, alkylamido
Dino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocar
Bonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy
, Cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl al
Kill, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
Sil-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
Carboxyl heteroaryl, carboxyl-substituted heteroaryl, carbo
Xyl heterocyclic, carboxy-substituted heterocyclic, cycloal
Killed, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thio
Alkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloa
Alkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl
Thioheterocyclic, substituted thioheterocyclic, heterocyclic
, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy,
Loaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
Heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamido
No, -OS (O)_Two-Alkyl, -OS (O)_Two-Substituted alkyl, -OS (O)_Two -Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl,
-OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic,-
OS (O)_Two-Substituted heterocyclic, -OSO_Two-NRR (where R is hydrogen or
Or alkyl), -NRS (O)_Two-Alkyl, -NRS (O)_Two-Substituted alkyl
, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O
)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O) _Two -Heterocyclic, -NRS (O)_Two-Substituted heterocyclic, -NRS
(O)_Two-NR-alkyl, -NRS (O)_Two-NR-substituted alkyl, -NRS (
O)_Two-NR-aryl, -NRS (O)_Two-NR-substituted aryl, -NRS (O
)_Two-NR-heteroaryl, -NRS (O)_Two-NR-substituted heteroaryl,-
NRS (O)_Two-NR-heterocyclic, -NRS (O)_Two-NR-substituted hete
Cyclic (where R is hydrogen or alkyl), mono- and di-alkyl
Amino, mono- and di- (substituted alkyl) amino, mono- and di-aryl
Amino, mono- and di-substituted arylamino, mono- and di-heteroaryl
Amino, mono- and di-substituted heteroarylamino, mono- and di-hete
Cyclic amino, mono- and di-substituted heterocyclic amino, and
And an asymmetric di-substituted amine, wherein the alkyl, substituted alkyl, aryl, substituted
Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitution
Asymmetric di-substituents having different substituents selected from the group consisting of substituted heterocyclics and amino groups protected by common protecting groups such as Boc, Cbz, formyl,
-Substituted amine) or -SO_Two-Alkyl, -SO_Two−substitution
Alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two -Heterocyclic, -SO_Two-Substituted heterocyclic, and -SO_TwoNR
Alkyl / substituted alkyl substituted by R (where R is hydrogen or alkyl)
(B) carboxyl and COOR (R is an alkyl group)
, Substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetero
Alkoxy) substituted with a substituent selected from the group consisting of
(C) aryl and heteroaryl; (d) —NR′R ′ (wherein, R ′ is each independently an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a cycloaryl
Alkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic
(Wherein at least one R ′ is a substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic).
When R ′ is cyclic alkyl and R ′ is substituted alkyl, at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
O_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two−substitution
Alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO _Two -Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two−
Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocycle
Rick, and -SO_Two(E) -alkoxy-NR "R", wherein R "is independently alkyl, Substitution
Alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete
Aryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
Selected from the group consisting of clicks (provided that each R ″ is a substituted alkyl
Wherein at least one substituent on the substituted alkyl moiety is alkoxy, substituted alkoxy,
Si, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl,
Amino, amidino, alkylamidino, thioamidino, aminoacyl, aminoca
Rubonylamino, aminothiocarbonylamino, aminocarbonyloxy, ant
Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl,
Carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl
Sil-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl ant
, Carboxyl-substituted aryl, carboxyl heteroaryl, carboxy
-Substituted heteroaryl, carboxyl heterocyclic, carboxyl-position
Substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,
Anidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl
, Substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohete
Loaryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohete
Cyclic, heterocyclic, substituted heterocyclic, cycloalco
Xy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy
Si, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl
Amino, oxythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O 2)_Two-Substituted alkyl, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -O
S (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic,-
OSO_Two-NRR (where R is hydrogen or alkyl), -NRS (O)_Two-Archi
, -NRS (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (
O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted heteroaryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two -Substituted heterocyclic, -NRS (O)_Two—NR-alkyl, —NRS (O 2)_Two-NR-substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O) _Two -NR-substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (
O)_Two-NR-substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic
H, -NRS (O)_Two-NR-substituted heterocyclic (where R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di- (substituted alkyl
L) amino, mono- and di-arylamino, mono- and di-substituted aryl
Amino, mono- and di-heteroarylamino, mono- and di-substituted hetero
Arylamino, mono- and di-heterocyclic amino, mono- and di-
-Substituted heterocyclic amino and unsymmetrical di-substituted amines,
Alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted hetero
Selected from the group consisting of aryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of asymmetric di-substituted amines having different substituents selected and an amino group protected by a conventional protecting group such as Boc, Cbz, formyl and the like.
Or -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic,
-SO_Two-Substituted heterocyclic, and -SO_TwoNRR wherein R is hydrogen or
Is an alkyl / substituted alkyl group substituted by alkyl); (f) substituted alkenyl or substituted alkynyl, provided that
At least one substituent on the nyl moiety is alkyl, substituted alkyl, aryl,
Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Group consisting of teloaryl, heterocyclic, and substituted heterocyclic
Selected, but when substituted by substituted alkyl, substituted alkyl
At least one substituent on the moiety on the aryl is an alkoxy, substituted alkoxy,
, Acylamino, thiocarbonylamino, acyloxy, alkenyl, amino,
Amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonyl
Amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy
Si, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxy
Sil, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-
Chloroalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,
Ruboxyl-substituted aryl, carboxyl heteroaryl, carboxyl-substituted
Heteroaryl, carboxyl heterocyclic, carboxy-substituted heterosa
Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinos
Rufone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio
Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl
, Substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic
, Heterocyclic, substituted heterocyclic, cycloalkoxy, substituted
Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, hetero
Cyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
Xythiocarbonylamino, -OS (O)_Two-Alkyl, -OS (O)_Two-Substitution
Lucil, -OS (O)_Two-Aryl, -OS (O)_Two-Substituted aryl, -OS (O
)_Two-Heteroaryl, -OS (O)_Two-Substituted heteroaryl, -OS (O)_Two-Heterocyclic, -OS (O)_Two-Substituted heterocyclic, -OSO_Two-N
RR (where R is hydrogen or alkyl), -NRS (O)_Two-Alkyl, -NR S (O)_Two-Substituted alkyl, -NRS (O)_Two-Aryl, -NRS (O)_Two-Substituted aryl, -NRS (O)_Two-Heteroaryl, -NRS (O)_Two-Substituted hetero
Aryl, -NRS (O)_Two-Heterocyclic, -NRS (O)_Two-Substitution
Cyclic, -NRS (O)_Two-NR-alkyl, -NRS (O)_Two-NR-
Substituted alkyl, -NRS (O)_Two-NR-aryl, -NRS (O)_Two-NR-
Substituted aryl, -NRS (O)_Two-NR-heteroaryl, -NRS (O)_Two-NR
-Substituted heteroaryl, -NRS (O)_Two-NR-heterocyclic, -NR S (O)_Two-NR-substituted heterocyclic (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,
No- and di-heteroarylamino, mono- and di-substituted heteroaryl
Amino, mono- and di-heterocyclic amino, mono- and di-substituted
Cyclic amino and unsymmetrical di-substituted amines,
Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
A heterocycle selected from the group consisting of heterocyclic and substituted heterocyclic
And an asymmetric di-substituted amine having an amino group protected by a conventional protecting group such as Boc, Cbz, formyl, etc.)
Is -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Alkenyl, -SO_Two-Substituted alkenyl, -SO_Two-Cycloalkyl, -SO_Two-Substituted cycloalkyl, -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, -SO_Two-Heterocyclic, -SO_Two-Substitution heterocyclic, and -SO_TwoAlkyl / substituted alkyl groups substituted by NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided that substituted aryl
At least one substituent on the oxy / heteroaryloxy is halogen,
Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy,
Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-di
Xylene, alkoxy, alkeneoxy, alkyneoxy, alkylamino
, Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl,
Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl
(H) other than amino, N-alkyl or N, N-dialkylurea); (h) -alkoxy saturated heterocyclic, -alkoxy saturated substituted heterosa
Click, -substituted alkoxy-heterocyclic, and -substituted alkoxy
(I) -O-heterocyclic and -O-substituted heterocyclic; (j) tetrazolyl; (k) -NR-SO_Two-Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least the alkyl moiety of the substituted alkylsulfonylamino
Another substituent is halogen, hydroxyl, amino, nitro, trifluoromethyl.
Tyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-di
Oxymethylene, 1,2-dioxyethylene, alkoxy, alkeneoxy, a
Ruquinoxy, alkylamino, alkenylamino, alkynylamino, alk
Carbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonyl
Ruamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl
(L) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino
(M) substituted alkoxy (provided that a substituent on the alkyl portion of the substituted alkoxy is not substituted with alkenylsulfonylamino and alkynylsulfonylamino)
Is alkoxy-NR''R '', unsaturated heterocyclyl, alkyloxy,
Oxy, heteroaryloxy, aryl, heteroaryl, and halo
Gen, hydroxyl, amino, nitro, trifluoromethyl, trifluorometh
Xy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2
-Dioxyethylene, alkoxy, alkeneoxy, alkyneoxy, alkyl
Amino, alkenylamino, alkynylamino, alkylcarbonyloxy,
Sil, alkylcarbonylamino, alkoxycarbonylamino, alkylsul
Substituted by honylamino, N-alkyl or N, N-dialkylurea
(N) amidines and amidines substituted with 1 to 3 substituents, wherein
Substituents are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
Independent of substituted alkynyl, aryl, heteroaryl and heterocyclic
(O) -C (O) NR "" R "", wherein R "" is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Alkenyl, substituted alk
Nil, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl
From substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group consisting of: Provided that one R ′ ″ is an unsaturated heterocyclylalkyl, aryl, heteroaryl, or halogen, hydroxyl, amino, nitro
B, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, al
Quinyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy,
Alkeneoxy, alkyneoxy, alkylamino, alkenylamino, alk
Nylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino,
Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or
Aryl / heteroaryl substituted by N, N-dialkylurea
In other cases, the other R ′ ″ is alkyl, substituted alkyl (other than unsaturated heterocyclyl-substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted
Alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted
(P) -NR¹²C (O) -R⁸(Where R⁸Is alkyl, substituted alkyl, cyclo
Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group¹²Is alkyl, substituted alkyl, aryl, substituted aryl,
Chloroalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, f
(Q) -SO_Two-Aryl, -SO_Two-Substituted aryl, -SO_Two-Heteroaryl, -SO_Two-Substituted heteroaryl, or -SO_Two-Alkyl; (r) -NR'C (O) NR⁹R⁹(Wherein R ′ is alkyl, substituted alkyl, ant
, Substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,
Substituted heteroaryl, heterocyclic and substituted heterocyclic
Each R⁹Is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group): (s) -NR'C (O) OR⁹(Wherein R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
Consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic
Selected from the group⁹Is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
Selected from the group consisting of heterocyclic, heterocyclic and substituted heterocyclic.
(T) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O)
NH-substituted heterocyclyl; Ar is aryl, heteroaryl, substituted aryl, or substituted heteroaryl
X is an integer from 1 to 4; R⁶Is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloa
Lucoxy, -O- (N-succinimidyl), -NH-adamantyl, -O-co
Rest-5-en-3-β-yl, —NHOY (where Y is hydrogen, alkyl,
Substituted alkyl, aryl, and substituted aryl), -NH (CH_Two)_pCOOY (expression
Wherein p is an integer from 1 to 8 and Y is as defined above), -OCH_TwoNR⁹ R^Ten(Where R⁹Is selected from the group consisting of -C (O) -aryl and -C (O) -substituted aryl;^TenIs hydrogen and -CH_TwoCOOR¹¹(Where R¹¹Is selected from the group consisting of alkyl)), and -NHSO_TwoZ (where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl)
, Heteroaryl, substituted heteroaryl, heterocyclic and substituted
Q is -C (X) NR⁷-(Wherein, R⁷Is selected from the group consisting of hydrogen and alkyl
X is selected from the group consisting of oxygen and sulfur)¹Is p-CH_Three-Φ-, R⁶Is methoxy, Q is -C (O) NH-,^TwoAnd R^ThreeAre linked to form a pyrrolidinyl group,^FiveIs p-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl-, p-[-OCH_TwoCH_TwoN (isopropyl)_Two] -Benzyl-, p-[-OCH_TwoCH_Two-1-pyrrolidinyl] -benzyl-, p-[-OCH_TwoCH_Two-1- (4-pyrrolidinyl) piperazinyl]-
Benzyl-, p-[-OCH_TwoCH_Two-N-morpholinyl] -benzyl-, or p
-[-OCH_TwoCH_Two-N-piperidinyl] -benzyl-)
And the pharmaceutically acceptable compounds thereof under conditions in which the compound binds to VLA-4
A pharmaceutical composition comprising one or more of the following salts: 26. The pharmaceutical composition according to claim 13, wherein R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl. . 27. R ¹ is 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl , 2- (methoxycarbonyl)
Phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH ₃ C (O) NH—) phenyl, 4-tri Fluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N -Methyl-3-methyl-5-chloropyrazole-4
- yl, phenethyl, 1-N-methyl-imidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, _{4-methyl-amidinophenyl, 4- [CH 3 SC (=} NH)] phenyl, 5-chloro-2 -Thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,
_{3,4-thiadiazol-2-yl, 4- [H 2 NC (S} )] phenyl, 4-A Minofeniru, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin -3-yl, pyrimidine-2-
27. The pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is selected from the group consisting of yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, and 1-methylpyrazol-4-yl. 28. R^TwoIs hydrogen, methyl, phenyl, benzyl,-(CH_Two) _Two -2-thienyl, and-(CH_Two)_TwoThe pharmaceutical composition according to claim 25, which is selected from the group consisting of -Φ. 29. The method of claim 25, wherein R ¹ and R ² are combined with a nitrogen atom bonded to R ² and a SO ₂ group bonded to R ¹ to form a heterocyclic group or a substituted heterocyclic group. The pharmaceutical composition according to any one of the preceding claims. 30. The medicament according to claim 25, wherein R ² and R ³ together with the nitrogen atom bonded to the R ² substituent and the carbon bonded to the R ³ substituent form a heterocyclic group or a substituted heterocyclic group. Composition. Is 31. R ^3, methyl, phenyl, benzyl, _{diphenylmethyl, -CH 2 CH 2 -COOH, -CH} 2 -COOH, 2- amidoethyl, Isobuchi Le, t- butyl, -CH ₂ O-benzyl, 26. The pharmaceutical composition according to claim 25, which is selected from the group consisting of: and hydroxymethyl. 32. The pharmaceutical composition according to claim 25, wherein Q is -C (O) NH- or -C (S) NH-. 33. R^FiveIs: 4- [NH_TwoCH_TwoC (O) NH-] benzyl, 4- [HOOCCH_TwoCH_TwoC (O
) NH-] benzyl, 4-[-NHC (O) CH_TwoNHBoc] benzyl, 4-[— NHC (O) CH (CH_Three) NHBoc] benzyl, 4-[— NHC (O) CH (CH_TwoΦ) NHBoc] benzyl, 4-[— NHC (O) CH_TwoNHC (O
) NH-3′-Methylphenyl] benzyl, 4-[— NHC (O) CH (NHB oc) (CH_Two)_FourNHCbz] benzyl, 4-[-NHC (O) CH_TwoCH (C (O) OCH_TwoΦ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH_TwoCH_TwoCH_TwoCH_TwoNH_Two) NHBoc] benzyl, 4- [H_Two NCH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- (BocHNCH_TwoCH_TwoCH_TwoC (O) NH-) benzyl, 4- [ΦCH_TwoOCH_Two(BocHN) CHC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoCH_TwoCH_TwoC (O) NH-] ben
Zyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH_ThreeN (Boc) CH_TwoCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoOCH_Two (H_TwoN) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH_TwoCH_TwoC (O) NH-] benzyl, 4- [ΦCH_TwoO (O) C (Cbz-NH) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [HO (O) C (
NH_Two) CHCH_TwoCH_Two-C (O) NH-] benzyl, 4- [CH_Three(N-Boc
) NCH_TwoC (O) NH-] benzyl, 4- [CH_ThreeNHCH_TwoC (O) NH-] benzyl, 4-[(CH_Three)_TwoNCH_TwoC (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxyphenyl-]-benzyl
, 4- [2-carboxymethylphenyl-]-benzyl, 4- [ΦCH_TwoOC (O) NHCH_TwoCH_TwoNH-] benzyl, 4-N [-(SO_Two) CH_Three] -CH_TwoCH_TwoCH_TwoN (CH_Three)_TwoBenzyl, 4-t-butyl-O (O) CCH_Two-O-benzyl NH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzene
Zyl) amino] benzyl, 4- (2-formyl-1,2,3,4-tetrahydro
Isoquinolin-3-yl-CH_TwoNH) benzyl, 4-[-OCH_TwoCH_Two-1'-
(4′-pyrimidinyl) -piperazinyl] -benzyl, 4-[— OCH_TwoCH_Two-(1'-piperidinyl) -benzyl, 4-[-OCH_TwoCH_Two-(1'-Pyrrolidini
Ru)] benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1'-piperidinyl)]-ben
Jill, 4-[(CH_Three)_TwoNCH_TwoCH_TwoCH_Two-O-] benzyl, 4-[(CH_Three) _Two NCH_TwoCH_TwoO-]-benzyl, 4-[-OCH_TwoCH_TwoCH_Two-(1 '-(4'-
Methylpiperazinyl))]-benzyl, 4-[— OCH_TwoCH_TwoCH_Two-4- (3 '
-Chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_TwoN (Φ) CH_TwoCH_Three] -Benzyl, 4-[-OCH_Two-3 '-(N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidini
Benzyl], 3-[-O- (N-methylpiperidin-4-yl] benzyl, 4
-[-O- (N-methylpiperidin-4-yl] benzyl, 4- [di-isoprop]
Ropyramino-CH_TwoCH_TwoO-]-benzyl, 4- [N-3-methylbutyl-N
-Trifluoromethanesulfonyl) amino] benzyl, 4-[-OCH_TwoCH_Two−
(N-morpholinyl)]-benzyl, 4-[— OCH_TwoCH (NHBoc) CH_Two Cyclohexyl] -benzyl, 4- [OCH_TwoCH_Two-(N-piperidinyl) -b
Undil, 4-[-OCH_TwoCH_TwoCH_Two-(4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH_TwoCH_Two-(N-homopiperidinyl)
-Benzyl, 4-[-OCH_TwoCH_TwoN (benzyl)_Two] -Benzyl, 3-[— O CH_TwoCH_TwoCH_TwoN (CH_Three)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five )_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoN (C_TwoH_Five)_Two] -Benzyl, 4-[-OCH_TwoCH_TwoCH_TwoN
(CH_Three) Benzyl) -benzyl, 4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl, [cyclopentylacetyleni
] -Benzyl, 4-[-C≡C-Φ-4′Φ] -benzyl, 4-[-C≡C-CH_Two-OS (O)_Two-4'-CH_Three-Φ] -benzyl, 4-[-C≡C-CH_Two NHC (O) NH_Two] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-COO CH_TwoCH_Three) Φ] -benzyl, 4-[— C≡C—CH (NH_Two) -Cyclohexyl] -benzyl, 4-[— C≡C—CH_Two—O-phenyl] -benzyl, 4-[— C≡C—CH_TwoOCH_Three] -Benzyl, 4-[— C≡C—CH_Two-O- (4'-C
(O) OC_TwoH_Five) Phenyl] -benzyl, 4-[— C≡C—CH_TwoCH (C (O) OCH_Three)_Two] -Benzyl, 4-[— C≡C—CH_TwoCH (NHC (O) CH_Three)
C (O) OH] -benzyl, 4-[-C≡C-CH_TwoNH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-
OCH_TwoCH_TwoCH_Two-(N-morpholino)]-benzyl, 4-[-OCH_TwoCOO
H] -benzyl, 4-[-OCH_TwoCOO-t-butyl] -benzyl, 4-[-N (SO_TwoCH_Three) (CH_Two)_Three-N (CH_Three)_Two] -Benzyl, 4-[-NHS (O
)_TwoCF_Three] -Benzyl, 4-[— C (＝ NH) NH_Two] -Benzyl, 4-[-N HSO_Two-CH_TwoCl] -benzyl, 4-[-OCH_TwoC (O) NH-benzyl] -benzyl, 4-[-OCH_TwoC (O) O-benzyl] -benzyl, 4-[-O CH_TwoC (O) OH] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] -benzyl,
-[-OCH_TwoC (O) NH_Two] -Benzyl, 4-[-OCH_TwoC (O) NH-t-butyl] -benzyl, 4-[-OCH_TwoCH_Two-1- (4-hydroxy-4-f
Enyl) -piperidinyl] -benzyl, 4-[-NHSO_Two-CH = CH_Two] -B
Nyl, 4-[-NHSO_Two-CH_TwoCH_TwoCl] -benzyl, 4-benzyl-benzyl, 4-[— OCH_TwoC (O) piperidin-1-yl] benzyl, 4-[-OCH_TwoC (O) N (CH (CH_Three)_Two)_TwoBenzyl, 4-amidinobenzyl, 4
-Acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4 (-N
HC (O) CH_TwoNHC (O) NH-fluorescein) benzyl, 4- (NHC (O) CH_TwoCH (NH_Two) COOH, (1-toluenesulfonylimidizole)
4-yl) -methyl-, [(1-N, N-dimethylaminosulfonyl) -imidi
Zol-4-yl] methyl-, 4- (N-toluenesulfonylamino) benzyl
26. The pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is selected from the group consisting of, and 4- [N-methyltrifluoroacetamido] phenyl. 34. R^{6 '}Is 2,4-dioxo-tetrahydrofuran-3-i
(3,4-enol), methoxy, ethoxy, isopropoxy, n-butoxy
, T-butoxy, cyclopentoxy, neopentoxy, 2-α-iso-propyl
-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylc
Clohexoxy, -NH_Two, Benzyloxy, -NHCH_TwoCOOH, -NHCH _Two CH_TwoCOOH, -NH-adamantyl, -NHCH_TwoCH_TwoCOOCH_TwoCH_Three,
-NHSO_Two-P-CH_Three-Φ, -NHOR⁸(Where R⁸Is hydrogen, methyl, isop
Ropyl or benzyl), O- (N-succinimidyl), -O-cholest-5
-En-3-β-yl, -OCH_Two-OC (O) C (CH_Three)_Three, -O (CH_Two)_Z NHC (O) W (wherein z is 1 or 2, W is pyrid-3-yl, N-meth
From tylpyridyl and N-methyl-1,4-dihydro-pyrid-3-yl
-NR "C (O) -R '(where R' is aryl, hetero
Aryl or heterocyclic, R '' is hydrogen or --CH_TwoC (O) OCH_TwoCH_Three26. The pharmaceutical composition according to claim 25, which is selected from the group consisting of: 35. The compound as described above, comprising: N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4- [3- (carboxy) propionamide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-L-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-alanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxylcarbonyl-D-phenylalanyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (fluorescein) thiouried] acetamido} -L-phenylalanine N -(Toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylglycyl) amino] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-
Methylphenyl) uried] acetamide {-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-Nε-carbobenzyloxy-L-lysyl) amino]
-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbobenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L-prolyl-4-[(Nα-tert
-Butoxylcarbonyl-L-lysyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (L-aspartyl) amino] -L-phenylalanine N- (toluene- 4-sulfonyl) -L-prolyl-4- (4-aminobutylamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxyl-carbonylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramide] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [4- (N-ter
t-butoxylcarbonyl-N-methylamino) butyramide] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(O-benzyl)
-L-seryl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [δ- (D, L-glutamyl) amino] -L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4-[(N-tert-
Butoxyl-carbonylsarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxyl-carbonylsarcosyl) amino]- L-
Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(sarcosyl) amino ] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(sarcosyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(N, N-dimethylglycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N, N-dimethyl Glycyl) amino] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxy Benzyloxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenyl] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 -[2- (methoxycarbonyl) phenyl] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-
Carbobenzyloxyamino) ethyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [3- (
N, N-dimethylamino) propyl] -N- [trifluoromethanesulfonyl]
Amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [4- [
(Tert-butoxycarbonyl) methoxy] benzyl] amino} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N, N-di [
4- (N, N-dimethylamino) benzyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N-[(2-
Formyl-1,2,3,4-tetrahydroisoquinolin-3-yl) methyl] amino} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [2- (N, N-dimethylamino) Ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L -Prolyl-4- [2- (N-ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N- Diisopropylamino) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3-cyclohexyl 2- (N-ter- butoxycarbonylamino) propoxy] -L- phenylalanine methyl ester N- (thiophene-2-sulfonyl) -L- prolyl -4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (5-chlorothiophen-2-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine N- ( 2,5-dichlorothiophen-3-sulfonyl) -L-prolyl-4-
[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (1-methylpyrazole-4-sulfonyl) -L-prolyl-4- [3-
(N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine methyl ester N- (Toluene-4-sulfonyl) -L-prolyl-3- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (thiazol-2-sulfonyl) -L-prolyl-4- [3- (N, N-
Dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl- N-benzylamino) propoxy] -L-phenylalanine methyl ester N- (1-methylimidazole-4-sulfonyl) -L-prolyl-4- [3
-(N, N-dimethylamino) propoxy] -L-phenylalanine N- (2-methylthiadiazole-5-sulfonyl) -L-prolyl-4- [
3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-thiaprolyl-4- [3- (N, N
-Dimethylamino) propoxy] -L-phenylalanine N- (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (3,3-dimethyl) prolyl-4
-[3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethyl Amino) propoxy] -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L -Phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- (thiamorpholine-3-carbonyl) -4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethoxy] -L-phenylalani N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(Cyclopentyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- {2-
[4- (phenyl) phenyl] ethynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Toluene-4-sulfonyloxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(Ureido) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [3-
(4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylalanyl-4- [2-
(1-aminocyclohex-1-yl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (phenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (methoxy)
Prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (methoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4- Sulfonyl) -L-prolyl-4- [3- (4-ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [3- (4- Ethoxycarbonylphenoxy) prop-1-ynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl] -D , L-Phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [4,4-di (methoxycarbonyl) but-1-ynyl -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (4-acetamido-4-carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) ) Sarkosyl-4- (4-acetamido-4)
-Carboxybut-1-ynyl) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- {3-[(4,5-
Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5 -Dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1
-Inyl} -D, L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (carboxy) phenoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L -Prolyl-4- {2- [4- (pyrimidin-2-yl) piperazin-1-yl] ethoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- ( Piperidin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4 -Sulfonyl) -L-prolyl-4- [3- (piperidin-1-yl) propoxy] -L-phenylalanine methyl ester N- Toluene-4-sulfonyl) -L- prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4-[(1-tert-
Butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (piperidin-1-yl) ethoxy] -L-phenylalanine N- (toluene -4-sulfonyl) -L-prolyl-4- {3- [4- (3-
Chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azepane-
1-yl) ethoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine methyl ester N -(Toluene-4-sulfonyl) -L-prolyl-3- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-Methylpiperazin-1-yl) propoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-3- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolyl-4- {2- [4- (3-
Methoxythien-2-yl) -4-hydroxypiperidin-1-yl] ethoxy} -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-3- (1-methylpiperidin-4-oxy ) -D, L-Phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (1-methylpiperidine-4-oxy) -D, L-phenylalanine N- (toluene-4-sulfonyl) -L -(5,5-Dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L- (1,1-dioxothiomorpholine- 3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine ethyl ester N- (toluene) 4-Sulfonyl) -L- (1,1-dioxothiomorpholine-3-carbonyl) -4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (toluene-4-sulfonyl)- L- (5,5-dimethyl) thiaprolyl-4- (1-methylpiperidine-4-oxy) -L-phenylalanine N- (α-toluenesulfonyl) -L-prolyl-4- (1-methylpiperidine-4- Oxy) -L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L- Prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine N- (toluene-4- Ruphonyl) -L-prolyl-4-N- (chloromethanesulfonyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-N- (vinylsulfonyl) amino-L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (N-trifluoromethanesulfonyl-N-isobutyl) amino-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl- 4-N- (vinylsulfonyl) amino-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-benzylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene- 4-sulfonyl) -L-prolyl-4-[(ben Carbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L- Prolyl-4-[(carboxy) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(carboxy) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) ) -L-Prolyl-4-[(aminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-
Butylaminocarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (4-phenyl-4-hydroxypiperidin-1-yl) ethoxy] -L-phenylalaninemethyl Ester N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidine-1
-Ylcarbonyl) methoxy] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4 -Sulfonyl) -L-prolyl-4-[(N, N-diisopropylaminocarbonyl) methoxy] -L-phenylalanine methyl ester N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (amidino) phenylalanine N -(Toluene-4-sulfonyl) sarcosyl-D, L-4- (aminocarbonyl) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methylacetamido) -L-phenylalanine isopropyl ester N -(Toluene-4-sulfonyl) L-prolyl-4- (N-methylacetamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N-methyltrifluoroacetamido) -L-phenylalanine methyl ester N- (toluene -4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl)- L-prolyl-L-4- (N-methylpiperidineoxy) -phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L- (4-methylpiperidineoxy ) Phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- ( 4-phenyl) -L-phenylalanine t-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-
A compound selected from the group consisting of phenylalanine, and pharmaceutically acceptable salts thereof, and any of the ester compounds listed above, wherein one ester is a methyl ester, an ethyl ester, an n-
An ester compound substituted by another ester selected from the group consisting of propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester. Item 29. The pharmaceutical composition according to Item 25. 36. A method for treating an inflammatory disease in a patient mediated by VLA-4, comprising administering the pharmaceutical composition of claim 25 to the patient. 37. The inflammatory disease is 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 cerebral injury, nephritis, retinitis,
37. The method of claim 36, wherein the method is selected from the group consisting of acute leukocyte-mediated lung injury, such as occurs in atopic dermatitis, psoriasis, myocardial ischemia, and adult respiratory distress syndrome.