KR20010022411A - Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4 - Google Patents

Abstract

The present invention relates to compounds that bind to VLA-4. Certain of these compounds also inhibit leukocyte adhesion and in particular leukocyte adhesion mediated by VLA-4. The compound is used in mammalian patients, such as human inflammatory diseases such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia It is useful for treating. The compounds may also be administered to treat inflammatory brain diseases such as multiple sclerosis.

Description

Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4}

Cross Reference of Related Application

This application claims the benefit of US Provisional Application No. 60 /, which is converted from US patent application Ser. No. 08 / 920,394, filed on July 31, 1997, in accordance with 37 CFR§ 1.53 (c) (2) (i). .

(Referred to as also α4β1 integrin and CD49d / CD29) helmeo and Takada ¹ (Helmer and Takada) a VLA-4 identified first by the person as a member of the cell surface receptor of the β1 integrin family which each of the two subunits α chain and β chains. VLA-4 includes α4 chain and β1 chain. There are at least nine β1 integrins, all of which share the same β1 chain and each has a characteristic α chain. All nine of these receptors bind to different complements of various cell matrix molecules such as fibronectin, laminin and collagen. For example, VLA-4 binds fibronectin. VLA-4 also binds to non-matrix molecules expressed by endothelial cells and other cells. These non-matrix molecules include VCAM-1 which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Characteristic epitopes of VLA-4 are involved in fibronectin and VCAM-1 binding activity and each activity has been shown to be independently inhibited ² .

Intracellular adhesion mediated by VLA-4 and another cellular receptor is associated with a number of inflammatory responses. Activated vascular endothelial cells at the site of injury or another site of inflammatory stimulation express molecules that are adherent to leukocytes. The mechanism by which leukocytes attach to endothelial cells involves the recognition of cell surface receptors on leukocytes and their corresponding cell surface molecules on endothelial cells. Once bound, the white blood cells travel along the vessel wall to access the damaged area, releasing chemical mediators against the infectious agent. For a review of adhesion receptors of the immune system, see Springer ³ and Osborn ⁴ .

Inflammatory brain diseases (eg empirical autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis) are examples of central nervous system diseases in which endothelial / leukocyte adhesion mechanisms destroy other healthy brain tissue. In patients with these inflammatory diseases, a large number of white blood cells migrate through the vascular brain barrier (BBB). Leukocytes release toxin mediators that destroy a wide range of tissues, impairing nerve function and causing paralysis.

In another organ system, tissue damage also occurs through attachment mechanisms that move or activate white blood cells. For example, it has been shown that early trauma following myocardial ischemia to cardiac tissue can be exacerbated by causing further damage with the influx of leukocytes into the damaged tissue [Vedder et al. ⁵ ]. Other inflammatory symptoms mediated by adhesion mechanisms include, for example, asthma ^6-8 , Alzheimer's disease, atherosclerosis ^9-10 , AIDS dementia ¹¹ , diabetes ^12-14 (including acute combustible diabetes), inflammatory bowel disease ¹⁵ (ulcers) Including colitis and Crohn's disease), multiple sclerosis ^16-17 , rheumatoid arthritis ^18-21 , tissue transplant ²² , tumor metastasis ^23-28 , meningitis, encephalitis, seizures and other cerebral damage, nephritis, retinitis, atopic dermatitis, psoriasis Acute leukocyte-mediated lung injury, such as that seen in myocardial ischemia and adult respiratory distress syndrome.

In view of the above, assays for determining the concentration of VLA-4 in biological samples comprising VLA-4 are useful, for example, in diagnosing VLA-4 mediated symptoms. In addition, although the understanding of leukocyte adhesion has advanced, the art only recently began using adhesion inhibitors for the treatment of inflammatory brain disease and another inflammatory condition ^29.30 . The present invention describes their use and another need.

Summary of the Invention

The present invention provides compounds that bind to VLA-4. The compound can be used, for example, in analyzing the presence of VLA-4 in a sample and is a pharmaceutical composition that inhibits cell adhesion mediated by VLA-4, eg binding of VCAM-1 to VLA-4. Can be used for Compounds of the present invention have a binding affinity where IC ₅₀ for VLA-4 is less than or equal to about 15 uM and this compound and its pharmaceutically acceptable salts are defined by Formula I below.

In the above formula,

R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl;

R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted Selected from the group consisting of heteroaryl, R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ form a heterocyclic or substituted heterocyclic group;

R ³ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and R ² is When not forming a heterocyclic group with R ¹ , R ² and R ³ may form a heterocyclic or substituted heterocyclic group together with a nitrogen atom bonded to R ² and a carbon atom bonded to R ³ . ;

R ⁵ is — (CH ₂ ) _x —Ar—R ^{5 ′} {wherein R ^{5 ′} is (a) substituted alkylcarbonylamino, provided that at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyhetero Aryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thio Aryl, substituted thio , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heteroaryl Click, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR- substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted Asymmetric disubstituted amines with different substituents selected from alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. Tea by A substituted alkyl group having an amino group, or an alkyl / substituted alkyl group, wherein the substituent is -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted egg Kenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (b) the alkoxy moiety is carboxyl and -COOR Alkoxyaryl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, (c) aryl and heteroaryl, (d) -NR ' R '[where each R' is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycle Roalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, wherein at least one R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic Is a click and, as a further condition, R 'is substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino , Amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl , Carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxy -Substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted Thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O ) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl,- OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted Aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic,- NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS ( O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic 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, and alkyl, substituted alkyl, aryl, substitution Asymmetric disubstituted amines having different substituents selected from aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Substituted alkyl group, or alkyl / substituted alkyl group, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterosai Click, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl), (e) -alkoxy-NR "R" where each R "is independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloal , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that if each R ″ is substituted alkyl, one or more of the substituents of the substituted alkyl moiety is alkoxy, substituted Alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy , Aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl , Carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guani Dino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, Substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl Amino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR ( 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 -hetero Aryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl,- NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl Having different substituents selected from heterocyclic and substituted heterocyclic A substituted alkyl group having an asymmetric disubstituted amine and an amino group blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or an alkyl / substituted alkyl group, wherein the substituents are -SO ₂ -alkyl,- SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted Aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR, wherein R is hydrogen or alkyl (F) substituted alkenyl or substituted alkynyl, provided that at least one of the substituents of the substituted alkenyl / alkynyl moiety is alkyl, substituted alkyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic When selected from the group consisting of, and substituted with substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amino Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted hetero Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioa , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl , -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted hetero Cyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic 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, and alkyl, substituted Asymmetric disubstituted amines with different substituents selected from alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. due to Substituted alkyl groups with blocked amino groups, or alkyl / substituted alkyl groups, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted Alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl,- SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (g) substituted with substituted aryloxy Heteroaryloxy, provided that at least one of the substituents of substituted aryloxy / heteroaryloxy is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1, 2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbo Substituents other than oxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl and N, N-dialkylurea], (h) -alkoxy-saturated heterocyclic, -alkoxy- Substituted saturated heterocyclics, -substituted alkoxy-heterocyclic and -substituted alkoxy-substituted saturated heterocyclics, (i) -O-heterocyclic and -O-substituted heterocyclics, (j) Tetrazolyl, (k) -NR-SO ₂ -substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least one of the substituents of the alkyl moiety of substituted alkylsulfonylamino is halogen, hydroxyl, amino, Nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino Alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, Substituents other than chelsulfonylamino, N-alkyl and N, N-dialkylureas), (l) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (m Substituted alkoxy, provided that the substituent of the alkyl moiety of the substituted alkoxy is alkoxy-NR " R ", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and halogen, hydroxyl, amino , Nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenyl Does not include aryl / heteroaryl substituted with amino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea ), (n) amidine and, alkyl, substituted alkyl, alkenyl , Amidine monosubstituted with a substituent independently selected from the group consisting of substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, (o) -C (O) NR '''R''' [Each R '''is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl , Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that one R '''is unsaturated heterocyclylalkyl, aryl, heteroaryl or halogen , Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, Alkylamino, alkenylamino, alkynylamino, alkylcarbonyl When aryl / heteroaryl substituted with acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, the remaining R '''is alkyl, substituted Alkyl (excluding unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic] , (p) -NR ¹² C (O) -R ⁸ , wherein R ⁸ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocylic Is selected from the group consisting of a click and a substituted heterocyclic, R ¹² is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted Heterocyclic), (q) -SO ₂ -Aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl or -SO ₂ -alkyl, (r) -NR'C (O) NR ⁹ R ⁹ , wherein R 'is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic) , (s) -NR'C (O) OR ⁹ , wherein R 'is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic And substituted heterocyclic, R ⁹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic), ( t) from the group consisting of -aminocarbonyl- (N-formylheterocyclyl) and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O) NH-substituted heterocyclyl And Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, and x is an integer from 1 to 4;

Q is —C (X) NR ⁷ —, where R ⁷ is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur.

In another embodiment, the compounds of the present invention can also be provided as prodrugs that are converted (eg, hydrolyzed and metabolized, etc.) to compounds of Formula (I) in vivo. In a preferred example of this embodiment, the carboxylic acid in the compound of formula (I) is modified into a group which is converted in vivo to a carboxylic acid, including salts thereof. In particularly preferred embodiments, the prodrug is a compound of Formula (IA) and a pharmaceutically acceptable salt thereof.

In the above formula,

R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl,

R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl and substituted Selected from the group consisting of heteroaryl, R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ can form a heterocyclic or substituted heterocyclic group ,

R ³ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ² is When not forming a heterocyclic group with R ¹ , R ² and R ³ are a heterocyclic group or a substituted heterocyclic group together with a nitrogen atom bonded to R ² and a carbon atom bonded to R ³ . Form the

R ⁵ is — (CH ₂ ) _x —Ar—R ^{5 ′} {wherein R ^{5 ′} is (a) substituted alkylcarbonylamino, provided that at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyhetero Aryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thio Aryl, substituted thio , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heteroaryl Click, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR- substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted aryl Amino, mono and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, Difference by asymmetric disubstituted amines having different substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. An amino-substituted alkyl group having a group, or alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted Al Kenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (b) the alkoxy moiety is carboxyl and -COOR Alkoxyaryl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (c) aryl and heteroaryl, (d) -NR ' R '[where each R' is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloal , Substituted cycloalkyl, heterocyclic and substituted heterocyclic, wherein at least one R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic And, as a further condition, when R 'is substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amino Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxy -Substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted Thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O ) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl,- OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) _2- NRR where R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted Aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O ) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic ( 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, and alkyl, substituted alkyl, aryl, substituted Done Asymmetric disubstituted amines having different substituents selected from aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Substituted alkyl group, or alkyl / substituted alkyl group, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterosai Click, -SO ₂ -substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl)], (e) -alkoxy-NR "R" where each R "is independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, he Teraryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that when each R ″ is substituted alkyl one or more of the substituents of the substituted alkyl moiety is alkoxy, substituted Alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, Aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, Carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino , Guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substitution Thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino , Oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS ( O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) _2- NRR where R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ - heteroaryl ah , -NRS (O) ₂ - substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - cyclic substituted heteroaryl, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS ( O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Ratios with different substituents selected from cyclic and substituted heterocyclics Ching-disubstituted amine, and Boc, Cbz and formyl substituted alkyl having the amino group blocked by conventional blocking groups such as mill group, and alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, - SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted Aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic and -SO ₂ NRR, where R is hydrogen or alkyl (F) substituted alkenyl or substituted alkynyl, provided that at least one of the substituents of the substituted alkenyl / alkynyl moiety is alkyl, substituted alkyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic And at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino when selected from the group , Alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl , Carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocylate Click, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thio Dicycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted Alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS ( O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heterocyclic , -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR-; substituted aryl, - NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted hetero Cyclic 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl , Asymmetric disubstituted amines having different substituents selected from substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Diamino-substituted alkyl group having a group, or alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl , -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -Heterocyclic, -SO ₂ -substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted hetero Aryloxy [provided that at least one of the substituents of substituted aryloxy / heteroaryloxy is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- Dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, ah Thread, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl and substituents other than N, N-dialkylurea], (h) -alkoxy-saturated heterocyclic, -alkoxy-substituted Saturated heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy-substituted saturated heterocyclic, (i) -O-heterocyclic and -O-substituted heterocyclic, (j) tetrazolyl (k) -NR-SO ₂ -substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least one of the substituents of the alkyl moiety of substituted alkylsulfonylamino is halogen, hydroxyl, amino, nitro, Trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alky Nylamino, Alkylcarbonyloxy, Acyl, Alkylcarbonylamino, Alkoxycarbonylamino, Alkylsulfonyl Substituents other than amino, N-alkyl and N, N-dialkylureas), (l) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (m) substitution Alkoxy, provided that the substituent of the alkyl moiety of substituted alkoxy is alkoxy-NR " R ", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and halogen, hydroxyl, amino, nitro , Trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, Does not include aryl / heteroaryl substituted with alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea), (n) amidines and, alkyl, substituted alkyl, alkenyl, substituted Amidine one to trisubstituted with a substituent independently selected from the group consisting of kenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, (o) -C (O) NR '''R'''[Where each R''' is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that one R '''is unsaturated heterocyclylalkyl, aryl, heteroaryl, halogen, hydroxyl , Amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, Alkenylamino, alkynylamino, alkylcarbonyloxy, acyl , Aryl / heteroaryl substituted with alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, the remaining R '''is alkyl, substituted alkyl (unsaturated) Heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic], (p ) -NR ¹² C (O) -R ⁸ , wherein R ⁸ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted Is selected from the group consisting of heterocyclic, R ¹² is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclo Click), (q) -SO ₂ -aryl, -S O ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl or -SO ₂ -alkyl, (r) -NR'C (O) NR ⁹ R ⁹ , wherein R 'is alkyl , Substituted alkyl, aryl, 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, substituted heteroaryl, heterocyclic and substituted heterocyclic), (s) —NR′C (O) OR ⁹ where R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted hetero is selected from the group consisting of cyclic, R ⁹ is , Alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 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, and 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 cycloalkoxy, -O- (N-succinimidyl ), -NH-adamantyl, O-cholest-5-en-3-β-yl, -NHOY, where Y is hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, -NH ( CH ₂ ) _p COOY, where p is an integer from 1 to 8, Y is as defined above, -OCH ₂ NR ⁹ R ¹⁰ [where R ⁹ is -C (O) -aryl and -C (O ) Is substituted from the group consisting of aryl, R ¹⁰ is selected from the group consisting of hydrogen and -CH ₂ COOR ¹¹ (wherein R ¹¹ is alkyl) and -NHSO ₂ Z (where Z is alkyl, Substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic),

Q is -C (X) NR ^7- , wherein R ⁷ is selected from the group consisting of hydrogen and alkyl, X is selected from the group consisting of oxygen and sulfur;

Provided that when R ¹ is p-CH ₃ -Φ, R ⁶ is methoxy, Q is -C (O) NH, and R ² and R ³ combine to form a pyrrolidinyl group, then R ⁵ is p -[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl-, p-[-OCH ₂ CH ₂ N (isopropyl) ₂ ] -benzyl-, p-[-OCH ₂ CH ₂ -1- pyrrolidinyl) -benzyl _{-, p - [- OCH 2} CH 2 -1- (4- pyrimidinyl) piperazinyl] -benzyl _{-, p - [- OCH 2} CH 2 -N- morpholinyl); -Benzyl-, or p-[-OCH ₂ CH ₂ -N-piperidinyl)]-benzyl-.

In the compounds of formulas (I) and (IA), preferably R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl. 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- (CH ₃ C (O) NH-) phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-tert-butylphenyl, 4-3 Tert-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazole-4- 1, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 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-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyri 3-yl, pyrimidin-2-yl, 4- (3'-dimethyl amino -n- propoxy) - it is selected from phenyl and 1-methylpyrazole-4-group of days.

A (CH _{2) 2} -Φ - Preferably R ² in the compound of Formula I and IA is selected from hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2} -2- thienyl and.

In one embodiment, R ¹ and R ² combine 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. Preferred heterocyclic and substituted heterocyclic groups include those having from 5 to 7 ring atoms having 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, wherein the ring is optionally fused with a phenyl or cyclohexyl ring To provide a fused ring heterocycle of 10 to 14 ring atoms having 2 to 4 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. In particular, preferred R ¹ / R ² bound to the group include, for example, benzisothiazolonyl (saccharin-2-yl).

4 to have one in the preferred embodiment, one or two heteroatoms selected from the R ² and R ³ are nitrogen, oxygen and sulfur in hwanjung together with the carbon atom bonded to the nitrogen atom and R ³ substituents bonded to the R ² substituent To form a heterocyclic group or a substituted heterocyclic group of six ring atoms, wherein the ring is unsubstituted or substituted with one or two substituents selected from fluoro, methyl, hydroxy, amino, phenyl, thiophenyl, thiobenzyl Substituted or fused with another ring, such as a phenyl or cycloalkyl ring, to provide a fused heterocycle of 10 to 14 ring atoms having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. The heterocyclic ring may be azetidinyl (eg L-azetidinyl), thiazolidinyl (eg L-thiazolidinyl), piperidinyl (eg L-piperidinyl), piperidinyl (eg L-piperidinyl), dihydroindolyl (eg L-2,3-dihydroindol-2-yl), tetrahydroquinolinyl (eg L-1,2,3,4-tetrahydroquinoline- 2-yl), thiomorpholinyl (eg L-thiomorpholin-3-yl), pyrrolidinyl (eg L-pyrrolidinyl); 4-hydroxypyrrolidinyl (such as 4-α- (or β-) hydroxy-L-pyrrolidinyl), 4-fluoropyrrolidinyl (such as 4-α- (or β-) fluoro -L-pyrrolidinyl), 3-phenylpyrrolidinyl (such as 3-α- (or β-) phenyl-L-pyrrolidinyl), 3-thiophenylpyrrolidinyl (such as 3-α (or β) thiophenyl-L-pyrrolidinyl), 4-aminopyrrolidinyl (eg 4-α- (or β-) amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (eg 3- substituted pyrrolidinyl such as α- (or β-) methoxy-L-pyrrolidinyl), 4,4-di-methylpyrrolidinyl; Substituted piperidinyl, such as 4-N-Cbz-piperidinyl; Substituted thiazolidinyl such as 5,5-dimethylthiazolidin-4-yl, 1,1-dioxo-thiazolidinyl; Substituted 1,1-dioxo-thiazolidinyl such as L-1,1-dioxo-5,5-dimethylthiazolidin-2-yl; 1,1-dioxothiomorpholinyl such as L-1,1-dioxo-thiomorpholin-3-yl and the like.

In the compounds of formula (I) and formula (IA), preferably R ³ is methyl, phenyl, benzyl, diphenylmethyl, -CH ₂ CH ₂ -COOH, -CH ₂ -COOH, 2-amidoethyl, iso-butyl, 3 All of the isomers that may result from substitution with tert-butyl, -CH ₂ O-benzyl and hydroxymethyl. In addition, in another preferred embodiment, R ³ and R ² may form a heterocyclic group or a substituted heterocyclic group together 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 isomers that may result from substitution with the following groups:

4- [NH ₂ CH ₂ C (O) NH-] benzyl, 4- [HOOCCH ₂ CH ₂ C (O) NH-] benzyl, 4-[-NHC (O) CH ₂ NHBoc] benzyl, 4-[- NHC (O) CH (CH ₃ ) NHBoc] benzyl, 4-[-NHC (O) CH (CH ₂ Φ) NHBoc] benzyl, 4-[-NHC (O) CH ₂ NHC (O) NH-3'- Methylphenyl] benzyl, 4-[-NHC (O) CH (NHBoc) (CH ₂ ) ₄ NHCbz] benzyl, 4-[-NHC (O) CH ₂ CH (C (O) OCH ₂ Φ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ) NHBoc] benzyl, 4- [H ₂ NCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl , 4- (BocHNCH ₂ CH ₂ CH ₂ C (O) NH-) benzyl, 4- [ΦCH ₂ OCH ₂ (BocHN) CHC (O) NH-] benzyl, 4- [CH ₃ NHCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH ₃ N (Boc) CH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4 -[ΦCH ₂ OCH ₂ (H ₂ N) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [ ΦCH ₂ O (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [OH (O) C (NH ₂ ) CHCH ₂ CH ₂ -C (O) NH-] Benzyl, 4- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl, 4- [CH ₃ NHCH ₂ C (O) NH-] benzyl, 4-[(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxylphenyl-]-benzyl, 4- [2-carboxymethylphenyl-]-benzyl, 4- [ΦCH ₂ O C (O) NHCH ₂ CH ₂ NH-] benzyl, 4-N [-(SO ₂ ) CH ₃ ] -CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] benzyl, 4-tert-butyl-O ( O) CCH ₂ -O-benzylNH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- (2-formyl-1,2,3, 4-tetrahydroisoquinolin-3-yl-CH ₂ NH) benzyl, 4-[-OCH ₂ CH ₂ -1 '-(4'-pyrimidinyl) -piperazinyl] -benzyl, 4-[-OCH ₂ CH _2- (1'-piperidinyl) -benzyl, 4-[-OCH ₂ CH _2- (1'-pyrrolidinyl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (1 ' -Piperidinyl)]-benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ O-]-benzyl, 4- [ -OCH ₂ CH ₂ CH _2- (1 '-(4'-methylpiperazinyl))]-benzyl, 4-[-OCH ₂ CH ₂ CH ₂ -4- (3'-chlorophenyl) -piperazine- 1-yl] -benzyl, 4-[-OCH ₂ CH ₂ N (Φ) CH ₂ CH ₃ ] -benzyl, 4-[-OCH ₂ -3 ′-(N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidinyl] benzyl, 3-[-O- (N-methylpiperidin-4-yl] benzyl, 4-[-O- (N- Methylpiperidin-4-yl] benzyl, 4- [di-iso-propylamino-CH ₂ CH ₂ O-]-benzyl, 4- [N-3-methylbutyl-N-trifluoromethane Sulfonyl) amino] benzyl, 4-[-OCH ₂ CH _2- (N-morpholinyl)]-benzyl, 4-[-OCH ₂ CH (NHBoc) CH ₂ cyclohexyl] -benzyl, 4- [OCH ₂ CH _2- (N-piperidinyl)]-benzyl, 4-[-OCH ₂ CH ₂ CH ₂ CH _2- (4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH ₂ CH _2- (N-homopiperidinyl) -benzyl, 4-[-OCH ₂ CH ₂ N (benzyl) ₂ ] -benzyl, 3-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl , 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) benzyl] -benzyl, 4- [2- (2-azabicyclo [3.2.2] octane- 2-yl) ethyl-O-] benzyl, [cyclopentylacetylenyl] -benzyl, 4-[-C≡C-Φ-4'Φ] -benzyl, 4-[-C≡C-CH ₂ -OS _{(O) 2 -4'-CH 3} -Φ] - benzyl, 4 - [- C≡C-CH 2 NHC (O) NH 2] - benzyl, 4 - [- C≡C-CH 2 -O- ( 4'-COOCH ₂ CH ₃ ) Φ] -benzyl, 4-[-C≡C-CH (NH ₂ ) -cyclohexyl] -benzyl, 4-[-C≡C-CH ₂ -O-phenyl] -benzyl , 4-[-C≡C-CH ₂ OCH ₃ ] -benzyl, 4-[-C≡C-CH ₂ -O- (4'-C (O) OC ₂ H ₅ ) phenyl] -benzyl, 4- [-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -Benzyl, 4-[-C≡C-CH ₂ CH (NHC (O) CH ₃ ) C (O) OH] -benzyl, 4-[-C≡C-CH ₂ NH- (4,5-dihydro -4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (N-morpholino)]-benzyl, 4-[-OCH ₂ COOH] -Benzyl, 4-[-OCH ₂ COO-tert-butyl] -benzyl, 4-[-N (SO ₂ CH ₃ ) (CH ₂ ) ₃ -N (CH ₃ ) ₂ ] -benzyl, 4-[- NHS (O) ₂ CF ₃ ] -benzyl, 4-[-C (= NH) NH ₂ ] -benzyl, 4-[-NHSO ₂ -CH ₂ Cl] -benzyl, 4-[-OCH ₂ C (O) NH-benzyl] -benzyl, 4-[-OCH ₂ C (O) O-benzyl] -benzyl, 4-[-OCH ₂ C (O) OH] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy-4- (3-methoxypyrrole-2-yl) -piperazinyl] -benzyl, 4-[-OCH ₂ C (O) NH ₂ ] -benzyl, 4-[-OCH ₂ C (O) NH-tert-butyl] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy-4-phenyl) -piperidinyl] -benzyl, 4-[-NHSO ₂ -CH = CH ₂ ] -benzyl, 4-[-NHSO ₂ -CH ₂ CH ₂ Cl] -benzyl, 4-benzyl-benzyl, 4-[-OCH ₂ C (O) piperidin-1-yl] benzyl, 4 -[-OCH ₂ C (O) N (CH (CH ₃ ) ₂ ) ₂ ] benzyl, 4-aminobenzyl, 4-acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4-(- NHC (O) CH ₂ NHC (O) NH-fluorescein) benzyl, 4- (NHC (O) CH ₂ CH (NH ₂ ) COOH, (1-toluenesulfonylimidizol-4-yl) -methyl-, [(1-N, N-dimethylaminosulfonyl) -imidizol-4-yl ] Methyl-, 4- (N-toluenesulfonyl-amino) 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, iso-propoxy, n-butoxy, 3 Tert-butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, -NH ₂ , Benzyloxy, -NHCH ₂ COOH, -NHCH ₂ CH ₂ COOH, -NH-adamantyl, -NHCH ₂ CH ₂ COOCH ₂ CH ₃ , -NHSO ₂ -p-CH ₃ -Φ, -NHOR ⁸ (where R ⁸ is hydrogen, methyl, iso-propyl or benzyl), O- (N-succinimidyl), -O-cholest-5-en-3-β-yl, -OCH ₂ -OC (O) C (CH ₃ ) ₃ , -O (CH ₂ ) _z NHC (O) W, wherein z is 1 or 2, W is pyrid-3-yl, N-methylpyridyl and N-methyl-1,4 -Dihydro-pyrid-3-yl], -NR "C (O) -R ', wherein R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH ₂ C (O) OCH ₂ CH ₃ ).

Preferred compounds falling within the ranges of Formula (I) and Formula (IA) include the following compounds and pharmaceutically acceptable salts thereof as well as one ester of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, iso One of the ester compounds mentioned below, substituted with another ester selected from the group consisting of butyl esters, secondary-butyl esters and tert-butyl esters:

N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (carboxy) propionamido] -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) thioureido] acetamido} -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine methyl ester;

N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-methylphenyl) ureido] acetamido} -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-butoxylcarbonyl-Nε-carbenzyloxy-L-lysyl) amino] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester;

N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-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-aminobutyramido) -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonylamino) butyramido] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramido] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonyl-N-methylamino) butyramido] -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-butoxylcarbonylsarcosyl) amino] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxylcarbonylsarcosyl) 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-dimethylglycyl) amino] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxybenzyloxy) -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-carbenzyloxyamino) ethyl] amino} -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbenzyloxyamino) 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-dimethylamino) propoxy] -L-phenylalanine;

N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3- (N, N-dimethylaminopropoxy] -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-tert-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-diethylamino) 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- (thiazole-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-dimethylamino) 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-phenylalanine;

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) sarcosyl-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- Inyl} -D, L-phenylalanine;

N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5-dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl}- 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-[(l-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-[(l-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- (azpan-1-yl) ethoxy] -L-phenylalanine;

N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azpan-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-methylpiperidine-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-sulfonyl) -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-[(benzyloxycarbonyl) methoxy] -L-phenylalanine methyl ester;

N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzyloxycarbonyl) 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-phenylalanine methyl ester;

N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidin-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 tert-butyl ester;

N- (toluene-4-sulfonyl) -L-prolyl-L-4- (N-methylpiperidinoxy) -phenylalanine tert-butyl ester;

N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiapropyl-L- (4-methylpiperidinoxy) phenylalanine tert-butyl ester;

N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine tert-butyl ester; And

N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine, a pharmaceutically acceptable salt thereof and one ester are methyl esters, ethyl esters and ester compounds mentioned above substituted with another ester selected from the group consisting of n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, secondary-butyl ester and tert-butyl ester.

The invention also provides a method for binding VLA-4 in a biological system, including contacting the biological sample with a compound of Formula I or IA under conditions that the compound binds to VLA-4.

Certain compounds of Formulas (I) and (IA) are also useful for alleviating VLA-4 mediated inflammation in vivo.

The invention also provides for a therapeutically effective amount of one or more of the compounds of Formula I or IA and pharmaceutically acceptable carriers thereof except that R ³ and R ⁵ are derived from L-amino acids or another similarly coordinated starting material. It provides a pharmaceutical composition comprising a. Racemic mixtures may also be used.

Pharmaceutical compositions can be used to treat VLA-4 mediated disease symptoms. The disease symptoms include, for example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute combustible diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, Tumor metastasis, peritonitis, encephalitis, seizures and other cerebral injuries, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte mediated lung injury that occurs in adult respiratory distress syndrome. Accordingly, the present invention also provides a method for treating an inflammatory disease in a patient mediated by VLA-4, comprising administering to the patient the pharmaceutical composition described above.

Preferred compounds of formulas (I) and (IA) include the compounds shown in Table I below.

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) 4-[-NHC (O) CH ^* (CH ₂ ø) NHBoc] -benzyl- (corresponding to ^* D-isomer) -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) [-NHC (O) CH ₂ NHC (O) NH-fluorescein] benzyl -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) 4- [BocNHCH ₂ C (O) NH] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHC (O) CH ₂ NHC (O) NH-m-methylphenyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHC (O) CH (NHBoc) (CH ₂ ) ₄ NHCbz] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHC (O) CH ₂ CH (NH ₂ ) COOH -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (H ₂ NCH ₂ CH ₂ CH ₂ C (O) NH) benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (Boc-HNCH ₂ CH ₂ CH ₂ C (O) NH) benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ NHCH ₂ CH ₂ CH ₂ -C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ (Boc) NCH ₂ CH ₂ CH ₂ -C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [øCH ₂ OCH ₂ (H ₂ N) CHC (O) NH] benzyl -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [HO (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [HO (O) C (H ₂ N) CHCH ₂ CH ₂ -C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ NHCH ₂ C (O) NH-] benzyl- -OCH ₂ CH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ NHCH ₂ C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p- [CH ₃ NHCH ₂ C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-O-CH (COOH) ø] -benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-o-carboxyphenyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [o-carboxymethylphenyl] -benzyl- -O-CH ₂ -ø p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [øCH ₂ OC (O) NHCH ₂ CH ₂ NH-]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [øCH ₂ OC (O) NHCH ₂ CH ₂ NH] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(tert-butyl-O (O) CCH ₂ -O-benzyl) -NH-] benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH ₂ NH-) benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-]-ø-CH _2- -OH p-CH ₃ -ø- -CH ₃ -CH ₂ OH (L isomer) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ O-]-benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = 5,5-dimethylthiazolidin-4-yl p-[(CH ₃ ) ₂ NCH ₂ CH ₂ O] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ O-]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ N (ø) CH ₂ CH ₃ ] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [di-iso-propylamino-CH ₂ CH ₂ O-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH (NHBoc) CH ₂ cyclohexyl] -benzyl -OCH ₃ 2-thienyl- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH 5-chloro-2-thienyl- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl- -OH 2,5-dichloro-4-thienyl R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH 1-N-methyl-4-pyrazolyl R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) m-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH 2-thiazolyl R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) benzyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) benzyl] -benzyl- -OCH ₃ 1-N-methyl-4-imidazolyl R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH 2-methyl-4-thiadiazolyl R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = thiazol-4-yl p-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH p-NC-ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O] benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = Cyclic-CH ₂ CH ₂ C (CH ₃ ) _2- p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O] benzyl- -OCH ₂ CH ₃

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -S-CH _2- (L-thiomorpholin-3-yl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-]-benzyl- -OH p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p- [cyclopentyl-C≡C-)-benzyl- -OH p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-ø-p-ø] -benzyl- -OH p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH ₂ -OS (O) ₂ -p-CH ₃ -ø] -benzyl -OH p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH ₂ NHC (O) NH ₂ ] -benzyl -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH ₂ -Op-COOCH ₂ CH ₃ -ø] -benzyl- -OH p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH (NH ₂ ) -cyclohexyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ -O-phenyl] -benzyl- -OH p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ -O-phenyl] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ -OCH ₃ ] -benzyl- -OH p-CH ₃ -ø- -CH ₃ H p- [C≡C-CH ₂ -OCH ₃ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ -Op-(-C (O) OC ₂ H ₅ ) phenyl] -benzyl- -OH p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ -Op-(-C (O) OC ₂ H ₅ ) phenyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl- -OH p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- -CH ₃ H -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)] benzyl -OH p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)] benzyl -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-O- (o-carboxyphenyl)]-benzyl -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ -4- (4-pyrimidinyl) -piperazinyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (4-piperidinyl) -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (4-pyrrolidinyl) -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH _2- (4-piperadinyl) -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ -]-(4-m-chlorophenyl) -piperazinyl] -benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) _{p - [- OCH 2 -3- (} N-Boc) - piperidinyl] - benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (N-morpholinyl)]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [OCH ₂ CH _2- (N-piperidinyl)]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ -1- (4-m-chlorophenyl) -piperazinyl] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (N-homopiperidinyl) -benzyl -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (N-homopiperidinyl) -benzyl -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ -1- (4-methyl) -piperazinyl] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) m-[-OCH ₂ CH _2- (1-pyrrolidinyl)]-benzyl- -OH

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH ₂ -1- (4-methyl) -piperazinyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (N-morpholino)]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ -1- (4-hydroxy-4- (3-methoxypyrrole-2-yl) -piperazinyl] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [O- (3- (N-Boc) -piperidinyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) m- [O- (N-methyl-piperidin-4-yl)]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-O- (N-methylpiperidin-4-yl)]-benzyl- -OH p-CH ₃ -ø- R ² / R ³ = Cyclic-CH ₂ -SC (CH ₃ ) _2- p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -SO ₂ -CH _2- (L-1,1-dioxothiomorpholin-3-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -SO ₂ -CH _2- (L-1,1-dioxothiomorpholin-3-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -SO ₂ -CH _2- (L-1,1-dioxothiomorpholin-3-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OH ø-CH _3- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHSO ₂ CF ₃ ] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHSO ₂ CF ₃ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHSO ₂ -CH ₂ Cl] -benzyl- -OCH ₃

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHSO ₂ -CH = CH ₂ ] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [N-3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [N-vinylsulfonyl) amino] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) NH-benzyl] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) O-benzyl] -benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) NH-benzyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) OH] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) NH ₂ ] -benzyl- -OCH ₃

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) NH ₂ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) NH-t-butyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ -1- (4-hydroxy-4-phenyl) -piperidinyl] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(piperidin-1-yl) C (O) CH ₂ -O-] benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ CH ₂ NC (O) CH ₂ -O-] benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ CH ₂ NC (O) CH ₂ -O-] benzyl- -OH p-CH ₃ -ø- -CH ₃ H p-[-C (= NH) NH ₂ ] -benzyl- -OH p-CH ₃ -ø- -CH ₃ H p-[-C (O) NH ₂ ] -benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methylacetamido) benzyl- -OCH (CH ₃ ) ₂

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methylacetamido) benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methyltrifluoroacetamido) benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) (1-toluenesulfonylimidizol-4-yl) methyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) 1-([N, N-dimethylaminosulfonyl] -imidazol-4-yl) methyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-toluenesulfonylamino) benzyl- -OCH ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-toluenesulfonylamino) benzyl- -OH p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p- (3-N, N-dimethylpropoxy) -benzyl- -OC (CH ₃ ) ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methyllipridinoxy) -benzyl- -OC (CH ₃ ) ₃

R ¹ R ² R ³ R ⁵ R ^{6 '} p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p- (N-methyllipridinoxy) -benzyl- -OC (CH ₃ ) ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (ø) -benzyl- -OC (CH ₃ ) ₃ p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (ø) -benzyl- -OH

The present invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.

Reference

The following publications, patent documents and patent applications are incorporated herein by superscript numbers.

¹ Hemler and Takada, European Patent Application Publication No. 330,506, published August 30, 1989

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

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¹¹ Sasseville, et al., Am. J. Path., 144: 27 (1994)

¹² Yang, et al., Proc. Nat. Acad. Science (USA), 90: 10494 (1993)

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¹⁸ van Dinther-Janssen, et al., J. Immunology, 147: 4207 (1991)

¹⁹ van Dinther- Janssen, et al., Annals. Rheumatic Dis., 52: 672 (1993)

²⁰ Elices, et al., J. Clin. Invest., 93: 405 (1994)

²¹ Postigo, et al., J. Clin. Invest., 89: 1445 (1991)

²² Paul, et al., Transpl. Proceed., 25: 813 (1993)

²³ Okarhara, et al., Can. Res., 54: 3233 (1994)

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²⁹ Kogan, et al., US Patent No. 5,510,332, issued April 23, 1996

³⁰ International Patent Appl. Publication No. WO 96/01644

All of the above publications, patent documents and patent applications are incorporated herein in their entirety to the same extent as if each of these documents were specifically and individually cited as a general reference.

As indicated above, the present invention relates to compounds which inhibit leukocyte adhesion, in particular leukocyte adhesion mediated by VLA-4. However, before further describing the present invention in detail, the following terms are first defined.

Justice

"Alkyl" as used herein is preferably an alkyl group having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Such terms are exemplified by groups such as methyl, t-butyl, n-heptyl and octyl and the like.

"Substituted alkyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, alkylthioamidino, aminoacyl, aminocarbonylamino , Aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl , Carboxyl substituted alkyl, carboxyl cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyheterocyclic, 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 heterocyclic, cycloalkoxy , Substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen Or alkyl), -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) _{2-heteroaryl,} -NRS (O) _{2-heteroaryl,} -NRS (O) _{2-substituted-} Cyclic Tero, -NRS (O) ₂ - cyclic substituted heteroaryl, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- Aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR- Heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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 Asymmetric disubstituted amines with different substituents selected from di-substituted heterocyclic amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, conventional Blocking group (e.g. Bo c, Cbz and formyl, etc.) substituted alkyl groups having amino groups blocked, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO _2- Preferably having 1 to 5 substituents selected from an alkyl / substituted alkyl group substituted with a heterocyclic, —SO ₂ -substituted heterocyclic and —SO ₂ NRR where R is hydrogen or alkyl Alkyl group of 1 to 10;

"Alkoxy" is, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, s-butoxy, n-pentoxy, n-hexoxy and Group "alkyl-O", including 1,2-dimethylbutoxy and the like.

"Substituted alkoxy" is a group "substituted alkyl-O".

"Acyl" refers to the group HC (O)-, alkyl-C (O)-, substituted alkyl-C (O)-, alkenyl-C (O)-, substituted alkenyl-C (O)-, alky Neyl-C (O)-, substituted alkynyl-C (O)-, cycloalkyl-C (O)-, substituted cycloalkyl-C (O)-, aryl-C (O)-, substituted aryl -C (O)-, heteroaryl-C (O)-, substituted heteroaryl-C (O)-, heterocyclic-C (O)-and substituted heterocyclic-C (O)-, where , Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted Heterocyclic is as defined above).

"Acylamino" refers to the group -C (O) NRR, wherein each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, each R is combined with a nitrogen atom to form a heterocyclic or substituted hetero Cyclic rings where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Heterocyclic and substituted heterocyclic as defined above).

"Thiocarbonylamino" refers to a group -C (S) NRR, wherein each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, each R is bonded to a nitrogen atom and heterocyclic or substituted Heterocyclic rings, 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 above).

"Acyloxy" refers to the group alkyl-C (O) O-, substituted alkyl-C (O) O-, alkenyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl -C (O) O-, substituted alkynyl-C (O) O-, aryl-C (O) O-, substituted aryl-C (O) O-, cycloalkyl-C (O) O-, Substituted cycloalkyl-C (O) O-, heteroaryl-C (O) O-, substituted heteroaryl-C (O) O-, heterocyclic-C (O) O-, and substituted heterocyclic -C (O) O- (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 above).

"Alkenyl" is preferably an alkenyl group having from 2 to 10 carbon atoms, more preferably from 2 to 6 carbon atoms, at least one alkenyl unsaturated position, preferably at 1 or 2 alkenyl unsaturated positions.

"Substituted alkenyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbon Nylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl substituted Alkyl, carboxyl cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyl heterocyclic, carboxyl substituted heterocyclic, cycloalkyl, substituted cycloalkyl, Guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloal , Thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (O) ₂ -alkyl, -OS (O) ₂ -substituted Alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -Heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O ) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl,- NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O ) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic ( 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, alkyl, substituted alkyl, aryl, substituted Asymmetric disubstituted amines with different substituents selected from aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, amino groups blocked with conventional blocking groups (e.g., Boc, Cbz and formyl, etc.) Having Substituted alkenyl groups or -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cyclo Alkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic and An alkenyl group having 1 to 5 substituents selected from the group consisting of alkenyl / substituted alkenyl groups substituted with —SO ₂ NRR where R is hydrogen or alkyl.

"Alkynyl" is an alkynyl group having 2 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and having at least one alkynyl unsaturated position, preferably 1 or 2 carbon atoms.

"Substituted alkynyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbon Nylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl substituted Alkyl, carboxyl cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyl heterocyclic, carboxyl substituted heterocyclic, cycloalkyl, substituted cycloalkyl, Guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloal , Thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted Heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted hetero Cyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic 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, alkyl, substituted alkyl , Asymmetric disubstituted amines having different substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, conventional blocking groups (e.g., Boc, Cbz and formyl, etc.) Blocked amino A substituted alkynyl group having a group or -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO _2- Substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted hetero An alkynyl group having 1 to 5 substituents selected from the group consisting of alkynyl / substituted alkynyl groups substituted with cyclic and —SO ₂ NRR where R is hydrogen or alkyl.

"Amidino" is a group And the term "alkylamidino" refers to one to three alkyl groups, such as alkyl ) Compound.

"Thioamidino" is a group Wherein R is hydrogen or alkyl.

"Aminoacyl" refers to the group -NRC (O) alkyl, -NRC (O) substituted alkyl, -NRC (O) cycloalkyl, -NRC (O) substituted cycloalkyl, -NRC (O) alkenyl, -NRC (O) substituted alkenyl, -NRC (O) alkynyl, -NRC (O) substituted alkynyl, -NRC (O) aryl, -NRC (O) substituted aryl, -NRC (O) heteroaryl, -NRC (O) substituted heteroaryl, -NRC (O) heterocyclic and -NRC (O) substituted heterocyclic, wherein R is hydrogen or alkyl 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 above).

"Aminocarbonyloxy" refers to the group -NRC (O) O-alkyl, -NRC (O) O-substituted alkyl, -NRC (O) O-alkenyl. -NRC (O) O-substituted alkenyl, -NRC (O) O-alkynyl, -NRC (O) O-substituted alkynyl, -NRC (O) O-cycloalkyl, -NRC (O) O -Substituted cycloalkyl, -NRC (O) O-aryl, -NRC (O) O-substituted aryl, -NRC (O) O-heteroaryl, -NRC (O) O-substituted heteroaryl, -NRC (O) O-Heterocyclic and -NRC (O) O-substituted heterocyclic, wherein 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 as defined above).

"Oxycarbonylamino" refers to the group -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, -OC (O) NR-substituted heteroaryl , -OC (O) NR-heterocyclic and -OC (O) NR-substituted heterocyclic, wherein R is hydrogen, alkyl, or each R is bonded to a nitrogen atom to be heterocyclic or substituted hetero Forms a cyclic ring, 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 above).

"Oxythiocarbonylamino" refers to the groups -OC (S) NH ₂ , -OC (S) NRR, -OC (S) NR-alkyl, -OC (S) NR-substituted alkyl, OC (S) NR- Alkenyl, OC (S) NR-substituted alkenyl, OC (S) NR-alkynyl, OC (S) NR-substituted alkynyl, OC (S) NR-cycloalkyl, OC (S) NR-substituted Cycloalkyl, OC (S) NR-aryl, OC (S) NR-substituted aryl, OC (S) NR-heteroaryl, OC (S) NR-substituted heteroaryl, OC (S) NR-heterosai Click and OC (S) NR-substituted heterocyclic, wherein R is hydrogen or alkyl, or each R combines with a nitrogen atom to form a heterocyclic or substituted heterocyclic ring, 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 above).

"Aminocarbonylamino" refers to the group -NRC (O) NRR, -NRC (O) NR-alkyl, -NRC (O) NR-substituted alkyl, -NRC (O) NR-alkenyl, -NRC (O) NR-substituted alkenyl, -NRC (O) NR-alkynyl, -NRC (O) NR-substituted alkynyl, -NRC (O) NR-aryl, -NRC (O) NR-substituted aryl,- NRC (O) NR-cycloalkyl, -NRC (O) NR-substituted cycloalkyl, -NRC (O) NR-heteroaryl, -NRC (O) NR-substituted heteroaryl, -NRC (O) NR- Heterocyclic and -NRC (O) NR-substituted heterocyclic wherein R is independently of each other hydrogen or alkyl, or each R is bonded to a nitrogen atom to form a heterocyclic or substituted heterocyclic ring One of the amino groups is interrupted by conventional blocking groups (e.g., Boc, Cbz, formyl, etc.) and is substituted by alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclo Alkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle And substituted heterocyclic are as defined above].

"Aminothiocarbonylamino" refers to the group -NRC (S) NRR, -NRC (S) NR-alkyl, -NRC (S) NR-substituted alkyl, -NRC (S) NR-alkenyl, -NRC (S ) NR-substituted alkenyl, -NRC (S) NR-alkynyl, -NRC (S) NR-substituted alkynyl, -NRC (S) NR-aryl, -NRC (S) NR-substituted aryl, -NRC (S) NR-cycloalkyl, -NRC (S) NR-substituted cycloalkyl, -NRC (S) NR-heteroaryl, -NRC (S) NR-substituted heteroaryl, -NRC (S) NR -Heterocyclic, and -NRC (S) NR-substituted heterocyclic wherein R is independently of each other hydrogen or alkyl, or each R is bonded to a nitrogen atom to form a heterocyclic or substituted heterocyclic ring Wherein one of the amino groups is blocked by conventional blocking groups (e.g., Boc, Cbz, formyl, etc.), and are alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero yarn Cyclic and substituted heterocyclics are as defined above].

"Aryl" or "Ar" is an unsubstituted aromatic carbocyclic group having 6 to 14 carbon atoms having a single ring (e.g. phenyl) or a multi-condensed ring (e.g. naphthyl or anthryl), wherein condensation Ring (eg, 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H) -one-7yl, etc.) may be aromatic or non-aromatic. Preferred aryls include phenyl and naphthyl.

"Substituted aryl" means hydroxy, acyl, acylamino, thiocarbonylamino, acryloxy, 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, carboxylaryl, carboxyl Substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyheterocyclic, carboxyl substituted heterocyclic, carboxyamido, cyano, thiol, thio Chel, 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, oxycarbonylamino, oxythiocarbonylamino, -S ( O) ₂ alkyl, -S (O) ₂ substituted alkyl, -S (O) ₂ cycloalkyl, -S (O) ₂ substituted cycloalkyl, -S (O) ₂ alkenyl, -S (O) ₂ Substituted alkenyl, -S (O) ₂ aryl, -S (O) ₂ substituted aryl, -S (O) ₂ heteroaryl, -S (O) ₂ substituted heteroaryl, -S (O) ₂ hetero Cyclic, -S (O) ₂ substituted heterocyclic, -S (O) ₂ alkyl, -S (O) ₂ substituted alkyl, -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, -S (O) ₂ NRR where R is hydrogen or alkyl, -NRS (O) ₂ alkyl, NRS (O) ₂ substitution Alkyl, NRS (O) ₂ aryl, NRS (O) ₂ substituted aryl, NRS (O) ₂ heteroaryl, NRS (O) ₂ substituted heteroaryl, NRS (O) ₂ heterocyclic, NRS (O) ₂ substituted heterocyclic, NRS (O) ₂ -NR alkyl, NRS (O) ₂ -NR substituted alkyl, NRS (O) ₂ -NR aryl, NRS (O) ₂ -NR substituted aryl, NRS (O ) ₂ -NR heteroaryl, NRS (O) ₂ -NR substituted heteroaryl, NRS (O) ₂ -NR heterocyclic and NRS (O) ₂ -NR substituted heterocyclic, wherein R is hydrogen or alkyl Mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic Amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted he Asymmetric disubstituted amines having different substituents selected from tercyclics and from 1 to 3 substituents selected from the group consisting of substituted aryl to amino groups blocked with conventional blocking groups (e.g., Boc, Cbz and formyl, etc.) Aryl group substituted or substituted with -SO ₂ NRR, wherein R is hydrogen or alkyl.

"Aryloxy" is a group aryl-O-, including, for example, phenoxy, naphthoxy, and the like.

"Substituted aryloxy" is a substituted aryl-O- group.

"Aryloxyaryl" is a group aryl-O aryl.

"Substituted aryloxyaryl" means hydroxy, acyl, acylamino, thiocarbonylamino, acryloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkoxy Neyl, 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, carboxylaryl , Carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyheterocyclic, carboxyl substituted heterocyclic, carboxyamido, cyano, tee Ol, 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, oxycarbonylamino, oxythiocarbonylamino, -S (O) ₂ alkyl, -S (O) ₂ substituted alkyl, -S (O) ₂ cycloalkyl, -S (O) ₂ substituted cycloalkyl, -S (O) ₂ alkenyl, -S ( O) ₂ substituted alkenyl, -S (O) ₂ aryl, -S (O) ₂ substituted aryl, -S (O) ₂ heteroaryl, -S (O) ₂ substituted heteroaryl, -S (O ) ₂ heterocyclic, -S (O) ₂ substituted heterocyclic, -S (O) ₂ alkyl, -S (O) ₂ substituted alkyl, -S (O) ₂ aryl, -S (O) ₂ Substituted aryl, -S (O) ₂ heteroaryl, -S (O) ₂ substituted hetero Aryl, -S (O) ₂ heterocyclic, -S (O) ₂ substituted heterocyclic, -S (O) ₂ NRR where R is hydrogen or alkyl, -NRS (O) ₂ alkyl, NRS (O) ₂ substituted alkyl, NRS (O) ₂ aryl, NRS (O) ₂ substituted aryl, NRS (O) ₂ heteroaryl, NRS (O) ₂ substituted heteroaryl, NRS (O) ₂ heterobetween Click, NRS (O) ₂ substituted heterocyclic, NRS (O) ₂ -NR alkyl, NRS (O) ₂ -NR substituted alkyl, NRS (O) ₂ -NR aryl, NRS (O) ₂ -NR substituted Aryl, NRS (O) ₂ -NR heteroaryl, NRS (O) ₂ -NR substituted heteroaryl, NRS (O) ₂ -NR heterocyclic and NRS (O) ₂ -NR substituted heterocyclic, wherein , R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted heteroarylamino, mono- And di-heterocyclic amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and One or two of an aryl ring selected from the group consisting of asymmetric disubstituted amines having different substituents selected from cyclic heterocyclics and substituted aryl to amino groups blocked with conventional blocking groups (e.g. Or an aryloxyaryl group substituted with 1 to 3 substituents or substituted with —SO ₂ NRR where R is hydrogen or alkyl.

"Cycloalkyl" is a cycloalkyl group of 3 to 8 carbon atoms having a single cyclic ring including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.

A "cycloalkenyl" is a cyclic alkenyl group having 3 to 8 carbon atoms that is single or multiple unsaturated but not aromatic.

"Substituted cycloalkyl" and "substituted cycloalkenyl" include oxo (= O), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amine, Amidino, alkylamidino, thionamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted Aryloxyaryl, halogen, hydroxy, cyano, nitro, carboxyl, carboxylalkyl, carboxyl substituted alkyl, carboxyl-cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted Heteroaryl, carboxyheterocyclic, carboxyl substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted Thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted hetero Aryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ alkyl, -OS (O) ₂ substituted alkyl, -OS (O) ₂ Aryl, -OS (O) ₂ substituted aryl, -OS (O) ₂ heteroaryl, -OS (O) ₂ substituted heteroaryl, -OS (O) ₂ heterocyclic, -OS (O) ₂ substituted Heterocyclic, -OS (O) ₂ heterocyclic, -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, NRS (O) ₂ substituted heteroaryl, NRS (O) ₂ heterocyclic, NRS (O) ₂ substituted heterocytes Click, 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 hetero Aryl, NRS (O) ₂ -NR substituted heteroaryl, NRS (O) ₂ -NR heterocyclic and NRS (O) ₂ -NR substituted heterocyclic, wherein R is hydrogen or alkyl, mono- And di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, alkyl, substitutions Asymmetric disubstituted amines having different substituents selected from alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and conventional blocking groups (e.g., Boc, Cbz, formyl) Substituted alkynyl groups having an amino group blocked, and the like -SO ₂ alkyl, -SO ₂ substituted alkyl, -SO ₂ alkenyl, -SO ₂ substituted alkenyl, -SO ₂ cycloalkyl , -SO ₂ substituted cycloalkyl, -SO ₂ aryl, -SO ₂ substituted aryl, -SO ₂ heteroaryl, -SO ₂ substituted heteroaryl, -SO ₂ heterocyclic, -SO ₂ substituted heterocyclic And cycloalkenyl, preferably a cycloalkyl group having 3 to 8 carbon atoms, having 1 to 5 substituents selected from alkynyl substituted alkynyl groups substituted with -SO ₂ NRR, wherein R is hydrogen or alkyl. Group.

"Cycloalkoxy" is an -O-cycloalkyl group.

"Substituted cycloalkoxy" is an -O-substituted cycloalkyl group.

"Guanidino" is a group -NRC (= NR) NRR, -NRC (= NR) NR alkyl, -NRC (= NR) NR substituted alkyl, -NRC (= NR) NR alkenyl, -NRC (= NR ) NR substituted alkenyl, -NRC (= NR) NR alkynyl, -NRC (= NR) NR substituted alkynyl, -NRC (= NR) NR aryl, -NRC (= NR) NR substituted aryl,- NRC (= NR) NR cycloalkyl, -NRC (= NR) NR substituted cycloalkyl, -NRC (= NR) NR heteroaryl, -NRC (= NR) NR substituted heteroaryl, -NRC (= NR) NR Heterocyclic and —NRC (═NR) NR substituted heterocyclic wherein R is independently of each other hydrogen and alkyl, and one of the amino groups is a conventional blocking group (e.g., Boc, Cbz, formyl, etc.) Blocked, 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 above].

"Guanidinosulfone" refers to the group -NRC (= NR) NRSO ₂ alkyl, -NRC (= NR) NRSO ₂ substituted alkyl, -NRC (= NR) NRSO ₂ alkenyl, -NRC (= NR) NRSO ₂ substitution 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 wherein R is independently of each other hydrogen and alkyl, 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 above.

"Halo" or "halogen" is fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.

"Heteroaryl" is an aromatic carboxylic group having 2 to 10 carbon atoms and having 1 to 44 ㅐ heteroatoms selected from oxygen, nitrogen and sulfur in the ring. 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" means hydroxy, acyl, acylamino, thiocarbonylamino, acryloxy, 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, carboxylaryl, Carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyheterocyclic, carboxyl substituted heterocyclic, carboxyamido, cyano, thiol , Thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cyclo Alkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino,- S (O) ₂ alkyl, -S (O) ₂ substituted alkyl, -S (O) ₂ cycloalkyl, -S (O) ₂ substituted cycloalkyl, -S (O) ₂ alkenyl, -S (O ) ₂ substituted alkenyl, -S (O) ₂ aryl, -S (O) ₂ substituted aryl, -S (O) ₂ heteroaryl, -S (O) ₂ substituted heteroaryl, -S (O) ₂ heterocyclic, -S (O) ₂ substituted heterocyclic, -S (O) ₂ alkyl, -S (O) ₂ substituted alkyl, -S (O) ₂ aryl, -S (O) ₂ substituted Aryl, -S (O) ₂ heteroaryl, -S (O) ₂ substituted heteroa Reel, -S (O) ₂ heterocyclic, -S (O) ₂ substituted heterocyclic, -S (O) ₂ NRR where R is hydrogen or alkyl, -NRS (O) ₂ alkyl, NRS (O) ₂ substituted alkyl, NRS (O) ₂ aryl, NRS (O) ₂ substituted aryl, NRS (O) ₂ heteroaryl, NRS (O) ₂ substituted heteroaryl, NRS (O) ₂ heterobetween Click, NRS (O) ₂ substituted heterocyclic, NRS (O) ₂ -NR alkyl, NRS (O) ₂ -NR substituted alkyl, NRS (O) ₂ -NR aryl, NRS (O) ₂ -NR substituted Aryl, NRS (O) ₂ -NR heteroaryl, NRS (O) ₂ -NR substituted heteroaryl, NRS (O) ₂ -NR heterocyclic and NRS (O) ₂ -NR substituted heterocyclic, wherein , R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di Heterocyclic amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted he Substituted with 1 to 3 substituents selected from the group consisting of amino groups in substituted aryls, blocked with asymmetric disubstituted amines having different substituents selected from cyclic and conventional blocking groups (e.g., Boc, Cbz and formyl, etc.) Or a heteroaryl group substituted with —SO ₂ NRR, wherein R is hydrogen or alkyl.

"Heteroaryloxy" is a group -O-heteroaryl and "substituted heteroaryloxy" is a group -O substituted heteroaryl.

"Heterocycle" or "heterocyclic" is a saturated or unsaturated group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring.

A "saturated heterocyclic" is a heterocycle of a single or multiple condensed ring in a ring (eg, carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, etc.).

An "unsaturated heterocyclic" is a nonaromatic heterocycle of a single or multiple condensed ring in a ring (eg, carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, etc.).

“Substituted heterocyclic” includes oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amindo, amidino, alkylamidino, Thionamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydr Roxy, cyano, nitro, carboxyl, carboxylalkyl, carboxyl substituted alkyl, carboxyl-cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl substituted aryl, carboxyheteroaryl, carboxyl substituted heteroaryl, carboxyheterocyclic , Carboxyl substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocyclo Kyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocycle Ryloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ alkyl, -OS (O) ₂ substituted alkyl, -OS (O) ₂ aryl, -OS ( O) ₂ substituted aryl, -OS (O) ₂ heteroaryl, -OS (O) ₂ substituted heteroaryl, -OS (O) ₂ heterocyclic, -OS (O) ₂ substituted heterocyclic,- OS (O) ₂ heterocyclic, -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, NRS (O) ₂ substituted heteroaryl, NRS (O) ₂ heterocyclic, NRS (O) ₂ substituted heterocyclic, NRS (O) ₂ -NR alkyl, NRS (O ) ₂ -NR substituted alkyl, NRS (O) ₂ -NR aryl, NRS (O) ₂ -NR substituted aryl, NRS (O) ₂ -NR heteroaryl, NRS (O) ₂ -NR substituted heteroaryl, NRS (O) ₂ -NR heterocyclic and NRS (O) ₂ -NR substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted Alkyl) amino, mono- and di-arylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted Substituted alkynyl groups having asymmetric disubstituted amines having different substituents selected from heteroaryls, heterocyclics and substituted heterocyclics and amino groups blocked with conventional blocking groups (e.g., Boc, Cbz and formyl, etc.) and -SO ₂ alkyl, -SO ₂ substituted alkyl, -SO ₂ alkenyl, -SO ₂ substituted alkenyl, -SO ₂ cycloalkyl, -SO ₂ substituted cycloalkyl Kiel, -SO ₂ aryl, -SO ₂ substituted aryl, -SO ₂ heteroaryl, -SO _{2-substituted} heteroaryl, -SO ₂ heterocyclic, -SO ₂ cyclic substituted heteroaryl, and -SO ₂ NRR (wherein , R is hydrogen or alkyl) heterocyclic group having 1 to 3 substituents selected from alkynyl substituted alkynyl groups.

Examples of heterocycles and heteroaryls are azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizin, isoindole, indole, dihydroindole, indazole, purine, quinolysin, Isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cynoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine , Isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazolidine, imidazoline, piperidine, piperazine, indolin, phthalimide, 1,2,3,4-tetrahydroiso Quinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, thiomorpholino, piperidinyl, pipe Including but not limited to Ralidine and Tetrahydrofuranyl.

A "saturated substituted heterocycle" is a substituted heterocycle of a single or multiple condensed ring having no unsaturation (eg, carbon to carbon unsaturation, carbon to nitrogen unsaturation and nitrogen to nitrogen unsaturation, etc.) in any ring.

An "unsaturated substituted heterocyclic" is a non-aromatic substituted heterocycle of a single or multiple condensed ring having unsaturated (eg, carbon to carbon unsaturation, carbon to nitrogen unsaturation and nitrogen to nitrogen unsaturation, etc.) in any ring .

"Heterocyclyloxy" is an -O-heterocyclic group and "substituted heterocyclyloxy" is an -O-substituted heterocyclic.

"Substituted alkylcarbonylamino" is -NHC (O)-substituted alkyl.

"Thiol" is a -SH group.

"Thioalkyl" is an -S alkyl group.

"Substituted thioalkyl" is an -S- substituted alkyl group.

"Thiocycloalkyl" is an -S- cycloalkyl group.

"Substituted thiocycloalkyl" is an -S- substituted cycloalkyl group.

"Thioaryl" is an -S-aryl group and "substituted thioaryl" is an -S substituted aryl group.

"Thioheteroaryl" is an -S-heteroaryl group and "substituted thioheteroaryl" is an -S substituted heteroaryl group.

"Thioheterocyclic" is a -S-heterocyclic group and "substituted thioheterocyclic" is a -S substituted heterocyclic group.

“Pharmaceutically acceptable salts” are pharmaceutically acceptable salts of the compounds of formula I wherein the salts are derived from various organic and inorganic counterions well known in the art, and salts are for example sodium, potassium, Salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, when calcium, magnesium, ammonium, tetraalkylammonium, etc., and the compounds of formula (I) contain basic functional groups And oxalate, and the like).

Compound manufacture

The compounds of the present invention can be prepared from starting materials that can be readily purchased using the following general methods and processes. It can be appreciated that, given typical or preferred method conditions (ie, reaction temperature, time, mole ratio of reactants, solvent, pressure, etc.), other method conditions may be used, unless stated otherwise. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by those skilled in the art by conventional optimization processes.

In addition, as will be apparent to those skilled in the art, conventional protecting groups can prevent certain functional groups from progressing in undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protection groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, which is incorporated herein by reference.

In addition, the compounds of the present invention may typically have one or more chiral centers. Thus, if desired, such compounds may be prepared or separated as pure stereoisomers, ie as individual enantiomers or diastereomers or as mixtures rich in one stereoisomer. All such stereoisomers (and mixtures rich in one of the stereoisomers) are included within the scope of the present invention unless otherwise noted. Pure stereoisomers (or mixtures rich in one of the stereoisomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. In addition, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography and chiral separation reagents.

In a preferred method of synthesis, compounds of formula (I) and formula (IA), wherein Q is -C (O) NR ⁷ , first combine the amino acid of formula (II) with sulfonyl chloride of formula (III) to provide the N-sulfonyl amino acid of formula (IV) It is manufactured by.

R ¹ -SO ₂ -Cl

In the above formula,

R ¹ to R ⁴ are as defined in formula (I) and formula (IA).

This reaction is typically carried out by contacting an amino acid of formula (II) with at least one equivalent, preferably about 1.1 to about 2 equivalents of sulfonyl chloride (III) in an inert diluent such as dichloromethane and the like. In general, the reaction is carried out for about 1 to about 24 hours in the temperature range of about -70 ℃ to about 40 ℃. Preferably, this reaction is carried out in the presence of a suitable base to capture the acid produced during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine and N-methylmorpholine and the like. The reaction can also be carried out under Schotten-Baumann-type conditions using an aqueous alkali (eg sodium hydroxide, etc.) as the base. At the end of the reaction, the resulting N-sulfonyl amino acid (IV) is recovered by conventional methods including neutralization, extraction, precipitation, chromatography and filtration.

The amino acids of formula (II) used in the reaction are known compounds or compounds which can be prepared from known compounds by conventional synthetic processes. Examples of amino acids suitable for use in this reaction include L-proline, trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline, trans-3-phenyl-L-proline, cis-3 -Phenyl-Ll-proline, L- (2-methyl) proline, L-pipelinic acid, L-azetidine-2-carboxylic acid, L-indolin-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-phenylalanine, 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 (cyclo Leucine), 1-aminocyclohexanecarboxylic acid, L-three And the like, but is not limited to this. If desired, corresponding carboxylic esters of amino acids of the formula (II) such as methyl esters, ethyl esters and the like can be used in the reaction with sulfonyl chloride (III). Subsequent hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, i.e. treatment with alkali metal hydroxides in an inert diluent such as methanol / water, gives N-sulfonyl amino acid (IV).

Similarly, sulfonyl chloride of formula III used in the reaction is a known compound or a compound which can be prepared from known compounds by conventional synthetic processes. Such compounds are typically prepared from the corresponding sulfonic acids, such as compounds of the formula R ¹ -SO ₃ H, wherein R ¹ is as defined above, using phosphorus trichloride and phosphorus pentachloride. Generally, this reaction is carried out with about 2 to about 5 molar equivalents of phosphorus trichloride and phosphorus pentachloride in an inert solvent (e.g., dichloromethane) for about 1 to about 48 hours in a temperature range of about 0 ° C to about 80 ° C. By contacting to provide sulfonyl chloride. In addition, sulfonyl chlorides of formula III can be prepared from the corresponding thiol compounds, such as compounds of formula R ¹ -SH where R ¹ is as defined above, by treating thiol with chlorine (Cl ₂ ) and water under conventional reaction conditions. It can manufacture.

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-tert-butylbenzenesulfonyl chloride, 4-bromo Benzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesul Ponyl chloride, 3,5-ditrifluorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride , 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride. 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophensulfonyl chloride, 2,5-dichloro-4-thiophensulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, 1-methyl-4- Imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonyl chloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride, and the like. Including but not limited to. If desired, sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used instead of sulfonyl chloride in the reaction to form the N-sulfonyl amino acid of formula IV.

Intermediate N- sulfonyl amino acid of formula (IV) (V) sulfonamide formula L (R ³⁾ of the CHCOOR (wherein, L is chloro, bromo, iodine, such as a leaving group such as mesylate and tosylate, and R ³ is the As defined and R is hydrogen or an alkyl group).

R ¹ -SO ₂ -NH-R ²

In the above formula,

R ¹ and R ² are as defined above.

The reaction is typically at least one equivalent, preferably 1.1 to 2, in an inert diluent (eg DMF) in the presence of a suitable base (eg triethylamine) at about 24 ° C. to about 27 ° C. for about 0.5 to about 4 hours. It is carried out by contacting an equivalent carboxylic acid derivative with sulfonamide V. The reaction is further described in Zuckermann et al., J. Am. Chem. Soc., 1992, 114, 10646-10647. Preferred carboxylic acid derivatives suitable for use in the reaction are α-chloro and α-bromocarboxylic acid esters such as tert-butyl bromoacetate and the like. When carboxylic esters are used in the reaction, the ester groups are hydrolyzed according to conventional procedures to yield the N-sulfonyl amino acids of formula IV.

Compounds of formula I are prepared by coupling the intermediate N-sulfonyl amino acid of formula IV with an amino acid derivative of formula VI.

In the above formula,

R ⁵ to R ⁷ are as defined above.

This coupling reaction is carried out using typically well known coupling reagents such as carbodiimide and BOP reagents (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) and the like. . Suitable carbodiimides include, for example, dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) and the like. If desired, polymer supported forms of carbodiimide coupling reagents can be used, including, for example, the compounds described in Tetrahedron Letters, 34 (48), 7685 (1993). In addition, well-known coupling promoters (such as N-hydroxysuccinimide and 1-hydroxybenzotriazole, etc.) can be used to promote the coupling reaction.

Such coupling reactions typically comprise from about 1 to about 2 equivalents of N-sulfonylamino acid (IV) in an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran and N, N-dimethylformamide, and the like. And at least one equivalent, preferably from about 1 to about 1.2 equivalents of the amino acid derivative (VI). Generally, this reaction is carried out for about 12 to about 24 hours in the temperature range of about 0 to about 37 ° C. At the end of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like.

The N-sulfonyl amino acid (IV) can also be converted to an acid halide coupled with an acid halide and amino acid derivative (VI) to provide a compound of formula (I). Acid halides of formula VI can be prepared by contacting a compound of formula VI with an inorganic acid halide (eg, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride) or preferably oxalyl chloride under conventional conditions. Generally, this reaction comprises from about 1 to 5 molar equivalents of inorganic acid halide or oxalyl chloride in an inert solvent such as dichloromethane or carbon trichloride for about 1 to about 48 hours at a temperature ranging from about 0 ° C to about 80 ° C. To use. Catalysts such as N, N-dimethylformamide can also be used for this reaction.

The acid halide of N-sulfonyl amino acid (IV) is then at least about 1 equivalent, preferably about about 1 equivalent, in an inert diluent (eg, dichloromethane) for about 1 to about 24 hours in a temperature range of about -70 to about 40 ° C. Contacting with 1.1 to about 1.5 equivalents of the amino acid derivative (VI). Preferably, this reaction is carried out in the presence of a suitable base to capture the acid produced during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. The reaction can also be carried out under the conditions of Shoten-Baomann type using an aqueous alkali (eg sodium hydroxide, etc.). At the end of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like.

In addition, the compounds of formula (I) can be prepared by first forming the diamino acid derivatives of formula (VII).

In the above formula,

R ² , R ³ and R ⁵ to R ⁷ are as defined above.

Diamino acid derivatives of formula (VII) are readily prepared by coupling amino acid derivatives of formula (VI) with amino acids of formula (II) using conventional amino acid coupling techniques and reagents (eg, carbodiimide, BOP reagents, etc.) as described above. It can manufacture. The diamino acid (VII) may then be sulfonated using the synthesis process described above to provide a compound of formula I with a sulfonyl chloride of formula III.

The amino acid derivatives of formula VI used in the reaction are known compounds or compounds which can be prepared from known compounds by conventional synthetic processes. For example, the amino acid derivatives of Formula VI can be C-alkylated with commercially available diethyl 2-acetamidomalonate (Alrich, Milwaukee, WI) using alkyl or substituted alkyl halides. Can be prepared. This reaction is typically carried out by treating diethyl 2-acetamidomalonate with at least one equivalent of alkyl or substituted alkyl halides with at least one equivalent of nathro ethoxide in reflux ethanol for about 6 to about 12 hours. The resulting C-alkylsubstituted malonate is then deacetylated, hydrolyzed and decarboxylated by heating in hydrochloric acid solution under reflux for about 6 to about 12 hours to afford amino acids, typically as hydrochloric acid salts.

Examples of amino acid derivatives of formula VI suitable for use in this 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-diiotytyrosine methyl ester, L-3-iodtyrosine methyl ester, and the like. Of course, if desired, another ester or amide of the compound may be used.

For ease of synthesis, compounds of formula I are typically prepared as esters in which R ⁶ is alkoxy or a substituted alkoxy group or the like. If desired, the ester group can be hydrolyzed using conventional conditions and reagents to produce the corresponding carboxylic acid. Typically, this reaction comprises at least one equivalent of alkali metal hydroxide (e.g. lithium hydroxide, ester) in an inert diluent (e.g. methanol or a mixture of methanol and water) for about 1 to about 12 hours at a temperature ranging from about 0 to about 24 ° C. Sodium hydroxide or potassium hydroxide). Benzyl esters can also be removed by hydrogenolysis using a palladium catalyst (eg palladium on carbon). The resulting carboxylic acid is optionally amine (eg β-alanine ethyl ester), hydroxyamine (eg hydroxylamine and N-hydroxysuccinimide using conventional coupling reagents and conditions described above. ), Alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and O-benzylhydroxylamine, and the like.

As will be apparent to those skilled in the art, other functional groups present in any substituents of the compounds of formula I are readily modified or derivatized before or after the coupling reactions described above using well known synthetic processes. You can. For example, the nitrogen groups present in the substituents of the compounds of formula (I) or intermediates thereof can be readily reduced by hydrogenation in the presence of a palladium catalyst (eg palladium on carbon). This reaction is typically carried out in an inert diluent (eg methanol) at a temperature of about 20 to about 50 ° C. for about 6 to about 24 hours. The compound having a nitrogen group on the R ⁵ substituent may be prepared using, for example, 4-nitrophenylalanine derivative in the coupling reaction.

Similarly, the pyridyl groups can be hydrogenated in the presence of a platinum catalyst (eg platinum oxide) in an acidic diluent to yield the corresponding piperidinyl homologue. Generally, this reaction is carried out in an acidic diluent (eg, a mixture of methanol and hydrochloric acid solution) for about 2 to about 24 hours at a temperature of about 20 to about 50 ° C. in a pressure range of about 20 to about 60 psi, preferably about 40 psi. This is accomplished by treating the pyridine compound with hydrogen in the presence of a catalyst. Compounds having pyridyl groups can be used in the coupling reactions described above, for example, β- (2-pyridyl)-, β- (3-pyridyl)-or β- (4-pyridyl) -L- It can be easily prepared using an alanine derivative.

In addition, when the R ⁵ substituent or intermediate thereof of the compound of formula I comprises a primary or secondary amino group, the amino group is for example an amide, sulfonamide, urea, thiourea, carbamate, secondary Or derivatization before or after coupling reactions to provide tertiary amines and the like. Compounds having a primary amino group on the R ⁵ substituent can be prepared, for example, by reducing the corresponding nitro compound as described above. The compounds may also be prepared by using amino acid derivatives of formula VI derived from lysine, 4-aminophenylalanine and the like in the coupling reaction.

By way of example, a compound of formula (I) wherein R ¹ is a (4-aminophenyl) methyl group or an intermediate thereof having a substituent comprising a primary or secondary amino group can be prepared using conventional acylating agents and the conditions providing the corresponding amides. Can be easily N-acylated. Such acylation reactions are typically in the presence of coupling reagents such as carbodiimide, BOP reagents such as benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate, and the like. In an inert diluent (e.g., dichloromethane, chloroform, acetonitrile, tetrahydrofuran and N, N-dimethylformamide, etc.) at least about 1 equivalent, preferably at least about It is carried out by reacting 1.1 to about 1.2 equivalents of the carboxylic acid with the amino compound. Preferably, accelerators (eg, N-hydroxysuccinimide and 1-hydroxybenzotriazole, etc.) are used to promote the acylation reaction. Examples of suitable carboxylic acids for use in this reaction include N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid Benzyl Ester, Benzoic Acid, N-tert-Butyloxycarbonylisonifecotic acid, N-methyl isonifecotic acid, N-tert-butyloxycarbonylnifecotic acid, N-tert-butyloxycarbon Nil-L-tetrahydroisoquinoline-3-carboxylic acid and N- (toluene-4-sulfonyl) -L-proline and the like.

Furthermore, the compounds of formula (I) or their intermediates comprising primary or secondary amino groups can be N-acylated using acyl halides or carboxylic anhydrides to produce the corresponding amides. Such reactions typically comprise at least about 1 equivalent, preferably about 1.1 to about 1.2 equivalents of acyl halide in an inert diluent (e.g., dichloromethane) in a temperature range of about -70 to about 40 ° C for about 1 to about 24 hours. Or by contacting the carboxylic anhydride with an amino compound. If desired, an acylation catalyst such as 4- (N, N-dimethylamino) pyridine can be used to promote the acylation reaction. The acylation reaction is preferably carried out in the presence of a suitable base to trap the acid produced during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine and N-methylmorpholine and the like. The reaction can also be carried out under Shoten-Baumann type conditions using an aqueous alkali (eg sodium hydroxide, etc.).

Examples of acyl halides and carboxylic anhydrides suitable for use in this reaction include 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-tri Fluoro-methylbenzoyl chloride, isnicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride and succinic anhydride, and the like. Carbamyl chloride (eg, N, N-dimethylcarbamyl chloride and N, N-diethylcarbamyl chloride, etc.) may also be used in this reaction to provide urea. Similarly, bicarbonates such as di-tert-butyl bicarbonate can be used to provide carbamates.

In a similar manner, the compounds of formula (I) or intermediates thereof comprising primary or secondary amino groups can be N-sulfonated using sulfonyl halides or sulfonic anhydrides to form sulfonamides. Sulfonyl halides and sulfonic anhydrides suitable for this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride and trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chloride (eg dimethylsulfamoyl chloride) can be used to provide sulfamides (eg> N-SO ₂ -N <).

In addition, primary and secondary amino groups or intermediates present in the substituents of the compounds of formula (I) can be reacted with isocyanates or thioisocyanates to obtain ureas or thioureas, respectively. Such reactions typically comprise at least 1 equivalent, preferably about 1.1 to about 1.2 equivalents of isocyanate or thioisocyanate in an inert diluent (e.g., toluene, etc.) for about 12 to about 24 hours in a temperature range of about 24 to about 37 ° C. This is done by contacting the amino compound. Isocyanates and thioisocyanates used in the reaction can be prepared from commercially available compounds using commercially or well known synthetic processes. For example, isocyanates and thioisocyanates are readily prepared by reacting a suitable amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include ethyl isocyanates, n-propyl isocyanates, 4-cyanophenyl isocyanates, 3-methoxyphenyl isocyanates, 2-phenylethyl isocyanates, methyl thioisocyanates, ethyl thioisocyanates, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3- (N, N-diethylamino) propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate and fluorescein isothiocia Nate (isomer I) and the like, but are not limited thereto.

In addition, when the compound of formula (I) or an intermediate thereof comprises a primary or secondary amino group, secondary or tertiary amino groups can be prepared by reducing alkylation of the amino groups using aldehydes or ketones. Such reactions are typically at least one equivalent, preferably from about 1.1 to about 72 hours, in an inert diluent (eg, methanol, tetrahydrofuran, mixtures thereof, etc.) for a temperature range of about 0 to about 50 ° C. for about 1 to about 72 hours. It is carried out by contacting the amino compound with at least one equivalent of reducing agent based on 1.5 equivalents of an aldehyde or ketone and an amino compound of a metal hydride. Suitable aldehydes and ketones for the reaction include, for example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like.

In a similar method, where the compound of formula (I) or intermediate thereof has a substituent comprising a hydroxyl group, the hydroxyl group is further modified before or after the coupling reaction to provide, for example, ether and carbamate or the like. Can be derivatized. Compounds having hydroxyl groups on the R ⁵ substituents can be prepared, for example, using amino acid derivatives of formula VI derived from tyrosine and the like in the above reactions.

By way of example, a compound of formula (I) or an intermediate thereof, for example having a substituent comprising a hydroxyl group, wherein R ⁵ is a (4-hydroxyphenyl) methyl group, can be readily O-alkylated to form ethers. . Such O-alkylation reactions are typically alkali or alkaline earth metal salts of hydroxyl groups by contacting a hydroxy compound with a suitable alkali or alkaline earth metal base (e.g. potassium carbonate) in an inert diluent (e.g. acetone and 2-butanone, etc.). Can be formed. Such salts are generally not separated, but in particular react in situ with at least one equivalent of alkyl or substituted alkyl halides or sulfonates such as alkyl chloride, bromide, iodine, mesylate or tosylate to provide ethers. Generally, the reaction is performed for about 24 to about 72 hours, in the temperature range of about 6 ° C to about 150 ° C. Preferably, when alkyl chloride or alkyl bromide is used in the reaction, a catalytic amount of sodium or potassium iodine is added to the reaction mixture.

Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl α-bromo Phenylacetate, 2- (N-ethyl-N-phenylamino) ethyl chloride, 2- (N, N-ethylamino) ethyl chlorolide, 2- (N, N-diisopropylamino) ethyl chloride, 2- ( N, N-dibenzylamino) ethyl chloride, 3- (N, N-ethylamino) propyl chloride, 3- (N-benzyl-N-methylamino) propyl chloride, N- (2-chloroethyl) morpholine, 2- (hexamethyleneimino) ethyl chloride, 3- (N-methylpiperazin) propyl chloride, 1- (3-chlorophenyl) -4- (3-chlorophenyl) piperazine, 2- (4-hydroxy 4-phenylpiperidine) ethyl chloride, N-tert-butyloxycarbonyl-3-piperidinemethyltosylate, and the like.

In addition, the hydroxyl groups present 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 (eg, 3- (N, N-dimethylamino) -1-propanol, etc.) is added in an inert diluent (eg, tetrahydrofuran) at about -10 ° C to about 5 ° C for about 0.25 to about 1 hour. For about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate. Then, about 1.0 to about 1.3 equivalents of a hydroxy compound (e.g., N-tert-butyltyrosine methyl ester) is added and the reaction mixture is stirred at a temperature of about 0 to about 30 ° C. for about 2 to about 48 hours To provide an O-alkylated product.

In a similar process, a compound of formula (I) or a derivative thereof comprising an aryl hydroxy group can be reacted with aryl iodine to give it as a diaryl ether. In general, the reaction is carried out in an inert diluent (eg xylene) at a temperature of about −25 to about 10 ° C. with a suitable base (eg sodium hydroxide) to form an alkali metal salt of the hydroxyl group. The salt is then treated with about 1.1 to about 1.5 equivalents of copper bromide dimethyl sulfide complex at a temperature range of about 10 to about 30 ° C. for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of aryl iodine (eg : Sodium 2-iodinebenzoate). Thereafter, the reaction is heated to a temperature of about 70 to about 150 ° C. for about 2 to about 24 hours to provide a diaryl ether.

In addition, the hydroxy containing compound may be readily derivatized to form carbamate. In one of the methods of making such carbamate, the hydroxy compound of formula (I) or a derivative thereof is prepared in an inert diluent (e.g. dichloromethane) at from about 1.0 to about 1.2 for about 0.5 to about 2.0 hours at about -25 to about 0 ° C. Contact with an equivalent of 4-nitrophenyl chloroformate. The resulting carbonate is treated with excess, preferably about 2 to about 5, equivalents of trialkylamine (e.g. triethylamine) for about 0.5 to about 2 hours, then about 1.0 to about 1.5 equivalents of primary or 2 Treatment with a tertiary amine gives a carbamate. Examples of suitable amines for use in the reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine and piperidine, and the like.

Further, in another method for preparing carbonates, the hydroxy containing compound is added to the inert diluent (e.g. dichloromethane) in a temperature range of about 25 to about 70 ° C. for about 2 to about 72 hours for about 1.0 to about 1.5 Contact with an equivalent of carbamyl chloride. Typically, this reaction is preferably carried out in the presence of a suitable base to capture the acid produced during the reaction. Suitable bases include, for example, tertiary amines such as triethylamine, diisopropylethylamine and N-methylmorpholine and the like. It is also preferred to add at least one equivalent (based on hydroxy compound) of 4- (N, N-dimethylamino) pyridine to the reaction mixture to promote the reaction. Examples of carbamyl chloride suitable for use in the reaction include dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.

In addition, when a compound of formula (I) or an intermediate thereof comprises primary or secondary hydroxyl groups, such hydroxyl groups can be readily converted to leaving groups, for example to form amines, sulfides and fluorides. It may be substituted to. For example, derivatives of 4-hydroxy-L-proline can be converted to the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives via nucleophilic substitution of the derivatized hydroxyl groups. have. In general, when chiral compounds are used in these reactions, the stereochemistry at the carbon atom bonded to the derivatized hydroxyl group is reversed.

These reactions are typically carried out by first converting hydroxyl groups to leaving groups (eg tosylate) by treating with pyridine at least one equivalent of sulfonyl halide (eg p-toluenesulfonyl chloride, etc.). This reaction is generally performed at a temperature of about 0 to about 70 ° C. for about 1 to about 48 hours. The resulting tosylate is then at least 1 equivalent in about 1 to about 12 hours in a temperature range of about 0 to about 37 ° C., for example, in an inert diluent (such as a mixture of N, N-dimethylformamide and water). By contacting sodium azide and tosylate, it can be easily substituted with sodium azide. The azido group is then reduced by, for example, a palladium catalyst on carbon to give an amino (-NH ₂ ) compound.

Similarly, tosylate groups can be readily substituted with thiols to form sulfides. The reaction is typically carried out in an inert diluent (eg N, N-dimethylformamide) in the presence of a suitable base (eg 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)). Performed by contacting at least one equivalent of thiol (eg, thiophenol) and tosylate at a temperature of from 0 to about 37 ° C. to provide sulfides. Tosylate is also treated with morpholinosulfur trifluoride in an inert diluent (eg dichloromethane) at a temperature ranging from about 0 to about 37 ° C. for a corresponding fluoro compound.

In addition, compounds of formula (I) or intermediates thereof having substituents comprising iodinearyl groups wherein R ¹ is a (4-iodophenyl) methyl group can be readily converted to non-aryl compounds before or after the coupling reaction. . Typically, the reaction is carried out in the presence of a palladium catalyst (eg palladium tetra (triphenylphosphine)) in an inert diluent (eg tetrahydrofuran) at a temperature ranging from about 24 to about 30 ° C. until the reaction is complete. It is carried out by treating an iodide compound with 1.1 to about 2 equivalents of arylzinc iodide. Such reactions are described, for example, in Rieke, J. Org. Chem. 1991, 56, 1445.

In some cases, the compound of formula (I) or intermediate thereof may include a substituent having one or more sulfur atoms. Such sulfur atoms include, for example, that the amino acids of formula II used in the reaction are L-thiazolidine-4-carboxylic acid, L- (5,5-dimethyl) thiazolidine-4-carboxylic acid and L-thiamorpholine If derived from -3-carboxylic acid or the like. If present, such sulfur atoms may be oxidized using conventional reagents and reaction conditions before or after the coupling reaction to provide sulfoxide or sulfone compounds. Suitable reagents for oxidizing sulfide compounds to sulfoxides include, for example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate, and the like. The oxidation reaction is typically carried out by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidant in an inert diluent (eg dichloromethane) for about 1 to about 24 hours in the temperature range of about -50 to about 75 ° C. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with an additional one or more equivalents of oxidant (eg, hydrogen peroxide, MCPBA, potassium permanganate, etc.). In addition, sulfones can be prepared directly by contacting sulfide with an excess of 2 equivalents, preferably an excess of oxidant. This reaction is described in "Advanced Organic Chemistry", 4th Ed., Pp. 1201-1202, Wiley Publisher (1992).

As described above, compounds of formula (I) having R ² substituents other than hydrogen use the N-substituted amino acids of formula (II) such as sarcosine and N-methyl-L-phenylalanine in the coupling reactions described above. Can be prepared. The compounds may also be prepared by N-alkylation of sulfonamides of formula I or IV, wherein R ² is hydrogen, using conventional synthetic processes. Typically, the N-alkylation reaction is at least one equivalent in the presence of a suitable base in an inert diluent (eg, acetone, 2-butanone, etc.) for about 2 to about 48 hours at a temperature ranging from about 25 ° C to about 70 ° C. Preferably it is carried out by contacting sulfonamide with 1.1 to 2 equivalents of alkyl or substituted alkyl halides. Examples of alkyl or substituted alkyl halides suitable for use in the reaction include, but are not limited to, methyl iodide.

In addition, sulfonamides of formula (I) or (IV) wherein R ² is hydrogen and R ¹ is a 2-alkoxycarbonylaryl group are cross-linked to form 1,2-benzisothiazol-3-one derivatives or homologues thereof. can do. The reaction is typically carried out in an inert diluent (e.g. tetrahydrofuran) with about 1.0 to 1.5 equivalents of a suitable base (e.g. alkali metal hydride) for about 2 to about 48 hours in the temperature range of about 0 ° C to about 30 ° C. Treatment with sulfonamides such as N- (2-methoxycarbonylphenylsulfonyl) glycine-L-phenylalanine benzyl ester results in the closure of 1,2-benzisothiazol-3-one derivatives.

Finally, compounds of formula I wherein Q is —C (S) NR ⁷ — may be prepared using amino thionoic acid derivatives in place of amino acid (II) in the synthesis process. Such amino thianoic acid derivatives are described in Shalaky, et al., J. Org. Chem., 61: 9045-9048 (1996) and Brain, et al., J. Org. Chem., 62: 3808-3809 (1997), incorporated herein by this reference.

Pharmaceutical formulation

When the compounds of formula (I) and (IA) are used as medicaments, they are generally administered in the form of pharmaceutical compositions. Such compounds may be administered by various routes of administration, such as oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. The compounds mentioned above are effective as both injectable and oral compositions. Such compositions are prepared by methods well known in the pharmaceutical art and comprise one or more active compounds.

The invention also includes pharmaceutical compositions containing, as active ingredient, one or more compounds of Formula (I) and (IA) in association with a pharmaceutically acceptable carrier. In preparing the compositions of the present invention, the active ingredient is generally mixed with excipients and may be diluted into excipients or enclosed in a carrier which may be in the form of capsules, sachets, paper or other containers. If an excipient is used as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may contain, for example, tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid) containing up to 10% by weight of the active compound. Medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaging powders.

In formulating a formulation, it may be necessary to grind the active compound to provide particles of the appropriate size prior to combining with other ingredients. If the active compound is substantially insoluble, it is usually milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is adjusted to be substantially uniformly distributed (eg about 40 mesh) in the formulation.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, Water, syrup and methyl cellulose. The formulations further include lubricants (eg, chalcopyrite, magnesium stearate and inorganic oils), wetting agents, emulsifiers and suspending agents, preservatives (methyl- and propylhydroxybenzoate), sweetening agents and flavoring agents. Compositions of the present invention may be formulated to release the active ingredient rapidly, continuously or delayed after administration to a patient using procedures known in the art.

The compositions are preferably formulated in unit dosage forms containing a dosage of about 5 to about 100 mg, more generally about 10 to about 30 mg of the active ingredient. The term "unit dosage form" is intended to be administered to human subjects and other mammals as unit doses containing a predetermined amount of the active substance calculated so that each unit, together with suitable pharmaceutical excipients, will produce the desired therapeutic effect. Means a physically distinct unit suitable for

The active compounds are effective over a wide range of doses and are generally administered in pharmaceutically effective amounts. However, the amount of compound administered substantially is considered to be determined by the physician in appropriate circumstances, including the condition to be treated, the route of administration chosen, the compound administered substantially, the age, weight, sensitivity and severity of the symptom of each patient.

When formulating solid compositions, such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the invention. When the above preformulated compositions are mentioned as homogeneous, this means that the active ingredients are uniformly dispersed throughout the composition so that they can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Such solid preformulations are subdivided into unit dosage forms of the type described above, for example, containing from 0.1 to about 500 mg of the active ingredient of the invention.

Tablets or pills of the present invention may be provided in a dosage form having the advantage of being continuously dispensed or mixed. For example, a tablet or pill may include an internal dosage component and an external dosage component in a form surrounding the internal dosage component. The two components can be separated by an enteric layer that acts to resist degradation in the stomach and allows the internal components to pass completely into the duodenum or delay release. Various materials can be used as the functional layer or coating, including many polymeric acids and shellac, cetyl alcohol and mixtures of cellulose acetate and polymeric acids.

Liquid forms in which the novel compositions of the present invention may be incorporated for oral or injection administration include liquids, suitable aqueous flavor syrups, aqueous or oily suspensions, and flavors with edible oils such as cotton oil, sesame oil, coconut oil or peanut oil. As well as emulsions and similar pharmaceutical vehicles.

Inhalation or blowing compositions include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid and solid compositions can include pharmaceutically acceptable excipients as described above. Preferably the composition is administered by the oral or nasal respiratory route for local or systemic effects. Preferably the composition in a pharmaceutically acceptable solvent can be nebulized by using an inert gas. The nebulized liquid may be inhaled directly from the spray device or the nebulizer may be attached to a face mask tent or an intermittent positive pressure breathing machine. The solution, suspension or powder composition may preferably be administered orally or nasal from the device that carries the formulation in a suitable manner.

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

Formulation Example 1

Hard gelatine capsules containing the following ingredients are prepared:

Ingredient amount (mg / capsule)

Active ingredient 30.0

Starch 305.0

Magnesium Stearate 5.0

The ingredients are mixed and filled into hard gelatin capsules in an amount of 340 mg.

Formulation Example 2

Tablet formulations are 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 components are blended and compressed to form tablets each weighing 240 mg.

Formulation Example 3

Anhydrous powder inhalation formulations are prepared comprising the following ingredients:

Component weight%

Active ingredient 5

Lactose 95

The active mixture is mixed with lactose and the mixture is added to anhydrous powder inhalation instrument.

Formulation Example 4

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

Ingredient amount (mg / tablet)

30.0 mg active ingredient

Starch 45.0mg

Microcrystalline Cellulose 35.0mg

Polyvinylpyrrolidone 4.0mg

(As a 10% solution in water)

Sodium carboxymethyl starch 4.5mg

Magnesium Stearate 0.5mg

Talc 1.0mg

120mg total

The active ingredient, starch and cellulose were prepared using No. 20 mesh U.S. Pass through sieve and mix thoroughly. A solution of polyvinyl-pyrrolidone was mixed with the resulting powder and then 16 mesh U.S. Pass it through a sieve. The granules thus obtained were dried at 50 ° C. to 60 ° C. and 16 mesh U.S. Pass it through a sieve. 30 mesh U.S. in advance Sodium carboxymethyl starch, magnesium stearate and talc passed through a sieve are added to the granules, followed by mixing and tableting on a tablet machine to give tablets weighing 150 mg each.

Formulation Example 5

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

Ingredient amount (mg / capsule product)

40.0 mg active ingredient

Starch 109.0mg

Magnesium Stearate 1.0mg

150.0 mg total

The active ingredient, cellulose, starch and magnesium stearate were blended and No. 20 Mesh U.S. It is passed through a sieve and filled into hard gelatin capsules in an amount of 150 mg.

Formulation Example 6

Suppositories containing 25 mg of each active ingredient are prepared as follows:

Ingredient amount

25 mg of active ingredient

Saturated fatty acid glyceride 2,000mg

The active ingredient is No. 60 mesh U.S. Pass through a sieve and suspend in pre-melted saturated fatty acid glycerides using the minimum heat required. The mixture is poured into a suppository mold of 2.0 g nominal capacity and cooled.

Formulation Example 7

Suppositories each containing 50 mg of drug per 5.0 ml dose are prepared as follows:

Ingredient amount

50.0 mg active ingredient

Xanthan Rubber 4.0mg

Sodium Carboxymethyl Cellulose (11%) / 50.0 mg

Microcrystalline Cellulose (89%)

Sucrose 1.75 g

Sodium benzoate 10.0mg

Filling of flavors and colorants

Make 5.0 ml with purified water.

Drugs, sucrose and xanthan rubber are blended and No. 10 mesh U.S. After passing through a sieve, it is mixed with a pre-prepared microcrystalline cellulose and sodium carboxymethyl cellulose solution in water. Sodium benzoate, flavors and colorants are diluted with some water and added with stirring. Sufficient water is added to obtain the required volume.

Formulation Example 8

Ingredient amount (mg / capsule product)

Active ingredient 15.0 mg

Starch 407.0mg

Magnesium Stearate 3.0mg

Total 425.0mg

The active ingredient, cellulose, starch and magnesium stearate are blended and No. 20 Mesh U.S. After passing through a sieve, it is filled into hard gelatin capsules in an amount of 560 mg.

Formulation Example 9

Intravenous formulations are prepared as follows:

Ingredient amount

Active ingredient 250.0 mg

Isotonic saline 1000ml

Formulation Example 10

Topical formulations can be prepared as follows:

Ingredient amount

1 to 10 g of active ingredient

30 g of emulsifying wax

20 g of liquid paraffin

Make 100 g with white soft paraffin.

The white soft paraffin is heated until it melts. Liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirred until dispersed. Cool until the mixture solidifies.

Another preferred formulation used in the method of the invention uses a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the invention in controlled amounts. The construction and use of transdermal patches for delivery of a medicament are well known in the art. See, for example, US Pat. No. 5,023,252, issued June 11, 1991, which is incorporated herein by reference. Such patches can be constructed in a continuous, reactionary fashion or in accordance with the delivery needs of the medicament.

If required or necessary, it may be introduced directly or indirectly into the brain. Direct techniques generally involve placing a drug delivery catheter via the blood brain barrier into the ventricle of the host. Implantable delivery systems used to deliver biological factors to specific anatomical regions of the body are described in US Pat. No. 5,011,472, which is incorporated herein by reference.

Generally preferred indirect techniques involve formulating the composition by converting the hydrophilic agent into a fat soluble agent to provide a drug incubation process. The incubation process is generally accomplished by blocking the hydroxy, carbonyl, sulfate and primary amino groups present on the medicament to make the medicament more soluble to facilitate passage through the blood brain barrier. Alternatively, delivery of the hydrophilic agent may be enhanced by intraarterial injection of hypertonic solution that may temporarily open the blood brain barrier.

Usage

Compounds of the invention can be used to bind VLA-4 (α ₄ β ₁ integrin) in biological samples and thus can be used to assay such samples, for example, for VLA-4. In the above assay, the compound is bound on a solid support and a VLA-4 sample is added. The amount of VLA-4 in the sample can be measured by conventional methods, such as sandwich ELISA assays. Alternatively, labeled VLA-4 can be used in a competition assay to determine the presence of VLA-4 in a sample. Other suitable assays are well known in the art.

Certain compounds of the invention also inhibit the attachment of leukocytes to endothelial cells mediated by VLA-4 in vivo and thus can be used in the treatment of diseases mediated by VLA-4. Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute combustible diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, Acute leukocyte-mediated lung injury, such as those occurring in rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, ataxia and other cerebral trauma, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and adult respiratory distress syndrome Included.

The biological activity of the identified compounds can be assayed in various systems. For example, the compound can be immobilized on a solid support to measure the adhesion of cells expressing VLA-4. Using the format described above, a myriad of compounds can be selected. Suitable cells for this assay include all white blood cells known to express VLA-4, such as T cells, B cells, monocytes, eosinophils and basophils. Numerous white blood cell lines can also be used, including for example Jurkat and U937.

The test compound also competitively inhibits binding between VLA-4 and VCAM-1, or a labeled compound known to bind VLA-4, such as a compound of the present invention, or an antibody against VLA-4. Test your abilities. In this assay, VCAM-1 can be immobilized on a solid surface. VCAM-1 may also be expressed as a recombinant fusion protein having an Ig (eg IgG) terminus that allows for detection of binding to VLA-4 in an immunoassay. Alternatively, VCAM-1 expressing cells such as activated endothelial cells or VCAM-1 transfected fibroblasts can be used. For assays that measure the ability to block adhesion to endothelial cells in the brain, the assays described in WO 91/05038 are particularly preferred. This publication is incorporated herein by reference in its entirety.

Many assay formats use labeled assay components. Labeling systems can take many forms. The label can be coupled directly or indirectly to the desired component of the assay according to methods well known in the art. Various marks can be used. The component can be labeled in one of several ways. The most common detection method is the use of ^{radiophotography} with ³ H, ¹²⁵ I, ³⁵ S, ¹⁴ C or ³² P labeled compounds. Non-radioactive labels include ligands that bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies that can act as specific binding pairs for labeled ligands. The choice of label depends on the sensitivity required, the ease of compounding and conjugation, the stability requirements and the available equipment.

Suitable in vivo models for demonstrating efficacy in treating an inflammatory response include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent on α4 integrin.

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

For diagnostic purposes, various labels can be bound to a compound to provide a detectable signal directly or indirectly. Thus, the compounds of the present invention can be modified in a variety of ways to suit a variety of end purposes while still retaining biological activity. In addition, various reactive sites can be introduced at the ends to bind particles, solid substrates, macromolecules and the like.

Labeled compounds can be used for a variety of in vivo or in vitro applications. For example, radionuclides (e.g. gamma-emitting radioisotopes such as technetium-99 or indium-111), fluorescent materials (e.g. fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds And various labels such as bioluminescent compounds and the like. One of ordinary skill in the art will recognize other labels suitable for binding to the complex or will be able to identify them using routine experimental methods. Combination of the above labels is accomplished using standard techniques common to those of ordinary skill in the art.

In vitro uses include diagnostic applications such as monitoring the inflammatory response by detecting the presence of white blood cells expressing VLA-4. Compounds of the invention can also be used to isolate or label the cells described above. As also mentioned above, the compounds of the present invention can be used to assay potential inhibitors of VLA-4 / VCAM-1 interactions.

For example, for in vivo diagnostic imaging to identify sites of inflammation, radioisotopes are commonly used according to well known techniques. Radioisotopes can bind to peptides directly or indirectly using intermediate functional groups. For example, chelating agents such as diethylenetriaminepentacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules are used to bind proteins to metal ion radioisotopes.

The complex can be labeled with paramagnetic isotopes for in vivo diagnostic purposes, as magnetic resonance imaging (MRI) or electron spin resonance (ESR), both well known in the art. In general, any conventional method for visualizing diagnostic images can be used. Generally gamma and positron emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI. Thus, compounds can be used to monitor the process of alleviating inflammatory responses in a subject. By measuring the increase or decrease in lymphocytes expressing VLA-4, one can determine whether a particular therapeutic regimen aimed at alleviating the disease is effective.

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

Inflammatory bowel disease is a generic term for two similar diseases referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an idiopathic chronic ulcerative inflammatory disease, characterized by granulomatous inflammatory response, with distinct bordering of all layers of the intestinal wall and invasion of conventional transverse walls. Although the disease mostly affects the terminal ileum and / or the colon, any gastrointestinal tract site from mouth to anus may be involved. Ulcerative colitis is an inflammatory response that is largely restricted to the mucosa and submucosa of the colon. Lymphocytes and macrophages are present in large numbers in lesions of inflammatory bowel disease, which can contribute to inflammatory damage.

Asthma is characterized by increased responsiveness of bronchial bronchial structures to various stimuli that increase paroxysmal narrowing of the bronchial airways. Stimulation releases various inflammatory mediators from IgE coated mast cells, including histamine, eosinophils and neutrophil chemotactic factors, leukotriene, prostaglandins and platelet activating factors. The release of these factors strengthens basophils, eosinophils and neutrophils, causing inflammatory damage.

Atherosclerosis is a disease of arteries (eg coronary, carotid, aortic and iliac). The underlying lesion, atherosclerosis, consists of thick lesion plaques in the endovascular membrane, with a lipid nucleus and a fibrous cap covering it. Atherosclerosis damages arterial blood flow, weakening the affected arteries. Myocardial infarction and cerebral infarction are the main consequences of this disease. Macrophages and leukocytes are enhanced in atherosclerosis, contributing to inflammatory damage.

Rheumatoid arthritis is a chronic recurrent inflammatory disease that primarily causes damage and destruction of joints. Rheumatoid arthritis generally affects the bovine joints of the hands and feet first, but may then affect the wrists, elbows, ankles, and knees. Arthritis results from the interaction of synovial cells with white blood cells that penetrate the synovial glands of the joint from the circulatory system (Paul, Immunology (3d ed., Raven Press, 1993)).

Another approach for compounds of the invention is to treat organ or transplant rejection mediated by VLA-4. In recent years, the efficacy of surgical techniques for implanting tissues and organs such as skin, kidneys, liver, heart, lungs, pancreas and bone marrow has been significantly improved. Perhaps a major problem that is noticeable is that in the beneficiary there is no satisfactory drug that causes immunotolerance to the transplanted allograft or organ. When allogeneic cells or organs are transplanted into a host (ie, the donor and the recipient are different individuals of the same kind), the host's immune system initiates an immune response (host versus graft disease) to the transplanted foreign antigen to repair the transplanted tissue. Easy to destroy CD8 ⁺ cells, CD4 cells and monocytes are all involved in rejection of transplanted tissue. Compounds of the invention that bind to α-4 integrins are particularly useful for blocking the allogeneic-induced immune response in beneficiaries, thereby inhibiting the involvement of such cells in transplanted tissue and organ disruption. Paul et al. , Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplant. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); and Anderson et al., APMIS 102, 23-27 (1994).

A related use of a compound of the invention that binds to VLA-4 is to modulate an associated immune response in "graft versus host disease (GVHD). Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal disease that occurs when immunologically competent cells are delivered to allograft recipients. In this situation, the donor's immune competent cells will attack the recipient's tissue. Skin, intestinal epidermis and liver tissue are frequently targeted and can be destroyed during GVHD. The disease is a particularly serious problem when immune tissues are implanted (eg bone marrow transplants), but GVHD is reported to be less severe in other cases, including heart or liver transplantation. The therapeutic agents of the present invention are particularly used to block the activation of donor T-cells and to inhibit their ability to lyse target cells in the host.

A further use of the compounds of the invention is to inhibit tumor metastasis. Some tumor cells are mentioned to express VLA-4, and compounds that bind VLA-4 block the attachment of these cells to endothelial cells. Steinback et al., Urol. res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 47-52 (1994); and Okahara et al., Cancer Res. 54, 3233-6 (1994).

Another use of the compounds of the present invention is to treat multiple sclerosis. Multiple sclerosis is a progressive neuropathic autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a special autoimmune reaction in which certain white blood cells begin to attack and destroy myelin, an insulating sheath covering nerve fibers. In multiple sclerosis animal models, the monoclonal antibodies of murine against VLA-4 have been shown to block the attachment of leukocytes to the endothelium, thereby inhibiting inflammation of the central nervous system in animals, thereby inhibiting subsequent paralysis ¹⁶ .

The pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Formulations suitable for use in the present invention can be found in the literature. Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

To enhance serum half-life, the compounds can be trapped in liposomes, introduced into the lumens of liposomes, prepared as colloids, or other conventional techniques can be used to provide extended serum half-life of the compounds. Various techniques can be used to prepare liposomes, for example, as described in US Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 to Szoka et al., Each of which is incorporated herein by reference. have.

The amount administered to the patient may vary depending on the substance to be administered, the purpose of administration (eg, prophylactic or therapeutic), the condition of the patient, the method of administration and the like. In therapeutic applications, the composition is administered to a patient suffering from the disease in an amount sufficient to treat or at least partially arrest the symptoms of the disease and its complications. Amounts suitable to achieve this are defined as "therapeutically effective amounts". The amount effective for this use depends on the judgment of the attending physician, which depends not only on the condition of the disease to be treated but also on the severity of inflammation, the age, weight and general condition of the patient.

The composition administered to the patient is in the pharmaceutical form described above. Such compositions may be sterilized or sterile filtered by conventional sterilization techniques. The resulting aqueous solution is packaged or lyophilized for such use and the lyophilized formulation is mixed with a sterile aqueous carrier prior to administration. The pH of the compound formulation is usually 3 to 11, more preferably 5 to 9, most preferably 7 to 8. It will be appreciated that the specific excipients, carriers or stabilizers described above may be used to form the pharmaceutical salt.

The therapeutic dosage of a compound of the present invention may vary depending on, for example, the particular use for which the treatment is to be made, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, dosages typically range from about 20 μg to about 500 μg, preferably from about 100 μg to about 300 μg per kilogram of body weight. For intranasal administration, a suitable dosage range is generally about 0.1 pg to 1 mg per kilogram of body weight. Effective dosages can be extrapolated from dose-response curves derived from in vivo or animal model test systems.

The following synthetic and biological examples are provided for the purpose of illustrating the invention and should not be construed in such a way as to limit the scope of the invention. Unless otherwise noted, all temperatures are in degrees Celsius.

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

aq or aq. = Aqueous

AcOH = acetic acid

bd = broad doublet

bm = broad multiline

bs = broad single line

Bn = benzyl

Boc = N-tert-butoxycarbonyl

Boc ₂ O = di-tert-butyl dicarbonate

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

Hexafluorophosphate

Cbz = carbobenzyloxy

CHCl ₃ = chloroform

CH ₂ Cl ₂ = dichloromethane

(COCl) ₂ = oxalyl chloride

d = doublet

dd = doublet of doublet

dt = doublet of triplets

DBU = 1,8-diazabicyclo [5.4.0] undec-7-yen

DCC = 1,3-dicyclohexylcarbodiimide

DMAP = 4-N, N-dimethylaminopyridine

DME = ethylene glycol dimethyl ether

DMF = N, N-dimethylformamide

DMSO = dimethyl sulfoxide

EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiamide

Hydrochloride

Et ₃ N = triethylamine

Et ₂ O = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

eq or eq. = Equivalent equivalence

Fmoc = N- (9-fluorenylmethoxycarbonyl)

FmocONSu = N- (9-fluorenylmethoxycarbonyl) succinimide

g = grams

h = hours

H ₂ O = water

HBr = bromic acid

HCl = hydrochloric acid

HOBT = 1-hydroxybenzotriazole anhydride

hr = hour

K ₂ CO ₃ = potassium carbonate

L = liter

m = polyline

MeOH = Methanol

mg = milligrams

MgSO ₄ = magnesium sulfate

mL = milliliters

mm = millimeters

mM = millimolar

mmol = millimoles

mp = melting point

N = normal

NaCl = Sodium Chloride

Na ₂ CO ₃ = sodium carbonate

NaHCO ₃ = sodium bicarbonate

NaOEt = Sodium Ethoxide

NaOH = sodium hydroxide

NH ₄ Cl = ammonium chloride

NMM = N-methylmorpholine

Phe = L-phenylalanine

Pro = L-Proline

psi = pounds per square inch

PtO ₂ = platinum oxide

q = quadruple

quint. = Quintet

rt = room temperature

s = single line

sat = saturated

t = triplet

t-BuOH = tert-butanol

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC or tlc = thin layer chromatography

Ts = tossile

TsCl = tosyl chloride

TsOH = tosylate

μL = microliters

In the examples below, all temperatures are in degrees Celsius (unless otherwise noted). As shown below, the above-mentioned compounds are prepared using the following method.

Method 1

N-Tosylation Method

The N-tosylation reaction of the appropriate amino acid is carried out via the method of literature: Cupps. Boutin and Rapoport J. Org. Chem. 1985, 50, 3972].

Method 2

Method for preparing methyl ester

Amino acid methyl esters are prepared using the method of Brenner and Huber. Helv. Chim. Acta 1953, 36, 1109.

Method 3

BOP Coupling Method

The desired dipeptide esters can be prepared by reacting a suitable N-protected amino acid (1 equivalent) with an appropriate amino acid ester, or by amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium Prepared by reaction with hexafluorophosphate [BOP] (2.0 equiv), triethyl amine (1.1 equiv) and DMF. The reaction mixture is stirred overnight at room temperature. The crude product is purified by flash chromatography to yield the dipeptide ester.

Method 4

Hydrogenation Method I

The hydrogenation reaction is carried out using 10% palladium on carbon (10% by weight) in methanol at 30 psi. The mixture is filtered through a pad of celite and concentrated to afford the desired amino compound.

Method 5

Hydrolysis Method I

LiOH (or NaOH) (0.95 equiv) is added to a cooled (0 ° C.) THF / H ₂ O solution (2: 1, 5-10 mL) of the appropriate ester. The temperature is maintained at 0 ° C. and the reaction completes in 1 to 3 hours. The reaction mixture is extracted with ethyl acetate and the aqueous phase is lyophilized to give the desired carboxylate salt.

Method 6

Ester Hydrolysis Method II

LiOH (1.1 equiv) is added to a cooled (0 ° C.) THF / H ₂ O solution (2: 1, 5-10 mL) of the appropriate ester. The temperature is maintained at 0 ° C. and the reaction completes in 1 to 3 hours. The reaction mixture is concentrated, the residue is dissolved in H ₂ O and the pH is adjusted to 2-3 using aqueous HCl. The reaction mixture is extracted with ethyl acetate and the combined organic layers are washed with brine, dried over MgSO ₄ , filtered and concentrated to give the desired acid.

Method 7

Ester Hydrolysis Method III

Suitable esters are dissolved in dioxane / H ₂ O solution (1: 1) and 0.9 equivalent of 0.5N NaOH is added. The reaction is stirred for 3-16 hours and then concentrated. The resulting residue is dissolved in H ₂ O and extracted with ethyl acetate. The aqueous phase is lyophilized to give the desired carboxylate sodium salt.

Method 8

Sulfonylation Method I

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

Method 9

Reductive Amination Method

Reductive amination of the appropriate aldehyde and Tos-Pro-p-NH2-Phe is carried out using acetic acid, sodium triacetoxyborohydride and methylene chloride, and the combined mixture is stirred overnight at room temperature. The crude product is purified by flash chromatography.

Method 10

How to remove a BOC

Anhydrous hydrochloric acid (HCl) gas is bubbled through a methanolic solution of the appropriate Boc-amino acid ester at 0 ° C. for 15 minutes and the reaction mixture is stirred for 3 hours. The solution is concentrated in syrup, dissolved in Et ₂ O and concentrated again. The process is repeated and the resulting solid is left overnight under high vacuum.

Method 11

Tert-Butyl Ester Hydrolysis Method I

Tertiary butyl ester is dissolved in CH ₂ Cl ₂ and treated with TFA. The reaction is complete within 1 to 3 hours when the reaction mixture is concentrated and the residue is dissolved in H ₂ O and lyophilized to give the desired acid.

Method 12

EDC Coupling Method I

Amino acid ester hydrochloride (1 equivalent), N-methylmorpholine (1.1-2.2), suitable for a CH ₂ Cl ₂ solution (5-20 mL) of N- (toluene-4-sulfonyl) -L-proline (1 equivalent) Equivalents) and 1-hydroxybenzotriazole (2 equivalents) are added, mixed and left in an ice bath followed by addition of 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equivalents). The reaction is left to rise to room temperature and stirred overnight. The reaction mixture is poured into H ₂ O and the organic phase is washed with saturated NAHCO ₃ , brine, anhydrous (MgSO ₄ or Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by column chromatography.

Method 13

EDC Coupling Method II

To a suitable NMF-protected DMF solution (5-20 mL), mix the appropriate amino acid ester hydrochloride (1 equiv), Et ₃ N (1.1 equiv) and 1-hydroxybenzotriazole (2 equiv) It is left to stand in an ice bath and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equiv) is added. The reaction is left to rise to room temperature and stirred overnight. The reaction mixture is partitioned between EtOAc and H ₂ O and the organic phase is washed with 0.2N citric acid, H ₂ O, saturated NaHCO ₃ , brine, anhydrous (MgSO ₄ or Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by column chromatography or preparative TLC.

Method 14

Sulfonylation Method II

Suitable sulfonyl chloride is dissolved in CH ₂ Cl ₂ and left in an ice bath. L-Pro-L-Phe-OMe.HCl (1 equiv) and Et ₃ N (1.1 equiv) are added and the reaction is left to warm to room temperature and stirred under nitrogen atmosphere overnight. The reaction mixture is concentrated, the residue is partitioned between EtOAc and H ₂ O, and the organic phase is washed with saturated NaHCO ₃ , brine, anhydrous (MgSO ₄ or Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by column chromatography or preparative TLC.

Method 15

Sulfonylation Method III

A solution of L-Pro-L-4- (3-dimethylaminopropyloxy) -Phe-OMe in CH ₂ Cl ₂ [prepared using the process described in Method 10] (1 equiv) in Et ₃ N (5 Equivalent) and then the appropriate sulfonyl chloride (1.1 equivalent). The reaction is left to warm to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture is concentrated, dissolved in EtOAc and washed with saturated NaHCO ₃ and 0.2N citric acid. The aqueous phase is basified with solid NaHCO 3 and the product is extracted with EtOAc. The organic phase is washed with brine, anhydrous (MgSO ₄ or Na ₂ SO ₄ ), filtered and concentrated. The crude methyl ester is purified by preparative TLC. The corresponding acid is prepared using the process described in Method 7.

Method 16

Hydrogenation Method II

To a methanol solution of azlactone (10-15 ml) is added NaOAc (1 equiv) and 10% Pd / C. The mixture is left in a hydrogenator at 40 psi H ₂ . After 8-16 hours, the reaction mixture is filtered through a pad of celite and the filtrate is concentrated to give the dehydrodipeptide methyl ester. The ester is dissolved in dioxane / H ₂ O (5-10 mL) and 0.5N NaOH (1.05 equiv) is added. It is stirred for 1-3 hours, then the reaction mixture is concentrated and the residue is redissolved in H ₂ O and washed with EtOAc. The aqueous phase is acidified with 0.2N HCl and the product is extracted with EtOAc. The combined organic phases are washed with brine (1 × 5 mL), dried (MgSO ₄ or Na ₂ SO ₄ ) filtered and concentrated to give the acid as an approximately 1: 1 mixture of diastereomers.

Method 17

Tert-Butyl Ester Hydrolysis Method II

Tert-butyl ester is dissolved in CH ₂ Cl ₂ (5 mL) and treated with TFA (5 mL). The reaction is completed within 1 to 3 hours when the reaction mixture is concentrated, and the residue is dissolved in H ₂ O and concentrated. The residue is redissolved in H ₂ O and lyophilized to give the desired product.

Example 1 (2)

Synthesis of N- (toluene-4-sulfonyl) -L-propyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl-L-4-aminophenylalanine methyl ester (2.00 g, 4.67 mmol) was converted to Boc-glycine (1.1 equiv, 0.9 g), Et ₃ N (2.2 equiv, 1.43 mL) and BOP reagent (1.1 equiv, 2.27 g) are dissolved in 50 mL of anhydrous DMF. The reaction mixture is stirred at rt for 12 h. EtOAc (100 ml) is added. The organic layer is washed with saturated NaHCO ₃ (50 ml), 10% citric acid (20 ml) and brine (5 × 50 ml). The organic layer is dried over MgSO ₄ . The solvent is evaporated under reduced pressure and the crude material is eluted on column chromatography (silica gel; CHCl ₃ / MeOH 9: 1). The desired ester (1.90 g, 3.1 mmol) is isolated in 66% yield. The ester is dissolved in MeOH: H ₂ O [1: 1] (40 ml) with NaOH (1.1 equiv, 1.76 mg) for 4 h at room temperature. EtOAc and water are added. The aqueous layer is collected and acidified to pH 2.5 with 1N HCl and reextracted with EtOAc. The organic layer is dried over MgSO ₄ . Filter the solvent under reduced pressure and evaporate to separate the title compound as an oil (1.33 g, 2.26 mmol) in 73% yield.

NMR data are 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 = 7.14 Hz), 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, 1H), 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, 3H), 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, 24.89 22.14, 14.77.

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

Example 2 (7)

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

The product of Example 1 (2) (1.33 g, 2.26 mmol) is dissolved in anhydrous dichloromethane (20 ml) with trifluoroacetic acid (1.00 mL) and the reaction mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure. The crude material is left under vacuum pump overnight, dissolved in methanol and cooled to 0 ° C. Ethyl ether is added and the product is collected as trifluoroacetate salt in 50% yield (660 mg, 1.09 mmol).

NMR data are 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 = 8.25Hz), 4.43 (m, 1H), 3.87 (m, 1H), 3.63 (s, 2H), 3.13-2.82 (m, 4H), 2.21 (s, 3H), 1.56- 1.26 (m, 4 H).

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, 42.72, 38.39, 32.20, 25.87, 22.09, 16.02.

Mass spectrum: (FAB) 489 (M &lt; + &gt;).

Example 3 (23)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (carboxy) propionamido] -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl-L-4-aminophenylalanine methyl ester (455 mg, 1 mmol) with Et ₃ N (1.1 equiv., 153 μl) and succinic anhydride (1.1 equiv., 110 mg) Together in DMF (10 ml). The desired monoester is isolated in 53% yield (288 mg, 0.52 mmol) as blowing agent. Monoester (80 mg, 0.15 mmol) is hydrolyzed with NaOH (2.2 equiv, 15 mg) in MeOH: H ₂ O 1: 1 (5 ml) for 4 h at room temperature. Water and EtOAc are added. The aqueous layer is collected and acidified to pH 2.5 with 1N HCl and reextracted with EtOAc. The organic layer is dried over MgSO ₄ . The solvent is filtered and evaporated under reduced pressure to separate the diacids as blowing agents.

NMR data are 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), 2.43 (s, 4H), 2.21 (s, 3H), 1.44- 1.29 (m, 4 H).

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, 121.66, 80.05, 63.81, 55.37, 51.17, 38.25, 38.25. , 32.24, 30.55, 25.89, 22.11.

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

Example 4 (27)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonyl-L-alanyl) amino] -L-phenylalanine

According to the experimental method described in Example 1 (2), N- (toluene-4-sulfonyl) -L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g, 0.337 mmol) was added to Et ₃ N ( Dissolve in 5 ml of DMF with 2.0 equiv, 95 μl, Boc-L-alanine (1.1 equiv., 70 mg) and BOP (1.1 equiv., 163 mg). The desired methyl ester is isolated as an oil in 49% yield (102 mg, 0.16 mmol). The ester is then hydrolyzed with NaOH (1.1 equiv, 8 mg) in a 1: 1 MeOH: H ₂ O solution (4 ml). Monoacid is isolated as an amorphous solid in quantitative yield.

NMR data are 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, 2H, 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 spectrum: (FAB) 603 (M + H).

Example 5 (28)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonyl-D-alanyl) amino] -L-phenylalanine

According to the experimental method described in Example 1 (2), N- (toluene-4-sulfonyl) -L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g, 0.337 mmol) was added to Et ₃ N ( Dissolve in 5 ml of DMF with 2.0 equiv, 95 μl, Boc-D-alanine (1.1 equiv., 70 mg) and BOP (1.1 equiv., 163 mg). The desired methyl ester is isolated as an oil in 33% yield (68 mg, 0.11 mmol). The ester is then hydrolyzed with NaOH (1.1 equiv, 5 mg) in a 1: 1 MeOH: H ₂ O solution (4 ml). Ilsan is separated as a film in quantitative yield.

NMR data are 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, 2H, 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 spectrum: (FAB) 603 (M + H).

Example 6 (29)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxycarbonyl-D-phenylalanyl) amino] -L-phenylalanine

According to the experimental method described in Example 1 (2), N- (toluene-4-sulfonyl) -L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g, 0.337 mmol) was added to Et ₃ N ( Dissolve in 5 ml of DMF with 2.0 equiv, 95 μl), Boc-L-phenylalanine (1.1 equiv, 99 mg) and BOP (1.1 equiv, 163 mg). The desired methyl ester is isolated as an oil in 16% yield (37 mg, 0.05 mmol). The ester is then hydrolyzed with NaOH (1.1 equiv, 3 mg) in a 1: 1 MeOH: H ₂ O solution (2 ml). Ilsan is separated as an amorphous solid in quantitative yield.

NMR data are 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), 3.44 (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, 129.36, 128.44, 127.64, 120.63, 81.16, 62.84, 62.84 50.26, 38.91, 37.90, 30.35, 28.81, 24.96, 22.11.

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

Example 7 (67)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (fluoresce) thioureido] acetamido} -L-phenylalanine

The product of Example 2 (7) is treated with NaHCO ₃ and Fluorescein Isothiocyanate (Isomer I purchased from Aldrich Chemical Company) in EtOH and H ₂ O. The mixture is acidified and the precipitate obtained is separated to give the title compound as an amorphous orange solid.

Mass spectrum: (+ FAB, 3-nitrobenzyl alcohol) 878 (MH &lt; + &gt;)

Example 8 (175)

Synthesis of N- (toluene-4-sulfonyl) -L-propyl-4-[(N-tert-butoxycarbonylgylsil) amino] -L-phenylalanine methyl ester

N- (toluene-4-sulfonyl) -L-prolyl-L- (4-nitro) phenylalanine methyl ester (2.00 g, 4.48 mmol) is dissolved in MeOH (10 mL) with a catalytic amount of 10% Pd on carbon. . Hydrogenate at room temperature for 12 hours at 40 psi. The reaction mixture is filtered over celite and the solvent is evaporated under reduced pressure to give a pink blowing agent in quantitative yield. The title compound is prepared therefrom with N-Boc glycine using the method described in Method 12.

NMR data are 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 = 8.37Hz), 5.40 (m, 1H), 4.82 (m, 1H), 4.07 (m, 1H), 3.91 (s, 2H), 3.76 (s, 3H), 3.40 (m, 1H ), 3.23 (m, 1H), 3.05 (m, 2H), 2.43 (s, 3H), 2.43 (m, 1H), 1.46 (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, 120.53, 80.50, 62.81, 54.00, 53.08, 50.25, 37.25, 37. 30.42, 28.93, 28.87, 24.81, 22.14.

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

Example 9 (306)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-methylphenyl) ureido] acetamido} -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) phenylalanine is reacted with 2- (3-m-tolyl-ureido) acetic acid (BOP, triethylamine, DMF) Prepare methyl ester (stirr overnight at room temperature). The crude product is purified by flash chromatography (silica. 9: 1 EtOAc: hexanes) to afford methyl esters. The methyl ester is hydrolyzed using 1M LiOH in THF. The title compound is separated as an acid / base workup as a white solid.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 12.8 (br s, 1H); 9.96 (s, 1 H); 8.70 (s, 1 H); 8.04 (d, 1 H, 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, 1 H); 7.16 (d, 3H, J = 8.56 Hz); 7.08 (t, 1 H, J = 7.79 Hz); 6.7 (d, 1 H, J = 7.68 Hz); 6.38 (t, 1 H, J = 5.6 Hz); 4.43 (m, 1 H); 4.1 (dd, 1H, J = 3.18, 8.23 Hz); 3.89 (d, 2H, J = 5.49 Hz); 3.3 (m, 1 H); 3.05 (m, 2 H); 2.92 (dd, 1H, J = 8.34, 13.63 Hz); 2.38 (s, 3 H); 2.22 (s, 3 H); 1.38-1.62 (m, 4 H).

IR (KBr, cm ^−! ): 3380, 2990, 1650, 1605, 1540, 1230, 1155, 660, 580, 545.

Mass spectrum: ((+) FAB, m / e (%)) 644 (100 [M + Na] &lt; + &gt;); 622 (25 [M + H] &lt; + &gt;).

Example 10 (380)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (L-aspartyl) amino] -L-phenylalanine

Boc-L-aspartic acid benzyl ester is used in place of Boc-glycine according to the process of Examples 1 (2) and 2 (7) to afford the title compound as a white solid. Melting Point: 163-170 ℃

NMR data are 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 spectrum: (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) is dissolved in dry DMF (50 ml) at room temperature. To this is added K ₂ CO ₃ (1.1 equiv, 440 mg) and ethyl α-bromophenyl acetate (1.1 equiv, 750 mg). The reaction is stirred for 12 hours at room temperature. Ethyl acetate (100 ml) is added and the organic layer is washed several times with brine. The organic layer is dried over MgSO ₄ . The solvent was filtered and evaporated under reduced pressure to separate the residue and then dissolved in MeOH 1: 1 (30 ml) with NaOH (1.1 equiv, 427 mg). The desired diacids are separated in 88% yield (754 mg, 1.33 mmol).

NMR data are 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 = 8.37 Hz), 5.48 (s, 1H), 4.51 (m, 1H), 3.87 (m, 1H), 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, 129.00, 117.18, 79.95, 63.94, 55.31, 38.00, 38.00. , 25.88, 22.32, 15.22.

Mass spectrum: (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 acidified by treatment with NaOH in dioxane and water, extracted, dried over MgSO ₄ , filtered and evaporated to afford the title compound as a clear oil.

NMR data are as follows:

¹ H NMR (CD ₃ OD w / CD ₃ ONa, 300 MHz): δ = 7.75 (d, J = 8.2, 2H), 7.44-7.40 (m, 5H), 7.29-7.21 (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, 3 H).

¹³ C NMR (CD ₃ OD w / 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 spectrum: (+ FAB, Glycerol) 537 (MH &lt; + &gt;).

Example 13 (178)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (methoxycarbonyl) phenyl] -L-phenylalanine benzyl ester

L-4-iodinephenylalanine [Phe (4-I) -OH] was evaporated by treatment with MeOH and HCl gas, followed by HCl. Obtain Phe (4-I) -OMe. The product was treated with N- (toluene-4-sulfonyl) -L-Pro-OH, EDAC, HOBT and Et ₃ N in DMF and aqueous treatment followed by N- (toluene-4-sulfonyl) -L-Pro- Obtain L-Phe (4-I) -OMe. The product was converted to 2- (methoxycarbonyl) phenylzinc iodide and Pd (PPh ₃ ) ₄ prepared by the method of Rieke (J. Org. Chem. 1991, 56, 1445) in THF. Treatment is followed by aqueous workup and flash chromatography to afford the title compound as a clear oil.

NMR data are 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), 4.11-4.07 (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), 2.09-2.04 (m, 1H), 1.58-1.45 (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, 131.2, 130.8, 130.6, 129.9, 129.7, 129.0, 128.4, 127.8, 127.1, 62.2, 53.3, 52.5, 52.0, 49.7, 37.6, 29.7, 24.2, 21.5.

Mass spectrum: (+ FAB, 3-nitrobenzyl alcohol) 565 (MH &lt; + &gt;).

Example 14 (35)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbenzyloxyamino) ethyl] amino} -L-phenylalanine

The product of Example 15 (172) (32 mg, 0.051 mmol) was dissolved in MeOH: H ₂ O 1: 1 (1 ml) in NaOH (1.1 equiv., 3 mg) according to the experimental method described in the synthesis of Example 3 (23). Hydrolyze using The title material is separated into quantitative material as blowing agent.

NMR data are 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, 1H), 3.12 (m, 2H), 2.78 (s, 1.5H), 2.54 (s, 1.5H), 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, 54.00, 53.77, 38.32, 32.19, 31.96, 22.24, 14.76.

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

Example 15 (172)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbenzyloxyamino) ethyl] amino} -L-phenylalanine methyl ester

N- (toluene-4-sulfonyl) -L-prolyl-Lp-amino-phenylalanine methyl ester (316 mg, 0.7 mmol) was added to NaCNBH ₃ (10.0 equiv, 446 mg) and carbobenzyloxy-glycinal (1.1 equiv) With a solution of KOAc-HOAc in anhydrous methanol (10 ml) [pH 6.5]. The reaction mixture is stirred overnight at room temperature and the solvent is evaporated under reduced pressure. EtOAc is added and the organic layer is washed with brine and dried over MgSO ₄ . The solvent is filtered off and evaporated before the crude material is eluted in a preliminary plate (silica gel, EtOAc / hexane 1: 1). The desired title compound is isolated as a film in 5% yield (40 mg, 0.06 mmol).

NMR data are as follows:

¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.71 (d, 2H, J = 6.90 Hz), 7.38 (m, 5H), 7.26 (m, 2H), 6.93 (d, 2H, J = 7.20 Hz), 6.54 (d, 2H, J = 7.50 Hz), 5.12 (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 spectrum: (FAB) 623 (M + H).

Example 16 (368)

N- (toluene-4-sulfonyl) -L-prolyl-L-4- {N- [3- (N, N-dimethylamino) propyl] -N- [trifluoromethanesulfonyl] amino}- Synthesis of L-phenylalanine Methyl Ester

The corresponding trifluoromethane sulfonamides are prepared by reacting N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) phenylalanine methyl ester with trifluoromethane sulfonyl anhydride in pyridine. . The compound is alkylated on the nitrogen of the trifluoromethane sulfonamide group using 3-dimethylamino-1-propanol in THF under Mitsunobu conditions. The product is obtained as a solid by evaporation of the solvent and washing with aqueous, followed by filtration and purification of the mixture. Melting point: 45-55 ° C

NMR data are as follows:

¹ H NMR (CDCl ₃ , 400 MHz): δ = 7.70 (d, 2H); 7.34 (d, 3 H); 7.25 (m, 3 H); 4.88 (m, 1 H); 4.10 (m, 1 H); 3.85 (brd s, 2 H); 3.79 (s, 3 H); 3.32 (m, 2 H); 3.08 (m, 2 H); 2.43 (s, 2 H); 2.18 (brd s, 5 H); 1.98 (brd s, 1 H); 1.75-1.30 (brd m, 9H).

IR (KBr, cm-1): 3400; 2970; 2800; 1750; 1675; 1525; 1450; 1400; 1350; 1225; 1200; 1165; 1150; 1100; 1075; 1000; 950; 825; 675; 600; 550.

Mass spectrum: (+ FAB) 663 ([M + H] &lt; + &gt;);603;507;438;306;191;155; 91.

Example 17 (510)

Synthesis of 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-aminobenzyl-L-phenylalanine to 4-N, N-dimethylaminobenzaldehyde (acetic acid, sodium triacetoxyborohydride, methylene chloride Reductive amination with) and stirring overnight at room temperature to prepare the methyl ester. The crude product is purified by flash chromatography to afford methyl ester and hydrolyzed according to method 6 to afford the title compound.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.7 (d, 2H, J = 8.34 Hz); 7.54 (d, 1 H, J = 5.71 Hz); 7.40 (d, 1 H, J = 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); 6.48 (d, 2H, J = 8.78 Hz); 4.39 (s, 4 H); 3.92 (dd, 1H, J = 2.85, 9.0 Hz); 3.78 (m, 1 H); 3.33 (s, 12 H); 2.86 (m, 4 H); 2.39 (s, 3 H); 1.62 (m, 1 H); 1.30 (m, 1 H); 1.09 (m, 2 H).

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

MS ((+) FAB, m / e (%)) 698 (20 [M + H] ⁻ ).

Elemental Analysis for C ₃₉ H ₄₆ N ₅ O ₅ Li3H ₂ O:

Calc .: C, 61.76; H, 6.91; 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) are dissolved in THF (200 ml) and cooled in an ice bath. Diethyl azodicarboxylate (16.2 g, 14.6 mL, 92.9 mmol) was added dropwise via syringe for 5 minutes and stirred for an additional 10 minutes, followed by cannula as a solution in 100 mL of THF as N-Boc-tyrosine methyl ester ( 24.9 g, 94.5 mmol) is added. The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 19 hours. The mixture is concentrated on a rotary evaporator and dissolved in Et ₂ O (500 ml). The mixture is extracted with 0.2N HCl (3 × 350 ml) and the combined acidic extracts are basified with solid NaHCO ₃ . The mixture was extracted with EtOAc (3 × 300 ml) and the combined extracts were dried over Na ₂ SO ₄ , vacuum filtered and evaporated to give N-Boc-L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester (26.5 g). , 82%).

N-Boc-L-4- (3-N, N-dimethylaminopropyloxy) phenylalanine methyl ester (26.5 g, 69.5 mmol) is dissolved in MeOH (300 ml) and saturated with HCl gas. The mixture is stirred for 3 hours and the distillate is removed under vacuum to give L-4- (3-N, N-dimethylaminopropyloxy) phenylalanine methyl ester dihydrochloride (23.6 g, 90%).

Couple N- (toluene-4-sulfonyl) -L-proline hydrate with L-4- (3-N, N-dimethylaminopropyloxy) -phenylalanine methyl ester dihydrochloride using the method described in Method 13. Ringing yields N- (toluene-4-sulfonyl) -L-prolyl-L-4- (3-N, N-dimethylaminopropyloxy) phenylalanine methyl ester (16.3 g, 89%). The title compound (14.71 g, 99%) is prepared via hydrolysis of the methyl ester with 0.5N NaOH in THF / water.

NMR data are 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 = 8.2 Hz), 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, 30.5, 27.3, 23.9, 21.4.

Mass spectrum: FAB m / e 562 (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 dissolved in L-4- (3-dimethylamino-propyloxy) phenylalanine methyl ester hydro according to the method described in Method 13. With chloride salt (see Example 18 (138) for preparation) (1.0 g, 2.4 mmol), HOBT (1.1 equiv, 356 mg), Et ₃ N (3.2 equiv, 1.1 ml) and EDC (1.1 equiv, 500 mg) Dissolve in DMF (100 ml). The title compound is isolated as an oil in 70% yield (900 mg, 1.7 mmol).

NMR data are 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 = 8.70Hz), 6.82 (d, 2H, J = 8.70Hz), 4.71 (m, 1H), 4.43 (m, 1H), 3.94 (t, 2H, J = 6.60Hz), 3.75 ( s, 3H), 3.69 (m, 1H), 3.51 (m, 1H), 3.14 (m, 1H), 2.91 (m, 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, 56.87, 54.01, 53.08, 45.95, 37.39, 31.85, 27.91, 27.91, 27.91 22.13.

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

Example 20 (284)

Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine

Triphenylphosphine (1.1 equiv) and 3-dimethylamino-1-propanol (1 equiv) are dissolved in THF and cooled in an ice bath. Diethyl azodicarboxylate (1 equiv) was added dropwise via syringe for 5 minutes and stirred for an additional 10 min before adding N-Boc-tyrosine methyl ester (1.02 equiv) as a solution in 100 ml THF via cannula. . The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 19 hours. The mixture is concentrated on a rotary evaporator and dissolved in Et ₂ O (500 ml). The mixture is extracted with 0.2N HCl (3 × 350 ml) and the combined acidic extracts are basified with solid NaHCO ₃ . The mixture was extracted with EtOAc (3 × 300 ml) and the combined extracts were dried over Na ₂ SO ₄ , filtered under vacuum and evaporated to afford N-Boc-L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester do.

N-Boc-L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester (26.5 g, 69.5 mmol) is dissolved in MeOH (300 ml) and saturated with HCl gas. The mixture is stirred for 3 hours and the distillate is removed under vacuum to give L-4- (3-dimethylaminopropyloxy) 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 di using the method described in Method 13. Coupling with hydrochloride to form N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -L-4- (3-dimethylaminopropyloxy) phenylalanine methyl ester (16.3 g, 89%) To obtain. The title compound is prepared via hydrolysis of the methyl ester with 0.5N NaOH in THF / water to give a solid. Melting Point:> 200 ° C (Decomposition)

NMR data are 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, 132.5, 135.4, 146.7 , 159.5, 170.9, 178.2.

Mass spectrum: (FAB +) 586 (M + H)

HPLC analysis: (microadsorption-MV C18 reverse phase, 4.6 × 150 mm; 1: 1 CH ₃ CN / H ₂ O with serpentine gradient 0.05% TFA; flow rate = 10 ml / min; l = 254 nm; sample volume = 20 ml) Development # 1: retention time of 2.988 minutes (100.0% purity) Development # 2: 3.098 minute residence time (100.0% purity).

Example 21 (287)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-dimethylamino) ethoxy] -L-phenylalanine

The title compound is prepared according to Example 20 (138), except that 2-dimethylaminoethanol is used instead of 3-dimethylamino-propanol.

NMR data are 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, J = 8.0 Hz), 7.01 ( d, 2H, J = 7.9 Hz), 6.71 (d, 2H, J = 7.8 Hz), 3.95 (m, 4H), 3.14-2.98 (4H), 2.57 (t, 2H, J = 5.6 Hz), 2.40 ( s, 3H), 2.18 (s, 6H), 1.74 (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 spectrum: FAB m / e 504 (M + H).

Example 22 (317)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N-ethyl-N-phenylamino) ethoxy] -L-phenylalanine methyl ester

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl in 2-butanone refluxed in the presence of potassium carbonate and sodium iodide with 2- (N-ethyl, N-phenyl) aminoethyl chloride Methyl esters are prepared by O-alkylation of the esters. The title compound is prepared using the method described in Method 7.

NMR data are 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 (3 H, m); 2.19 (3H, s); 2.85-3.0 (2H, m); 3.12 (1H, doublet of doublets, J = 6,10, 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, doublet of doublets, J = 7,6,7 Hz); 6.55 (1H, t, J = 8, 8 Hz); 6.65 (2H, doublet, J = 10 Hz); 6,8 (2H, doublet, J = 10 Hz); 7.1 (4H, m); 7.38 (2H, doublet, J = 10 Hz); 7.64 (2H, doublet, J = 10 Hz); 8,1 (1H, d, J = 10 Hz).

MS: + FAB, m / z 594 ([MH] &lt; + &gt;, 45%), 157 (100%)

Example 23 (321)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-diisopropylamino) ethoxy] -L-phenylalanine

O-alkylated N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2-diisopropylaminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide Prepare methyl ester. The title compound is prepared as a solid using the method described in Method 7. Melting Point: 121-124 ° C

NMR data are 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 (1 H, m); 2.38 (3 H, s); 2.7 (2H, t, J = 8, 8 Hz); 2.9 (2H, m); 3.0 (2H, q, J = 5, 5, 5 Hz); 3.1 (1H, doublet of doublets, J = 3,4,3 Hz); 3.35 (1 H, s); 3.78 (1H, t, J = 7, 7 Hz); 3.8 (2H, t, J = 5, 5 Hz); 3.95 (1H, doublet, J = 10 Hz); 6.5 (1H, doublet, J = 10 Hz); 6.65 (1H, doublet, J = 10 Hz); 6.85 (1H, doublet, J = 10 Hz); 6.9 (1H, doublet, J = 10 Hz); 7.4 (2H, doublet, J = 10 Hz); 7.62 (1 H, m); 7.75 (2H, doublet, J = 10 Hz).

MS: + FAB, m / z 560 ([MH] &lt; + &gt;, 70%), 154 (100%)

Example 24 (333)

Synthesis of N- (thiophene-2-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

Method 15 is used to prepare the title compound and separate as a white hygroscopic solid. Melting Point:> 200 ℃

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 8.03 (br s, 1H); 7.74 (m, 2 H); 7.26 (br s, 1 H); 7.04 (d, 2H, J = 7.0 Hz); 6.75 (d, 2H, J = 6.0 Hz); 4.16 (m, 1 H); 4.06 (m, 1 H); 3.85 (m, 2 H); 3.33 (m, 1 H), 3.13-3.00 (br m, 3 H); 2.62 (m, 2 H); 2.35 (s, 3 H); 1.90 (m, 2 H); 1.75 (m, 1 H); 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, 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 spectrum: (PI-FAB) 532, (M) ⁺ .

Example 25 (334)

Synthesis of N- (5-chlorothiophen-2-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

Method 15 is used to prepare the title compound and separate as a white, hygroscopic solid. Melting Point:> 200 ℃

NMR data are as follows:

¹ NMR (DMSO-d _{6 ′} 300 MHz): δ = 7.62 (m, 2H); 7.74 (m, 2 H); 6.99 (m, 2 H); 6.71 (m, 2 H); 6.71 (m, 2 H); 4.05 (m, 1 H); 3.92 (m, 3 H); 3.26 (m, 1 H); 3.09-2.97 (br m, 3H); 2.30 (m, 2 H); 2.13 (s, 6 H); 1.82 (m, 2 H); 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 spectrum: (PI-FAB) 588, (M + Na) ⁺ .

Example 26 (336)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (N, N-diethylamino) ethoxy] -L-phenylalanine

O-alkylated N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2-diethylaminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide To prepare the ester. The title compound is prepared as a solid using the method described in Method 7. Melting point: 105 to 109 ° C.

NMR data are 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 (2 H, m); 2.18 (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, doublet of doublets, J = 5,4,5 Hz); 3.9 (2H, t, J = 3, 3 Hz); 4.1 (1H, doublet, J = 8 Hz); 6.68 (2H, doublet, J = 10 Hz); 6.95 (2H, doublet, J = 10 Hz); 7.05 (2H, doublet, J = 10 Hz); 7.4 (2H, doublet, J = 10 Hz); 7.63 (1H, doublet, J = 4 Hz); 7.73 (2H, t, J = 4, 4 Hz).

MS: + ESI, m / z 532.4 ([M−H] &lt; + &gt;, 100%).

Example 27 (340)

Synthesis of N- (2,5-dichlorothiophen-3-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

Method 15 is used to prepare the title compound and separate as a white hygroscopic solid. Melting Point:> 200 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 300 MHz): δ = 7.77 (d, 1H, J = 6.6 Hz); 7.43 (s, 1 H); 7.07 (d, 2H, J = 7.4 Hz); 6.76 (d, 2H, J = 7.4 Hz); 4.33 (m, 1 H); 4.15 (m, 1 H); 3.89 (t, 2H, J = 6.1 Hz); 3.29 (m, 2 H); 2.97 (m, 2 H); 2.57 (t, 2H, J = 7.1 Hz); 2.31 (s, 6 H); 1.85 (m, 4 H); 1.65 (m, 2 H).

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 spectrum: (PI-FAB) 600, (M) ⁺ .

Example 28 (341)

Synthesis of N- (1-methylpyrazole-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

N-methylpyrazole is added to chilled (0 ° C.) chlorosulfonic acid to prepare N-methylpyrazole sulfonyl chloride. The reaction mixture is warmed to room temperature and heated to 100 ° C. overnight under N ₂ stream. The reaction mixture is then cooled to room temperature and cooled to 0 ° C. Thionyl chloride (2.5 equiv) is added to the solution and the reaction is stirred at room temperature for 30 minutes and then warmed to 70 ° C. for 2 hours. The reaction is cooled to room temperature and cooled in an ice bath. Water and ice are slowly added to the reaction mixture to precipitate a white solid which is collected by filtration. The desired sulfonyl chloride is washed with cold water and hexanes. Method 15 is used to prepare the title compound and separate as a white hygroscopic solid. Melting Point:> 200 ℃

NMR data are as follows:

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

O-alkylated N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 3-diethylaminopropyl chloride in 2-butanone refluxed in the presence of potassium carbonate and sodium iodide To prepare the ester.

NMR data are 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, doublet of doublets, J = 8,10,8 Hz); 3.35 (1H, doublet of doublets, J = 8,4,8 Hz); 3.6 (3H, s); 3.94 (2H, t, J = 6.6 Hz); 4.1 (1 H, m); 4.48 (1H, doublet of doublets, J = 8,6,8 Hz); 6.8 (2H, doublet, J = 10 Hz); 7.1 (2H, doublet, J = 10 Hz); 7.4 (2H, doublet, J = 10 Hz); 7.7 (2H, doublet, J = 10 Hz); 8.2 (1H, doublet, J = 10 Hz).

MS: + ESI, m / z 560.5 ([M−H] &lt; + &gt;, 100%).

Example 30 (351)

Synthesis of N- (thiazole-2-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

Sulfonyl chlorides are prepared from thiols as taught in Roblin and Clapp, JACS, 72, 4890, 1950. The title compound is prepared using Method 15 and separated as a white hygroscopic solid. Melting point:> 200 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 8.24 (d, 1H, J = 3.1 Hz); 8.15 (d, 1 H, 3.1 Hz); 7.63 (d, 1 H, J = 5.0 Hz); 6.98 (d, 2H, J = 8.6 Hz); 6.70 (d, 2H, J = 8.6 Hz); 4.24 (m, 1 H); 3.88 (m, 3 H); 3.36 (m, 2 H); 3.28-2.98 (m, 2 H); 2.31 (t, 2H, J = 7.0 Hz); 2.12 (s, 6 H); 1.83-1.79 (br m, 4H); 1.79 (m, 1 H); 1.45 (m, 1 H).

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 spectrum: (PI-FAB) 555, (M-H + Na) ⁺ .

Example 31 (353)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N-methyl-N-benzylamino) propoxy] -L-phenylalanine

The title compound is prepared as a solid from the product of Example 33 (356) using the method described in Method 7. Melting point: 87-90 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 7.75 (d, 2H, J = 10 Hz); 7.65 (d, 1 H, J = 4 Hz); 7.4 (d, 2H, J = 10 Hz); 7.18-7.3 (m, 5 H); 6.96 (d, 2H, J = 10 Hz); 6.65 (d, 2H, J = 10 Hz); 3.97 (d, 1 H, J = 4 Hz); 3.91 (t, 2H, J = 4,4 Hz); 3.8 (q, 1H, J = 2,2,2 Hz); 3.42 (s, 2 H); 2.95-3.1 (m, 4 H); 2.42 (t, 2H, J = 8,8 Hz); 2.38 (s, 3 H); 2.08 (s, 3 H); 1.85 (t, 2H, 6,6 Hz); 1.7 (m, 1 H); 1.3 (bs, 4 H).

Example 32 (354)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (N, N-diethylamino) propoxy] -L-phenylalanine

The title compound is prepared as a solid from the product of Example 29 (346) using the method described in Method 7. Melting point: 76 to 82 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 1.0 (6H, t, J = 8,8 Hz); 1.38 (2H, m); 1.4-1.8 (4H, m); 2.38 (3 H, 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, doublet of doublets, J = 5,5,5 Hz); 3.15 (1H, doublet of doublets, J = 4,5,4 Hz); 3.9 (2H, t, J = 5, 5 Hz); 4.0 (1H, t, J = 6.6 Hz); 4.1 (1 H, m); 6.7 (2H, doublet, J = 10 Hz); 6.95 (2H, doublet, J = 10 Hz); 7.4 (2H, doublet, J = 10 Hz); 7.7 (1H, doublet, J = 4 Hz); 7.75 (2H, doublet, 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

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl as 3- (N-benzyl, N-methyl) aminopropyl chloride in 2-butanone refluxed in the presence of potassium carbonate and sodium iodide O-alkylation of the ester affords the title compound as a solid. Melting point: 60-70 ° C.

Example 34 (372)

Synthesis of N- (1-methylimidazole-4-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

Method 15 is used to prepare the title compound and separate as a white hygroscopic solid. Melting Point:> 200 ℃

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 300 MHz): δ = 7.86 (s, 1H); 7.82 (s, 1 H); 7.63 (d, 1 H, J = 5.6 Hz); 6.96 (d, 2H, J = 8.2 Hz); 6.97 (d, 2H, J = 8.2 Hz); 4.12-4.09 (br m, 1 H); 3.89 (t, 2H, J = 6.5 Hz); 3.70 (s, 3 H); 3.13 (m, 2 H); 3.00 (m, 2 H); 2.33 (t, 2H, 7.2 Hz); 2.13 (s, 6 H); 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, 33.9, 30.6, 27.3, 24.0, 21.9.

Mass spectrum: (PI-FAB) 552, (M-H + Na) ⁺ .

Example 35 (373)

Synthesis of N- (2-methylthiadiazole-5-sulfonyl) -L-prolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

Sulfonyl chlorides are prepared from thiols as taught in Roblin and Clapp, JACS, 72, 4890, 1950. Method 15 is used to prepare the title compound and separate as a white hygroscopic solid. Melting Point:> 200 ℃

NMR data are as follows:

¹ H NMR (DMSOd 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, 1 H; 5.8 Hz); 3.96-3.89 (br m, 3H); 3.37-3.23 (br m, 2H); 3.02 (m, 1 H); 2.95 (m, 1 H); 2.82 (s, 3 H); 2.39 (t, 2H, J = 7.0 Hz); 2.13 (s, 6 H); 1,83 (m, 3 H); 1.80-1.40 (m, 3 H).

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, 30.9, 27.2, 24.1, 22.3, 15.9.

Mass spectrum: (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 is prepared as in Example 18 (138) except that L-thiaproline is used instead of L-proline.

NMR data are 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, 1 H), 2.99 (m, 2 H), 2.80 (m, 1 H), 2.55 (m, 2 H), 2.35 (m, 1 H); 2.25 (s, 6 H), 2.22 (s, 3 H), 1.79 (m, 2 H).

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, 52.92, 45.30, 38.33, 34.73, 27.94, 24.74, 22.16.

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

Example 37 (472)

Synthesis of N- (4-cyanobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine methyl ester

The title compound is prepared according to the method specified in the preparation method of Example 20 (284).

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), 6.80-6.77 (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 (CDCI ₃ ): δ = 179.9, 168.2, 158.8, 141.1, 133.7, 130.9, 128.1, 117.9, 115.2, 74.2. 66.7, 56.9, 55.3, 53.9, 53.0, 51.1, 46.0, 38.0, 29.9, 28.0, 24.4.

Example 38 (514)

Synthesis of N- (toluene-4-sulfonyl) -L- (thiamorpholine-3-carbonyl) -4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine

L-thiamorpholine-5-carboxylic acid was prepared by the method of Larsson and Carlson (Acta Chemica Scan. 1994. 48, 517-525) and using N- (toluene- 4-Sulfonyl) -L-thiamorpholine-5-carboxylic acid is prepared. The title compound is prepared according to the method specified in the preparation method of Example 20 (284).

NMR data are 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), 6.58-6.54 (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, 169.4, 159.6, 159.5, 146.3, 146.1, 138.9, 138.9, 132.8, 132.4, 131.8, 130.5, 129.8, 129.2, 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 sodium xylene (60% in oil, 1.1 equiv, 228 mg) in xylene (50 ml) at 0 ° C. Add to the suspension. The reaction mixture is stirred for 5 minutes and copper bromide dimethyl sulfide complex (1.4 equiv, 1.48 g) is added. The reaction mixture is stirred at 23 ° C. for 0.5 h. 2-iodo sodium benzoate (1.5 equiv, 8.06 mmol) is added and the reaction mixture is refluxed for 12 h. EtOAc (100 ml) is added and the organic layer is washed with NH ₄ Cl, 10% HCl and brine and dried over MgSO ₄ . The crude material is eluted on column chromatography (silica gel) with CHCl ₃ : MeOH 9: 1 and the title compound is separated as an oil.

NMR data are as follows:

¹ H NMR (300 MHz, CDCI 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, 3H), 2.05 (m, 1H), 1.55 (m, 3H).

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

Example 40 (309)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [4- (pyrimidin-2-yl) piperazin-1-yl] ethoxy} -L-phenylalanine

Methyl esters are prepared by Mitsunobu reaction of N- (toluene-4-sulfonyl) -L-propyl-L-tyrosine methyl ester according to the method described in the preparation method of Example 20 (284). The title compound is obtained as a solid using the method described in Method 7. Melting point: 102-105 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 1.35 (4H, s); 1.4 (1 H, m); 1.76 (1 H, m); 2.38 (3 H, s); 2.5 (2H, m); 2.66 (2H, t, J = 8, 8 Hz); 2.9-3.1 (4H, m); 3.68 (4H, t, J = 5, 5 Hz); 3.8 (1H, q, J = 4, 6, 4 Hz); 3.95 (1H, doublet of doublets, J = 2,10,2 Hz); 4.05 (2H, t, 6,6 Hz); 6.6 (1H, t, J = 5, 5 Hz); 6.7 (2H, doublet, J = 10 Hz); 6.96 (2H, doublet, J = 10 Hz); 7.4 (2H, doublet, J = 10 Hz); 7.65 (1H, doublet, J = 4 Hz); 7.74 (2H, doublet, J = 10 Hz); 8.35 (2H, doublet, J = 5 Hz).

Example 41 (310)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (piperidin-1-yl) propoxy] -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 1- (2-chloropropyl) piperidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide Alkylation to produce the methyl ester. The title compound is prepared as a solid using the method described in Method 7. Melting point: 122-125 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 7.74 (d, 2H, J = 10 Hz); 7.65 (d, 1 H, J = 4 Hz); 7.4 (d, 2H, J = 10 Hz); 6.96 (d, 2H, J = 10 Hz); 6.65 (d, 2H, J = 10 Hz); 3.96 (dd, 1H, J = 2,6,2 Hz); 3.9 (t, 3H, J = 7,7 Hz); 2.95-3.1 (m, 4 H); 2.46 (t, 1 H, J = 2,2 Hz); 2.38 (s, 3 H); 2.33 (t, 2H, J = 8,8 Hz); 2.24 (m, 2 H); 1.78 (m, 3 H); 1.45 (t, 4H, J = 5,5 Hz); 1.38 (m, 4 H).

Example 42 (311)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (pyrrolidin-1-yl) ethoxy] -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 1- (2-chloroethyl) pyrrolidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide Alkylation to produce the methyl ester. The title compound is prepared as a solid using the method described in Method 7. The title compound is prepared as a solid using the method described in Method 7. Melting point: 127 to 130 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 7.73 (d, 2H, J = 10 Hz); 7.65 (d, 1 H, J = 4 Hz); 7.4 (d, 2H, J = 10 Hz); 6.95 (d, 2H, J = 10 Hz); 6.65 (d, 2H, J = 10 Hz); 3.95 (t, 3H, J = 4,6 Hz); 3.7 (q, 1H, J = 2,4,2 Hz); 2.95-3.1 (m, 4 H); 2.72 (t, 2H, J = 6, 6 Hz); 2.48 (m, 3 H); 2.38 (s, 3 H); 1.74 (m, 1 H); 1.64 (t, 4H, J = 4, 4 Hz); 1.42 (m, 1 H); 1.37 (s, 3 H)

Example 43 (316)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {3- [4- (3-chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl with 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide Methyl esters are prepared by O-alkylating the -L-tyrosine methyl ester. The title compound is prepared as a solid using the method described in Method 7. Melting point: 116 to 118 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.74 (d, 2H, J = 10 Hz); 7.65 (d, 1 H, J = 4 Hz); 7.4 (d, 2H, J = 10 Hz); 7.2 (t, 1H, J = 8,8 Hz); 6.96 (d, 2H, J = 10 Hz); 6.9 (s, 1 H); 6.85 (d, 1 H, J = 10 Hz); 6.75 (d, 1 H, J = 10 Hz); 6.7 (d, 2H, J = 10 Hz); 3.95 (d, 2H, J = 8 Hz); 3.92 (t, 1 H, J = 8,8 Hz); 3.83 (q, 1 H, J = 5,4,5 Hz); 3.6 (t, 1 H, 5,5 Hz); 3.15 (t, 4H, J = 4.4 Hz); 2.95-3.1 (m, 4 H); 2.5 (m, 3 H); 2.45 (t, 2H, J = 8,8 Hz); 2.38 (s, 3 H); 1.84 (t, 2 H, J = 7,7 Hz); 1.75 (m, 1 H); 1.4 (q, 1H, J = 8,10,8 Hz); 1.35 (s, 2 H).

Example 44 (318)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(l-butoxycarbonylpiperidin-3-yl) methoxy] -L-phenylalanine methyl ester

Potassium carbonate N- (toluene-4-sulfonyl) -L-prolyl-O-[(1 -tert-butoxycarbonyl) -piperidin-3-yl) methyl] -L-tyrosine methyl ester And N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with N-Boc-3-piperidinemethyl tosylate in 2-butanone refluxed in the presence of sodium iodide. Prepared as a solid by alkylation. Melting point: 60-62 ° C.

The title compound is obtained as a solid from the product using the method described in Method 7. Melting point: 82-84 ° C

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 12.77 (br s, 1H); 8.00 (d, 1H, J = 7.9 Hz); 7.68 (d, 2H, J = 8.3 Hz); 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, 1 H); 4.10 (m, 1 H); 3.78 (m, 3 H); 3.07 (dd, 1H, J = 9.7, 4.1 Hz); 2.95 (dd, 1H, J = 19 Hz, 5.1 Hz); 2.90 (dd, 1H, J = 19 Hz); 2.8 (m, 2 H); 1.80 (m, 2 H); 1.58 (m, 4 H); 1.34 (br s, 14 H).

IR (KBr, cm ⁻¹ ): 3400, 2900, 1745, 1700, 1525, 1450, 1350, 1250, 1160, 850, 800, 700, 650, 600.

Mass spectrum: (FAB, m / e (%)) 652 (75, (M + Na ⁺ )); 530.2 (75); 224 (100).

Example 45 (322)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (morpholin-4-yl) ethoxy] -L-phenylalanine

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with N- (2-chloroethyl) morpholine was methylated (cesium carbonate, DMF) at 60 ° C. under argon for 72 hours to methyl Prepare esters. The product is purified by flash column chromatography (silica, EtOAc) to afford methyl ester as a gray blowing agent. The title compound is obtained as a solid using the method described in Method 6. Melting point: 99-101 ° C.

NMR data are as follows.

NB contains trace amounts of Tos-Pro-Phe (NMR).

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 7.73 (d, 2H, J = 8.6 Hz); 7.62 (d, 1 H, J = 5.5 Hz); 7.40 (d, 2H, J = 8.2 Hz); 6.69 (d, 2 H); 3.95 (m, 3 H); 3.8 (m, 1 H); 3.55 (m, 4 H); 3.1 (m, 3 H); 2.62 (t, 2H, J = 4 Hz); 2.4 (m, 4 H); 2.38 (s, 3 H); 1.7 (m, 2 H); 1.4 (m, 3 H).

IR (KBr, cm ⁻¹ ): 3400, 2950, 2850, 1610, 1510, 1425, 1340, 1245, 1150, 1125, 825, 800, 675, 575, 525.

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

Example 46 (325)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (piperidin-1-yl) ethoxy] -L-phenylalanine

A methyl ester was prepared by reacting N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with piperidineethanol according to the method described in the preparation method of Example 20 (284). do. The title compound is prepared as a solid using the method described in Method 7. Melting point: 102-106 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.73 (d, 2H, J = 8 Hz); 7.60 (d, 1 H, 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, 3 H); 3.84 (dd, 1H, J = 5.2, 4.8 Hz); 2.97-3.10 (m, 4 H); 2.56 (t, 2H, J = 5.9 Hz); 2.38 (br s, 6 H); 1.72 (m, 1 H); 1.34-1.48 (m, 10 H).

IR (KBr, cm ⁻¹ ): 3400, 2900, 1660, 1610, 1510, 1450, 1350, 1150, 875, 675, 600, 550.

Mass spectrum: (FAB, m / e (%)) 542 (100, (M ⁻ H)): 196 (10); 155 (75).

Example 47 (326)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- {3- [4- (3-chlorophenyl) piperazin-1-yl] propoxy} -L-phenylalanine methyl ester

N- (toluene-4-sulfonyl-L-prop with 1- (2- (chlorophenyl) -4- (3-chloropropyl) piperidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide Methyl esters are prepared by O-alkylating the Rollyl-L-tyrosine methyl ester.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 8.2 (d, 1H, J = 10 Hz); 7.68 (d, 2H, J = 10 Hz); 7.4 (d, 2H, J = 10 Hz); 7.19 (t, 1 H, J = 8,8 Hz); 7.13 (d, 2H, J = 10 Hz); 6.9 (s, 1 H); 6.85 (d, 1 H, J = 10 Hz); 6.82 (d, 2H, J = 10 Hz); 6.75 (d, 1 H, J = 10 Hz); 4.45 (q, 1H, J = 8,5,8 Hz); 4.08 (t, 1 H, J = 4,4 Hz); 3.94 (t, 2H, J = 5,5 Hz); 3.3 (s, 3 H); 3.12 (bs, 4 H); 3.1 (t, 1H, J = 8.8 Hz); 2.96 (m, 2 H); 2.47 (m, 3 H); 2.38 (s, 3 H); 1.85 (t, 2H, J = 6, 6 Hz); 1.57 (m, 3 H); 1.4 (m, 1 H).

MS: EI, m / z 682/684 ([M−H] &lt; + &gt;, 18%), 209 (26%).

Example 48 (327)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azpan-1-yl) ethoxy] -L-phenylalanine

The title compound is prepared as a solid from the product of Example 49 (328) using the method described in Method 7. Melting point: 105-107 ° C.

NMR data are as follows

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.75 (t, 2H, J = 8,8 Hz); 7.45 (d, 1 H, J = 8 Hz); 7.4 (t, 2 H, J = 8,8 Hz); 7.05 (d, 1 H, J = 10 Hz); 6.96 (d, 1 H, J = 10 Hz); 6.7 (d, 1 H, J = 10 Hz); 4.1 (t, 1H, J = 5,5 Hz); 3.92 (t, 3H, J = 8,8 Hz); 3.82 (m, 1 H); 3.6 (t, 1 H); 2.8 (t, 2H, J = 6,6 Hz); 2.66 (d, 4H, J = 5 Hz); 2.5 (d, 3H, J = 10 Hz); 1.76 (t, 1 H, 7, 7 Hz); 1.65 (m, 1 H); 1.5 (bs, 6H); 1.43 (t, 2H, J = 8,8 Hz); 1.36 (m, 2 H); 1.28 (s, 1 H); 1.15 (s, 1 H).

Example 49 (328)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azpan-1-yl) ethoxy] -L-phenylalanine methyl ester

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2- (hexamethylene-imino) ethyl chloride in 2-butanone refluxed in the presence of potassium carbonate and sodium iodide Alkylation to give the title compound as a solid. Melting point: 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

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 3- (N-methylpiperazin) propyl chloride in 2-butanone refluxed in the presence of potassium carbonate and sodium iodide Alkylation to produce the methyl ester.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 8.2 (t, 1H, J = 10, 10 Hz); 7.7 (t, 2H, J = 10, 12 Hz); 7.4 (d, 2H, 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, 3 H); 3.08 (q, 1H, J = 6, 4, 4 Hz); 3.0 (dd, 1H, J = 12, 4, 4 Hz); 2.9 (m, 2 H); 2.38 (s, 3 H); 2.2-2.35 (m, 10 H); 2.12 (s, 3 H); 1.8 (t, 2H, J = 6, 6 Hz); 1.55 (m, 3 H); 1.41 (m, 1 H).

MS: + ESI, m / z 587 ([M−H] &lt; + &gt;, 100%).

Example 51 (355)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (4-methylpiperazin-1-yl) propoxy] -L-phenylalanine

The title compound is prepared as a solid from the product of Example 50 (347) using the method described in Method 7. Melting point: 80-83 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 7.75 (d, 2H, J = 10 Hz); 7.63 (d, 1 H, J = 4 Hz); 7.4 (d, 2H, J = 10 Hz); 7.05 (d, 2H, J = 10 Hz); 6.95 (d, 2H, J = 10 Hz); 6.67 (d, 2H, J = 10 Hz); 4.1 (d, 1H, J = 8 Hz); 3.94 (d, 1 H, J = 8 Hz); 3.9 (t, 2H, J = 5,5 Hz); 3.8 (bs, 1 H); 3.08 (m, 1 H); 2.91 (d, 1 H, J = 10 Hz); 2.85 (dd, 2H, J = 6, 18, 6 Hz); 2.38 (s, 3 H); 2.15-2.35 (m, 8 H); 2.14 (s, 3 H); 1.78 (q, 2H, J = 6,8,6 Hz); 1.7 (m, 1 H); 1.4 (m, 1 H); 1.37 (m, 2 H).

Example 52 (345)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine methyl ester

The title compound is prepared as a solid by reacting trifluoromethanesulfonic anhydride with N- (toluene-4-sulfonyl) -L-prolyl- (4-amino) phenylalanine methyl ester in pyridine. Melting point: 75-78 ° C.

Example 53 (370)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-N- (trifluoromethanesulfonyl) amino-L-phenylalanine

The title compound is prepared from the product of Example 52 (345) using the method described in Method 6.

NMR data are as follows:

¹ H NMR (CDCl ₃ , 400 MHz): δ = 8.08 (s, 1H); 7.7 (d, 2 H); 7.56 (d, 1 H); 7.34 (d, 2 H); 7.22 (s, 2 H); 4.85 (m, 1 H); 4.16 (m, 1 H); 3.40 (m, 3 H); 3.09 (m, 2 H); 2.44 (s, 3 H); 1.86 (m, 1 H); 1.50 (m, 3 H).

IR (KBr, cm ⁻¹ ): 3390; 2950; 1750; 1650; 1525; 1425; 1375; 1340; 1200; 1150; 950; 825; 625; 590; 550.

Mass spectrum: (+ ESI) 564 ([M + H] &lt; + &gt;);530;462;406;362;342;335; 157.

Example 54 (387)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-benzylaminocarbonyl) methoxy] -L-phenylalanine methyl ester

Alkylation of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with N-benzyl-2-chloroacetamide with potassium carbonate under argon overnight, Sodium iodide, refluxing butanone) to afford the title compound. The product is purified by flash column chromatography (silica, 1: 1 hexanes: EtOAc) to give methyl ester as a white solid. Melting point: 57-59 ° C.

Example 55 (389)

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

The title compound is prepared as a solid from the product of Example 4 (387) using the method described in Method 6. Melting point: 79-81 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.2 (br s, 1H); 8.60 (t, 1 H); 8.03 (d, 1 H, J = 7.9 Hz); 7.70 (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, 2 H); 4.42 (m, 1 H); 4.31 (d, 2H, J = 6.3 Hz); 4.10 (m, 1 H); 3.0-3.2 (m, 2 H); 2.8-2.9 (m, 2 H); 2.38 (s, 3 H); 1.2-1.6 (m, 4 H).

IR (KBr, cm ⁻¹ ): 3400, 2950, 1725, 1660, 1525, 1510, 1450, 1350, 1240, 1150, 1080, 670, 575, 550.

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

Example 56 (390)

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

Flash column chromatography (silica, 1) by alkylating N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine ester with tert-butyl bromoacetate (potassium carbonate under argon for 72 hours, DMF) After purification with: 1 hexanes: EtOAc), N- (toluene-4-sulfonyl) -L-prolyl-LO- (tert-butoxycarbonylmethyl) -tyrosine methyl ester is obtained as a white solid. Melting point: 55 ° C.

N- (toluene-4-sulfonyl) -L-prolyl-LO- (tert-butoxycarbonylmethyl) -tyrosine to N- (toluene-4-sulfonyl) using the method described in Method 6 Prepared from -L-prolyl-LO- (tert-butoxycarbonylmethyl) -tyrosine methyl ester. Melting point: 69-70 ° C.

The title compound is prepared from N- (toluene-4-sulfonyl) -L-prolyl-L-O- (tert-butoxycarbonylmethyl) -tyrosine by reaction with formic acid. The formic acid is removed and triturated with ether to give the desired compound as a white solid. Melting point: 70-73 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 12.85 (br s, 2H); 8.01 (d, 1 H, J = 7.9 Hz); 7.69 (d, 2H, J = 8.3 Hz); 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, 2 H); 4.42 (m, 1 H); 4.10 (m, 1 H); 3.08 (m, 1 H); 2.95 (m, 2 H); 2.38 (s, 3 H); 1.5 (m, 4 H).

IR (KBr, cm ⁻¹ ): 3350, 2950, 1730, 1625, 1510, 1425, 1340, 1175, 1160, 1075, 825, 675, 575, 550.

Mass spectrum: (FAB, m / e (%)) 513 (100, (M + Na ⁺ )), 491 (75, (M + H ⁺ )).

Example 57 (407)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(aminocarbonyl)]-L-phenylalanine methyl ester

N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2-chloroacetamide (potassium carbonate, sodium iodide, butanon refluxed under argon for 48 hours) to give the title compound Manufacture. The product is purified by flash column chromatography (silica, EtOAc, 5% MeOH in EtOAc) to afford the title compound as a white solid. Melting point: 60 to 64 ° C.

Example 58 (408)

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

The title compound is obtained as a solid from the product of Example 57 (407) using the method described in Method 6. Melting point: 195-196 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₅ , 400 MHz): δ = 12.2 (br s, 1H); 8.02 (d, 1 H, J = 8.1 Hz); 7.69 (d, 2H, J = 8.3 Hz); 7.47 (br s, 1 H); 7.40 (d, 2H, J = 7.9 Hz); 7.35 (br s, 1 H); 7.14 (d, 2H, J = 8.6 Hz); 6.84 (d, 2H, J = 8.6 Hz); 4.40 (m, 1 H); 4.35 (s, 2 H); 4.11 (dd, 1 H); 3.09 (m, 1 H); 2.91 (dd, 1 H); 2.39 (s, 3 H); 1.45-1.55 (m, 3 H); 1.40 (m, 1 H).

IR (KBr, cm ⁻¹ ): 3500, 3350, 3250, 2950, 1725, 1675, 1660, 1560, 1510, 1450, 1400, 1350, 1225, 1200, 1150, 1050, 825, 660, 575, 550.

Mass spectrum: (FAB, m / e (%)) 488 (100, (MH) ⁻ )).

Example 59 (409)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butylaminocarbonyl) methoxy] -L-phenylalanine

Alkylating N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester with 2-chloro-N-tert-butylacetamide (potassium carbonate and sodium iodide in butanone refluxed under argon overnight) To prepare a methyl ester. The product is purified by flash column chromatography (silica, 1: 1 hexanes: EtOAc) to give methyl ester as a white solid. The title compound is obtained as a solid using the method described in Method 6. Melting point: 88-89 ° C.

NMR data are as follows:

¹ H NMR (DMSO-d ₆ , 400 MHz): δ = 12.2 (br s, 1H); 8.02 (d, 1 H, J = 8 Hz); 7.68 (d, 2H, J = 8.3 Hz); 7.39 (d, 3H, J = 8 Hz); 7.14 (d, 2H, J = 8.8 Hz); 6.82 (dd, 2H, J = 8.4 Hz); 4.4 (m, 1 H); 4.32 (s, 2 H); 4.10 (dd, 1H, J = 2.9, 8 Hz); 3.07 (m, 1 H), 3.0 (dd, 1 H, J = 18.7, 27.5 Hz); 2.94 (dd, 1H, J = 17.8, 26 Hz); 2.39 (s, 3 H); 1.5 (m, 3 H); 1.4 (m, 1 H); 1.29 (s, 9 H).

IR (KBr, cm ⁻¹ ): 3400, 2950, 1745, 1675, 1525, 1450, 1350, 1225, 1160, 1075, 825, 675, 575, 540.

Mass spectrum: (FAB, m / e (%)) 544 (100, (M + H ⁺ )).

Example 60 (410)

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (4-phenyl-4-hydroxypiperidin-1-yl) ethoxy] -L-phenylalanine methyl ester

Alkylation of N- (toluene-4-sulfonyl) -L-prolyl-LO- (2-chloroethyl) tyrosine methyl ester with 4-hydroxy-4-phenyl piperidine (refluxing under argon for 72 hours) Potassium carbonate and sodium iodide) in the rice fields to produce methyl esters. The product is purified by flash column chromatography (silica, 5% methanol in chloroform) to give methyl ester as white blowing agent. The title compound is prepared as a solid using the method described in Method 6. Melting point: 122-123 ° C.

NMR data are as follows:

¹ H NMR (DMSOd ₆ , 400 MHz): δ = 7.72 (m, 2H); 7.61 (d, 1 H, J = 5.5 Hz); 7.39 (d, 2H, J = 7.2 Hz); 7.28 (m, 2 H); 7.17 (m, 1 H); 7.04 (d, 1 H, J = 8.8 Hz); 6.96 (d, 1H, J = 8.6 Hz); 6.71 (dd, 2H, J = 2.4, 8.8 Hz); 4.75 (s, 1 H); 4.1 (m, 1 H); 4.0 (m, 2 H); 3.9 (q, 1 H); 3.8 (q, 1 H); 2.8-3.1 (m, 4H, overlapping signal); 2.7 (m, 4H, overlapping signal); 2.38 (s, 3 H); 1.65 (m, 2 H); 1.55 (m, 2 H); 1.4 (m, 2 H).

IR (KBr, cm ⁻¹ ): 3375, 2890, 1660, 1610, 1510, 1390, 1325, 1250, 1160, 1075, 1040, 700, 675, 575, 530.

Mass spectrum: (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-cyanophenylalanine methyl ester (see Example 61 (381)) (167 mg, 0.388 mmol) was dissolved in pyridine (6 ml) followed by H Bubble ₂ S gas until saturated. The mixture is stirred for 19 hours and then the distillate is removed under an N ₂ stream. The residue is dissolved in EtOAc (50 ml) and washed with 5% KHSO ₄ (2 × 25 ml). The organic solution is dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to afford N- (toluene-4-sulfonyl) sarcosyl-D, L-4-thiocarboxamidophenylalanine methyl ester. Thioamide is dissolved in acetone (10 ml). Iodomethane (1 ml) is added and the mixture is heated to reflux for 1 hour. The distillate was removed in vacuo to afford N- (toluene-4-sulfonyl) sarcosyl-D, L-4-methylthioimidephenylalanine methyl ester hydroiodide (256 mg, 0.67 mmol). Thioimidate is dissolved in MeOH (5 ml). Ammonium acetate (52 mg, 0.67 mmol) is added and the mixture is heated to reflux for 1.5 h. The solvent was removed in vacuo and the residue was purified by preparative TLC (90: 10: 1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) and N- (toluene-4-sulfonyl) sarcosyl-D, L-4-amidino Obtain phenylalanine methyl ester (75 mg, 38%). The title compound is prepared by hydrolysis with methyl ester using 0.5N NaOH in THF / water (66 mg, 87%).

NMR data are 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), 2.54 (s, 3H), 2.40 (s, 3H).

Mass spectrum: FAB m / e 433 (M + H).

Example 62 (381)

Synthesis of N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (aminocarbonyl) phenylalanine

Coupling N- (toluene-4-sulfonyl) sarcosine with 4-cyanophenylalanine methyl ester hydrochloride (prepared via the method of Wagner, Voight and Vieweg Pharmazie 1984, 39, 226-230) To give N- (toluene-4-sulfonyl) sarcosyl-D, L-4-cyanophenylalanine methyl ester. Compounds are prepared by hydrolyzing the methyl esters with 0.5 N NaOH in THF / water.

N- (toluene-4-sulfonyl) sarcosyl-D, L-4-cyanophenylalanine methyl ester (300 mg, 0.699 mmol) is slurried in EtOH (3 ml). NaOH (10N, 98 μl) and H ₂ O ₂ (475 μl, 5.5 mmol) are added. The white precipitate leaches immediately after heating the mixture to 50 ° C. for 16 hours. The mixture is cooled to room temperature and acidified with HCl (6N). The mixture is diluted with water (20 ml) and extracted with chloroform (4 x 25 ml). The organic extract is dried (Na ₂ SO ₄ ), filtered and recrystallized from methanol to give the compound as a white solid (135 mg, 45%).

NMR data are as follows:

¹ H NMR (DMSO-d ₆ ): δ = 8.31 (br d, 1H, J = 3.6 Hz), 7.92 (br s, 1H), 7.72 (d, 2H, J = 7.8 Hz), 7.62 (d, 2H , J = 7.9 Hz), 7.40-7.21 (5H), 4.47 (m, 1H), 3.59 (m, 2H), 3.15 (m, 1H), 2.94 (m, 1H), 2.53 (s, 3H), 2.39 (s, 3 H).

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 spectrum: FAB m / e 434 (M + H).

Another compound prepared by the method described above includes the compounds set forth in Table II below, as in Examples 63-135.

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ NHCH ₂ CH ₂ CH ₂ -C (O) NH-] benzyl- -OH 68 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ (Boc) NCH ₂ CH ₂ CH ₂ -C (O) NH-] benzyl- -OH 69 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [øCH ₂ OCH ₂ (H ₂ N) CHC (O) NH] benzyl -OH 70 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [HO (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl- -OH 71 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [HO (O) C (H ₂ N) CHCH ₂ CH ₂ -C (O) NH-] benzyl- -OH 72 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl- -OH 73 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl- -OH 74 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ NHCH ₂ C (O) NH-] benzyl- -OCH ₂ CH ₃ 75

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [CH ₃ NHCH ₂ C (O) NH-] benzyl- -OH 76 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p- [CH ₃ NHCH ₂ C (O) NH-] benzyl- -OH 77 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl- -OH 78 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl- -OH 79 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(tert-butyl-O (O) CCH ₂ -O-benzyl) NH-] benzyl- -OCH ₃ 80 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH ₂ NH-) benzyl- -OH 81 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH (NHBoc) CH ₂ cyclohexyl] -benzyl -OCH ₃ 82

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) m-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl- -OH 83 p-CH ₃ -ø- R ² / R ³ = Cyclic-CH ₂ CH ₂ C (CH ₃ ) _2- p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O] benzyl- -OH 84 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O] benzyl- -OCH ₂ CH ₃ 85 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl- -OCH ₃ 86 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl- -OH 87 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl- -OCH ₃ 88 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [2- (2-azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl- -OH 89 p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p- (cyclopentyl-C≡C-)-benzyl- -OH 90

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-ø-p-ø] -benzyl- -OH 91 p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH ₂ -OS (O) ₂ -p-CH ₃ -ø] -benzyl- -OH 92 p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH ₂ NHC (O) NH ₂ ] -benzyl- -OH 93 p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH ₂ -Op-COOCH ₂ CH ₃ -ø] -benzyl- -OH 94 p-CH ₃ -ø- H -CH ₂ -ø (L-isomer) p-[-C≡C-CH (NH ₂ ) -cyclohexyl] -benzyl- -OH 95 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ -O-phenyl] -benzyl- -OH 96 p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ -O-phenyl] -benzyl- -OH 97 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ -OCH ₃ ] -benzyl- -OH 98 p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ -OCH ₃ ] -benzyl- -OH 99 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ -Op-(-C (O) OC ₂ H ₅ ) phenyl] -benzyl- -OH 100 p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ -Op-(-C (O) OC ₂ H ₅ ) phenyl] -benzyl- -OH 101

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl- -OH 102 p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl- -OH 103 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) -OH 104 p-CH ₃ -ø- -CH ₃ H -OH 105 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-C≡C-CH ₂ NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl) benzyl- -OH 106 p-CH ₃ -ø- -CH ₃ H p-[-C≡C-CH ₂ NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)] benzyl- -OH 107 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ CH _2- (1-piperadinyl)]-benzyl- -OCH ₃ 108 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) m-[-OCH ₂ CH _2- (1-pyrrolidinyl)]-benzyl- -OH 109 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH _2- (N-morpholino)]-benzyl- -OH 110

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ CH ₂ -1- (4-hydroxy-4- (3-methoxypyrrole-2-yl) -piperazinyl] -benzyl- -OCH ₃ 111 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-O- (3- (N-Boc) -piperidinyl] -benzyl- -OH 112 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) m-[-O- (N-methyl-piperidin-4-yl] -benzyl- -OH 113 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-O- (N-methylpiperidin-4-yl)]-benzyl- -OH 114 p-CH ₃ -ø- R ² / R ³ = Cyclic-CH ₂ -SC (CH ₃ ) _2- p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃ 115 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -SO ₂ -CH _2- (L-1,1-dioxothiomorpholin-3-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃ 116 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -SO ₂ -CH _2- (L-1,1-dioxothiomorpholin-3-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OCH ₂ CH ₃ 117

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ CH ₂ -SO ₂ -CH _2- (L-1,1-dioxothiomorpholin-3-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OH 118 p-CH ₃ -ø- R ² / R ³ = cyclic-CH ₂ -SC (CH ₃ ) _2- (L-5,5-dimethylthiazolidin-4-yl) p-[(1-methylpiperidin-4-yl) -O-] benzyl- -OH 119 ø-CH _3- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(1-methylpiperidin-4-yl) -O-]-benzyl- -OCH ₂ CH ₃ 120 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHSO ₂ -CH ₂ CH] -benzyl- -OCH ₃ 121 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-NHSO ₂ -CH = CH ₂ ] -benzyl- -OCH ₃ 122 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- [N-3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl- -OCH ₃ 123 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(N-vinylsulfonyl) amino] benzyl- -OH 124

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[-OCH ₂ C (O) O-benzyl] -benzyl- -OCH ₃ 125 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(piperidin-1-yl) C (O) CH ₂ -O-] benzyl- -OH 126 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ CH) ₂ NC (O) CH ₂ -O-] benzyl- -OCH ₃ 127 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p-[(CH ₃ ) ₂ CH) ₂ NC (O) CH ₂ -O-] benzyl- -OH 128 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methylacetamido) benzyl- -OCH (CH ₃ ) ₂ 129 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methylacetamido) benzyl- -OH 130 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-methyltrifluoroacetamido) benzyl- -OCH ₃ 131 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) (1-toluenesulfonylimidazol-4-yl) methyl- -OCH ₃ 132

R ¹ R ² R ³ R ⁵ R ^{6 '} Example Number p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) 1-([N, N-dimethylaminosulfonyl] -imidazol-4-yl) methyl- -OCH ₃ 133 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-toluenesulfonylamino) benzyl- -OCH ₃ 134 p-CH ₃ -ø- R ² / R ³ = cyclic 3 carbon atom (L-pyrrolidinyl) p- (N-toluenesulfonylamino) benzyl- -OH 135

In addition, the following compounds were prepared as in Examples 136 to 140.

Example 136

N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- [3- (N, N-dimethylamino) propoxy] -L-phenylalanine tert-butyl ester synthesis

The title compound is prepared except that N-Boc-tyrosine tert-butyl ester is used instead of N-Boc-tyrosine methyl ester:

MS: [(+) ESI]. [M + H] ⁺ 620.

Example 137

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4- (N-methylpiperidineoxy) phenylalanine) tertiary butyl ester

Tos-Pro-OH is BOP coupled with Tyr-O-1-methyl piperidine tert-butyl ester (prepared by Mitsunobu reaction) to prepare the title compound. The crude product is 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 for C ₃₁ H ₄₃ N ₃ O ₆ S

Calculated: C, 63.57; H, 7. 40; N, 7.17.

Found: C, 63.11; H, 7. 37; N, 6.96.

Example 138

Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L- (4- (N-methyl (piperidineoxy) phenylalanine tert-butyl ester

Prepare the title compound according to the method described in Example 137 using the appropriate starting material.

Elemental Analysis for C ₃₂ H ₄₅ N ₃ O ₆ S ₂ · 0.25 CH ₂ Cl ₂

Calculated: C, 58.85; H, 7.02; N, 6.43.

Found: 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

The title compound was converted to (N- (toluene-4-sulfonyl) -L-prolyl as taught in the corresponding triflate [Tilley and coworkers, J. Org. Chem., 55, 906, 1990). -L-tyrosine tert-butyl ester). Dipeptide (505 mg, 0.8 mmol), catalytic amount of tetrakis (triphenyl-hospin) palladium (O), potassium carbonate (201 mg, 1.5 equiv), phenylboronic acid (199 mg, 2.0 equiv) and 15 ml of toluene with stirring Reflux over time. Ethyl acetate is added and the organic layer is washed with water, 1N NaOH, brine and dried over magnesium sulfate. Immediately after filtration the solvent is evaporated under reduced pressure. The crude material is purified by preparative plate (1: 1 ethyl acetate: hexane). The silica gel is washed several times with acetonitrile and ethyl acetate. The combined fractions are evaporated and the residue is dried under reduced pressure.

NMR data are as follows.

¹ H NMR (CDCl ₃ , 300 MHz): δ = 7.70 (m, 1H); 7.57 (m, 3.5 H), 7.45 (m, 3.5 H); 7.28 (m, 5 H); 4.78 (m, 1 H); 4.06 (m, 1 H); 3.30 (m, 2 H); 3.06 (m, 2 H); 2.40 (s, 3 H); 2.05 (m, 1 H); 1.42 (s, 9 H).

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, 126.98, 82.65, 62.15, 53.74, 49.49, 37.43, 29.67, 29.67 27.78, 23.92, 21.37.

Example 140

Synthesis of N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine

The title compound is prepared from the product of Example 139 using the method described in Method 11.

NMR data are as follows.

¹ H NMR (CD ₃ OD, 300 MHz): δ = 8.05 (m, 1H); 7.71 (d, 2H, J = 8.24 Hz); 7.55 (m, 4 H); 7.30 (m, 8 H); 4.71 (m, 1 H); 4.09 (m, 1 H); 3.30 (m, 3.30); 3.15 (m, 3 H); 2.37 (s, 3 H); 1.78 (m, 1 H); 1.62 (m, 4 H).

¹³ C NMR (CD ₃ OD): δ = 174.27, 145.88, 142.25, 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 .

Example 141

In vitro assays to determine candidate compounds that bind to VLA-4

In vitro assays are used to evaluate candidate compounds that bind to α ₄ β ₁ integrin. Compounds that bind in this assay can be used to assess VCAM-1 concentrations in biological samples by conventional assays (eg, competitive assays). The assay is sensitive to low IC ₅₀ values of about 1 nM.

High levels of α ₄ β ₁ integrin person expressing T- cell line, U reukaet (Jurkat) cells (e:. American Type Culture Collection NOs TIB 152, TIB 153 , and CRL 8163) with α ₄ to interact with the soluble VCAM-1 The activity of β ₁ integrins is measured. VCAM-1 interacts with the cell surface in an α ₄ β ₁ integrin-dependent manner. Yednock, et al., J. Bio. Chem., 1995, 270: 28740.

Recombinant soluble VCAM-1 is expressed as a chimeric fusion protein comprising seven extracellular domains of VCAM-1 on the N-terminus and a human IgG ₁ heavy chain constant region on the C-terminus. VCAM-1 fusion proteins are prepared and purified by the methods described in Yednock, supra.

Jurkat cells are grown in RPMI 1640 supplemented with 10% fetal bovine serum, phenylsilin, streptomycin and glutamine as described in Yednock, supra.

Incubate Jurkat cells with 1.5 mM MnCl ₂ and 5 μg / ml 15/7 antibody for 30 minutes on ice. Mn ⁺² activates the receptor to increase ligand binding and 15/7 recognizes the activated / ligand bound form of α ₄ β ₁ integrin and immobilizes the molecule in this form to interact with VCAM-1 / α ₄ β ₁ integrin It is a monoclonal antibody that stabilizes (see Yednock, et al., Supra). Antibodies similar to the 15/7 antibodies were prepared by another researcher. Luque, et al., 1996, J. Bio. Chem. 271: 11067 and can be used for this assay.

Cells are incubated for 30 minutes at room temperature with candidate compounds at various concentrations ranging from 66 μM to 0.01 μM using standard 5-point serial dilutions. 15 μL of soluble recombinant VCAM-1 fusion protein is added to Jurkat cells and incubated on ice for 30 minutes (Ynock et al., Supra).

Cells are then washed twice and resuspended in PE-bound goth F (ab ') ₂ anti-mouse IgG Fc (Immunotech, Westbrook, ME) at a ratio of 1: 200 and incubated on dark ice for 30 minutes. Cells are washed twice and analyzed with a standard fluorescent activated cell sorter (“FACS”) as described in Yednock, et al., Supra.

Compounds having IC ₅₀ values of about 15 μM or less have a binding affinity for α ₄ β ₁ .

When tested in this assay, each of the compounds of Examples 1-135 has an IC ₅₀ value of 15 μM or less.

Example 142

In vitro saturation assay to determine candidate compounds that bind to α ₄ β ₁

In vivo assays for determining plasma concentrations of compounds required to be activated in an empirical autoimmune encephalomyelitis (“EAE”) model, as described in the following examples or in another in vivo model, are described below.

Eurkat cells of the logarithmic proliferative phase are washed and resuspended in normal animal plasma containing 20 μg / ml of 15/7 antibody as described in the Examples above.

Jurkat cells were obtained from peripheral blood of animals treated with normal plasma samples or candidate compounds containing amounts of known candidate compounds in varying concentrations ranging from 66 μM to 0.01 μM using standard 12 point serial dilutions to standard curves. Dilute 2-fold with one plasma sample.

Then phosphate-buffered saline (“PBS”) containing 2% fetal bovine serum, and 1 mM of calcium chloride and magnesium chloride, respectively, to incubate the cells for 30 minutes at room temperature and remove unbound 15/7 antibodies. Wash twice with

The phycoerythrin-bound goth F (ab ') ₂ term adsorbed for any nonspecific cross-reactivity by incubation with 5% serum of animal species to be studied and then incubated in the dark at 4 ° C. for 30 minutes. Cells are exposed to mouse IgG Fc (Immunotech, Westbrook, ME).

Cells are washed twice with assay medium and resuspended in the same medium. The cells were then described in Yednock et al. J. Bio. Assay as standard fluorescent activated cell sorter ("FACS") as described in Chem., 1995, 270: 28740.

The data is then graphed as fluorescent versus dose in the normal dose-response mode. Dosage concentrations leading to the upper plateau of the curve represent the concentrations required to obtain efficacy in the in vivo model.

The assay also can be used to determine the plasma concentration required to saturate the binding sites of other integrins, such as α ₄ is most closely and β ₁ associated α ₉ β ₁ integrin (Reference: Palmer et al, 1993, J Cell Bio., 123: 1289). The binding is the result of inflammatory symptoms mediated by α ₉ β ₁ integrin, eg, airway hypersensitivity and obstruction in chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion after angioplasty, kidney disease In vivo for inflammatory symptoms mediated by α ₉ β ₁ integrins, including fibrosis and glomerular scars, arterial stenosis, synovial hyperplasia in rheumatoid arthritis, and inflammation and scarring that develop as a result of ulcerative colitis and Crohn's disease. You can expect usefulness.

Thus, the assay described above was performed by human colon cancer cell line SW 480 (ATCC # CCL228) transfected with cDNA encoding α ₉ integrin instead of Jurkat cells to determine α ₉ β ₁ integrin binding (see Yokosaki et al. , 1994, J. Bio. Chem., 269: 26691). As a control, SW 480 cells expressing α and β ₁ subunits can be used.

Accordingly, another aspect of the invention relates to a method for treating a disease in a mammalian patient mediated by α ₉ β ₁ , comprising administering to the patient a therapeutically effective amount of a compound of the invention. The compound is preferably administered in the pharmaceutical composition described herein above. The daily pharmaceutical dosage may vary depending on the age, weight and symptoms of the patient and such factors can be readily identified by the attending clinician. However, in a preferred embodiment, the compound is administered at about 20-500 μg / kg per day.

Example 143

In vivo evaluation

Empirical autoimmune (or allergic) encephalomyelitis (“EAE”), a standard multiple sclerosis model, is used to determine the effect of candidate compounds in reducing motor damage in rats or guinea pigs. The reduction in motor damage is based on blocking adhesion between leukocytes and endothelial cells and is associated with the anti-inflammatory activity of candidate compounds. This model was previously described in Keszthelyi et al., Neurology, 1996, 47: 1053-1059 and delays the onset of the disease.

The brain and spinal cord of adult Hertley guinea pigs are disrupted in the same volume of phosphate-buffered saline. An equal volume of Freund's complete adjuvant (100 mg of Mycobacterium tuberculosis + 10 ml of Freoint's incomplete adjuvant) is added to the crush. The mixture is emulsified by repeatedly circulating it through a 20 ml syringe using a peristaltic pump for about 20 minutes.

Female Lewis rats (2 to 3 months, 170 to 220 g) or Huttley guinea pigs (20 days, 180 to 200 g) are anesthetized with isoflurane and injected into the flanks three times in 0.1 ml each. Motor impairment develops after approximately 9 days.

Candidate compound treatments begin on day 8 prior to onset of symptoms. The compound is administered subcutaneously (“SC”), orally (“PO”) or intraperitoneally (“IP”). Doses are 10 mg / kg to 200 mg / kg for 5 days and typical dosages are 10 to 100 mg / kg SC, 10 to 50 mg / kg PO and 10 to 100 mg / kg IP.

Antibody GG5 / 3 against α ₄ β ₁ integrin, which delays the onset of symptoms, is used as a positive control and injected subcutaneously at 3 mg / kg on days 8 and 11.

Weight and exercise damage are measured daily. Motor impairment is graded with the following clinical scores.

0 no change

1 tail breakdown or paralysis

Breakdown of 2 hind legs

3 hind limb paralysis

4 death or death

If the onset of symptoms is delayed, for example, the candidate compound is considered active if the clinical score indicates less than 2 or if weight loss is slow compared to the control.

When tested in this bioassay, the compounds of Examples 5, 12, 18 and 20 are active.

Example 144

Asthma Model Embodiment

Inflammatory symptoms mediated by α ₄ β ₁ integrins include, for example, airway hypersensitivity and obstruction that develop in chronic asthma. The asthma model that can be used to study the in vivo effects of the compounds of the present invention for the treatment of asthma is described below.

See Abraham et al., J. Clin. Invest, 93: 776-787 (1994) and Abraham et al, Am J. Respir Crit Care Med, 156: 696-703 (1997), the compounds of the present invention are formulated with aerosol and Administration is given to sheep hypersensitive to the Ascaris suum antigen. Compounds of the invention that have a protective effect on reducing early antigen-induced bronchial responses and / or blocking late airway responses, eg, antigen-induced late response and airway hypersensitivity (“AHR”) are described above. It is considered to be active in the model.

An allergic amount that exhibits both early and late bronchial responses to the inhaled Ascaris islet antigen is used to study the airway effects of the candidate compounds. After local anesthesia with 2% lidocaine, the balloon catheter is advanced through the nasal cavity into the lower esophagus. The animal is then intubated with an intratracheal tube that has been cuffed through another nasal cavity with a flexible fiberoptic bronchoscope as a guide.

Pleural pressure is assessed according to Abraham (1994). Aerosols (see Formulation below) are synthesized using a disposable medical nebulizer that provides an aerosol with a mass mean aerodynamic diameter of 3.2 μm as determined using the Andersen cascade impactor. The nebulizer is connected to a dosimeter consisting of a solenoid valve and a source of compressed air (20 psi). Direct the output of the nebulizer to the plastic T-piece and connect one end of it to the inlet of the piston respirator. Activate the solenoid valve for 1 second at the beginning of the inhalation cycle of the respirator. The aerosol is delivered at a rate of 500 ml of V _T and 20 breaths per minute. Only 0.5% sodium bicarbonate solution is used as a control.

Accumulated concentration-response curves for carbacol can be prepared according to Abraham (1994) to assess bronchial sensitivity. Bronchial biopsies can be performed before and after treatment and 24 hours after antigen administration. Bronchial biopsies can be performed in accordance with Abraham (1994).

Abrasive macrophage in vitro adhesion studies can be performed according to Abraham (1994) and the percentage of adherent cells is calculated.

Aerosol formulations

A solution of 30.Omg / mL candidate compound in 0.5% sodium bicarbonate / saline is prepared using the following method.

A. Preparation of 0.5% Sodium Bicarbonate / Saline Stock Solution: 100.0 mL

ingredient g / 100.0ml Final concentration Sodium bicarbonate 0.5g 0.5% Saline 100.0ml titration amount 100% proper amount

Way:

1. Add 0.5 g sodium bicarbonate to a 100 ml volumetric flask.

2. Add about 90.0 ml of saline and sonicate until dissolved.

3. Titrate to 100.0ml with saline and mix thoroughly.

B. Preparation of 30.0 mg / mL Candidate Compound: 10.0 ml

ingredient g / 10.0ml Final concentration Candidate compounds 0.300g 30.0mg / ml 0.5% Sodium Bicarbonate / Saline Stock Solution 10.0 ml titration 100% proper amount

Way:

1. Add 0.300 g of the candidate compound to a 10.0 ml volumetric flask.

2. Add about 9.7 ml of 0.5% sodium bicarbonate / saline stock solution.

3. Sonicate until the candidate compound is completely dissolved.

4. Titrate to 10.0 ml with 0.5% sodium bicarbonate / saline stock solution and mix thoroughly.

Conventional oral formulations have been used to show that the compounds of the invention are active in this model.

Claims (37)

Compounds of formula (I) and pharmaceutically acceptable salts thereof. Formula I In the above formula, R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl; R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted Selected from the group consisting of heteroaryl, R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ form a heterocyclic or substituted heterocyclic group; R ³ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and R ² is When not forming a heterocyclic group with R ¹ , R ² and R ³ may form a heterocyclic or substituted heterocyclic group together with a nitrogen atom bonded to R ² and a carbon atom bonded to R ³ . ; R ⁵ is — (CH ₂ ) _x —Ar—R ^{5 ′} {wherein R ^{5 ′} is (a) substituted alkylcarbonylamino, provided that at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyhetero Aryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thio Aryl, substituted thio , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heteroaryl Click, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR- substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted Asymmetric disubstituted amines with different substituents selected from alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. Tea by A substituted alkyl group having an amino group, or an alkyl / substituted alkyl group, wherein the substituent is -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted egg Kenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (b) the alkoxy moiety is carboxyl and -COOR Alkoxyaryl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, (c) aryl and heteroaryl, (d) -NR ' R '[where each R' is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycle Roalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, wherein at least one R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic Is a click and, as a further condition, R 'is substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino , Amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl , Carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxy -Substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted Thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O ) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl,- OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted Aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic,- NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS ( O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic 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, and alkyl, substituted alkyl, aryl, substitution Asymmetric disubstituted amines having different substituents selected from aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Substituted alkyl group, or alkyl / substituted alkyl group, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterosai Click, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl), (e) -alkoxy-NR "R" where each R "is independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloal , Heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that if each R ″ is substituted alkyl, one or more of the substituents of the substituted alkyl moiety is alkoxy, substituted Alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy , Aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl , Carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guani Dino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, Substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl Amino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR ( 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 -hetero Aryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl,- NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl Having different substituents selected from heterocyclic and substituted heterocyclic A substituted alkyl group having an asymmetric disubstituted amine and an amino group blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or an alkyl / substituted alkyl group, wherein the substituents are -SO ₂ -alkyl,- SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted Aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR, wherein R is hydrogen or alkyl (F) substituted alkenyl or substituted alkynyl, provided that at least one of the substituents of the substituted alkenyl / alkynyl moiety is alkyl, substituted alkyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic When selected from the group consisting of, and substituted with substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amino Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted hetero Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioa , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl , -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted hetero Cyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic 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, and alkyl, substituted Asymmetric disubstituted amines with different substituents selected from alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. due to Substituted alkyl groups with blocked amino groups, or alkyl / substituted alkyl groups, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted Alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl,- SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (g) substituted with substituted aryloxy Heteroaryloxy, provided that at least one of the substituents of substituted aryloxy / heteroaryloxy is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1, 2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbo Substituents other than oxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl and N, N-dialkylurea], (h) -alkoxy-saturated heterocyclic, -alkoxy- Substituted saturated heterocyclics, -substituted alkoxy-heterocyclic and -substituted alkoxy-substituted saturated heterocyclics, (i) -O-heterocyclic and -O-substituted heterocyclics, (j) Tetrazolyl, (k) -NR-SO ₂ -substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least one of the substituents of the alkyl moiety of substituted alkylsulfonylamino is halogen, hydroxyl, amino, Nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino Alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, Substituents other than chelsulfonylamino, N-alkyl and N, N-dialkylureas), (l) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (m Substituted alkoxy, provided that the substituent of the alkyl moiety of the substituted alkoxy is alkoxy-NR " R &quot;, unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and halogen, hydroxyl, amino , Nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenyl Does not include aryl / heteroaryl substituted with amino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea ), (n) amidine and, alkyl, substituted alkyl, alkenyl , Amidine monosubstituted with a substituent independently selected from the group consisting of substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, (o) -C (O) NR '''R''' [Each R '''is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl , Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that one R '''is unsaturated heterocyclylalkyl, aryl, heteroaryl or halogen , Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, Alkylamino, alkenylamino, alkynylamino, alkylcarbonyl When aryl / heteroaryl substituted with acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, the remaining R '''is alkyl, substituted Alkyl (excluding unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic] , (p) -NR ¹² C (O) -R ⁸ , wherein R ⁸ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocylic Is selected from the group consisting of a click and a substituted heterocyclic, R ¹² is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted Heterocyclic), (q) -SO ₂ -Aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl or -SO ₂ -alkyl, (r) -NR'C (O) NR ⁹ R ⁹ , wherein R 'is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, each R ⁹ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic) , (s) -NR'C (O) OR ⁹ , wherein R 'is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic And substituted heterocyclic, R ⁹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic), ( t) from the group consisting of -aminocarbonyl- (N-formylheterocyclyl) and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O) NH-substituted heterocyclyl And Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, and x is an integer from 1 to 4; 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. Compounds of Formula (IA) and pharmaceutically acceptable salts thereof. Formula IA In the above formula, R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl and substituted Selected from the group consisting of heteroaryl, R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ can form a heterocyclic or substituted heterocyclic group , R ³ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ² is When not forming a heterocyclic group with R ¹ , R ² and R ³ are a heterocyclic group or a substituted heterocyclic group together with a nitrogen atom bonded to R ² and a carbon atom bonded to R ³ . Form the R ⁵ is — (CH ₂ ) _x —Ar—R ^{5 ′} {wherein R ^{5 ′} is (a) substituted alkylcarbonylamino, provided that at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyhetero Aryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thio Aryl, substituted thio , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heteroaryl Click, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR- substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted aryl Amino, mono and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, Difference by asymmetric disubstituted amines having different substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. An amino-substituted alkyl group having a group, or alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted Al Kenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (b) the alkoxy moiety is carboxyl and -COOR Alkoxyaryl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (c) aryl and heteroaryl, (d) -NR ' R '[where each R' is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloal , Substituted cycloalkyl, heterocyclic and substituted heterocyclic, wherein at least one R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic And, as a further condition, when R 'is substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amino Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxy -Substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted Thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted Cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O ) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl,- OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) _2- NRR where R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted Aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O ) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic ( 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, and alkyl, substituted alkyl, aryl, substituted Done Asymmetric disubstituted amines having different substituents selected from aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Substituted alkyl group, or alkyl / substituted alkyl group, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterosai Click, -SO ₂ -substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl)], (e) -alkoxy-NR "R" where each R "is independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, he Teraryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that when each R ″ is substituted alkyl one or more of the substituents of the substituted alkyl moiety is alkoxy, substituted Alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, Aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, Carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyl heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino , Guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substitution Thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino , Oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS ( O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) _2- NRR where R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ - heteroaryl ah , -NRS (O) ₂ - substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - cyclic substituted heteroaryl, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS ( O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Ratios with different substituents selected from cyclic and substituted heterocyclics Ching-disubstituted amine, and Boc, Cbz, formyl, and typical substituted alkyl groups having amino groups blocked by a blocking group, and alkyl / substituted alkyl groups, such as ((wherein the substituents are -SO ₂ - alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO _2- Substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic, and -SO ₂ NRR, wherein R is hydrogen or alkyl (F) substituted alkenyl or substituted alkynyl, provided that at least one of the substituents of the substituted alkenyl / alkynyl moiety is alkyl, substituted alkyl, aryl, substituted Aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic And when substituted with substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amyl Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted hetero Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thio Cycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted Alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -Heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O ) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl,- NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocycle Ric, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted aryl Amino, mono and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, Blocked by asymmetric disubstituted amines having different substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. Done Diamino-substituted alkyl group having a group, or alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl , -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -Heterocyclic, -SO ₂ -substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted hetero Aryloxy [provided that at least one of the substituents of substituted aryloxy / heteroaryloxy is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- Dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, Thread, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl and substituents other than N, N-dialkylurea], (h) -alkoxy-saturated heterocyclic, -alkoxy-substituted Saturated heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy-substituted saturated heterocyclic, (i) -O-heterocyclic and -O-substituted heterocyclic, (j) tetrazolyl (k) -NR-SO ₂ -substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least one of the substituents of the alkyl moiety of substituted alkylsulfonylamino is halogen, hydroxyl, amino, nitro, Trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alky Nylamino, Alkylcarbonyloxy, Acyl, Alkylcarbonylamino, Alkoxycarbonylamino, Alkylsulfo Substituents other than amino, N-alkyl and N, N-dialkylureas), (l) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (m) substitution Alkoxy, provided that the substituent of the alkyl moiety of substituted alkoxy is alkoxy-NR " R &quot;, unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and halogen, hydroxyl, amino, nitro , Trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, Does not include aryl / heteroaryl substituted with alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea), (n) amidines and, alkyl, substituted alkyl, alkenyl, substituted Amidine one to trisubstituted with a substituent independently selected from the group consisting of alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, (o) -C (O) NR '''R' Wherein each R ′ is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that one R '''is unsaturated heterocyclylalkyl, aryl, heteroaryl, halogen, Hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino Alkenylamino, Alkynylamino, Alkylcarbonyloxy, Ah , Aryl / heteroaryl substituted with alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, the remaining R '''is alkyl, substituted alkyl (unsaturated) Heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic], (p ) -NR ¹² C (O) -R ⁸ , wherein R ⁸ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted Is selected from the group consisting of heterocyclic, R ¹² is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclo Click), (q) -SO ₂ -aryl,- SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl or -SO ₂ -alkyl, (r) -NR'C (O) NR ⁹ R ⁹ , wherein R 'is alkyl , Substituted alkyl, aryl, 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, substituted heteroaryl, heterocyclic and substituted heterocyclic), (s) —NR′C (O) OR ⁹ where R ′ is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted hetero is selected from the group consisting of cyclic, R ⁹ is , Alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 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, and 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 cycloalkoxy, -O- (N-succinimidyl ), -NH-adamantyl, O-cholest-5-en-3-β-yl, -NHOY, where Y is hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, -NH ( CH ₂ ) _p COOY, where p is an integer from 1 to 8, Y is as defined above, -OCH ₂ NR ⁹ R ¹⁰ [where R ⁹ is -C (O) -aryl and -C (O ) Is substituted from the group consisting of aryl, R ¹⁰ is selected from the group consisting of hydrogen and -CH ₂ COOR ¹¹ (wherein R ¹¹ is alkyl) and -NHSO ₂ Z (where Z is alkyl, Substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic), Q is -C (X) NR ^7- , wherein R ⁷ is selected from the group consisting of hydrogen and alkyl, X is selected from the group consisting of oxygen and sulfur; Provided that when R ¹ is p-CH ₃ -Φ, R ⁶ is methoxy, Q is -C (O) NH, and R ² and R ³ combine to form a pyrrolidinyl group, then R ⁵ is p -[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl-, p-[-OCH ₂ CH ₂ N (isopropyl) ₂ ] -benzyl-, p-[-OCH ₂ CH ₂ -1- pyrrolidinyl) -benzyl _{-, p - [- OCH 2} CH 2 -1- (4- pyrimidinyl) piperazinyl] -benzyl _{-, p - [- OCH 2} CH 2 -N- morpholinyl); -Benzyl-, or p-[-OCH ₂ CH ₂ -N-piperidinyl)]-benzyl-. The compound of claim 1 or 2, wherein R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl. The compound of claim 3, wherein 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-tert-butylphenyl, 4-tert-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazole 4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 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-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyri 3-yl, pyrimidin-2-yl, 4- (3'-dimethyl amino -n- propoxy) -phenyl, and 1-methyl-pyrazole compound is selected from the group consisting of 4-days. Article according to one of the preceding claims, R ² is hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2} -2- thienyl and - (CH ₂₎ a compound selected from the group consisting of ₂ -Φ. 3. A compound according to claim 1 or 2, wherein R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ form a heterocyclic group or a substituted heterocyclic group. ^{3. The} compound of claim 1, wherein R ² and R ³ are a nitrogen atom bonded to a R ² substituent and a carbon bonded to a R ³ substituent together to form a heterocyclic group or a substituted heterocyclic group. The compound of claim 1 or 2, wherein R ³ is methyl, phenyl, benzyl, diphenylmethyl, -CH ₂ CH ₂ -COOH, -CH ₂ -COOH, 2-amidoethyl, iso-butyl, tert- A compound selected from the group consisting of butyl, -CH ₂ O-benzyl and hydroxymethyl. 3. The compound of claim 1, wherein Q is —C (O) NH— or —C (S) NH—. 4. The method according to claim 1 or 2, R ⁵ is 4- [NH ₂ CH ₂ C (O) NH-] benzyl, 4- [HOOCCH ₂ CH ₂ C (O) NH-] benzyl, 4-[-NHC (O) CH ₂ NHBoc] benzyl, 4 -[-NHC (O) CH (CH ₃ ) NHBoc] benzyl, 4-[-NHC (O) CH (CH ₂ Φ) NHBoc] benzyl, 4-[-NHC (O) CH ₂ NHC (O) NH- 3'-methylphenyl] benzyl, 4-[-NHC (O) CH (NHBoc) (CH ₂ ) ₄ NHCbz] benzyl, 4-[-NHC (O) CH ₂ CH (C (O) OCH ₂ Φ) -NHCbz ] Benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ) NHBoc] benzyl, 4- [H ₂ NCH ₂ CH ₂ CH ₂ C (O) NH Benzyl, 4- (BocHNCH ₂ CH ₂ CH ₂ C (O) NH-) benzyl, 4- [ΦCH ₂ OCH ₂ (BocHN) CHC (O) NH-] benzyl, 4- [CH ₃ NHCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH ₃ N (Boc) CH ₂ CH ₂ CH ₂ C (O) NH-] Benzyl, 4- [ΦCH ₂ OCH ₂ (H ₂ N) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [ΦCH ₂ O (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [OH (O) C (NH ₂ ) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl, 4- [CH ₃ NHCH ₂ C (O) NH-] benzyl, 4-[(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxylphenyl-]-benzyl, 4- [2-carboxymethylphenyl-]-benzyl, 4 -[ ΦCH ₂ OC (O) NHCH ₂ CH ₂ NH-] benzyl, 4-N [-(SO ₂ ) CH ₃ ] -CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] benzyl, 4-tert-butyl- O (O) CCH ₂ -O-benzylNH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- (2-formyl-1,2, 3,4-tetrahydroisoquinolin-3-yl-CH ₂ NH) benzyl, 4-[-OCH ₂ CH ₂ -1 '-(4'-pyrimidinyl) -piperazinyl] -benzyl, 4- [ -OCH ₂ CH _2- (1'-piperidinyl) -benzyl, 4-[-OCH ₂ CH _2- (1'-pyrrolidinyl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- ( 1'-piperidinyl)]-benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ O-]-benzyl, 4 _{- [- OCH 2 CH 2 CH} 2 - (1 '- (4'- methyl-piperazinyl))] - _{benzyl, 4 - [- OCH 2 CH} 2 CH 2 -4- (3'- chlorophenyl) -piperazin Razin-1-yl] -benzyl, 4-[-OCH ₂ CH ₂ N (Φ) CH ₂ CH ₃ ] -benzyl, 4-[-OCH ₂ -3 ′-(N-Boc) -piperidinyl]- Benzyl, 4-[-O- (3- (N-Boc) -piperidinyl] benzyl, 3-[-O- (N-methylpiperidin-4-yl] benzyl, 4-[-O- ( N- methyl piperidin-4-yl] benzyl, 4- [di-iso-propylamino -CH ₂ CH ₂ O -] - benzyl, 4- [N-3- methyl-butyl -N- trifluoroacetate Methanesulfonyl) amino] _{benzyl, 4 - [- OCH 2 CH} 2 - (N- morpholinyl)] - _{benzyl, 4 - [- OCH 2 CH} (NHBoc) CH 2 cyclohexyl] benzyl, 4- [OCH ₂ CH _2- (N-piperidinyl)]-benzyl, 4-[-OCH ₂ CH ₂ CH ₂ CH _2- (4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH ₂ CH _2- (N-homopiperidinyl) -benzyl, 4-[-OCH ₂ CH ₂ N (benzyl) ₂ ] -benzyl, 3-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ]- Benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) benzyl] -benzyl, 4- [2- (2-azabicyclo [3.2.2] octane -2-yl) ethyl-O-] benzyl, [cyclopentylacetylenyl] -benzyl, 4-[-C≡C-Φ-4'Φ] -benzyl, 4-[-C≡C-CH _{2- OS (O) 2 -4'-CH} 3 -Φ] - benzyl, 4 - [- C≡C-CH 2 NHC (O) NH 2] - benzyl, 4 - [- C≡C-CH 2 -O- (4′-COOCH ₂ CH ₃ ) Φ] -benzyl, 4-[-C≡C-CH (NH ₂ ) -cyclohexyl] -benzyl, 4-[-C≡C-CH ₂ -O-phenyl]- Benzyl, 4-[-C≡C-CH ₂ OCH ₃ ] -benzyl, 4-[-C≡C-CH ₂ -O- (4'-C (O) OC ₂ H ₅ ) phenyl] -benzyl, 4 -[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl, 4-[-C≡C-CH ₂ CH (NHC (O) CH ₃ ) C (O) OH] -benzyl, 4-[-C≡C-CH ₂ NH- (4, 5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (N-morpholino)]-benzyl, 4-[- OCH ₂ COOH] -benzyl, 4-[-OCH ₂ COO-tert-butyl] -benzyl, 4-[-N (SO ₂ CH ₃ ) (CH ₂ ) ₃ -N (CH ₃ ) ₂ ] -benzyl, 4-[-NHS (O) ₂ CF ₃ ] -benzyl, 4-[-C (= NH) NH ₂ ] -benzyl, 4-[-NHSO ₂ -CH ₂ Cl] -benzyl, 4-[-OCH ₂ C (O) NH-benzyl] -benzyl, 4-[-OCH ₂ C (O) O-benzyl] -benzyl, 4-[-OCH ₂ C (O) OH] -benzyl, 4-[-OCH ₂ CH ₂ 1 - (4-hydroxy-4- (3-methoxypyrid-roll 2-yl) piperazinyl] -benzyl, 4 - [- OCH ₂ C (O) NH _2] -benzyl, 4- [ -OCH ₂ C (O) NH-tert-butyl] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy-4-phenyl) -piperidinyl] -benzyl, 4-[- NHSO ₂ -CH = CH ₂ ] -benzyl, 4-[-NHSO ₂ -CH ₂ CH ₂ Cl] -benzyl, 4-benzyl-benzyl, 4-[-OCH ₂ C (O) piperidin-1-yl ] Benzyl, 4-[-OCH ₂ C (O) N (CH (CH ₃ ) ₂ ) ₂ ] benzyl, 4-aminobenzyl, 4-acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4-(-NHC (O) CH ₂ NHC (O) NH-fluorescein) benzyl , 4- (NHC (O) CH ₂ CH (NH ₂ ) COOH, (1-toluenesulfonylimidizol-4-yl) -methyl-, [(1-N, N-dimethylaminosulfonyl) -already Dizol-4-yl] methyl-, 4- (N-toluenesulfonyl-amino) benzyl and 4- [N-methyltrifluoroacetamido) phenyl. The compound of claim 2, wherein R ⁶ is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, tert- Butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, -NH ₂ , benzyl Oxy, -NHCH ₂ COOH, -NHCH ₂ CH ₂ COOH, -NH-adamantyl, -NHCH ₂ CH ₂ COOCH ₂ CH ₃ , -NHSO ₂ -p-CH ₃ -Φ, -NHOR ⁸ (where R ⁸ Is hydrogen, methyl, iso-propyl or benzyl), O- (N-succinimidyl), -O-cholest-5-en-3-β-yl, -OCH ₂ -OC (O) C (CH ₃ ) ₃ , -O (CH ₂ ) _z NHC (O) W, wherein z is 1 or 2, W is pyrid-3-yl, N-methylpyridyl and N-methyl-1,4-di Hydro-pyrid-3-yl] and -NR "C (O) -R 'wherein R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH ₂ C ( O) OCH ₂ CH ₃ ). N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (carboxy) propionamido] -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) thioureido] acetamido} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-methylphenyl) ureido] acetamido} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-butoxylcarbonyl-Nε-carbenzyloxy-L-lysyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-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-aminobutyramido) -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonylamino) butyramido] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramido] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonyl-N-methylamino) butyramido] -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-butoxylcarbonylsarcosyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxylcarbonylsarcosyl) 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-dimethylglycyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxybenzyloxy) -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-carbenzyloxyamino) ethyl] amino} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbenzyloxyamino) 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-dimethylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3- (N, N-dimethylaminopropoxy] -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-tert-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-diethylamino) 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- (thiazole-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-dimethylamino) 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-phenylalanine; 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) sarcosyl-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- Inyl} -D, L-phenylalanine; N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5-dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl}- 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-[(l-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-[(l-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- (azpan-1-yl) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azpan-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-methylpiperidine-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-sulfonyl) -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-[(benzyloxycarbonyl) methoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzyloxycarbonyl) 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-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidin-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 tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolyl-L-4- (N-methylpiperidinoxy) -phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiapropyl-L- (4-methylpiperidinoxy) phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine tert-butyl ester; And N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine, a pharmaceutically acceptable salt thereof and one ester are methyl esters, ethyl esters and ester compounds mentioned above substituted with another ester selected from the group consisting of n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, secondary-butyl ester and tert-butyl ester. A method of binding VLA-4 in a biological sample, including contacting the compound of Formula IA and a pharmaceutically acceptable salt thereof with a biological sample under conditions that the compound binds to VLA-4 Formula IA In the above formula, R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl and substituted Selected from the group consisting of heteroaryl, R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ can form a heterocyclic or substituted heterocyclic group , R ³ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ² is When not forming a heterocyclic group with R ¹ , R ² and R ³ are a heterocyclic group or a substituted heterocyclic group together with a nitrogen atom bonded to R ² and a carbon atom bonded to R ³ . Form the R ⁵ is — (CH ₂ ) _x —Ar—R ^{5 ′} {wherein R ^{5 ′} is (a) substituted alkylcarbonylamino, provided that at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyhetero Aryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thio Aryl, substituted thio , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heteroaryl Click, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR- substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted aryl Amino, mono and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, Difference by asymmetric disubstituted amines having different substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. A substituted alkyl group having an amino group, and alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted Al Kenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (b) the alkoxy moiety is carboxyl and -COOR Alkoxyaryl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (c) aryl and heteroaryl, (d) -NR ' R '[where each R' is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, heterocyclic and substituted heterocyclic, wherein at least one R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic, As a further condition, when R 'is substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino , Alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl , Carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl- Substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cyclo Alkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS ( O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR Wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl , -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS ( O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, wherein , R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di-substituted alkylamino, 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, and alkyl, substituted alkyl, aryl, substituted ah , Asymmetric disubstituted amines having different substituents selected from heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Substituted alkyl groups, and alkyl / substituted alkyl groups, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -Cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic , -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl), (e) -alkoxy-NR "R" where each R ″ is independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete Aryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that when each R ″ is substituted alkyl one or more of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy , Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyl Heteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, sphere Anidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thio Heterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxy Thiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR ( Wherein R is hydrogen or alkyl), -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl,- NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O ) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic And asymmetric with different substituents selected from substituted heterocyclics Substituted alkyl groups having disubstituted amines and amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, and alkyl / substituted alkyl groups wherein the substituents are -SO ₂ -alkyl, -SO ₂ -Substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl , -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR, wherein R is hydrogen or alkyl ), (F) substituted alkenyl or substituted alkynyl, provided that at least one of the substituents of the substituted alkenyl / alkynyl moiety is alkyl, substituted alkyl, aryl, substituted aryl, Consisting of cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic And when substituted with substituted alkyl, one or more of the substituents of the substituted alkyl moiety may be alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amino Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted hetero Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thio Cycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted Alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -Heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O ) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl,- NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocycle Ric, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic, 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted Asymmetric disubstituted amines having different substituents selected from heteroaryls, heterocyclics and substituted heterocyclics, and substituted alkyls having amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Group, or alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl al, -SO ₂ - cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -Substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided substituted aryl At least one of the substituents of oxy / heteroaryloxy is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2- Dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxyca Substituents other than alkylamino, alkylsulfonylamino, N-alkyl and N, N-dialkylurea], (h) -alkoxy-saturated heterocyclic, -alkoxy-substituted saturated heterocyclic, -substituted alkoxy -Heterocyclic and -substituted alkoxy-substituted saturated heterocyclic, (i) -O-heterocyclic and -O-substituted heterocyclic, (j) tetrazolyl, (k) -NR-SO ₂ Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least one of the substituents of the alkyl moiety of the substituted alkylsulfonylamino is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy , Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl , Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl and N, N-dialkylurea Substituents other than), (l) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (m) substituted alkoxy, provided that a substituent of an alkyl moiety of the substituted alkoxy Alkoxy-NR "R", unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, Alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbon Does not include aryl / heteroaryl substituted with alkylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea), (n) amidine and alkyl, substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Amidine monosubstituted with a substituent independently selected from the group consisting of aryl, heteroaryl and heterocyclic, (o) -C (O) NR '''R''', wherein each R ''' Independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of cyclic and substituted heterocyclic, provided that one R '''is unsaturated heterocyclylalkyl, aryl, heteroaryl or halogen, hydroxyl, amino, nitro, trifluoromethyl, tri Fluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyl Oxy, acyl, alkylcarbonylamino, alkoxycarbon For aryl / heteroaryl substituted with amino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, the remaining R '''is alkyl, substituted alkyl (excluding unsaturated heterocyclyl substituted-alkyl) Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic], (p) -NR ¹² C (O)- R ⁸ where R ⁸ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic R ¹² is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic), (q) -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl , -SO ₂ -substituted heteroaryl or -SO ₂ -alkyl, (r) -NR'C (O) NR ⁹ R ⁹ , wherein R 'is alkyl, substituted alkyl, aryl, 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, substituted heteroaryl, heterocyclic, and substituted heterocyclic), (s) -NR'C (O) OR ⁹ , wherein R Is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ⁹ is hydrogen , Alkyl, substituted alkyl, cycloal , Substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic), (t) -aminocarbonyl- (N-formyl Heterocyclyl) 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 hydroxy, 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O- (N -Succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-β-yl, -NHOY, where Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl ), -NH (CH ₂ ) _p COOY (where p is an integer from 1 to 8, Y is as defined above), -OCH ₂ NR ⁹ R ¹⁰ [where R ⁹ is -C (O) -aryl And -C (O) -substituted aryl, R ¹⁰ is selected from the group consisting of hydrogen and -CH ₂ COOR ¹¹ , wherein R ¹¹ is alkyl; and -NHSO ₂ Z, wherein , Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic), Q is -C (X) NR ^7- , wherein R ⁷ is selected from the group consisting of hydrogen and alkyl, X is selected from the group consisting of oxygen and sulfur; Provided that when R ¹ is p-CH ₃ -Φ, R ⁶ is methoxy, Q is -C (O) NH-, and R ² and R ³ combine to form a pyrrolidinyl group, then R ⁵ is p-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, p-[-OCH ₂ CH ₂ N (isopropyl) ₂ ] -benzyl-, p-[-OCH ₂ CH ₂ -1- pyrrolidinyl) -benzyl _{-, p - [- OCH 2} CH 2 -1- (4- pyrimidinyl) piperazinyl] -benzyl _{-, p - [- OCH 2} CH 2 -N- morpholinyl); -Benzyl, or p-[-OCH ₂ CH ₂ -N-piperidinyl)]-benzyl-. 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. The compound of claim 14, wherein 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-tert-butylphenyl, 4-tert-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazole 4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 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-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyri 3-yl, pyrimidin-2-yl, 4- (3'-dimethyl amino -n- propoxy) - is selected from phenyl and 1-methylpyrazole-4-group of days. 14. The method of claim 13 wherein, R ² is hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2} -2- thienyl and - is selected from the group consisting of (CH _{2) 2} -Φ. The method of claim 13, wherein R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ form a heterocyclic group or a substituted heterocyclic group. 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 group or a substituted heterocyclic group. The compound of claim 13, wherein R ³ is methyl, phenyl, benzyl, diphenylmethyl, —CH ₂ CH ₂ —COOH, —CH ₂ —COOH, 2-amidoethyl, iso-butyl, tert-butyl, —CH ₂ O-benzyl and hydroxymethyl. The method of claim 13, wherein Q is —C (O) NH— or —C (S) NH—. The compound of claim 13, wherein R ⁵ is 4- [NH ₂ CH ₂ C (O) NH-] benzyl, 4- [HOOCCH ₂ CH ₂ C (O) NH-] benzyl, 4-[-NHC (O) CH ₂ NHBoc] benzyl, 4-[-NHC (O) CH (CH ₃ ) NHBoc] benzyl, 4-[-NHC (O) CH (CH ₂ Φ) NHBoc] benzyl, 4-[-NHC (O) CH ₂ NHC (O) NH-3′-methylphenyl] benzyl, 4-[-NHC (O) CH (NHBoc) (CH ₂ ) ₄ NHCbz] benzyl, 4-[-NHC (O) CH ₂ CH (C (O) OCH ₂ Φ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ) NHBoc] benzyl, 4- [H ₂ NCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- (BocHNCH ₂ CH ₂ CH ₂ C (O) NH-) benzyl, 4- [ΦCH ₂ OCH ₂ (BocHN) CHC (O) NH-] benzyl, 4- [ CH ₃ NHCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH ₃ N (Boc) CH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- [ΦCH ₂ OCH ₂ (H ₂ N) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O ) NH-] benzyl, 4- [ΦCH ₂ O (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [OH (O) C (NH ₂ ) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl, 4- [CH ₃ NHCH ₂ C (O) NH-] benzyl, 4- [(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxyphenyl-]-benzyl, 4- [2-carboxylme Tylphenyl-]-benzyl, 4- [ΦCH ₂ OC (O) NHCH ₂ CH ₂ NH-] benzyl, 4-N [-(SO ₂ ) CH ₃ ] -CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] Benzyl, 4-tert-butyl-O (O) CCH ₂ -O-benzylNH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- (2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH ₂ NH) benzyl, 4-[-OCH ₂ CH ₂ -1 '-(4'-pyrimidinyl)- Piperazinyl] -benzyl, 4-[-OCH ₂ CH _2- (1'-piperidinyl) -benzyl, 4-[-OCH ₂ CH _2- (1'-pyrrolidinyl)]-benzyl, 4- [-OCH ₂ CH ₂ CH _2- (1'-piperidinyl)]-benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ -O-]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (1 '-(4'-methylpiperazinyl))]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- 4- (3'-Chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH ₂ CH ₂ N (Φ) CH ₂ CH ₃ ] -benzyl, 4-[-OCH ₂ -3'- (N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidinyl] benzyl, 3-[-O- (N-methylpiperidine-4- Il] benzyl, 4-[-O- (N-methylpiperidin-4-yl] benzyl, 4- [di-iso-propylamino-CH ₂ CH ₂ O-]-benzyl, 4- [N-3 -methyl Till in -N- trifluoro methanesulfonyl) amino] _{benzyl, 4 - [- OCH 2 CH} 2 - (N- morpholinyl)] - _{benzyl, 4 - [- OCH 2 CH} (NHBoc) CH 2 cyclohexyl] -Benzyl, 4-[-OCH ₂ CH _2- (N-piperidinyl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (4-m-chlorophenyl) -piperazin-1-yl] -Benzyl, 4-[-OCH ₂ CH _2- (N-homopiperidinyl) -benzyl, 4-[-OCH ₂ CH ₂ N (benzyl) ₂ ] -benzyl, 3-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ]- Benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) benzyl] -benzyl, 4- [2- (2- Azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl, [cyclopentylacetylenyl] -benzyl, 4-[-C≡C-Φ-4'Φ] -benzyl, 4- [ -C≡C-CH ₂ -OS (O) ₂ -4'-CH ₃ -Φ] -benzyl, 4-[-C≡C-CH ₂ NHC (O) NH ₂ ] -benzyl, 4-[-C ≡C-CH ₂ -O- (4'-COOCH ₂ CH ₃ ) Φ] -benzyl, 4-[-C≡C-CH (NH ₂ ) -cyclohexyl] -benzyl, 4-[-C≡C- CH ₂ -O-phenyl] -benzyl, 4-[-C≡C-CH ₂ OCH ₃ ] -benzyl, 4-[-C≡C-CH ₂ -O- (4'-C (O) OC ₂ H ₅ ) phenyl] -benzyl, 4-[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl, 4-[-C≡C-CH ₂ CH (NHC (O) CH ₃ ) C (O) OH]- Benzyl, 4-[-C≡C-CH ₂ NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (N-morpholino)]-benzyl, 4-[-OCH ₂ COOH] -benzyl, 4-[-OCH ₂ COO-tert-butyl] -benzyl, 4-[-N (SO ₂ CH ₃ ) (CH ₂ ) ₃ -N (CH ₃ ) ₂ ] -benzyl, 4-[-NHS (O) ₂ CF ₃ ] -benzyl, 4-[-C (= NH) NH ₂ ] -benzyl, 4- [ -NHSO ₂ -CH ₂ Cl] -benzyl, 4-[-OCH ₂ C (O) NH-benzyl] -benzyl, 4-[-OCH ₂ C (O) O-benzyl] -benzyl, 4-[-OCH ₂ C (O) OH] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy-4- (3-methoxypyrrole-2-yl) -piperazinyl] -benzyl, 4- [-OCH ₂ C (O) NH ₂ ] -benzyl, 4-[-OCH ₂ C (O) NH-tert-butyl] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy -4-phenyl) -piperidinyl] -benzyl, 4-[-NHSO ₂ -CH = CH ₂ ] -benzyl, 4-[-NHSO ₂ -CH ₂ CH ₂ Cl] -benzyl, 4-benzyl-benzyl, 4-[-OCH ₂ C (O) piperidin-1-yl] benzyl, 4-[-OCH ₂ C (O) N (CH (CH ₃ ) ₂ ) ₂ ] benzyl, 4-amidinobenzyl, 4 Acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4-(-NHC (O) CH ₂ NHC (O) NH-Fluorescein) benzyl, 4- (NHC (O) CH ₂ CH (NH ₂ ) COOH, (1-toluenesulfonylimidizol-4-yl) -methyl-, [(1-N , N-dimethylaminosulfonyl) -imidizol-4-yl] methyl-, 4- (N-toluenesulfonyl-amino) benzyl and 4- [N-methyltrifluoroacetamido) phenyl The method chosen. The compound of claim 13, wherein R ^{6 ′} is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, tertiary -Butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4-β-methoxycyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, -NH ₂ , Benzyloxy, -NHCH ₂ COOH, -NHCH ₂ CH ₂ COOH, -NH-adamantyl, -NHCH ₂ CH ₂ COOCH ₂ CH ₃ , -NHSO ₂ -p-CH ₃ -Φ, -NHOR ⁸ (where R ⁸ is hydrogen, methyl, iso-propyl or benzyl), O- (N-succinimidyl), -O-cholest-5-en-3-β-yl, -OCH ₂ -OC (O) C (CH ₃ ) ₃ , -O (CH ₂ ) _z NHC (O) W, wherein z is 1 or 2, W is pyrid-3-yl, N-methylpyridyl and N-methyl-1,4 -Dihydro-pyrid-3-yl], -NR "C (O) -R ', wherein R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH ₂ C (O) OCH ₂ CH ₃ ). The compound of claim 13, wherein the compound is N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (carboxy) propionamido] -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) thioureido] acetamido} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-methylphenyl) ureido] acetamido} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-butoxylcarbonyl-Nε-carbenzyloxy-L-lysyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-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-aminobutyramido) -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonylamino) butyramido] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramido] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonyl-N-methylamino) butyramido] -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-butoxylcarbonylsarcosyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxylcarbonylsarcosyl) 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-dimethylglycyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxybenzyloxy) -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-carbenzyloxyamino) ethyl] amino} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbenzyloxyamino) 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-dimethylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3- (N, N-dimethylaminopropoxy] -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-tert-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-diethylamino) 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- (thiazole-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-dimethylamino) 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-phenylalanine; 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) sarcosyl-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- Inyl} -D, L-phenylalanine; N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5-dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl}- 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-[(l-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-[(l-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- (azpan-1-yl) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azpan-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-methylpiperidine-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-sulfonyl) -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-[(benzyloxycarbonyl) methoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzyloxycarbonyl) 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-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidin-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 tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolyl-L-4- (N-methylpiperidinoxy) -phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiapropyl-L- (4-methylpiperidinoxy) phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine tert-butyl ester; And N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine, pharmaceutically acceptable salts thereof, and one ester is methyl ester, ethyl ester, n-propyl ester, And is selected from the group consisting of said ester compounds substituted with another ester selected from the group consisting of isopropyl ester, n-butyl ester, isobutyl ester, secondary-butyl ester and tert-butyl ester. The method of claim 23, wherein the compound is N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of formula (IA) at a condition that the compound binds to VLA-4. Formula IA In the above formula, R ¹ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, R ² is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl and substituted Selected from the group consisting of heteroaryl, R ¹ and R ² together with the nitrogen atom bonded to R ² and the SO ₂ group bonded to R ¹ can form a heterocyclic or substituted heterocyclic group , R ³ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ² is When not forming a heterocyclic group with R ¹ , R ² and R ³ are a heterocyclic group or a substituted heterocyclic group together with a nitrogen atom bonded to R ² and a carbon atom bonded to R ³ . Form the R ⁵ is — (CH ₂ ) _x —Ar—R ^{5 ′} {wherein R ^{5 ′} is (a) substituted alkylcarbonylamino, provided that at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyhetero Aryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thio Aryl, substituted thio , Thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy , Heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) _2- Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O ) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OSO ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ - heterocyclic, -NRS (O) ₂ - substituted heteroaryl Click, -NRS (O) ₂ -NR- alkyl, -NRS (O) ₂ -NR- substituted alkyl, -NRS (O) ₂ -NR- aryl, -NRS (O) ₂ -NR- substituted aryl , -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-substituted aryl Amino, mono and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, Difference by asymmetric disubstituted amines having different substituents selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and conventional blocking groups such as Boc, Cbz and formyl, etc. A substituted alkyl group having an amino group, and alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted Al Kenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl); (b) the alkoxy moiety is carboxyl and -COOR Alkoxyaryl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (c) aryl and heteroaryl, (d) -NR ' R '[where each R' is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, heterocyclic and substituted heterocyclic, wherein at least one R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic, As a further condition, when R 'is substituted alkyl, at least one of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino , Alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl , Carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl- Substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thio Aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cyclo Alkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -Substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS ( O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR Wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl , -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS ( O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, wherein , R is hydrogen or alkyl), mono- and di-alkylamino, mono- and di-substituted alkylamino, 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, and alkyl, substituted alkyl, aryl, substituted ah , Asymmetric disubstituted amines having different substituents selected from heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Substituted alkyl groups, and alkyl / substituted alkyl groups, wherein the substituents are -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -Cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic , -SO ₂ -substituted heterocyclic or -SO ₂ NRR (where R is hydrogen or alkyl), (e) -alkoxy-NR "R" where each R ″ is independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hete Aryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that when each R ″ is substituted alkyl one or more of the substituents of the substituted alkyl moiety is alkoxy, substituted alkoxy , Acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl Oxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyl Heteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, sphere Anidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thio Heterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxy Thiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR ( Wherein R is hydrogen or alkyl), -NRS (O) ₂ -alkyl, -NRS (O) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl,- NRS (O) ₂ -substituted heteroaryl, -NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocyclic, -NRS (O) ₂ -NR-alkyl, -NRS (O ) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted heterocyclic, 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic And asymmetric with different substituents selected from substituted heterocyclics Substituted alkyl groups having disubstituted amines and amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, and alkyl / substituted alkyl groups wherein the substituents are -SO ₂ -alkyl, -SO ₂ -Substituted alkyl, -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl , -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -substituted heterocyclic or -SO ₂ NRR, wherein R is hydrogen or alkyl ), (F) substituted alkenyl or substituted alkynyl, provided that at least one of the substituents of the substituted alkenyl / alkynyl moiety is alkyl, substituted alkyl, aryl, substituted aryl, Consisting of cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic And when substituted with substituted alkyl, one or more of the substituents of the substituted alkyl moiety may be alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amino Dino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl Alkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted hetero Cyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thio Cycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, hetero Aryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted Alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -Heterocyclic, -OS (O) ₂ -substituted heterocyclic, -OS (O) ₂ -NRR, wherein R is hydrogen or alkyl, -NRS (O) ₂ -alkyl, -NRS (O ) ₂ -substituted alkyl, -NRS (O) ₂ -aryl, -NRS (O) ₂ -substituted aryl, -NRS (O) ₂ -heteroaryl, -NRS (O) ₂ -substituted heteroaryl,- NRS (O) ₂ -heterocyclic, -NRS (O) ₂ -substituted heterocycle Ric, -NRS (O) ₂ -NR-alkyl, -NRS (O) ₂ -NR-substituted alkyl, -NRS (O) ₂ -NR-aryl, -NRS (O) ₂ -NR-substituted aryl, -NRS (O) ₂ -NR-heteroaryl, -NRS (O) ₂ -NR-substituted heteroaryl, -NRS (O) ₂ -NR-heterocyclic, -NRS (O) ₂ -NR-substituted Heterocyclic, 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-heterocyclicamino, mono- and di-substituted heterocyclic amino, and alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted Asymmetric disubstituted amines having different substituents selected from heteroaryls, heterocyclics and substituted heterocyclics, and substituted alkyls having amino groups blocked by conventional blocking groups such as Boc, Cbz and formyl, etc. Group, or alkyl / substituted alkyl groups (wherein the substituents are -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl al, -SO ₂ - cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic, -SO ₂ -Substituted heterocyclic and -SO ₂ NRR (where R is hydrogen or alkyl); (g) substituted aryloxy and substituted heteroaryloxy, provided substituted aryl At least one of the substituents of oxy / heteroaryloxy is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2- Dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxyca Substituents other than alkylamino, alkylsulfonylamino, N-alkyl and N, N-dialkylurea], (h) -alkoxy-saturated heterocyclic, -alkoxy-substituted saturated heterocyclic, -substituted alkoxy -Heterocyclic and -substituted alkoxy-substituted saturated heterocyclic, (i) -O-heterocyclic and -O-substituted heterocyclic, (j) tetrazolyl, (k) -NR-SO ₂ Substituted alkyl, wherein R is hydrogen, alkyl or aryl, provided that at least one of the substituents of the alkyl moiety of the substituted alkylsulfonylamino is halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy , Alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl , Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl and N, N-dialkylurea Substituents other than), (l) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (m) substituted alkoxy, provided that a substituent of an alkyl moiety of the substituted alkoxy Alkoxy-NR "R", unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, Alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbon Does not include aryl / heteroaryl substituted with alkylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea), (n) amidine and alkyl, substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Amidine monosubstituted with a substituent independently selected from the group consisting of aryl, heteroaryl and heterocyclic, (o) -C (O) NR '''R''', wherein each R ''' Independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of cyclic and substituted heterocyclic, provided that one R '''is unsaturated heterocyclylalkyl, aryl, heteroaryl or halogen, hydroxyl, amino, nitro, trifluoromethyl, tri Fluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyl Oxy, acyl, alkylcarbonylamino, alkoxycarbon For aryl / heteroaryl substituted with amino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, the remaining R '''is alkyl, substituted alkyl (excluding unsaturated heterocyclyl substituted-alkyl) Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic], (p) -NR ¹² C (O)- R ⁸ where R ⁸ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic R ¹² is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic), (q) -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl , -SO ₂ -substituted heteroaryl or -SO ₂ -alkyl, (r) -NR'C (O) NR ⁹ R ⁹ , wherein R 'is alkyl, substituted alkyl, aryl, 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, substituted heteroaryl, heterocyclic, and substituted heterocyclic), (s) -NR'C (O) OR ⁹ , wherein R Is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ⁹ is hydrogen , Alkyl, substituted alkyl, cycloal , Substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic), (t) -aminocarbonyl- (N-formyl Heterocyclyl) 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 hydroxy, 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O- (N -Succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-β-yl, -NHOY, where Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl ), -NH (CH ₂ ) _p COOY (where p is an integer from 1 to 8, Y is as defined above), -OCH ₂ NR ⁹ R ¹⁰ [where R ⁹ is -C (O) -aryl And -C (O) -substituted aryl, R ¹⁰ is selected from the group consisting of hydrogen and -CH ₂ COOR ¹¹ , wherein R ¹¹ is alkyl; and -NHSO ₂ Z, wherein , Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic), Q is -C (X) NR ^7- , wherein R ⁷ is selected from the group consisting of hydrogen and alkyl, X is selected from the group consisting of oxygen and sulfur; Provided that when R ¹ is p-CH ₃ -Φ, R ⁶ is methoxy, Q is -C (O) NH-, and R ² and R ³ combine to form a pyrrolidinyl group, then R ⁵ is p-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, p-[-OCH ₂ CH ₂ N (isopropyl) ₂ ] -benzyl-, p-[-OCH ₂ CH ₂ -1- pyrrolidinyl) -benzyl _{-, p - [- OCH 2} CH 2 -1- (4- pyrimidinyl) piperazinyl] -benzyl _{-, p - [- OCH 2} CH 2 -N- morpholinyl); -Benzyl, or p-[-OCH ₂ CH ₂ -N-piperidinyl)]-benzyl-. The pharmaceutical composition 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. 27. The compound of claim 26, wherein 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-tert-butylphenyl, 4-tert-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazole 4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 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-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyri 3-yl, pyrimidin-2-yl, 4- (3'-dimethyl amino -n- propoxy) -phenyl, and 1-methylpyrazole-pharmaceutical composition is selected from the group consisting of 4-days. 26. The method of claim 25 wherein, R ² is hydrogen, methyl, phenyl, benzyl, - (CH _{2) 2} -2- thienyl and - (CH ₂₎ a pharmaceutical composition is selected from the group consisting of ₂ -Φ. The pharmaceutical composition of claim 25, wherein R ¹ and R ² form a heterocyclic group or a substituted heterocyclic group together with a nitrogen atom bonded to R ² and a SO ₂ group bonded to R ¹ . The pharmaceutical composition of 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. The compound of claim 25, wherein R ³ is methyl, phenyl, benzyl, diphenylmethyl, —CH ₂ CH ₂ —COOH, —CH ₂ —COOH, 2-amidoethyl, iso-butyl, tert-butyl, —CH ₂ O-benzyl and hydroxymethyl selected from the group consisting of. The pharmaceutical composition of claim 25, wherein Q is -C (O) NH- or -C (S) NH-. The compound of claim 25, wherein R ⁵ is 4- [NH ₂ CH ₂ C (O) NH-] benzyl, 4- [HOOCCH ₂ CH ₂ C (O) NH-] benzyl, 4-[-NHC (O) CH ₂ NHBoc] benzyl, 4-[-NHC (O) CH (CH ₃ ) NHBoc] benzyl, 4-[-NHC (O) CH (CH ₂ Φ) NHBoc] benzyl, 4-[-NHC (O) CH ₂ NHC (O) NH-3′-methylphenyl] benzyl, 4-[-NHC (O) CH (NHBoc) (CH ₂ ) ₄ NHCbz] benzyl, 4-[-NHC (O) CH ₂ CH (C (O) OCH ₂ Φ) -NHCbz] benzyl, 4-Φ-benzyl, 4-[-NHC (O) CH (CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ) NHBoc] benzyl, 4- [H ₂ NCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- (BocHNCH ₂ CH ₂ CH ₂ C (O) NH-) benzyl, 4- [ΦCH ₂ OCH ₂ (BocHN) CHC (O) NH-] benzyl, 4- [ CH ₃ NHCH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- (N-methylpiperidine-4-oxy) -benzyl, 4- [CH ₃ N (Boc) CH ₂ CH ₂ CH ₂ C (O) NH-] benzyl, 4- [ΦCH ₂ OCH ₂ (H ₂ N) CHC (O) NH-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O ) NH-] benzyl, 4- [ΦCH ₂ O (O) C (Cbz-NH) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [OH (O) C (NH ₂ ) CHCH ₂ CH ₂ -C (O) NH-] benzyl, 4- [CH ₃ (N-Boc) NCH ₂ C (O) NH-] benzyl, 4- [CH ₃ NHCH ₂ C (O) NH-] benzyl, 4- [(CH ₃ ) ₂ NCH ₂ C (O) NH-] benzyl, 4-[-O-CH (COOH) Φ] benzyl, 4- [2-carboxyphenyl-]-benzyl, 4- [2-carboxylme Tylphenyl-]-benzyl, 4- [ΦCH ₂ OC (O) NHCH ₂ CH ₂ NH-] benzyl, 4-N [-(SO ₂ ) CH ₃ ] -CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] Benzyl, 4-tert-butyl-O (O) CCH ₂ -O-benzylNH] benzyl, 4- [N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- (2-formyl-1,2,3,4-tetrahydroisoquinolin-3-yl-CH ₂ NH) benzyl, 4-[-OCH ₂ CH ₂ -1 '-(4'-pyrimidinyl)- Piperazinyl] -benzyl, 4-[-OCH ₂ CH _2- (1'-piperidinyl)]-benzyl, 4-[-OCH ₂ CH _2- (1'-pyrrolidinyl)]-benzyl, 4 -[-OCH ₂ CH ₂ CH _2- (1'-piperidinyl)]-benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ -O-] benzyl, 4-[(CH ₃ ) ₂ NCH ₂ CH ₂ -O-]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (1 '-(4'-methylpiperazinyl))]-benzyl, 4-[-OCH ₂ CH ₂ CH ₂ -4- (3'-Chlorophenyl) -piperazin-1-yl] -benzyl, 4-[-OCH ₂ CH ₂ N (Φ) CH ₂ CH ₃ ] -benzyl, 4-[-OCH ₂ -3 ' -(N-Boc) -piperidinyl] -benzyl, 4-[-O- (3- (N-Boc) -piperidinyl] benzyl, 3-[-O- (N-methylpiperidine-4 -Yl] benzyl, 4-[-O- (N-methylpiperidin-4-yl] benzyl, 4- [di-iso-propylamino-CH ₂ CH ₂ O-]-benzyl, 4- [N- 3-methyl Butyl-N-trifluoromethanesulfonyl) amino] benzyl, 4-[-OCH ₂ CH _2- (N-morpholinyl)]-benzyl, 4-[-OCH ₂ CH (NHBoc) CH ₂ cyclohexyl] -Benzyl, 4-[-OCH ₂ CH _2- (N-piperidinyl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (4-m-chlorophenyl) -piperazin-1-yl] -Benzyl, 4-[-OCH ₂ CH _2- (N-homopiperidinyl) -benzyl, 4-[-OCH ₂ CH ₂ N (benzyl) ₂ ] -benzyl, 3-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ]- Benzyl, 4-[-OCH ₂ CH ₂ N (C ₂ H ₅ ) ₂ ] -benzyl, 4-[-OCH ₂ CH ₂ CH ₂ N (CH ₃ ) benzyl] -benzyl, 4- [2- (2- Azabicyclo [3.2.2] octan-2-yl) ethyl-O-] benzyl, [cyclopentylacetylenyl] -benzyl, 4-[-C≡C-Φ-4'Φ] -benzyl, 4- [ -C≡C-CH ₂ -OS (O) ₂ -4'-CH ₃ -Φ] -benzyl, 4-[-C≡C-CH ₂ NHC (O) NH ₂ ] -benzyl, 4-[-C ≡C-CH ₂ -O- (4'-COOCH ₂ CH ₃ ) Φ] -benzyl, 4-[-C≡C-CH (NH ₂ ) -cyclohexyl] -benzyl, 4-[-C≡C- CH ₂ -O-phenyl] -benzyl, 4-[-C≡C-CH ₂ OCH ₃ ] -benzyl, 4-[-C≡C-CH ₂ -O- (4'-C (O) OC ₂ H ₅ ) phenyl] -benzyl, 4-[-C≡C-CH ₂ CH (C (O) OCH ₃ ) ₂ ] -benzyl, 4-[-C≡C-CH ₂ CH (NHC (O) CH ₃ ) C (O) OH]- Benzyl, 4-[-C≡C-CH ₂ NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl)]-benzyl, 4-[-OCH ₂ CH ₂ CH _2- (N-morpholino)]-benzyl, 4-[-OCH ₂ COOH] -benzyl, 4-[-OCH ₂ COO-tert-butyl] -benzyl, 4-[-N (SO ₂ CH ₃ ) (CH ₂ ) ₃ -N (CH ₃ ) ₂ ] -benzyl, 4-[-NHS (O) ₂ CF ₃ ] -benzyl, 4-[-C (= NH) NH ₂ ] -benzyl, 4- [ -NHSO ₂ -CH ₂ Cl] -benzyl, 4-[-OCH ₂ C (O) NH-benzyl] -benzyl, 4-[-OCH ₂ C (O) O-benzyl] -benzyl, 4-[-OCH ₂ C (O) OH] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy-4- (3-methoxypyrrole-2-yl) -piperazinyl] -benzyl, 4- [-OCH ₂ C (O) NH ₂ ] -benzyl, 4-[-OCH ₂ C (O) NH-tert-butyl] -benzyl, 4-[-OCH ₂ CH ₂ -1- (4-hydroxy -4-phenyl) -piperidinyl] -benzyl, 4-[-NHSO ₂ -CH = CH ₂ ] -benzyl, 4-[-NHSO ₂ -CH ₂ CH ₂ Cl] -benzyl, 4-benzyl-benzyl, 4-[-OCH ₂ C (O) piperidin-1-yl] benzyl, 4-[-OCH ₂ C (O) N (CH (CH ₃ ) ₂ ) ₂ ] benzyl, 4-amidinobenzyl, 4 Acetamidobenzyl, 4- (N-methyl) acetamidobenzyl, 4-(-NHC (O) CH ₂ NH C (O) NH-fluorescein) benzyl, 4- (NHC (O) CH ₂ CH (NH ₂ ) COOH, (1-toluenesulfonylimidizol-4-yl) -methyl-, [(1- N, N-dimethylaminosulfonyl) -imidizol-4-yl] methyl-, 4- (N-toluenesulfonyl-amino) benzyl and 4- [N-methyltrifluoroacetamido) phenyl Pharmaceutical composition selected from. The compound of claim 25, wherein R ^{6 ′} is 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, tertiary -Butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4-β-methoxycyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, -NH ₂ , Benzyloxy, -NHCH ₂ COOH, -NHCH ₂ CH ₂ COOH, -NH-adamantyl, -NHCH ₂ CH ₂ COOCH ₂ CH ₃ , -NHSO ₂ -p-CH ₃ -Φ, -NHOR ⁸ (where R ⁸ is hydrogen, methyl, iso-propyl or benzyl), O- (N-succinimidyl), -O-cholest-5-en-3-β-yl, -OCH ₂ -OC (O) C (CH ₃ ) ₃ , -O (CH ₂ ) _z NHC (O) W, wherein z is 1 or 2, W is pyrid-3-yl, N-methylpyridyl and N-methyl-1,4 -Dihydro-pyrid-3-yl], -NR "C (O) -R ', wherein R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH ₂ C (O) OCH ₂ CH ₃ ) . The compound of claim 25, wherein the compound is N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxyl-carbonylgylsil) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(glycyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (carboxy) propionamido] -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) thioureido] acetamido} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(N-tert-butoxylcarbonylgylsil) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4- {2- [3- (3-methylphenyl) ureido] acetamido} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-butoxylcarbonyl-Nε-carbenzyloxy-L-lysyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [γ- (α-benzyl-Nα-carbenzyloxy-L-aspartyl) amino] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(Nα-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-aminobutyramido) -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonylamino) butyramido] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-methylamino) butyramido] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [4- (N-tert-butoxylcarbonyl-N-methylamino) butyramido] -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-butoxylcarbonylsarcosyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4-[(N-tert-butoxylcarbonylsarcosyl) 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-dimethylglycyl) amino] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- (α-carboxybenzyloxy) -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-carbenzyloxyamino) ethyl] amino} -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- {N- [2- (N-carbenzyloxyamino) 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-dimethylamino) propoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -N-methyl-L-serinyl-4- [3- (N, N-dimethylaminopropoxy] -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-tert-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-diethylamino) 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- (thiazole-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-dimethylamino) 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-phenylalanine; 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) sarcosyl-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- Inyl} -D, L-phenylalanine; N- (toluene-4-sulfonyl) sarcosyl-4- {3-[(4,5-dihydro-4-oxo-5-phenyloxazol-2-yl) amino] prop-1-ynyl}- 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-[(l-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-[(l-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- (azpan-1-yl) ethoxy] -L-phenylalanine; N- (toluene-4-sulfonyl) -L-prolyl-4- [2- (azpan-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-methylpiperidine-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-sulfonyl) -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-[(benzyloxycarbonyl) methoxy] -L-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(benzyloxycarbonyl) 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-phenylalanine methyl ester; N- (toluene-4-sulfonyl) -L-prolyl-4-[(piperidin-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 tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolyl-L-4- (N-methylpiperidinoxy) -phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiapropyl-L- (4-methylpiperidinoxy) phenylalanine tert-butyl ester; N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine tert-butyl ester; And N- (toluene-4-sulfonyl) -L-prolyl- (4-phenyl) -L-phenylalanine, a pharmaceutically acceptable salt and one ester thereof is methyl ester, ethyl ester, n-propyl ester, iso A pharmaceutical composition selected from the group consisting of ester compounds substituted with another ester selected from the group consisting of propyl esters, n-butyl esters, isobutyl esters, secondary-butyl esters and tert-butyl esters. A method of treating an inflammatory disease mediated by VLA-4, comprising administering the pharmaceutical composition of claim 25 to a patient. 37. The disease according to claim 36, wherein the inflammatory disease is asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute combustible diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation And acute leukocyte mediated lung injury as seen in tumor metastasis, meningitis, encephalitis, seizures and other cerebral injuries, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and adult respiratory distress syndrome.