KR20020009607A - Carboxylic acid derivatives that inhibit the binding of integrins to their receptors - Google Patents

Abstract

The present invention provides a method for inhibiting the binding of? ₄ ? ₁ integrin to its receptor, for example, VCAM-1 (vascular cell sorter molecule-1) and fibronectin; Compounds that inhibit such binding; To pharmaceutical active compositions containing such compounds and to the use of such compounds for use in agents for the inhibition or prevention of disease states in which such inhibition or [alpha] _{4 [} beta] _i is involved.

Description

BACKGROUND OF THE INVENTION [0002] Carboxylic acid derivatives inhibit the binding of integrins to their receptors.

When tissues are infected or damaged by microorganisms, leukocytes play a major role in the inflammatory response. One of the most important aspects of the inflammatory response is cell sorption. Generally, leukocytes are found to circulate through the bloodstream. However, when a tissue is infected or damaged, white blood cells recognize the infected or damaged tissue, bind it to the capillary wall, and then move through the capillary to the affected or damaged tissue. This process is mediated by a class of proteins called cell sorbent molecules.

Leukocytes are divided into three types: granulocytes, monocytes, and lymphocytes. The integrin [alpha] _{4 [} beta] ₁ (also referred to as very late antigen-4 (VLA-4)) is a heterologous epitope expressed on the surface of monocytes, lymphocytes and granulocytes (eosinophils and basophils) It is a dimeric protein. This protein plays a key role in cell adsorption through its ability to recognize and bind VCAM-1 and fibronectin (a protein associated with endothelial cells that make up the inner wall of a capillary).

Upon infection or damage of capillary surrounding tissue, endothelial cells express a series of adsorbing molecules, including VCAM-1, which is important for binding leukocytes to fight infections. Leukocytes bind with specific adsorbing molecules to slow down the flow and roll along the activated endothelium before binding to VCMA-1 or fibronectin. At this time, monocytes, lymphocytes, basophils and eosinophils can be firmly combined with the VCAM-1 or fibronectin on the blood vessel wall via the α ₄ β ₁ integrin. There is evidence that these interactions are also related to their initial rolling process as well as migration of leukocyte cells to damaged tissues.

Although leukocyte migration to wound sites may assist in combating infection and destroying foreign materials, in many cases this migration can not be controlled, leading to leukocyte populations and widespread tissue damage. Thus, compounds that can block this process may be useful as therapeutic agents. In this respect, it may be beneficial to develop inhibitors that inhibit the binding of leukocytes to VCAM-1 and fibronectin.

Some of the diseases that may be treated by inhibition of alpha ₄ beta ₁ binding include but are not limited to arteriosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, transplant rejection, Type I diabetes is included. In addition to being found in some white blood cells, α ₄ β ₁ is also found in many cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. α ₄ β ₁ related cell adhesion have been suggested that are involved in metastasis of certain cancers. Thus, inhibitors of? ₄ ? ₁ binding may be useful in the treatment of some types of cancer.

Separation and purification of peptides that inhibit the binding of [alpha] _{4 [} beta] _l to proteins is described in U.S. Patent No. 5,510,332. Peptides that inhibit binding are described in WO 95/15973, EP 0 341 915, EP 0 422 938 A1, USP 5,192,746 and WO 96/06108. Novel compounds useful for the inhibition and prevention of cell adsorption and cell adhesion-mediated pathology are described in WO 96/22966, WO 98/04247 and WO 98/04913.

It is therefore an object of the present invention to provide a novel compound which is an inhibitor of? ₄ ? ₁ binding and a pharmaceutical composition containing such a novel compound.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula (I): < EMI ID =

In this formula,

Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;

q is an integer from 3 to 10;

A is selected from ^{O, S, C (R 16} ) (R 17) , and the group consisting of NR ^6;

E is selected from the group consisting of CH ₂ , O, S and NR ⁷ ;

J is selected from the group consisting of O, S, and NR ⁸ ;

T is selected from the group consisting of C (O) and (CH _{2) b} (wherein, b is an integer from 0 to 3);

M is selected from the group consisting of ^{C (R 9) (R 10} ) and (CH _{2) u} (wherein, u is an integer from 0 to 3);

L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n wherein n is an integer of 0 or 1;

X is _{CO 2 B, PO 3 H 2} , SO 3 H, SO 2 NH 2, SO 2 NHCOR 12, OPO 3 H 2, C (O) NHC (O) R 13, C (O) NHSO 2 R 14, Is selected from the group consisting of hydrogen, hydroxyl, tetrazolyl, and hydrogen;

W is selected from the group consisting of C, CR < ¹⁵ > and N;

^{B, R 1, R 2,} R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16 , and R ¹⁷ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , nitro, , carboxy, -N (C ₁ -C _{3 alkyl) -C (O) (C 1} -C 3 alkyl), -NHC (O) N ( C 1 -C 3 alkyl) C (O) NH (C 1 - C ₃ alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkylamino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C (O) O- (C 1 -C 3 ) alkyl, -C (O) NH- (C 1 -C 3) alkyl, -C (O) N (C 1 -C 3 _{alkyl) 2, -CH = NOH, -PO} 3 H 2, -OPO 3 H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diaryl Amino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhetero Cycle reel, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and It is selected from the group consisting of a -C (O) NH ^{(benzyl), B, R 1, R} 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11 , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are unsubstituted or substituted with one or more electron donating or electron withdrawing groups, and when L is NR ¹¹ , R ⁴ and R ¹¹ together form a ring R ⁹ and R ¹⁰ may form a ring together, and when A is NR ⁶ and at least one Y is CR ¹ , R ¹ and R ⁶ may form a ring together.

In formula I, preferred compounds are A is NR ^6, E is NR ^7, J is O, M is ^{C (R 9) (R 10} ), q is 4 or 5, T is (CH _{2) b} (wherein, b L is (CH ₂ ) _n wherein n is 0, X is CO ₂ B, W is C or CR ¹⁵ , R ⁴ is aryl, alkylaryl, aralkyl, heterocyclyl, alkyl heterocyclyl or ^{heterocyclylalkyl, R 6, R 7, R} 9, those, wherein R ¹⁰ and R ¹⁵ are independently hydrogen or lower alkyl.

More particularly, the compounds of the present invention may be represented by the formula II: or a pharmaceutically acceptable salt thereof:

In this formula,

Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;

q is an integer from 3 to 7;

T is selected from the group consisting of C (O) and (CH _{2) b} (wherein, b is an integer from 0 to 3);

L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n wherein n is an integer of 0 or 1;

W is selected from the group consisting of C, CR < ¹⁵ > and N;

B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, (C ₁ -C ₃ alkyl) -C (O) R 2, wherein R ₁ , R 2, R ₃ , R 4 and R _{5 are the same or different} and are selected from the group consisting of hydrogen, alkyl, alkoxy, alkenoxy, alkoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, (C ₁ -C ₃ alkyl), -NHC (O) N ( C 1 -C 3 alkyl) C (O) -NH (C 1 -C 3 alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkylamino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C (O) O- (C 1 -C 3) alkyl, -C (O) NH- (C 1 -C 3) Alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, Alkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyl Heterocyclyl, heterocyclylalkyl , Sulfonyl, -SO ₂ - (C ₁ -C ₃ alkyl), -SO ₃ - (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are unsubstituted or substituted with one or more electrons is substituted with a donor or an electron withdrawing group, L is NR ¹¹ be when, R ⁴ and R ¹¹ may form a ring together, and R ⁹ and R ¹⁰ taken together may form a ring, a is NR ⁶ and at least one Y that may form a ring with CR in case of ^1, R ¹ and R ^6.

Preferred compounds of formula II are those, wherein q is 4 or 5, W is C or CR ¹⁵ , T is (CH ₂ ) _b where b is 0 and L is (CH ₂ ) _n , zero) and, R ⁴ is aryl, alkylaryl, aralkyl, and heterocyclyl, alkyl-heterocyclyl or heterocyclylalkyl, R ^6, R ^7, R ^9, R ¹⁰ and R ¹⁵ are independently hydrogen or Lower alkyl.

More specifically, the compounds of the present invention may be represented by the formula (III) or a pharmaceutically acceptable salt thereof:

In this formula,

Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;

q is an integer from 2 to 5;

T is selected from the group consisting of C (O) and (CH _{2) b} (wherein, b is an integer from 0 to 3);

L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n wherein n is an integer of 0 or 1;

B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), alkoxy, alkoxy, alkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , nitro, amino, cyano, carboxy, -C ₃ alkyl), -NHC (O) N ( C 1 -C 3 alkyl) C (O) -NH (C 1 -C 3 alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkylamino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C (O) O- (C 1 -C 3) alkyl, -C (O) NH- (C 1 -C 3) alkyl, - C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, Alkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl , Heterocyclylalkyl, _{Carbonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH (benzyl) R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹¹ are unsubstituted or substituted with one or more electron donating or electron withdrawing groups substituted and, when L is NR ¹¹ il, R ⁴ and R ¹¹ may form a ring together, and R ⁹ and R ¹⁰ taken together may form a ring, when a is NR ⁶ and at least one Y CR ¹ il , R ¹ and R ⁶ may form a ring together.

Preferred formula III compounds R ⁵ is hydrogen, alkyl, aryl, cycloalkyl, alkyl, heterocyclyl, heterocyclyl alkyl, or heterocycle of the reel, wherein T is (CH _{2) b} (wherein, b is 0), Wherein L is (CH ₂ ) _n (wherein n is 0), Y is CR ¹ and C (R ² ) (R ³ ), and q is 2 or 3.

In formula (III), a part of molecules May be the following molecule: < RTI ID = 0.0 >

, And .

In this formula,

R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, CF _3, nitro, amino, cyano, carboxy, -N (C ₁ -C _{3 alkyl) -C (O) (C 1} -C 3 alkyl), -NHC (O) N ( C 1 -C 3 alkyl) _{C (O) -NH (C 1} -C 3 alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkylamino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C ( _{O) O- (C 1 -C 3} ) alkyl, -C (O) NH- (C 1 -C 3) alkyl, -C (O) N (C 1 -C 3 alkyl) _2, -CH = NOH, _{-PO 3 H 2, -OPO 3 H} 2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkyl, alkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, aryl amino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkyl, alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 alkyl ), -SO ₃ - (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH (benzyl) groups; c is an integer from 0 to 2; d is an integer from 0 to 3; e is an integer from 0 to 4; f is 0 or 1;

In one embodiment, R ⁵ is alkylaryl, R ⁴ is aryl, T is (CH ₂ ) _b where b is 0, and L is (CH ₂ ) _n , And each of B, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ is independently hydrogen.

Preferred compounds are:

(Phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid,

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[2-oxo- 1- (phenylmethyl) -4- Pyridinyl] amino} carbonyl) amino] propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-ethyl- 3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({6-methyl-2-oxo-1- (phenylmethyl) -4 - [(phenylmethyl) oxy] -1,2-dihydro-3-pyridinyl} amino) Yl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2,4- dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({4-amino-1 - [(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methyloxy) phenyl) propanoic acid,

(3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (3,4-dimethylphenyl) propanoic acid,

(3S) -3 - {[({4-amino-1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (4-methylphenyl) propanoic acid,

(3S) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (1,4- Pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid,

(Propylamino) -1,2-dihydro-3-pyridinyl] amino} carbonyl) -2,3- Amino] -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-bromophenyl) methyl] -4-methyl- -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid,

(2 - {[2- (methyloxy) ethyl] oxy} ethyl) oxy] -2-oxo-1, , 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-hydroxy- Yl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4 - [(1,1- dimethylethyl) amino] -2-oxo-1,2-dihydro- Decyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- 3-phenylpropanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4- [4-methyltetrahydro- -3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [4- (methyloxy) phenyl] propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3,5-dimethylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3- (methyloxy) phenyl] propanoic acid,

(3S) -3- [3,5-bis (methyloxy) phenyl] -3 - {[({1- [ Dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} amino} carbonyl) } -3- [4-methylphenyl] propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3- (trifluoromethyl) phenyl] propanoic acid,

(Ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1,2,3,4-tetrahydroisoquinoline; 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({4- (1-azetanyl) -1 - [(2- chlorophenyl) methyl] Carbonyl] amino} -3- (4-methylphenyl) propanoic acid,

(2 - {[2- (methyloxy) ethyl] oxy} ethyl) oxy] ethyl} -1,3- Oxy) -1,2-dihydro-3-pyridinyl} amino} carbonyl) amino] -3- (4-

(3S) -3 - {[({1 - [(2- fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid,

(2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- Carbonyl] amino} -3- (4-methylphenyl) propanoic acid,

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -5- 3- (4-methylphenyl) propanoic acid,

(3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2- - dihydro-3-pyridinyl) amino) carbonyl) amino) propanoic acid,

(3S) -3 - ((((1 - ((2- chlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) -Methylphenyl) propanoic acid,

(3S) -3 - ((((1 - ((2- fluorophenyl) methyl) -2-oxo-1,2-dihydro-3- pyridinyl) amino) carbonyl) 4-methylphenyl) propanoic acid,

(3S) -3 - ((((1 - ((2-bromophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) 4-methylphenyl) propanoic acid,

(3S) -3 - (((1 - ((2,4-dichlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) (4-methylphenyl) propanoic acid,

(2-chloro-6-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid,

(3S) -3 - ((((1 - ((2-chlorophenyl) methyl) -4-hydroxy- -3- (4-trifluoromethyl) oxy) phenyl) propanoic acid and salts thereof.

Also included are derivatives such as esters, carbamates, amines, amides, optical isomers and prodrugs.

The present invention also relates to a pharmaceutical composition comprising a physiologically acceptable diluent and at least one compound of the invention.

The present invention also provides a method of inhibiting the binding of a ₄ beta ₁ integrin to VCAM-1, including exposing cell expressing alpha ₄ beta ₁ integrin to cells expressing VCAM-1 in the presence of an inhibitory effective amount of a compound of the invention. . VCAM-1 may be present on the surface of vascular endothelial cells, antigen presenting cells or other cell types. α ₄ β ₁ may be present on the surface of leukocytes such as monocytes, lymphocytes, granulocytes, stem cells, or other cells that naturally express α ₄ β ₁ .

The present invention is generally directed to inhibiting the binding of [alpha] _{4 [} beta] ₁ integrin to its receptor, such as VCAM-1 (vascular cell sorter molecule-1) and fibronectin. Further, the present invention provides pharmaceutically active compositions and the art pharmaceutical controlling the disease symptoms of the α ₄ β ₁ are involved in an active composition or preparation, or use of said compound for the prevention of which contains a compound, those compounds that inhibit this binding .

Term Definition

The term "alkyl" as used herein, particularly the C _x C ₁ -C derived from a saturated hydrocarbon by the removal of one hydrogen atom that is not marked as ₁₂ -C _y linear or branched, substituted or unsubstituted, saturated chain Radicals. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and t-butyl.

The term " alkenyl " as used herein refers to a substituted or unsubstituted straight or branched or substituted branched alkenyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl, and the like.

The term " alkynyl " as used herein refers to a substituted or unsubstituted straight or substituted or unsubstituted flanking alkynyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl, and the like.

"Alkyl", "alkenyl", "alkynyl" or "alkoxy", "the term" lower "as used in front of refers to C ₁ -C ₆ unit for each functional group, for example, lower alkyl is C ₁ -C ₆ Alkyl "

The term " aliphatic acyl " as used herein refers to alkyl-C (O) -, alkenyl-C (O) - and alkynyl-C (O) Alkyl ", " alkenyl ", and " alkynyl " are as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propionyl and methylpropionyl.

The term " cycloalkyl " as used herein refers to an aliphatic ring system having from 3 to 10 carbon atoms and from 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, Lt; / RTI > The cycloalkyl group may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide And may be unsubstituted or substituted with one, two or three substituents independently selected.

&Quot; Cycloalkyl " includes cis or trans forms. The substituent may also be at the endo or exo position of the bridged bicyclic system.

The term " cycloalkenyl " as used herein refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and at least one double bond. Examples of such cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

The term " cycloalkylalkyl ", as used herein, refers to a cycloalkyl group attached to a lower alkyl radical, including, but not limited to, cyclohexylmethyl.

The term " halo " or " halogen " as used herein refers to I, Br, Cl or F.

As used herein, the term " haloalkyl " refers to lower alkyl radicals to which one or more halogen substituents are attached, examples of which include chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl.

The term " alkoxy " as used herein refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, .

The term " alkenoxy ", as used herein, refers to a radical of the formula alkenyl-O, wherein alkenyl is as defined above, with the proviso that the radical is not an enol ether. Examples of suitable alkenoxy include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy, and the like.

The term " alkynoxy ", as used herein, alone or in combination, refers to a radical of the formula alkynyl-O-, with the proviso that the radical is not an - Examples of suitable alkynoxy include, but are not limited to, propargyloxy, 2-butynyloxy, and the like.

As used herein, the term " carboxyl " refers to a carboxylic acid radical -C (O) OH.

The term " carboxy " as used herein means -C (O) O-.

The term " thioalkoxy " refers to a thioether radical of the formula alkyl-S- wherein alkyl is as defined above.

The term " carboxaldehyde " as used herein refers to -C (O) R, wherein R is hydrogen.

As used herein, the term "carboxyamide" or "amide" refers to -C (O) NR _a R _b , wherein R _a and R _b are each independently hydrogen, alkyl or other suitable substituent.

As used herein, the term " alkoxyalkoxy " refers to R _c OR _d O wherein R _c is lower alkyl as defined above and R _d is alkylene- (CH ₂ ) _{n '} -, wherein n'Lt; / RTI > Representative examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy.

As used herein, the term " alkylamino " refers to R _c NH, wherein R _c is a lower alkyl group, including ethylamino and butylamino.

The term " alkenylamino ", as used herein, alone or in combination, refers to a radical of the formula alkenyl-NH- or (alkenyl) ₂ N- (where the term " alkenyl " It is not an enamine. Examples of such alkenylamino radicals include allyl amino radicals.

The term " alkynylamino " as used herein refers to the formula alkynyl-NH- or (alkynyl) ₂ N- (wherein the term "alkynyl" is defined above), with the proviso that the radical is not an amine. Examples of such alkynylamino radicals include propargylamino radicals.

The term "dialkylamino" as used herein refers to R _f R _g N- wherein R _f and R _g are independently selected from lower alkyl, examples include diethylamino and methylpropylamino .

The term " amino " as used herein refers to H ₂ N-.

As used herein, the term " alkoxycarbonyl " refers to the above alkoxy group bonded to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl.

The term " aryl " or " aromatic ", as used herein, alone or in combination, refers to a substituted or unsubstituted carbocyclic aromatic group having from about 6 to 12 carbon atoms (e.g., phenyl, naphthyl, indenyl, indanyl Or anthracenyl) or a heterocyclic aromatic group containing one or more endocyclic N, O or S atoms (e.g., furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, , 4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, Benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, furyl, 4H-quinolyl, imidazolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, Tease , Isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, phthiridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxy Ziryl, pyrazolo [1,5-c] triazinyl, etc.). &Quot; Aralkyl " and " alkylaryl " use the term " alkyl " as defined above. The ring may be substituted plural times.

The term " aralkyl ", as used herein, alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms "alkyl" and "aryl" are defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolylmethyl, furylmethyl, imidazolylmethyl, indolylmethyl, .

The term " arylalkenyl ", as used herein, alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms "aryl" and "alkenyl" are as defined above.

The term " arylamino ", as used herein, alone or in combination, refers to a radical of the formula aryl-NH-, wherein aryl is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino (anilido), naphthylamino, 2-, 3- and 4-pyridylamino, and the like.

The term " biaryl ", as used herein, alone or in combination, refers to a radical of the formula aryl-aryl, wherein aryl is as defined above.

The term " thioaryl ", as used herein, alone or in combination, refers to a radical of the formula aryl-S-, wherein aryl is as defined above. An example of a thioaryl radical is a thiophenyl radical.

The term " aroyl ", as used herein, alone or in combination, refers to a radical of the formula aryl-CO-, wherein aryl is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl, and the like.

The term " heterocyclyl ", as used herein, alone or in combination, refers to a non-aromatic 3- to 10-membered ring containing one or more endocyclic N, O or S atoms. The heterocycle can also be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, , Oxo, arylsulfonyl, and aralkylaminocarbonyl. ≪ / RTI >

As used herein, the term " alkylheterocyclyl " refers to the alkyl group attached to the parent moiety through a heterocyclyl group, examples of which include 2-methyl-5-thiazolyl, 2- Ethyl-2-thienyl.

As used herein, the term " heterocyclylalkyl " refers to the heterocyclyl group attached to the parent molecular moiety through an alkyl group, examples of which include 2-thienylmethyl, 2-pyridinylmethyl and 2- Ethyl) ethyl.

As used herein, the term "amino day" of the formula R _h C (NR _i R _j) (NR _k R _l) - a hemiacetal _{(wherein, R h, R i, R} j, R k and R _l are independently Hydrogen, alkyl, or other suitable substituent).

The term "ester" as used herein refers to -C (O) R _m (wherein, R _m is hydrogen, alkyl or other suitable substituent).

The term "carbamate" as used herein is a compound that stems from the carbamic acid NH ₂ C (O) OH.

The use of the term includes substituted and unsubstituted moieties. Substituents may be selected from the group consisting of alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyls, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, Alkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocycle Or one or more groups such as alkyl, alkoxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, Linker is typically selected from the group consisting of -C-, -C (O) -, -NH-, -S-, -S (O) -, -O-, -C (O) O- or -S Is a short chain of one to three atoms, including any combination. The ring may be substituted plural times.

The term " electron-withdrawing " or " electron donation " refers to the ability of a substituent to attract or donate electrons as compared to hydrogen when hydrogen is present at the same position on one molecule. These terms are well understood by those skilled in the art and are described in detail in Advanced Organic Chemistry by J. March, 1985, pp. 16-18: incorporated herein by reference). Examples of electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxamido, aryl, quaternary ammonium, trifluoromethyl and aryl lower alkanoyl. Examples of electron donors include hydroxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto and disulfide. Those skilled in the art will recognize that the substituents may have electron donating or electron withdrawing properties under different chemical conditions. The present invention also includes any combination of substituents selected from those groups.

Most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary Amino, lower alkylamino, di (lower alkyl) amino, amine lower alkylmercapto, mercaptoalkyl, alkylthio and alkyl (lower alkyl) amino, lower alkyl, lower alkenyl, lower alkynyl, sulfonium salt, hydroxy, lower alkoxy, Dithio.

The term " composition " as used herein includes products that contain a particular component in a specified amount, as well as products in which certain components are formulated, either directly or indirectly, in a specified amount.

The rings indicated in formulas I, II and III may be mono-cyclic heterocycle or aromatic ring or bicyclic ring.

The dotted line used in formulas I, II and III indicates that the bond between atoms Y and W may be a double bond or a single bond when W and / or Y is a substituent such as N, C or CH. Accordingly, the ring denoted by Y in the above formula may be saturated or unsaturated depending on the selected substituent of W and / or Y. [

An aryl, an alkyl, a cycloalkyl, a heterocyclyl group, or a substituent suitable for a ring denoted Y and W in the above-mentioned general formulas I and II, or an alcohol, amine or hetero Atom or a combination of aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or heterocyclyl group. Linkers typically contain one to three, including all combinations of C, C = O, CO ₂ , O, N, S, S = O, SO ₂ such as ether, amide, amine, urea, sulfamide, sulfonamide It is a short chain of atoms.

For example, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ in the above Formulas I, II and III are independently selected from the group consisting of hydrogen, alkyl, phenyl, thienylmethyl Thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzothiophene- Thiazolylmethyl, phenethylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl, benzylsulfanylmethyl, benzylsulfanylmethyl, phenethylsulfanylmethyl, phenethylsulfanylmethyl, 3-methoxybenzylmethyl, , 4 - ((2-toluidinocarbonyl) amino) benzyl, 2-pyridinylethyl, 2- (lH-indol-3-yl) ethyl, lH-benzylimidazol- 4-aminophenyl, 4-aminobenzyl, phenylsulfonylmethyl, 4- (acetylamino) phenyl, 4-methoxyphenyl, 4-aminophenyl Phenyl, 4- (benzylsulfonyl) amino) phenyl, 2-aminophenyl, 2 Methylphenyl, isopropyl, 2-oxo-1-pyrrolidinyl, 3- (methylsulfanyl) propyl, (propylsulfanyl) methyl, octylsulfanylmethyl, 3- (Methylbenzyl) amino) benzyl, methylsulfanyl, hydroxy, chloro, fluoro, bromo, ureido, amino, methanesulfonylamino, Lt; / RTI > methyl.

R ⁴ substituents in formulas I, II and III include but are not limited to 1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6- 2-thienylmethyl, phenyl, methylsulfanyl, phenylsulfanyl, phenethylsulfanyl, phenylsulfanyl, benzylsulfanyl, , 4-bromo-2-thienyl, 3-methyl-2-thienyl, 4-methylphenyl, 3,5-bis (methoxyoxy) phenyl, 4- (methoxyoxy) , 3- (methoxyoxy) phenyl, 3,4,5-tris (methoxyoxy) phenyl, 2,3-dihydro-1-benzofuran- (Trifluoromethyl) phenyl, 4- (1,1-dimethylethyl) phenyl, 3,5-dimethylphenyl, 4-hydroxyphenyl, 3,4- 3-methylphenyl, 2,3-dihydro-inden-5-yl, 2-methylphenyl, 2,6-bis (Methyloxy) phenyl, 2,6-di 4-ethylphenyl, 4- (ethyloxy) phenyl, methyl, 2- (4-fluorophenyl) phenyl, 4-chlorophenyl, Propyl or 4,5-dihydro-l, 3-oxazol-2-yl.

Two independent R ¹ , R ² , R ³ and R ⁵ groups may be joined together to form a ring.

R ⁴ and R ¹¹ are connected to form a ring such as 1-pyrrolidino, 1-piperidino, 4-methyl-1-piperazino, 4-acetyl-1-piperazino and 4-morpholino .

R ⁹ and R ¹⁰ may be connected to form a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Abbreviation

The meanings of the abbreviations used in the following reaction schemes and examples are as follows:

BOC is t-butyloxycarbonyl; DMF is dimethylformamide; THF is tetrahydrofuran; DME is dimethoxyethane; DMSO is dimethyl sulfoxide; NMM is N-methylmorpholine; DIPEA is diisopropylethylamine; CDI is 1,1'-carbonyldiimidazole, TBS is Tris-buffered saline; Ms is methanesulfonyl; TMEDA may be N, N, N ', N'-tetramethylethylenediamine; DCE is 1,2-dichloroethane; NCS is N-chlorosuccinimide; NBS is N-bromosuccinimide; DPPA is diphenylphosphoryl azide; DEAD is diethyl azodicarboxylate; TFAA is trifluoroacetic anhydride; DCM is dichloromethane; LHMDS is lithium bis (trimethylsilyl) amide; And Cbz is benzyloxycarbonyl. Abbreviations for amino acids are: C is L-cysteine; D is L-aspartic acid; E is L-glutamic acid; G is glycine; H is L-histidine; I is L-isoleucine; L is L-leucine; N is L-asparagine; P is L-proline; Q is L-glutamine; S is L-serine; T is L-threonine; V is L-valine; And W is L-tryptophan.

An example of a procedure that can be used to synthesize the compounds of the above formula can be illustrated by the following scheme. A detailed description of representative compounds according to the present invention is described in the Examples below.

Scheme 1 illustrates the procedure described in Example 1.

Scheme 2 illustrating the procedure of Example 2 is as follows:

Scheme 3 illustrating the procedure of Example 3 is as follows:

Reaction Scheme 4 illustrating the procedure of Example 4 is as follows:

Reaction Scheme 5 illustrating the procedure of Example 5 is as follows:

Scheme 6 illustrating the procedure of Example 6 is as follows:

Scheme 7 illustrating the procedure of Example 7 is as follows:

Scheme 8 illustrating the procedure of Example 8 is as follows:

Reaction Scheme 9 illustrating the procedure of Example 9 is as follows:

Reaction Scheme 10 illustrating the procedure of Example 10 is as follows:

Reaction Scheme 11 illustrating the procedure of Example 11 is as follows:

Reaction Scheme 12 illustrating the procedure of Example 12 is as follows:

Reaction Scheme 13 illustrating the procedure of Example 13 is as follows:

Reaction Scheme 14 illustrating the procedure of Example 14 is as follows:

Reaction Scheme 15 illustrating the procedure of Example 15 is as follows:

Reaction Scheme 16 illustrating the procedure of Example 16 is as follows:

Reaction Scheme 17 illustrating the procedure of Example 17 is as follows:

Reaction Scheme 18 illustrating the procedure of Example 18 is as follows:

Scheme 19 illustrating the procedure of Example 19 is as follows:

Scheme 20 illustrating the procedure of Example 20 is as follows:

Reaction Scheme 21 illustrating the procedure of Example 21 is as follows:

Scheme 22 illustrating the procedure of Example 22 is as follows:

Scheme 23 illustrating the procedure of Example 23 is as follows:

Scheme 24 illustrating the procedure of Example 24 is as follows:

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term " pharmaceutically acceptable salts " means salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. within the purview of pure medical judgment, . Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66: 1. Salts may be prepared in situ during the final isolation and purification of the compounds of the present invention or may be prepared by separately reacting the free base functionality with a suitable organic acid. Representative acid addition salts include but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, (Isothiocyanate), lactate, maleate, methanesulfonate (isothiocyanate), lactate, maleate, methanesulfonate, isophthalate, isophthalate, , Nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate , Phosphate, glutamate, bicarbonate, p-toluene sulfonate and undecanoate . Also, basic nitrogen-containing groups include methyl, ethyl, propyl, and lower alkyl halides such as butyl chloride, bromide, and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; Decyl, lauryl, myristyl and long chain halides such as stearyl chloride, bromide and iodide; Arylalkyl halides such as benzyl and phenethyl bromide, and the like. Whereby water-soluble or lipid-soluble or dispersible products are obtained. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared by reacting a carboxylic acid containing moiety with a suitable base (e.g., hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or ammonia or organic 1 With a primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, and non-toxic quaternary ammonia and amine cations (ammonium, tetramethylammonium, Tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium). Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanol diamine, diethanolamine, piperidine, piperazine, and the like.

Dosage forms for topical administration of the compounds of the present invention include powders, sprays, ointments and inhalants. The active compound is mixed with the pharmaceutically acceptable carrier and other necessary preservatives, propellants or buffers under sterile conditions. In addition, eye drops, ointments, powders and solutions belong to the scope of the present invention.

The actual dose of the active ingredient contained in the pharmaceutical composition of the present invention may vary depending on the amount of active compound, the composition, and the mode of administration effective to achieve the therapeutic response required for the particular patient. The selected dose level will depend on the activity of the particular compound, the route of administration, the severity of the disease symptoms, and the patient ' s condition and medical history. One skilled in the art, however, is well aware that the dose of the compound is determined at a level lower than is necessary to achieve the desired therapeutic effect and then gradually increased until the desired effect is achieved.

A therapeutically effective amount of a compound according to the present invention used in the above and other treatments may be used in pure form or, if present in such form, be in the form of a pharmaceutically acceptable salt, ester or prodrug. Alternatively, the compound may be administered as a pharmaceutical composition containing the compound in combination with one or more pharmaceutically acceptable excipients. Term " therapeutically effective amount " of a compound of the invention means an amount of a compound sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment. However, it will be understood by one of ordinary skill in the art that the total daily dose of the compounds and compositions of the present invention is determined by the attending physician in a reasonable medical judgment. The particular therapeutically effective dose level for a particular patient will depend upon the disease to be treated and its severity; The activity of the specific compound used; The particular composition used; Age, weight, health, sex and diet of the patient; The time of administration of the particular compound employed, the route of administration and the rate of excretion of the particular compound employed; Treatment period; Factors involved in the combination or concurrent use of the particular compound employed, and other factors well known in the medical arts. For example, those skilled in the art are well aware that the dose of the compound may be determined at a level lower than is necessary to achieve the desired therapeutic effect and then gradually increased until the desired effect is achieved.

The total daily dose of a compound according to the present invention administered to a human or lower animal is from about 0.0001 to about 1000 mg / kg / day. A more preferred dose for oral administration is about 0.001 to about 5 mg / kg / day. If necessary, an effective daily dose may be divided into several doses for the purpose of administration. As a result, a single dose composition may contain an amount or a divided dose that constitutes the daily dose.

The present invention also provides a pharmaceutical composition comprising a compound of the present invention that is formulated with one or more pharmaceutically acceptable non-toxic carriers. The pharmaceutical composition may be formulated specifically for oral administration in solid or liquid form, for parenteral injection or rectal administration.

The pharmaceutical composition of the present invention may be administered to a human or other mammal by oral, rectal, parenteral, sub-retinal, in vivo, intraperitoneal, topical (including powders, ointments or drops), oral, . The term " parenteral " as used herein means a mode of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

In another aspect, the invention provides a pharmaceutical composition comprising a component of the invention and a physiologically acceptable diluent. The present invention is also directed to compositions comprising one or more physiologically acceptable non-toxic diluents, carriers, adjuvants or vehicles (collectively referred to as diluents) for parenteral injection, intranasal delivery, solid or liquid oral, rectal or topical administration ≪ RTI ID = 0.0 > and / or < / RTI >

The composition may also be delivered via a catheter for local delivery to a target site via a coronary stent (a tube device consisting of a fine wire network) or a biodegradable polymer. In addition, the compounds can complex with ligands, such as antibodies, for targeted targeted delivery.

Compositions suitable for parenteral injection may include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions which are physiologically acceptable, and sterile powders for redissolving with sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (olive oil), injectable organic esters (e.g. ethyl oleate) ≪ / RTI >

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The action of microorganisms can be inhibited by various antibacterial and antifungal agents (eg, parabens, chlorobutanol, phenol, sorbic acid, etc.). In addition, osmo-regulators such as sugars, sodium chloride and the like can be used. Absorption retarding agents (e.g., aluminum monostearate and gelatin) can be used to achieve delayed absorption of the injectable drug.

Suspensions may contain, in addition to the active compound, suspending agents (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, Etc.).

In some cases, the absorption of the drug from the subcutaneous or intramuscular injection may be slowed to sustain the effect of the drug. This can be achieved by using low-water-soluble crystals or liquid suspensions of amorphous material. The absorption rate of the drug depends on the dissolution rate, and the dissolution rate depends on the crystal size and the crystal form. Alternatively, delayed absorption of the parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

The injectable depot form is prepared by forming a microcapsule matrix of the drug into a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). In addition, depot injectable preparations are prepared by entrapping the drug in liposomes or microemulsions which are body-fit compatible.

The injectable preparation may be sterilized, for example, by filtration through a bacterial-capture filter or by incorporating the sterilizing agent in the form of a sterile solid composition which may be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such a solid dosage form, the active compound may be admixed with one or more inert pharmaceutically acceptable excipients or carriers (e.g., sodium citrate or dicalcium phosphate) and / or a) fillers such as starch, lactose, sucrose, glucose C) humectant (e. G., Glycerol), d) disintegrating agents (e. G., Mannitol and silicic acid), b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, (Eg paraffin), f) an absorption promoter (eg quaternary ammonium compound), g) a wetting agent (eg, sodium carbonate, (I. E., Talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof) ≪ / RTI > In the case of capsules, tablets and pills, the dosage form may also comprise a buffering agent.

Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms of tablets, dragees, pills, and granules may be prepared with shelled products and shells, such as shellac, which are well known in the art of enteric and other pharmaceutical applications. They may optionally contain an opacifying agent and may also be formulated so that they release only the active ingredient or preferentially release the active ingredient, optionally in a delayed manner at a particular site of the intestinal tract. Examples of embedding compositions that can be used include polymeric materials and waxes.

The active compound may also be present in microencapsulated form, if necessary, with one or more of the above-described excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may be formulated with water or other solvents, solubilizing agents and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, Such as, for example, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn, seed, olive, castor and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, May contain an inert diluent used.

In addition to inert diluents, the oral compositions may also contain adjuvants such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents and perfuming agents.

Compositions for rectal or vaginal administration are preferably formulated with suitable non-irritating adjuvants or carriers (e. G., Cocoa butter, polyethylene glycol or suppositories) for dissolving the active compound in the rectum or vagina, Wax). ≪ / RTI >

The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid materials. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any physiologically acceptable, non-toxic, and acid-decomposable lipids capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are the natural and synthetic phospholipids and phosphatidyl choline (lecithin) used separately or together.

Methods for forming a reformate are described, for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33].

As used herein, the term " pharmaceutically acceptable prodrugs " refers to those compounds which are suitable for use without undue toxicity, irritation and allergic reactions, in contact with the tissues of humans and lower animals under rational medical judgment, As well as the amphoteric forms of the compounds of the present invention, as well as the prodrugs of the compounds of the present invention which are effective for the intended use. The prodrugs of the present invention can be rapidly converted into parent compounds of the above formula in vivo, for example, by hydrolysis in blood. For more information on this, see T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). The contents of this document are incorporated herein by reference.

Compounds of the invention formed by in vivo conversion of different compounds administered to mammals are also included within the scope of the present invention.

The compounds of the present invention may exist as stereoisomers in which an asymmetric or chiral center is present. These stereoisomers are R or S depending on the arrangement of the vicinal substituents of the chiral carbon atom. The present invention includes various stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers and diastereomers. The individual stereoisomers of the compounds of the present invention may be prepared by synthesis from commercially available starting materials having asymmetric or chiral centers or by preparing racemic mixtures as known to those skilled in the art and then separating them. Examples of these separation methods include: (1) coupling a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers and separating the optically pure product from the supplements by recrystallization or chromatography, or (2) Is a direct separation of the mixture of optical enantiomers in the < RTI ID = 0.0 > HPLC < / RTI >

The compounds of the present invention may exist in solvated as well as unsolvated forms and include hydrated forms such as semi-hydrates. Generally, the solvated forms with pharmaceutically acceptable solvents such as water and ethanol are equivalent to the unsolvated forms for the purposes of the present invention.

In another aspect, the invention includes a method for inhibiting the binding of α ₄ β ₁ to VCAM-1. The method of the present invention can be used in vivo or in vitro. According to the method of the present invention, cells expressing? ₄ ? ₁ integrin are exposed to VCAM-1 expressing cells in the presence of a controlled amount of a compound of the present invention.

α ₄ cells expressing β ₁ integrin is a polynucleotide (e.g., genomic DNA or cDNA) encoding a cell type, or α ₄ β ₁ integrin expressing α ₄ β ₁ integrin on natural white blood cell, mast cell or other cell surface Lt; RTI ID = 0.0 > expression vector. ≪ / RTI > In a particularly preferred embodiment, the alpha ₄ beta ₁ integrin is present on the surface of leukocytes such as monocytes, lymphocytes or granulocytes (e.g., basophils or eosinophils).

The cell expressing VCAM-1 may be a natural cell (e. G., Endothelial cell) or a cell transfected with an expression vector containing a polynucleotide encoding VCAM-1. Methods for producing transfected cells expressing VCAM-1 are well known in the art.

When VCAM-1 is present on the cell surface, its expression is preferably induced by inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-4 and interleukin-1 [beta].

When cells expressing? ₄ ? ₁ integrin and VCAM-1 are present in a living organism, the compounds of the invention are administered to the living organism in an effective amount. Preferably, the compound is present in the pharmaceutical composition of the present invention. The method of the present invention is particularly useful for treating diseases associated with unregulated migration of leukocytes into damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergies, multiple sclerosis, lupus, inflammatory bowel disease, transplant rejection, contact hypersensitivity, type I diabetes, leukemia and brain cancer. Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral delivery.

In addition, the present invention provides a method for selectively inhibiting the binding of α ₄ β ₁ integrin to a protein comprising exposing the integrin α ₄ β ₁ in the presence of the compounds of the invention of an effective inhibiting amount of a protein. In a preferred embodiment, the alpha ₄ beta ₁ integrin is expressed on the surface of cells that have been transformed to express natural or alpha ₄ beta ₁ integrin.

The protein to which the alpha ₄ beta ₁ integrin binds may be expressed on the cell surface or be part of an extracellular matrix. A particularly preferred protein is fibronectin or invasin.

The ability of the compounds of the present invention to inhibit binding is described in detail in the Examples below. These embodiments are presented to describe preferred aspects and utility of the present invention and should not be construed as limiting the invention as described in the claims appended hereto.

Example 1

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-ethyl- Synthesis of 3- (4-methylphenyl) propanoic acid (10)

Step 1 : Compound 1 (20.8 g, 135 mmol) was dissolved in methanol (270 mL) and palladium on carbon (10% Pd dry weight, Degussa E101 NE / W, about 50% water content, 5.75 g, 2.7 mmol Pd) Was added. The atmosphere was replaced with hydrogen (five times with vacuum and balloon hydrogen), the mixture was stirred overnight and then filtered. The filtrate was concentrated in vacuo and the residue was taken up in a 1: 1 hexane: ethyl acetate mixture and washed with a 4: 1 mixture of water and saturated NaHCO ₃ , saturated NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 2 (12.43 g, 74%) as a white solid. This material was used without further purification.

Step 2 : Compound 2 (2.64 g, 21.3 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 <0> C. The cold solution was treated sequentially with triethylamine (3.6 mL, 25.6 mmol) and trimethylacetyl chloride (2.90 mL, 23.4 mmol). The solution was stirred at room temperature for 6 hours and then refluxed overnight. The mixture was partitioned between dichloromethane and aqueous NaOH (2N). The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated to give 3.33 g (75%) of the compound 3.

Step 3 : Compound 3 (0.50 g, 2.4 mmol) was dissolved in anhydrous THF (9.6 mL) and TMEDA (1.1 mL, 7.2 mmol) under a dry nitrogen atmosphere. The resulting solution was cooled to -20 to -10 [deg.] C and n-butyllithium (1.6M in hexane, 2.25mL) and t-butyllithium (1.7M in pentane, 2.1mL) were added dropwise continuously via syringe. After 30 minutes, the bath temperature was raised to -5 to 0 DEG C and ethyl iodide (0.77 mL, 9.6 mmol) was treated with a syringe. The solution was stirred at 0 &lt; 0 &gt; C for 2 hours and then at room temperature overnight. The mixture was then sodium borohydride with methanol and concentrated to dryness. The residue was purified by filtration through silica gel, eluting with 3: 1 hexane: ethyl acetate, and recrystallized with hexanes to give compound 4 (0.32 g, 56%).

Step 4 : Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial acetic acid (4.5 mL) and treated with potassium iodide (0.65 g, 3.9 mmol). The resulting mixture was heated in an oil bath adjusted to 115 DEG C for 1.0 hour. The mixture was cooled, diluted with water and the pH adjusted to 6 with 2N NaOH and 2N HCl. The mixture was extracted with chloroform (4 times). The combined extracts were washed with aqueous sodium thiosulfate, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 5 (0.25 g, 86%) as a white solid. This material was used without further purification.

Step 5 : Compound 5 (0.25 g, 1.1 mmol) was dissolved in THF (45 mL) and a solution of potassium bis (trimethylsilyl) amide (0.5 M in toluene, 2.7 mL) was added dropwise at 0 ° C. The resulting solution was treated with 2-chlorobenzyl bromide (0.16 mL, 1.2 mmol) and the solution was allowed to warm to room temperature overnight. The mixture was partitioned between 2N HCl and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed (SiO ₂ , elution gradient 4: 1 to 2: 1 hexane: ethyl acetate) to give compound 6 (0.16 g, 41%).

Step 6 : Compound 6 (0.16 g, 0.46 mmol) was suspended in 1: 1 water: conc. HCl (4.6 mL). The suspension was refluxed for 4 hours to dissolve the compound. The mixture was cooled, diluted with water and then extracted with diethyl ether. The aqueous layer was basified with an excess of saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 7 (0.081 g, 67%).

Step 7 : Compound 7 (0.080 g, 0.30 mmol) was dissolved in 1,2-dichloroethane (1.2 mL) and DIPEA (0.115 mL, 0.66 mmol) and cooled to 0 <0> C. The cold solution was treated rapidly with phosgene solution (1.93M in toluene, 0.170 mL, 0.33 mmol). After 30 minutes a solution of compound 8 (0.068 g, 0.33 mmol) in 1,2-dichloroethane (0.5 mL) was added rapidly via syringe. The resulting mixture was heated to 55 &lt; 0 &gt; C for 1 hour. The mixture was partitioned between dichloromethane and 2N HCl. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO4 and filtered. The filtrate was concentrated to give compound 9 (0.110 g, 74%).

Step 8 : Compound 9 (0.11 g, 0.22 mmol) was dissolved in 2: 1 THF: water (0.88 mL) and treated with 2N NaOH solution (0.33 mL). Methanol was added dropwise until a homogeneous solution was obtained. The mixture was stirred for 20 minutes, diluted with water and washed with ethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-ethyl-2- ] Amino} -3- (4-methylphenyl) propanoic acid (10, 0.095 g, 92%).

Example 2

(3S) -3 - {[({6-methyl-2-oxo-1- (phenylmethyl) -4 - [(phenylmethyl) oxy] -1,2-dihydro-3-pyridinyl} amino) Yl] amino} -3- (4-methylphenyl) propanoic acid (15)

Step 1: was added benzyl bromide (2.31g, 13.5mmol) to a suspension of acetone (50mL) solution of compound 11 (1.0g, 5.9mmol) and _{K 2 CO 3 (2.40g, 17.6mmol} ). Cooling the reaction solution and the mixture was refluxed over night and partitioned between ethyl acetate and saturated NaHCO _3. The organic layer was washed with dilute HCl and brine, dried over magnesium sulfate, filtered and the filtrate was concentrated to give compound 12 (1.60 g, 80%).

Step 2 : Compound 12 (0.30 g, 0.86 mmol), zinc powder (0.30 g, 4.6 mmol) and saturated aqueous NH ₄ Cl (0.30 mL) were mixed in MeOH (18 mL). The mixture was stirred at room temperature for 1 hour and then additional zinc (0.30 g, 4.6 mmol) was added. The resulting heterogeneous mixture was refluxed overnight. Was filtered and the filtrate was concentrated under reduced pressure, the hot mixture the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 13 (0.18 g, 66%).

Step 3 : Compound 13 (0.30 g, 0.94 mmol) and DIPEA (0.40 mL, 2.3 mmol) were dissolved in CH ₂ Cl ₂ and the mixture was cooled to 0 ° C. Phosgene (1.9 M in toluene, 0.55 ml, 1.0 mmol) was added dropwise to the solution. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 15 min and then 8 (0.19 g, 0.94 mmol) in CH ₂ Cl ₂ (2 mL) was added. The resulting solution was stirred overnight at room temperature and then poured into ethyl acetate and washed with saturated aqueous NaHCO _3, 1N HCl and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with hexane: ethyl acetate increasing the residue from 1: 1 to 1: 2 yielded compound 14 (0.33 g, 64%).

Step 4 : A solution of 14 (0.33 g, 0.6 mmol) in THF (6 mL) was treated with 2 N NaOH (2 mL). MeOH was added until a homogeneous solution was obtained. The reaction mixture was stirred at room temperature for 30 minutes and poured into water (50 mL). The aqueous layer was washed with diethyl ether (twice) and then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (2x). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (3S) -3 - {[({6-methyl-2-oxo- 1- (phenylmethyl) -4 - [(phenylmethyl) oxy] (Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid (15, 0.26 g, 90%) as a gray solid. Melting point: 124-126 占 폚.

Example 3

(3S) -3 - {[({4-amino-1 - [(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid (22)

Step 1 : To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF (120 mL) at 0 <0> C was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 15 minutes and then 2-chlorobenzyl chloride (12.3 g, 76.4 mmol) was added. After stirring at 55 &lt; 0 &gt; C overnight, the mixture was poured into ice water and washed twice with ethanol. The aqueous layer was acidified and the resulting precipitate was filtered to give compound 16 (14.7 g, 85%).

Step 2 : POCl ₃ (30.0 ml, 322 mmol) was added via syringe at room temperature under a dry nitrogen atmosphere to a flask containing a rubber plug sealed compound 16 (8.00 g, 28.6 mmol) and balloon. The nitrogen line was removed and the reaction mixture was stirred at 70 &lt; 0 &gt; C overnight, then poured onto ice (300 ml) and stirred for 30 min. The resulting mixture was extracted with dichloromethane (300 ml) and the organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 17 (7.3 g, 86%) as a dark brown solid.

Step 3 : A solution of compound 17 (2.1 g, 7.05 mmol), methanol (55 ml) and aqueous ammonium hydroxide (28-30%, 70.0 ml, 1.14 mol) in a 250 ml flask equipped with a balloon- Lt; / RTI &gt; The reaction mixture was heated to 65 &lt; 0 &gt; C for 60 hours with only balloon opening. The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 18 (1.5 g, 76%) as a brown solid.

Step 4 : To a solution of compound 18 (0.3 g, 1.02 mmol) in methanol (50 ml) at room temperature was added successively saturated aqueous ammonium chloride (2 ml) and zinc dust (0.30 g, 4.6 mmol). After stirring at room temperature for 30 min, additional zinc was added (0.30 g, 4.6 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N NaOH. The solution was filtered and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 19 (0.21 g, 78%) as a brown solid.

Step 5 : A solution of compound 19 (0.10 g, 0.38 mmol), NMM (0.040 mL, 0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF (5 mL) was heated to 50 <0> C overnight. The mixture was cooled and diluted with ethyl acetate (60 mL). The organic layer was washed with 0.5N NaOH (3 x 30 mL) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was 9: CHCl _3, increasing to 3:: from 1 to 17 to give the, eluting with MeOH flash chromatography to give compound 21 (0.120g, 65%) on silica gel to a yellow foam.

Step 6 : A solution of compound 21 (0.120 g, 0.25 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). Methanol was added until a homogeneous solution was obtained. The reaction mixture was stirred at room temperature for 30 minutes and poured into water (50 ml). The aqueous layer was washed with diethyl ether (twice) and then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (2x). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (3S) -3 - {[({4-amino- 1 - [(2- chlorophenyl) methyl] -6- methyl-oxo-1,2-dihydro- Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid (22, 0.100 g, 89%) as a gray solid. Melting point: 145-147 占 폚.

Example 4

(3S) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (methyloxy) Amino] -3- (4-methylphenyl) propanoic acid

Step 1 : To a solution of compound 23 (10.00 g, 64.0 mmol) in anhydrous DMF (130 mL) at 0 <0> C was added NaH (60% dispersion in mineral oil, 5.90 g, 147 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 15 min and then 2-chlorobenzyl chloride (13.4 g, 83.3 mmol) was added. After stirring overnight at 55 [deg.] C, the mixture was poured into ice water and washed with ethanol (2x). The aqueous layer was acidified and the resulting precipitate was filtered to give compound 24 (13.5 g, 75%).

Step 2 : A suspension of 24 (1.0 g, 3.6 mmol), K ₂ CO ₃ (0.85 g, 6.2 mmol) and MeI (1.18 g, 8.3 mmol) in acetone (20 mL) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ , 1N HCl and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 25 (0.74 g, 70%).

(3S) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (methyloxy) -2-oxo- Hydroxy-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid. MS: Calcd: (M + H) &lt; ⁺ & gt ^; = 469.93; Found: (M + H) &lt; ⁺ & gt ^; = 470.01.

Example 5

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-fluoro- Synthesis of 3- (4-methylphenyl) propanoic acid

Step 1 : Compound 3 (0.65 g, 3.1 mmol) was dissolved in anhydrous THF (12.4 mL) and TMEDA (0.90 mL, 6 mmol) under a dry nitrogen atmosphere. The resulting solution was cooled to -15 to -10 C and n-butyllithium (1.6 M in hexane, 7.75 mL, 12.4 mmol) was added dropwise via syringe. After 1.5 hours a solution of N-fluorobenzenesulfonimide (1.07 g, 3.4 mmol) in THF (5 mL) was added dropwise via syringe to the cooling solution. The solution was stirred at 0 &lt; 0 &gt; C for 1 hour and then at room temperature for 3 hours. The mixture was diluted with water and sodium borohydride and extracted with chloroform (4 times). The combined organic extracts were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography to give the (SiO _2, plug gel, 4: 1 ethyl acetate from 3: 1 to hexane) Compound 26 (0.177g, 25%).

(3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-fluoro-2-oxo-1,2-dihydro- 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid. MS: Calculated: (M + H) &lt; ⁺ & gt ^; = 458.12; Found: (M + H) &lt; ⁺ & gt ^; = 458.01.

Example 6

(3S) -4-chloro-3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Synthesis of 3- (4-methylphenyl) propanoic acid

Step 1 : Compound 3 (0.65 g, 3.1 mmol) was dissolved in THF (21 mL) and TMEDA (1.20 mL, 7.75 mmol) and cooled to -15 <0> C. The solution was treated with n-butyllithium (1.6 M in hexane, 4.8 mL, 7.8 mmol). The mixture was maintained between -20 and -10 [deg.] C for 1 hour and cooled to -78 [deg.] C. The apparatus was placed under a positive outlet of nitrogen and solid N-chlorosuccinimide (0.45 g, 3.4 mmol) was added. The reaction was slowly warmed to room temperature and then stirred overnight. The mixture was diluted with water and sodium borohydride and extracted with chloroform (4 times). The organic layers were combined, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from hexane to give 27 (0.25 g, 33%).

(3S) -4-chloro-3 - {[({1- [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 - pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid.

Example 7

(3S) -4-bromo-3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo- Synthesis of 3- (4-methylphenyl) propanoic acid

Step 1 : Compound 3 (2.00 g, 9.6 mmol) was dissolved in anhydrous THF (32 mL) and TMEDA (2.20 mL, 14.4 mmol) under a dry nitrogen atmosphere. The resulting solution was cooled to -20 to -10 [deg.] C and n-butyllithium (1.60 M in hexane, 18.0 mL, 28.8 mmol) was added dropwise via syringe. After the addition was complete, the solution was cooled to -78 C and bromine (0.49 mL, 10.5 mmol) was added dropwise via syringe. The solution was slowly warmed to room temperature overnight, then quenched with water and extracted with chloroform. The organic layer was dried with MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give compound 28 (1.32 g, 48%) as a tan white solid.

(3S) -4-bromo-3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro- 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid.

Example 8

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- Synthesis of 3- (4-methylphenyl) propanoic acid (32)

Step 1 : To a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 ml) at room temperature was added successively saturated ammonium chloride (1.5 ml) and zinc dust (1.5 g, 23 mmol). After stirring at room temperature for 30 minutes, additional zinc dust (1.5 g, 23 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered while heating and the filtrate was concentrated under reduced pressure. HCl (1 N) was added to the resulting residue until the pH was about 4 and the resulting precipitate was collected by filtration to give 29 (0.80 g, 57%) as a brown solid.

Step 2 : A solution of 29 (0.26 g, 1.0 mmol) and CDI (0.25 g, 1.6 mmol) in DMF (10 mL) was heated to 70 <0> C overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with 1N HCl (3 times) and brine. The organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure to give compound 30 (0.14 g, 50%) as a brown solid.

Step 3 : A solution of compound 30 (0.1 g, 0.36 mmol) and compound 8 (0.082 g, 0.40 mmol) in anhydrous DMF (5 mL) was heated to 70 <0> C overnight. The mixture was cooled, diluted with ethyl acetate and washed with 1N HCl (3 times) and brine. The organic layer was dried with MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ) eluting with 9: 1 CHCl ₃ : MeOH to give 31 (0.17 g, 97%).

Step 4 : A solution of 31 (0.170 g, 0.35 mmol) in THF (3 mL) was treated with 2N NaOH (1 mL). Methanol was added until a homogeneous solution was formed. The reaction mixture was stirred at room temperature for 30 min and poured into H ₂ O (50 mL). The aqueous layer was washed with diethyl ether (2X) and then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (2x). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- ) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid (32, 0.150 g, 94%) as a gray solid. Melting point: 113-115 [deg.] C.

Example 9

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- Synthesis of 3- (4-methylphenyl) propanoic acid

Step 1: Compound 33 (Example 1 prepared from compound 28 according to the procedure described in, 0.20g, 0.50mmol) was dissolved in DMF (1.8mL) and water (0.7mL) and K ₃ PO ₄ (0.39g, 1.86 mmol) and phenylboronic acid (0.113 g, 0.93 mmol). The resulting mixture was purged with oxygen (5 times between vacuum and nitrogen) and tetrakis (triphenylphosphine) palladium (0) (8.7 mg, 0.050 mmol) was added. The mixture was oxygenated as before and heated to 90 &lt; 0 &gt; C overnight. The mixture was cooled, diluted with water and extracted with ethyl acetate (twice). The combined extracts were washed with brine, dried over magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure. The residue was suspended in 1: 1 water: concentrated HCl (2 mL) and acetonitrile (0.5 mL). The suspension was refluxed for 1 hour and then allowed to cool and partitioned between ethyl acetate and saturated aqueous NaHCO _3. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography to give the (SiO _2, 3 hexane / ethyl acetate 1) to give compound 34 (0.115g, 94%). This material was used without further purification.

(3S) -3 - {[({1- [(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3 - pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid.

_{^{1 H NMR (400MHz, CD 3}} OD): δ 2.25 (s, 3H), 2.50 (m, 2H), 4.89 (t, J = 5.9Hz, 1H), 5.34 (s, 2H), 6.40 (d, J (D, J = 8.0 Hz, 2H), 7.18 (m, 1H), 7.28 (m, 2H), 7.35 ), 7.43 (m, 1 H), 7.49 (m, 3 H).

Example 10

(Phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid (43)

Step 1 : Compound 35 (2.00 g, 18.2 mmol) was dissolved in 30 mL of anhydrous methanol. To this solution was added benzylamine (1.97 g, 18.2 mmol) and triethylamine (2.0 g, 20.0 mmol). The reaction mixture was stirred at 50 &lt; 0 &gt; C for 3 hours and concentrated under reduced pressure. The residue was partitioned between water and CH ₂ Cl ₂ . The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 36 (2.3 g, 82%).

Step 2 : To a solution of compound 37 (3.50 g, 26.5 mmol) in ethanol (10 mL) and pyridine (5 mL) was added isovaleraldehyde (2.8 mL, 27 mmol) and piperidine (1 mL). The reaction mixture was heated at reflux for 3 hours and concentrated under reduced pressure. The residue was partitioned between 2N HCl (15 mL) and ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 2: 1 hexane: ethyl acetate to give compound 38 (3.6 g, 67%).

Step 3 : A solution of compound 38 (2.5 g, 12.48 mmol) and compound 36 (2.52 g, 13.7 mmol) in anhydrous methanol (25 mL) was heated to reflux vigorously for 3 hours, cooled and then concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 2: 1 hexane: ethyl acetate, to give compound 39 (2.75 g, 69%).

Step 4 : NBS (1.4 g, 8.0 mmol), K ₂ CO ₃ (11.0 g, 80.0 mmol) and benzoyl peroxide (50 mg, 0.20 mmol) were added to a solution of compound 39 (2.5 g, 7.9 mmol) in CCl ₄ ). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature, then diluted with water and extracted with CH ₂ Cl ₂ . The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 3: 1 hexane: ethyl acetate, to give compound 40 (0.62 g, 25%).

Step 5 : Compound 40 (0.60 g, 1.9 mmol) was treated with 2N NaOH (5 mL) and THF (3 mL). The resulting mixture was stirred at room temperature for 2 hours, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 41 (560 mg, 98%).

Step 6 : To a solution of 41 (0.56 g, 1.86 mmol) in anhydrous benzene (10 mL) was added diphenylphosphoryl azide (0.56 g, 2.0 mmol) and triethylamine (2.02 g, 2.0 mmol). The reaction mixture was heated to 90 &lt; 0 &gt; C for 1 hour and then a solution of compound 8 (0.39 g, 1.9 mmol) in benzene (2 mL) was added. The reaction was stirred for an additional hour at 90 &lt; 0 &gt; C, cooled to room temperature, then diluted with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 7: 3 ethyl acetate: hexanes to give compound 42 (0.38 g, 40%).

Step 7 : To a solution of compound 42 (0.35 g, 0.7 mmol) in a 1: 1 mixture of THF: MeOH (8 mL) was added 2N NaOH (8 mL). The reaction was stirred at room temperature for 3 h, acidified with 2N HCl (10 mL) and then extracted with ethyl acetate (20 mL). The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give (3S) -3 - [({[2-methyl- Amino) -3- (4-methylphenyl) propanoic acid (43, 250 mg, 75%) as a white solid. MS: Calculated: (M + H) &lt; ^- = 477.25 m / z; ^{found: (M + H) - =} 477.17 m / z

Example 11

(4S) -3 - [({[2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbonyl) amino] -3- - methylphenyl) propanoic acid

Step 1 : A solution of 36 (2.3 g, 15.5 mmol) and 44 (3.36 g, 15.5 mmol) in anhydrous ethanol (35 mL) was refluxed for 3 h and concentrated. The residue was chromatographed on silica gel eluting with 1: 1 ethyl acetate: hexanes to give 45 (1.87 g, 55% yield).

(3S) -3 - {[({[2-methyl-6-oxo- 1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid.

_{^{1 H NMR (400MHz, CD 3}} OD) δ 2.28 (s, 3H), 2.35 (s, 3H), 2.57 (m, 2H), 5.16 (m, 1H), 5.30 (s, 2H), 7.13 (m, 4H), 7.30 (m, 5H), 8.50 (s, 1 H).

Example 12

(Ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1,2,3,4-tetrahydroisoquinoline; 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid

Step 1 : To a solution of 46 (prepared according to the procedure described in Example 3, 0.50 g, 1.8 mmol) in THF (10 mL) at 0 C was added NaH (60% dispersion in mineral oil, 0.23 g, 5.1 mmol) . The mixture was stirred at 0 &lt; 0 &gt; C for 10 min and then ethyl isocyanate (0.65 g, 9.15 mmol) was added. The mixture was stirred at room temperature over the weekend, sodium borohydride was added with 1N HCl and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 47 (0.60 g). This material was used without purification.

4 - [({ethyl [(ethylamino) carbonyl] amino} propanoic acid was prepared from compound 47 according to the procedure described in Example 3. MS: m / e = Carbonyl) amino] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid. Melting point: 128-130 占 폚.

Example 13

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid

Step 1 : To a solution of 48 (2.00 g, 9.70 mmol) in anhydrous DMF (25 mL) at 0 C was added NaH (60% dispersion in mineral oil, 0.89 g, 22 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 15 minutes and then 2-chlorobenzyl chloride (2.03 g, 12.6 mmol) was added. At 55 ℃ After stirring overnight the mixture was poured into ice water and washed with Et ₂ O ₍₂ times). The aqueous layer was acidified and the resulting precipitate was filtered to afford 49 (3.45 g). This material was used without further purification.

(3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- 3-quinolinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid. Melting point: 134-136 &lt; 0 &gt; C.

Example 14

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -5- Synthesis of 3- (4-methylphenyl) propanoic acid (56)

Step 1 : To a suspension of 51 (1.67 g, 9.81 mmol) in DMF (33 mL) at room temperature under a dry nitrogen atmosphere was successively added 2-chlorobenzylamine (1.30 mL, 10.8 mmol) and EDCl (2.35 g, 12.3 mmol) . In which the resulting mixture at room temperature and stirred vigorously for 5 hours, diluted with ethyl acetate and washed with 2N HCl, water (3 times), saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 52 (2.55 g, 100%) as a pale yellow solid.

Step 2 : A solution of 52 (555 mg, 2.17 mmol) and 3-dimethylamino-2-methylpropenal (738 mg, 6.5 mmol) in anhydrous ethanol (4.3 mL) and glacial acetic acid (0.22 mL) was heated to reflux overnight. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with 2N HCl (twice), water and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrate was chromatographed on silica gel, eluting with increasing ratio of hexane: ethyl acetate to 7: 3 to 1: 1 and finally eluting with 19: 19: 2 hexane: ethyl acetate: methanol to give compound 53 (182 mg, 27%) as a yellow oil.

Step 3 : To a solution of 53 (167 mg, 0.55 mmol) in THF (3 mL) was added 2N NaOH (1 mL) and methanol (2 mL). The resulting mixture was stirred for 15 min, diluted with water and then extracted with ethyl acetate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 54 (139 mg, 91%) as a white solid.

Step 4 : DPPA (0.29 mL, 1.34 mmol) was added via syringe to a suspension of compound 54 (175 mg, 0.63 mmol) in THF (6.7 mL) and DIPEA (0.23 mL, 1.34 mmol) at room temperature under a dry nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 minutes and then heated to reflux for 3.5 hours. The mixture was cooled to room temperature and a solution of 8 (278 mg, 1.34 mmol) in THF (6.0 mL) was added via cannula with THF (0.7 mL) rinse. The resulting mixture was stirred overnight at room temperature and diluted with ethyl acetate and washed with 2N HCl (2 times), saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting sequentially with 7: 3, 3: 2 and 1: 1 hexane: ethyl acetate to give compound 55 (60 mg, 20%) as a colorless oil.

Step 5 : To a solution of compound 55 (60 mg, 0.12 mmol) in THF (3 mL) was added 0.192 N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL). The resulting mixture was stirred at room temperature for 24 hours and then diluted with water. The organic solvent was removed under reduced pressure and the resulting aqueous mixture was extracted with ethyl ether. The aqueous layer was lyophilized to give (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -5- methyl-2-oxo-1,2-dihydro- } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, sodium salt (56, 56 mg, 95%). MS calcd for (C ₂₄ H ₂₃ ClN ₃ O ₄ ) ^- 452.14 m / z; Found 451.99 m / z.

Example 15

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[2-oxo-1- (2-thienylmethyl) -1,2-dihydro- Dinyl] amino} carbonyl) amino] propanoic acid (62)

Step 1 : To a solution of 2-thiophenemethanol (1.015 g, 8.89 mmol) in CH ₂ Cl ₂ (17.8 ml) cooled to 0 ° C under a dry nitrogen atmosphere was added triethylamine (2.98 ml, 21.4 mmol) and methanesulfonyl Chloride (0.69 ml, 8.9 mmol) was successively added via syringe. The resulting mixture was stirred at 0 &lt; 0 &gt; C for 15 minutes and then 2-hydroxy-3-nitropyridine (1.496 g, 10.7 mmol) and 4-dimethylaminopyridine (catalyst) were added. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was diluted with ethyl acetate and diluted with 2N HCl, water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 39 (585 mg) as a yellow waxy solid.

Step 2 : Iron (154 mg, 2.8 mmol, -325 mesh) was added to a solution of compound 58 (330 mg, 1.40 mmol) in glacial acetic acid (6.6 ml) at room temperature under a dry nitrogen atmosphere. The resulting solution was heated at 60 &lt; 0 &gt; C for 20 minutes with vigorous stirring in an oil bath. The mixture was cooled to room temperature, diluted with ethyl acetate and then filtered through celite. The filtrate was washed with water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. Filtration through silica gel, eluting with hexane: ethyl acetate, increasing the residue from 1: 1 to 1: 3, yielding compound 59 (188 mg, 12% for two steps) as a green solid.

Step 3 : To a solution of 59 (111 mg, 0.54 mmol) in CH ₂ Cl ₂ (2.7 ml) cooled to 0 ° C under a dry nitrogen atmosphere was added N, N-diisopropylethylamine (0.23 ml, 1.30 mmol) (0.31 ml, 1.9 M in toluene, 0.59 mmol) was added sequentially via syringe. The resulting mixture was stirred at 0 &lt; 0 &gt; C for 15 minutes and a solution of beta -amino ester 60 (167 mg, 0.70 mmol) in CH ₂ Cl ₂ (2.7 ml) was added via cannula with CH ₂ Cl ₂ rinse . The resulting mixture was allowed to warm to room temperature and then diluted with ethyl acetate was stirred for 2 h and washed with 2N HCl, water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1: 1 hexane: ethyl acetate to give compound 61 (231 mg, 91%) as a purple foam.

Step 4 : To a solution of ester 61 (227mg, 0.48mmol) in THF (6ml) at room temperature was added NaOH (2ml, 2N in water, 4mmol) and methanol (sufficient to make clear solution, approx. 2ml). The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 62 (191 mg, 90%) as a white solid.

_{^{1 H NMR (400MHz, CD 3}} SOCD 3) δ 2.63 (d, J = 7.3Hz, 2H), 4.99 (dt, J = 8.4, 7.3Hz, 1H), 5.30 (s, 2H), 5.98 (m, 2H J = 8.1 Hz, 1H), 6.85 (d, J = 7.5, 7.0 Hz, 1H), 6.78 (Dd, J = 7.0, 1.8 Hz, 1H), 7.44 (dd, J = J = 5.1, 1.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 7.5, 1.8 Hz, 1H), 8.40 (s, 1H).

Example 16

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[(3S) -2-oxo-1- (2-thienylmethyl) hexahydro- ] Amino} carbonyl) amino] propanoic acid (68)

Step 1 : To a solution of N-α-t-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-ornithine 63 (1.00 g, 2.73 mmol) and cesium carbonate (1.33 g, 4.1 mmol Was added iodomethane (0.22 ml, 3.3 mmol) via syringe. The resulting mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate and washed with water, 10% Na ₂ S ₂ O ₅ , saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give ester 64 (1.21 g) as a pale yellow oil. This material contained DMF but was used without purification.

Step 2 : To a solution of compound 64 (0.86 g, theoretically 1.94 mmol) in methanol (10 ml) at 0 C under a dry nitrogen atmosphere was added palladium on charcoal (300 mg, 10% Pd, decane E101 NE / W, wet, 50 wt% water). The nitrogen atmosphere was replaced by hydrogen (5 replications of hydrogen supplied in vacuo and balloon) and the mixture was stirred for 30 min at 0 &lt; 0 &gt; C and then poured into a flask containing 2-thiophenecarboxaldehyde (177 mg, 1.58 mmol) Direct filtration. The mixture was concentrated (water bath at room temperature) and the residue was taken up in dichloroethane (6 ml). To this solution was added sodium triacetoxyborohydride (479 mg, 2.26 mmol) and the mixture was stirred for 2 h, then diluted with ethyl acetate and washed with saturated NaHCO ₃ (twice) and brine. The organic phase was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with 7: 3 hexane: ethyl acetate to give lactam 65 (75 mg, 12% for two steps) as a colorless oil.

Step 3 : HCl (7.2 ml, 4.0 M in dioxane, 28.8 mmol) was added via syringe to a flask containing compound 65 (89 mg, 0.29 mmol), which was sealed with a rubber plug at room temperature under a dry nitrogen atmosphere. The nitrogen needle was removed and the mixture in a sealed flask was stirred overnight. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ . The organic phase was dried with magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give amine 66 (60 mg, 100%) as a pale yellow oil. This material was used without purification.

Step 4 : Carbonyldiimidazole (51 mg, 0.32 mmol) was added to a solution of β-amino ester 60 (75 mg, 0.32 mmol) in CH ₂ Cl ₂ (0.6 ml) at room temperature under a dry nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of amine 66 (60 mg, 0.29 mmol) in CH ₂ Cl ₂ (0.6 ml) was added via cannula with 0.2 ml of CH ₂ Cl ₂ rinse. It was stirred for 3 days the resulting mixture at room temperature, diluted with ethyl acetate, 2N NCl (2 times), washed with water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with hexane: ethyl acetate increasing the ratio from 1: 1 to 2: 3 to give urea 67 (110 mg, 80%).

Step 5 : To a solution of Urea 67 (108 mg, 0.23 mmol) in THF (3 ml) at room temperature was added NaOH (1 ml, 2 N in water, 2 mmol) and methanol (sufficient to make clear solution, approx. 2 ml). The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 68 (92 mg, 90%) as a white foam.

_{^{1 H NMR (400MHz, CD 3}} SOCD 3) δ 1.45 (m, 1H), 1.76 (m, 2H), 2.62 (m, 2H), 3.25 (m overlapping _{H 2 O, 2H), 4.01} (m, 1H ), 4.59 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 15.0 Hz, 1H), 4.96 J = 8.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.75 J = 5.1, 3.3 Hz, 1H), 7.03 (dd, J = 3.3, 1.5 Hz, 1H), 7.42 (dd, J = 5.1, 1.5 Hz, 1H), 12.06 1H).

Example 17

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[(3S) 3-yl] amino} carbonyl) amino] propanoic acid (74)

Step 1 : To a solution of Nt-butoxycarbonyl-L-aspartic acid a-benzyl ester (2.10 g, 6.5 mmol) in dimethoxyethane (15 ml) cooled to -15 캜 (bath temperature) under a dry nitrogen atmosphere 4-Methylmorpholine (0.71 ml, 6.5 mmol) and isobutyl chloroformate (0.84 ml, 6.5 mmol) were successively added using a syringe. The resulting mixture was stirred for 2 minutes, filtered and the solid cake was washed with dimethoxyethane (10 ml). The filtrate was recooled to -15 deg. C (bath temperature) and a solution of sodium borohydride (370 mg, 9.7 mmol) in water (3 ml) was added and water (100 ml) was added immediately. The mixture was extracted with ethyl acetate (three times) and the combined organic layers were then cold (0 ℃) HCl (0.2N) , washed with water, saturated NaHCO ₃ and brine. The resulting organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 69 (2.50 g) as a colorless oil. This material contained some of the non-reduced mixed anhydrides but was used without purification.

Step 2: oxide of save chloride CH ₂ Cl ₂ (8ml) To a solution of (2.4ml, CH ₂ 2.0M, 4.8mmol of Cl ₂₎ in dry CH ₂ Cl ₂ (30ml) cooled to -65 under a nitrogen atmosphere ℃ A solution of methylsulfoxide (0.55 ml, 7.8 mmol) was added using a syringe. The resulting mixture was stirred at -65 ℃ for 15 minutes and then CH ₂ Cl ₂ (29ml) was added via cannula with a solution of alcohol 69 (1.00g, 3.2mmol) and CH ₂ Cl ₂ (3ml) rinse. The mixture was stirred at -65 &lt; 0 &gt; C for 3 hours and then warmed to -20 &lt; 0 &gt; C (bath temperature). Triethylamine (0.96 ml, 6.9 mmol) was added followed by water (20 ml). The aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give aldehyde 70 as a white solid. This material was used immediately without purification.

Step 3 : To a solution of the crude aldehyde 70 (3.2 mmol in theory) and 2-aminomethylthiophene (402 mg, 3.55 mmol) in dichloroethane (13 ml) at room temperature under a dry nitrogen atmosphere was added sodium triacetoxyborohydride (959 mg, 4.5 mmol). The resulting mixture was stirred overnight at room temperature, diluted with ethyl acetate and washed with saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1: 1 hexane: ethyl acetate to give Lactam 71 (220 mg, 23% over three steps) as a white solid.

Step 4 : HCl (1.50 ml, 4.0 M in dioxane, 6.0 mmol) was added via syringe to compound 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml) sealed with a rubber plug at room temperature under a dry nitrogen atmosphere. The nitrogen needle was removed and the mixture in a sealed flask was stirred for 5 hours. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ . The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give amine 72 (129 mg, 89%) as a pale yellow oil. This material was used without purification.

Step 5 : Carbonyldiimidazole (112 mg, 0.69 mmol) was added to a solution of amine 72 (123 mg, 0.63 mmol) in CH ₂ Cl ₂ (1.5 ml) at room temperature under a dry nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of? -Amino ester 60 (164 mg, 0.69 mmol) in CH ₂ Cl ₂ (0.8 ml) was added via cannula with 0.2 ml of CH ₂ Cl ₂ rinse . It was stirred overnight, diluted with ethyl acetate and the resulting mixture at room temperature, 2N NCl (2 times), washed with water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 49: 1 chloroform: methanol to give urea 73 (230 mg, 80%) as a colorless oil. The oil slowly solidified on standing.

Step 6 : To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) at room temperature was added NaOH (1 ml, 2N in water, 2 mmol) and methanol (1 ml). The resulting mixture was stirred for 1 hour, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 74 (181 mg, 84%) as a white foam.

_{^{1 H NMR (400MHz, CD 3}} SOCD 3) δ 1.64 (m, 1H), 2.30 (m, 1H), 2.64 (m, 2H), 3.20 (m, 2H), 4.17 (dd, J = 8.8, 8.4Hz J = 7.0 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 6.77 (s, 2H) (m, 1H), 6.80-6.90 (m, 2H), 6.96-7.04 (m, 2H), 7.45 (dd, J = 5.1, 0.7 Hz, 1H), 12.10 (br.

Example 18

Amino] -3- (4-methylphenyl) propanoic acid Synthesis of (3S) -3 - [({[5-chloro-2-

Step 1 : To a mixture of 2-phenylmethyl-3-chlorophenol (5.00 g, 22.9 mmol) in ethanol (20 mL) and 6N HCl (50 mL) was added KNO ₃ (2.30 g, 22.9 mmol) and NaNO ₂ (20 mg, Were successively added. The resulting mixture was stirred for 2 hours, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 99 (6.0 g, 100%).

Step 2 : To a solution of compound 99 (6.0 g, 22.8 mmol) in methanol (360 mL) was added zinc powder (6.0 g, 92 mmol) and saturated aqueous NH ₄ Cl (6 mL). The resulting homogeneous mixture was refluxed overnight. The hot mixture was filtered and the filtrate was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 100 (2.93 g, 55%).

Step 3 : DIPEA (0.40 mL, 2.4 mmol) and phosgene (1.93 M in toluene, 0.60 mL, 1.2 mmol) were successively added to a solution of compound 25 (0.20 g, 0.96 mmol) in CH ₂ Cl ₂ at 0 ° C. Respectively. The resulting mixture was allowed to warm to room temperature and stirred for 20 minutes and then re-cooled to 0 &lt; 0 &gt; C. To this mixture was added dropwise a solution of 100 (0.25 g, 1.1 mmol) in CH ₂ Cl ₂ . The resulting mixture was warmed to room temperature overnight, diluted with water and then extracted with CH ₂ Cl ₂ . The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with hexane: ethyl acetate, increasing the volume from 9: 1 to 5: 1 to give compound 101 (60 mg, 12%).

(Phenylmethyl) phenyl] amino} carbonyl) amino] -3- (2-hydroxy-3- 4-methylphenyl) propanoic acid.

_{^{1 H NMR (400MHz, CD 3}} SO 2 CD 3) δ 2.26 (s, 3H), 2.58 (dd, J = 15.8, 6.6Hz, 1H), 2.67 (dd, J = 15.8, 8.4Hz, 1H), 3.49 (s, 2H), 4.88 (m, 1H), 7.00-7.70 (m, 1H), 11.95 (br.s, 1H).

Example 19

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({butyl [2,5-dioxo-1- (phenylmethyl) tetrahydro- ] Amino} carbonyl) amino] propanoic acid Synthesis of

Step 1 : A solution of N-benzylmaleimide (2.60 g, 13.9 mmol) and n-butylamine (1.00 g, 13.7 mmol) in THF (15 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane: ethyl acetate, increasing the ratio from 4: 1 to 2: 1 to give compound 102 (3.25 g, 90%).

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({butyl [2,5-dioxo-1- Methyl) tetrahydro-1H-pyrrol-3-yl] amino} carbonyl) amino] propanoic acid: mp 80-85 ° C.

Example 20

(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[1- (cyclopentylmethyl) -2-oxo- Amino} carbonyl) amino] propanoic acid Synthesis of

Step 1 : Cyclopentanemethanol (178 mg, 1.78 mmol) was added to a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol) in CH ₂ Cl ₂ (14 mL) Phosphine (551 mg, 2.1 mmol) was added. The solution was stirred at 0 &lt; 0 &gt; C for 15 min and diethyl azodicarboxylate (366 mg, 2.1 mmol) was added dropwise via syringe. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then at room temperature overnight. The mixture was washed with methanol (20 mL) and sodium borohydride and washed with water (twice). The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 1: 1 hexane: ethyl acetate to afford 103 (299 mg, 96% yield) as a yellow solid.

3 - [({[1- (cyclopentylmethyl) -2-oxo-pyrrolidine-3- 1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.2-1.7 (m, 8H), 2.34 (m, 1H), 2.81 (dd, J =, 1H), 2.95 (dd, J =, 1H), 3.92 (d, J = 7.7 Hz, 2H), 5.30 (m, 1H), 5.92 (m, 2H), 6.30 (t, J = 7.1 Hz, 1H), 6.68-7.00 (m, 5H), 8.33 Hz, 1 H), 8.89 (s, 1 H).

Example 21

(2-thiophenylmethyl) amino] phenyl} amino) carbonyl] amino} propanoic acid &lt; EMI ID =

Step 1 : To a solution of 2-thiophenecarboxaldehyde (0.48 g, 4.0 mmol) in dichloromethane was added 3-nitroaniline (0.51 g, 3.7 mmol). The solution was concentrated to dryness and taken up in 1,2-dichloroethane (16 mL). Molecular sieves (3 A, 1.1 g) were added followed by NaBH (OAc) ₃ (1.01 g, 4.8 mmol). The solution was stirred at room temperature overnight, diluted with chloroform and then washed with water. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 104 (0.72 g, 84%).

Step 2 : To a solution of compound 104 (0.30 g, 1.3 mmol) in CH ₂ Cl ₂ (5.2 mL) and triethylamine (0.215 mL, 1.5 mmol) at 0 ° C was added trifluoroacetic anhydride (0.193 mL, 1.4 mmol) Was added. The solution was stirred at 0 &lt; 0 &gt; C for 15 minutes, the ice bath was removed and the mixture was stirred for an additional 15 minutes. The mixture was diluted with CH ₂ Cl ₂ and washed with 2N HCl, water and brine. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 105 (0.38 g, 100%) as a yellow solid.

Step 3 : To a solution of 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL) and acetic acid (2.6 mL) at room temperature was added Fe powder (0.36 g, 6.5 mmol) and TLC indicated complete disappearance of compound 105 Lt; RTI ID = 0.0 &gt; 40 C. &lt; / RTI &gt; The mixture was filtered through celite and washed with chloroform. The filtrate was diluted with saturated sodium bicarbonate, the chloroform layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (elution gradient 6: 1 to 4: 1 hexane: ethyl acetate) to give compound 106 (0.102 g, 25%).

(3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({3- [ Phenyl} amino) carbonyl] amino} propanoic acid.

_{^{1 H NMR (400MHz, CD 3}} SO 2 CD 3) δ 2.50 (m, 2H overlapping DMSO), 4.37 (d, J = 5.9Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.8 (d, J = 8.8, 7.7 Hz, 1 H), 6.06 (t, J = 5.8 Hz, J = 5.1, 1.1 Hz, 1H), 6.90 (s, 1H), 6.94 (dd, J = 5.2, 3.7 Hz, 1H) (s, 1 H).

Example 22

Synthesis of 3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3 - [({[2-oxo- -3-pyridinyl] amino} carbonyl) amino] propanoic acid

Step 1 : To a solution of (1S, 2R, 5S) - (+) - menthyl (R) -p-toluenesulfinate (3.00 g, 10.2 mmol) in THF (25.5 mL) Trimethylsilyl) amide (1.0 M in THF, 15.3 mL) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 6 hours and then cooled to 0 &lt; 0 &gt; C. Piperonal (3.06 g, 20.4 mmol) and CsF (3.10 g, 20.4 mmol) were added dropwise rapidly and the suspension was stirred at room temperature for 36 h. The reaction solution was saturated with NH ₄ Cl sodium borohydride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane and dichloromethane to give 108 (1.36 g, 46%).

Step 2 : Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to a suspension of Zn powder (2.00 g, 30.5 mmol) in THF (20.2 mL) and refluxed for 15 min. The suspension was cooled to 0 C and compound 108 (0.87 g, 3.0 mmol) was added. The suspension was warmed to room temperature and stirred overnight. The mixture was saturated with a minimum amount of saturated NH ₄ Cl sodium borohydride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (eluent gradient 6: 1 to 4: 1 hexane: ethyl acetate) to give compound 109 (0.607 g, 61% to 80% conversion).

Step 3 : To a solution of 109 (0.700 g, 1.70 mmol) in methanol (4.3 mL) at 0 C was added trifluoroacetic acid (0.26 mL, 3.4 mmol). The solution was stirred at 0 ° C for 2 hours and then concentrated to dryness under reduced pressure while keeping the external temperature below 30 ° C. The residue was taken up in diethyl ether and washed with 2N HCl (2 times). The combined aqueous layers were carefully basified with excess saturated NaHCO ₃ and extracted with diethyl ether. The ether layer was dried with magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 110 (0.326 g, 80%).

2-difluoro-3 - [({[2-oxo-1- (2 - thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid. MS: Calculated (MH) ^- = 476.07; Found (MH) ^- = 476.00.

Example 23

(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[9-oxo-8- (phenylmethyl) -2,3,4,5,8,9-hexahydro -1H-pyrido [3,4-b] azepin-1-yl] carbonyl} amino) propanoic acid

Step 1 : To a solution of compound 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) and TMEDA (1.60 mL, 10.8 mmol) under -20 캜 was added n-butyllithium (1.6 M in hexanes, 3.4 mL, 5.4 mmol ) And t-butyllithium (1.7 M in pentane, 2.5 mL, 4.3 mmol) were successively added dropwise by syringe. The temperature was allowed to warm to -10 to 0 &lt; 0 &gt; C and held for 2 hours. 1,4-Dibromobutane (1.75 mL, 14.7 mmol) was added rapidly to the resulting mixture, and the solution was warmed to room temperature and then stirred for 4 days. Sodium borohydride, the reaction with water and extracted with CHCl _{3 (3} times). The combined extracts were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with 4: 1 hexane: ethyl acetate, to give compound 111 (0.41 g, 44%). ({[9-oxo-8- (phenylmethyl) -2, 3-dihydroxy- 3,4,5,8,9-hexahydro-1H-pyrido [3,4-b] azepin-1-yl] carbonyl} amino) propanoic acid. MS: Calculated (MH) ^- = 488.18; Found (MH) ^- = 488.21.

Example 24

(3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- - hydroxyphenyl) propanoic acid Synthesis of

Step 1 : To a solution of compound 112 (prepared according to the procedure described in Example 15, 0.19 g, 0.39 mmol) in CH ₂ Cl ₂ at 0 ° C under nitrogen was added BBr ₃ (1.0 M in CH ₂ Cl ₂ , 1.2 mL, 1.2 mmol) was added via syringe. The mixture was slowly warmed to room temperature and then stirred overnight. The mixture was diluted with water and stirred for 30 minutes and was further diluted with saturated aqueous NaHCO ₃ in. The organic layer was washed with water and the aqueous layers were combined and then acidified with 2N HCl and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give (3S) -3 - {[({1- [(2- chlorophenyl) methyl] (Dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-hydroxyphenyl) propanoic acid (113, 120 mg, 70%).

_{^{1 H NMR (400MHz, CD 3}} SO 2 CD 3) δ 2.95 (d, J = 5.2Hz, 2H), 5.28 (s, 2H), 5.35 (ddd, J = 9.2, 4.8, 4.4Hz, 1H), 6.33 (m, 3H), 7.37 (dd, J = 7.7, 1.5 Hz, IH), 6.40 (d, J = , 8.35 (dd, J = 7.6, 1.5 Hz, 1 H), 8.80 (s, 1 H).

The compounds of Tables 1, 2 and 3 can be obtained using the synthetic procedures described above.

Example 25

The procedure for linking the 26-amino acid peptide (CDELPQLVTLPHPNLHGPEILDVPST) containing the CS1 sequence of fibronectin with the N-terminal Cys to the maleimide activated albumin can be used to determine the efficacy of the synthesized compounds. Bovine serum albumin (BSA) and CS1-conjugated ovalbumin were coated on 96-well polystyrene plates at 0.5 g / ml in TBS (50 mM TRIS, pH 7.5; 150 mM NaCl) for 16 hours at 4 캜. The plate was washed 3 times with TBS and blocked with TBS containing 3% BSA for 4 hours at room temperature. Before testing the blocked plate was washed three times with binding buffer _{(TBS; 1 mM MnCl 2 1} mM MgCl 2;; 1 mM CaCl 2). Fluorescently labeled Ramos cells with calcein AM were resuspended in binding buffer (10 ⁷ cells / ml) and diluted 1: 2 with the same buffer containing or not containing compound. 100 &lt; 3 &gt; M. Immediately, cells were added to wells (2.5 x 10 ⁵ cells / well) and cultured at 37 ° C for 30 minutes. After washing three times with binding buffer, the adsorbed cells were lysed and quantitated by fluorescence spectrometry. The results are shown in Tables 1 to 3. The IC ₅₀ values measured in μM in Tables 1 and 3 are defined as the dose (μM) required to induce 50% inhibition. The lower the IC ₅₀ value and the greater the inhibition rate, the higher the efficiency of the compound to inhibit cell adsorption.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[(3S) -2-oxo-1- (2-thienylmethyl) hexahydro- ] Amino} carbonyl) amino] propanoic acid 0.2 Calculated (MH) ^- = 444.12; found (MH) ^- = 444.08. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[(3S) 3-yl] amino} carbonyl) amino] propanoic acid 15 Calculated (MH) ^- = 430.11; found (MH) ^- = 430.06 (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[(3R) -2-oxo-1- (2-thienylmethyl) hexahydro- ] Amino} carbonyl) amino] propanoic acid 2 Calculated (MH) ^- = 444.12; Found (MH) ^- = 444.05 (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[2-oxo-1- (2-thienylmethyl) -1,2-dihydro- Dinyl] amino} carbonyl) amino] propanoic acid 0.9 Calculated (MH) ^- = 440.09; Found (MH) ^- = 439.98. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[((3S) ] Benzyl} hexahydro-3-pyridinyl] amino} carbonyl} amino) propanoic acid 0.0003 Calculated (MH) ^- = 586.23; Found (MH) ^- = 586.17. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[2-oxo-1- {4 - [(2-toluidinocarbonyl) amino] benzyl} , 2-dihydro-3-pyridinyl] amino} carbonyl} amino) propanoic acid 0.001 Calculated (MH) ^- = 582.20; Found (MH) ^- = 582.20. (3S) -1- {4 - [(2-methylbenzyl) amino] benzyl} -2-oxo Hexahydro-pyridinyl] amino] carbonyl) amino) propanoic acid none none (2-oxo-1- (2-thienylmethyl) -1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] propanoic acid 20 Calculated (MH) ^- = 496.15; Found (MH) ^- = 496.10. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[(3S) -2-oxo- 1- (2-thienylmethyl) ) Amino] propanoic acid 0.015 Calculated (MH) ^- = 458.13; Found (MH) ^- = 458.09.

compound IC ₅₀ (nM) Mass spectral data (m / z) (Phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 475.23; Found (MH) ^- = 475.02. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[2-oxo- 1- (phenylmethyl) -4- Dinyl] amino} carbonyl) amino] propanoic acid 10 Calculated (MH) ^- = 476.18; Found (MH) ^- = 475.99. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[9-oxo-8- (phenylmethyl) -2,3,4,5,8,9-hexahydro Pyrido [3,4-b] azepin-1-yl] carbonyl} amino) propanoic acid 4000 Calculated (MH) ^- = 488.18; Found (MH) ^- = 488.19. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-ethyl- 3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 466.15; Found (MH) ^- = 465.95. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid 4 Calculated (MH) ^- = 480.17; Found (MH) ^- = 480.00. (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 5 Calculated (MH) ^- = 454.15; Found (MH) ^- = 454.09. (3S) -3 - {[({6-methyl-2-oxo- (phenylmethyl) -4 - [(phenylmethyl) oxy] Amino} -3- (4-methylphenyl) propanoic acid 5 Calculated (MH) ^- = 524.22; Found (MH) ^- = 524.02. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2,4- dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 467.15; Found (MH) ^- = 467.00.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(2,4-dichlorophenyl) methyl] -4-methyl- } -3- (4-methylphenyl) propanoic acid 30 Calculated (MH) ^- = 486.10; Found (MH) ^- = 485.95. (3S) -3 - {[({4-amino-1 - [(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 467.15; Found (MH) ^- = 467.14. (3S) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (methyloxy) Amino] -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 468.13 Found (MH) ^- = 467.97. (3S) -3 - {[({4-chloro-1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 472.08; Found (MH) ^- = 471.91. (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- [3-methyl-4- (methyloxy) phenyl] propanoic acid 15 Calculated (MH) ^- = 482.15; Found (MH) ^- = 481.93. (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- [4- (methyloxy) phenyl] propanoic acid 3 Calculated (MH) ^- = 470.15; Found (MH) ^- = 470.01. (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (3,4-dimethylphenyl) propanoic acid 10 Calculated (MH) ^- = 468.17; Found (MH) ^- = 468.05. (3S) -3 - {[({4-amino-1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 453.13; Found (MH) ^- = 453.01. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-fluoro- -3- (4-methylphenyl) propanoic acid 15 Calculated (MH) ^- = 456.12; found (MH) ^- = 455.94.

compound IC ₅₀ (nM) Mass spectral data (m / z) (Phenylamino) -1,2-dihydro-3-pyridinyl] amino} carbonyl) -2,3- Amino] -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 529.16; Found (MH) ^- = 529.02. (2-pyridinylamino) -1,2-dihydro-3-pyridinyl] amino} -1- Carbonyl) amino] -3- (4-methylphenyl) propanoic acid 15 Calculated (MH) ^- = 530.16; Found (MH) ^- = 529.99. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 454.11; Found (MH) ^- = 454.05. (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -2-oxo-4 - [(2- pyridinylmethyl) amino] -1,2-dihydro- } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 15 Calculated (MH) ^- = 544.17; Found (MH) ^- = 544.03. (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -2-oxo-4 - [(3- pyridinylmethyl) amino] -1,2-dihydro- } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 544.17; Found (MH) ^- = 544.02. (3S) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (1,4- Pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid One Calculated (MH) ^- = 523.17; Found (MH) ^- = 523.02. (Propylamino) -1,2-dihydro-3-pyridinyl} amino) carbonyl] -2-oxo- Amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 495.18; Found (MH) ^- = 495.04. (3S) -3 - {[({1 - [(2-fluorophenyl) methyl] -4-methyl- -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 436.17; Found (MH) ^- = 435.99. (3S) -3 - {[({1 - [(2,6-dichlorophenyl) methyl] -4-methyl- } -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 486.10; Found (MH) ^- = 485.95.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3R) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-methyl- Carbonic acid 30 Calculated (MH) ^- = 376.11; Found (MH) ^- = 376.00. (3S) -3 - {[({1 - [(2-bromophenyl) methyl] -4-methyl- -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 496.09; Found (MH) ^- = 495.87. (4-methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- Methylphenyl) propanoic acid 30 Calculated (MH) ^- = 418.17; Found (MH) ^- = 417.96. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid 8 Calculated (MH) ^- = 484.12 found (MH) ^- = 484.03. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 514.15; Found (MH) ^- = 514.00. (3S) -3 - {[({4-bromo-1 - [(2- chlorophenyl) methyl] -2-oxo- -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 516.03; Found (MH) ^- = 515.90. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-hydroxy- - dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid 20 Calculated (MH) ^- = 484.09; Found (MH) ^- = 484.03. (2 - {[2- (methyloxy) ethyl] oxy} ethyl) oxy] -2-oxo-1, , 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 2 Calculated (MH) ^- = 556.18 Found (MH) ^- = 556.03. (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-hydroxy- Yl] amino} -3- (4-methylphenyl) propanoic acid 15 Calculated (MH) ^- = 468.13; Found (MH) ^- = 468.05.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4 - [(1,1- dimethylethyl) amino] -2-oxo-1,2-dihydro- Decyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 3 Calculated (MH) ^- = 509.20; Found (MH) ^- = 509.06. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3-phenylpropanoic acid 10 Calculated (MH) ^- = 440.10; Found (MH) ^- = 440.04. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4- [4-methyltetrahydro- -3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 3 Calculated (MH) ^- = 536.20; Found (MH) ^- = 536.12. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [4- (methyloxy) phenyl] propanoic acid 5 Calculated (MH) ^- = 470.11; Found (MH) ^- = 470.05. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3,4,5-tris (methyloxy) phenyl] propanoic acid 20 Calculated (MH) ^- = 530.13; Found (MH) ^- = 530.05. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3,5-dimethylphenyl) propanoic acid 15 Calculated (MH) ^- = 468.13; Found (MH) ^- = 468.08. (3-methyl-5-isoxazolyl) amino] -2-oxo-1,2-dihydro- 3-pyridinyl} amino) carbonyl] amino} -3- (4- (methyl) phenyl) propanoic acid 15 Calculated (MH) ^- = 534.15; Found (MH) ^- = 534.01. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 454.17; Found (MH) ^- = 454.04. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3- (methyloxy) phenyl] propanoic acid 5 Calculated (MH) ^- = 470.11; Found (MH) ^- = 470.03.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- [3,5-bis (methyloxy) phenyl] -3 - {[({1- [ Dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid 3 Calculated (MH) ^- = 500.12; found (MH) ^- = 500.07. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid 8 Calculated (MH) ^- = 504.13; Found (MH) ^- = 504.06. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3- (trifluoromethyl) phenyl] propanoic acid 20 Calculated (MH) ^- = 508.04; Found (MH) ^- = 508.09. (Ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1,2,3,4-tetrahydroisoquinoline; 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 2 Calculated (MH) ^- = 595.21; Found (MH) ^- = 594.97. (3S) -3 - {[({4- (1-azetanyl) -1 - [(2- chlorophenyl) methyl- Yl] amino} -3- (4-methylphenyl) propanoic acid 5 Calculated (MH) ^- = 493.16; Found (MH) ^- = 493.05. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (4-fluorophenyl) propanoic acid 30 Calculated (MH) ^- = 458.09; Found (MH) ^- = 458.03. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3-fluorophenyl) propanoic acid 40 Calculated (MH) ^- = 458.09; Found (MH) ^- = 458.06. (2 - {[2- (methyloxy) ethyl] oxy} ethyl) oxy] ethyl} -1,3- Oxy) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid 2 Calculated (MH) ^- = 600.21; Found (MH) ^- = 600.10. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [4- (trifluoromethyl) phenyl] propanoic acid 25 Calculated (MH) ^- = 508.09; Found (MH) ^- = 508.02.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(2- fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid 30 Calculated (MH) ^- = 438.15; Found (MH) ^- = 438.07. (2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- Carbonyl] amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 472.11; found (MH) ^- = 472.06. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [4- (1,1-dimethylethyl) phenyl] propanoic acid 400 Calculated (MH) ^- = 496.16; Found (MH) ^- = 496.11. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -5- 3- [4- (methylphenyl) propanoic acid 70 Calculated (MH) ^- = 452.14; Found (MH) ^- = 451.99. Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) -3-hydroxy- Carbonyl] amino} propanoic acid 30 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.07. (3S) -3 - [({[1 - [(2-methyl-6-oxo- 1- (phenylmethyl) -4- (2-pyridinyl) -1,6- ] Amino} carbonyl) amino] -3- [4- (methylphenyl) propanoic acid 25 Calculated (M + H) &lt; ⁺ & gt ^; = 498.22; Found (M + H) &lt; ⁺ & gt ^; = 498.10. Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) -3-hydroxy- Carbonyl] amino} propanoic acid 30 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.03. 3-pyridinyl} amino) carbonyl] amino} -3- (4-hydroxy-3- (3,4-dichlorophenyl) propanoic acid 40 Calculated (MH) ^- = 508.02; Found (MH) ^- = 507.97.

compound IC ₅₀ (nM) Mass spectral data (m / z) (Phenylmethyl) -3-azepanyl] amino} carbonyl) amino] propane (hereinafter referred to as &quot; mountain 0.015 Calculated (MH) ^- = 452.18; Found (MH) ^- = 452.10. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[ Carbonyl] amino} propanoic acid 0.04 Calculated (MH) ^- = 477.18; Found (MH) ^- = 477.14. (2-thio-phenyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino ] Propanoic acid 0.6 Calculated (MH) ^- = 410.11; found (MH) ^- = 410.00. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[2- oxo- 1- (phenylmethyl) -1,2-dihydro- } Carbonyl) amino] propanoic acid 0.5 Calculated (MH) ^- = 434.13; Found (MH) ^- = 434.05. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(4-methylphenyl) methyl] -2-oxo- Pyridinyl} amino) carbonyl] amino} propanoic acid One Calculated (MH) ^- = 448.14; Found (MH) ^- = 448.02. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[(1 - {[4- (methyloxy) phenyl] methyl} -2- Hydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid 3 Calculated (MH) ^- = 464.14; Found (MH) ^- = 468.03. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(3- methylphenyl) methyl] -2-oxo- Pyridinyl} amino) carbonyl] amino} propanoic acid 1.5 Calculated (MH) ^- = 448.15; Found (MH) ^- = 448.04. (3S) -3- [3,5-bis (methyloxy) phenyl] -3 - [({[2-oxo- 1- (2-thiophenylmethyl) -1,2-dihydro- ] Amino} carbonyl) amino] propanoic acid 0.7 Calculated (MH) ^- = 456.12; found (MH) ^- = 456.00.

compound IC ₅₀ (nM) Mass spectral data (m / z) (2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} Carbonyl) amino] propanoic acid 0.8 Calculated (MH) ^- = 426.11; Found (MH) ^- = 426.00. (3S) -3 - [({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- Trifluoromethyl) phenyl] propanoic acid &lt; RTI ID = 0.0 &gt; 2.5 Calculated (MH) ^- = 464.09; Found (MH) ^- = 463.99. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[3- (phenyloxy) phenyl] amino} carbonyl) amino] propanoic acid 50 Calculated (MH) ^- = 419.12; found (MH) ^- = 418.97. (2-thiophenylmethyl) amino] phenyl} amino) carbonyl] amino} propanoic acid &lt; EMI ID = 5 Calculated (MH) ^- = 438.11; Found (MH) ^- = 438.00. (3S) -3- (1, 3-benzodioxol-5-yl) -3 - {[ - pyridinyl} amino) carbonyl] amino} propanoic acid 0.8 Calculated (MH) ^- = 468.09; Found (MH) ^- = 468.01. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[(2- oxo-1 - {[3- (trifluoromethyl) phenyl] - dihydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid 0.8 Calculated (MH) ^- = 502.12; found (MH) ^- = 502.03. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[(2- oxo-1 - {[4- (trifluoromethyl) phenyl] - dihydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid 1.6 Calculated (MH) ^- = 502.12; found (MH) ^- = 502.01. (2-thio-phenyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl ) Amino] propanoic acid 1.6 Calculated (MH) ^- = 414.09; Found (MH) ^- = 414.01. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[ - pyridinyl} amino) carbonyl] amino} propanoic acid 3 Calculated (MH) ^- = 468.09; Found (MH) ^- = 467.99.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({[(1 - {[2- (methyloxy) phenyl] methyl} -2- Hydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid 0.5 Calculated (MH) ^- = 464.14; Found (MH) ^- = 464.04. (2-thio-phenyl) -1,2-dihydro-3-pyridinyl] amino} Carbonyl) amino] propanoic acid 1.4 Calculated (MH) ^- = 426.11; Found (MH) ^- = 426.02. (3S) -3 - [({[2- oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] One Calculated (MH) ^- = 396.10; Found (MH) ^- = 396.01. (3S) -3 - [({[2- oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3- pyridinyl] amino} carbonyl) amino] -3- , 5-tris (methyloxy) phenyl] propanoic acid 0.3 Calculated (MH) ^- = 486.13; Found (MH) ^- = 485.98. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo- - pyridinyl} amino) carbonyl] amino} propanoic acid 0.3 Calculated (MH) ^- = 468.08; Found (MH) ^- = 468.03. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(4- fluorophenyl) methyl] -2- 3-pyridinyl} amino) carbonyl] amino} propanoic acid 2 Calculated (MH) ^- = 452.12; Found (MH) ^- = 452.00. Synthesis of 3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3 - [({[2-oxo- -3-pyridinyl] amino} carbonyl) amino] propanoic acid > 100 Calculated (MH) ^- = 476.07; Found (MH) ^- = 476.00. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({2-oxo- 1- [3- (phenyloxy) propyl] -1,2-dihydro- - pyridinyl} amino) carbonyl] amino} propanoic acid 14 Calculated (MH) ^- = 478.16; Found (MH) ^- = 478.09. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(3,4- dichlorophenyl) methyl] -2- -3-pyridinyl} amino) carbonyl] amino} propanoic acid 4 Calculated (MH) ^- = 502.05; Found (MH) ^- = 501.98.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(3,5- dichlorophenyl) methyl] -2- -3-pyridinyl} amino) carbonyl] amino} propanoic acid 5 Calculated (MH) ^- = 502.05; Found (MH) ^- = 501.94. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[1- (cyclopentylmethyl) -2-oxo- Amino} carbonyl) amino] propanoic acid 6 Calculated (MH) ^- = 426.16; Found (MH) ^- = 426.09. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({2-oxo- 1- [2- (2-thiophenyl) ethyl] -3-pyridinyl} amino) carbonyl] amino} propanoic acid 15 Calculated (MH) ^- = 454.09; Found (MH) ^- = 453.99. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- - methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 440.14; Found (MH) ^- = 440.09. (3S) -3- (2,3-dihydro-1-benzofuran-5-yl) -3 - [({[2- oxo- 1- (2-thiophenylmethyl) -3-pyridinyl] amino} carbonyl) amino] propanoic acid 0.14 Calculated (MH) ^- = 438.11; Found (MH) ^- = 437.99. (3-fluorophenyl) -3 - [({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl ) Amino] propanoic acid 3 Calculated (MH) ^- = 414.09; Found (MH) ^- = 413.99. (3S) -3 - [({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) Trifluoromethyl) phenyl] propanoic acid &lt; RTI ID = 0.0 &gt; 1.5 Calculated (MH) ^- = 464.09; Found (MH) ^- = 463.99. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[6-oxo- 1- (phenylmethyl) -1,6-dihydro- } Carbonyl) amino] propanoic acid 0.5 Calculated (MH) ^- = 434.13; Found (MH) ^- = 434.02. (Trifluoromethyl) phenyl] -3 - [({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro- 3-pyridinyl] amino} carbonyl) amino] propanoic acid 0.35 Calculated (MH) ^- = 482.08; Found (MH) ^- = 481.97.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- [4- (1,1-dimethylethyl) phenyl-3 - [({[2-oxo- 1- (2-thiophenylmethyl) -1,2-dihydro- ] Amino} carbonyl) amino] propanoic acid 2 Calculated (MH) ^- = 452.16; Found (MH) ^- = 452.02. (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({butyl [2,5-dioxo-1- (phenylmethyl) tetrahydro- ] Amino} carbonyl) amino] propanoic acid 70 Calculated (MH) ^- = 494.19; Found (MH) ^- = 494.12. (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] , 4,5-tris (methoxyoxy) phenyl] propanoic acid 0.04 Calculated (MH) ^- = 516.16; Found (MH) ^- = 516.02. (3S) -3 - {[({1 - [(2,6-dichlorophenyl) methyl] -2-oxo- (4-methylphenyl) propanoic acid 0.2 Calculated (MH) ^- = 474.10; found (MH) ^- = 474.04. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] - fluoro-3- (trifluoromethyl) phenyl] propanoic acid 0.2 Calculated (MH) ^- = 512.10; Found (MH) ^- = 512.04. (3S) -3 - {[({1 - [(2- fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] 4-methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 422.15; Found (MH) ^- = 422.01. (2-methylphenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} propanoic acid 0.1 Calculated (MH) ^- = 418.18; Found (MH) ^- = 418.02. (3S) -3 - {[({1- [(2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] 4-methylphenyl) propanoic acid 0.05 Calculated (MH) ^- = 484.09; Found (MH) ^- = 484.03. (3S) -3 - {[({1 - [(2,4-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] (4-methylphenyl) propanoic acid 0.4 Calculated (MH) ^- = 474.10; found (MH) ^- = 474.05.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] , 3-dihydro-1-benzofuran-5-yl) propanoic acid 0.04 Calculated (MH) ^- = 466.11; Found (MH) ^- = 466.00. (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo- - pyridinyl} amino) carbonyl] amino} propanoic acid 2 Calculated (MH) ^- = 468.09; Found (MH) ^- = 467.97. (3S) -3- (4-methylphenyl) -3 - ({[(2- oxo-1 - {[2- (trifluoromethyl) Amino] carbonyl} amino) propanoic acid One Calculated (M + H) ^- = 474.10; found (M + H) ^- = 474.09. (3S) -3 - {[({1 - [(2,5-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] (4-methylphenyl) propanoic acid 0.15 Calculated (M + H) ^- = 474.10; found (M + H) ^- = 474.04. (2R) -2 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] mountain 50 Calculated (MH) ^- = 424.10; found (MH) ^- = 423.99. (2R) -2 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] amino} Carbonic acid 80 Calculated (MH) ^- = 410.08; found (MH) ^- = 409.95. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- , 5-dimethylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 452.14; Found (MH) ^- = 451.96. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} mountain 0.1 Calculated (MH) ^- = 424.10; found (MH) ^- = 424.07. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] - (methyloxy) phenyl] propanoic acid 0.1 Calculated (MH) ^- = 454.11; Found (MH) ^- = 454.01.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- - hydroxyphenyl) propanoic acid 0.1 Calculated (MH) ^- = 440.10; found (MH) ^- = 440.00. (3S) -3 - ({[(1 - {[3- (methyloxy) phenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] carbonyl} - (4-methylphenyl) propanoic acid 0.2 Calculated (MH) ^- = 434.17; Found (MH) ^- = 434.01. (3S) -3 - {[({1- [(2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] 3,4,5-tris (methyloxy) phenyl] propanoic acid 0.08 Calculated (MH) ^- = 558.09; Found (MH) ^- = 557.87. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- , 4-dimethylphenyl) propanoic acid 0.09 Calculated (M + H) &lt; ^- &gt; = 454.15; Found (M + H) ^- = 454.07. (3S) -3 - [({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino) carbonyl) amino] -3- 0.8 Calculated (MH) ^- = 437.12; found (MH) ^- = 437.06. (3S) -3- (4-methylphenyl) -3 - [({[3- (phenylmethyl) phenyl] amino} carbonyl) amino] propanoic acid 10 Calculated (MH) ^- = 387.17; Found (MH) ^- = 387.00. (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] -Methyl-4- (methyloxy) phenyl] propanoic acid 0.04 Calculated (MH) ^- = 468.13; Found (MH) ^- = 468.01. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- -Hydroxy-3-methylphenyl) propanoic acid 0.07 Calculated (MH) ^- = 454.11; Found (MH) ^- = 454.00. (3S) -3 - {[({1 - [(2,3-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] (4-methylphenyl) propanoic acid 0.35 Calculated (MH) ^- = 472.08; Found (MH) ^- = 471.94.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - [({[1- [1,1'-biphenyl] -2-ylmethyl) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid 2.5 Calculated (MH) ^- = 480.19; Found (MH) ^- = 480.05. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- - methylphenyl) propanoic acid 0.2 Calculated (MH) ^- = 438.12; found (MH) ^- = 438.00. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] amino} -3- - methylphenyl) propanoic acid 3 Calculated (MH) ^- = 438.12; found (MH) ^- = 437.99. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] amino} -3- , 3-dihydro-lH-inden-5-yl) propanoic acid 0.3 Calculated (MH) ^- = 464.13; Found (MH) ^- = 464.03. (3S) -3 - {[({1 - [(2-cyanophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] 4-methylphenyl) propanoic acid 0.1 Calculated (M + H) ^- = 431.18; Found (M + H) ^- = 431.09. (2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- Pyridinyl} amino) carbonyl] amino} propanoic acid 6 Calculated (MH) ^- = 484.14; Found (MH) ^- = 483.96. (3S) -3 - {[({1 - [(3-hydroxyphenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] 4-methylphenyl) propanoic acid 0.2 Calculated (M + H) ^- = 420.18; Found (M + H) &lt; ^- &gt; = 422.05. (2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyridinyl] amino} carbonyl) amino] -3- Methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 419.17; Found (MH) ^- = 419.03. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-oxo-1,4- dihydro-3- pyridinyl} amino) carbonyl] amino} -3- - methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 438.12; found (MH) ^- = 438.10.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- (4-methylphenyl) -3 - {[({1 - [(2-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} propanoic acid One Calculated ^{(M + H) - = 451.17} ; Found ^{(M + H) - = 451.07} . (4-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} propanoic acid One Calculated (M + H) ^- = 451.17; Found (M + H) ^- = 451.09. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] amino} -3- , 6-dihydroxyphenyl) propanoic acid 3 Calculated (MH) ^- = 456.10; Found (MH) ^- = 456.04. (3S) -3 - {[({1 - [(2,6- difluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 0.3 Calculated (MH) ^- = 440.14; Found (MH) ^- = 440.00. (3S) -3 - {[({1 - [(2,4-difluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 1.3 Calculated (MH) ^- = 440.14; Found (MH) ^- = 439.96. (3S) -3 - {[({1 - [(2,5-difluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 0.8 Calculated (MH) ^- = 440.14; Found (MH) ^- = 439.96. (2-chlorophenyl) methyl] -2-methyl-6-oxo-1,6-dihydro-5-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 0.09 Calculated (MH) ^- = 453.13; Found (MH) ^- = 453.00. (2-chloro-6-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 456.11; Found (MH) ^- = 455.94. (2-bromo-5-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid 0.5 Calculated (MH) ^- = 500.06; found (MH) ^- = 499.91.

compound IC ₅₀ (nM) Mass spectral data (m / z) (2-chloro-4-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 0.35 Calculated (MH) ^- = 456.11; Found (MH) ^- = 455.93. (3S) -3 - {[({1- [(2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] 3-methyl-4- (methyloxy) phenyl] propanoic acid 0.2 Calculated (MH) ^- = 512.08 found (MH) ^- = 511.96. (3S) -3 - {[({1 - [(3,5-dimethyl-4-isoxazolyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid 3 Calculated (MH) ^- = 423.17 Found (MH) ^- = 423.02. (4-methylphenyl) -3 - {[({2-oxo-1 - [(2,4,6-trimethylphenyl) methyl] Amino) carbonyl] amino} propanoic acid 2.5 Calculated (MH) ^- = 446.21; Found (MH) ^- = 446.08. (2-methyl-1,3-thiazol-4-yl) methyl] -2-oxo-1,2-dihydro- -3-pyridinyl} amino) carbonyl] amino} propanoic acid One Calculated (MH) ^- = 425.13; Found (MH) ^- = 424.99. (1 - {[4- (1,1-dimethylethyl) phenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] carbonyl} Amino) -3- (4-methylphenyl) propanoic acid 6 Calculated (MH) ^- = 460.22; Found (MH) ^- = 460.07. (3S) -3 - [({[1- (1,3-benzoxazol-2-ylmethyl) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] 3- (4-methylphenyl) propanoic acid > 10 Calculated (MH) ^- = 445.15; Found (MH) ^- = 445.01. (2-hydroxyphenyl) amino] -2-oxoethyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] Carbonyl} amino) -3- (4-methylphenyl) propanoic acid > 10 Calculated (MH) ^- = 463.16; Found (MH) ^- = 463.06. (2-chloro-6-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 4 Calculated (MH) ^- = 483.11; Found (MH) ^- = 483.01.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(5-chloro-2- fluorophenyl) methyl] -2-oxo- -3- (4-methylphenyl) propanoic acid 2.5 Calculated (MH) ^- = 456.11; Found (MH) ^- = 456.00. (3S) -3 - {[({1 - [(2-Amino-6- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid 2 Calculated (MH) ^- = 453.13; Found (MH) ^- = 453.02. (Trifluoromethyl) phenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] Carbonyl} amino) -3- (4-methylphenyl) propanoic acid 3 Calculated (MH) ^- = 490.14; Found (MH) ^- = 489.99. (3S) -3 - {[({1 - [(5-chloro-2- thiophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid 1.3 Calculated (MH) ^- = 440.08; Found (MH) ^- = 443.97. (2-bromo-5-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 2 Calculated (MH) ^- = 527.06; Found (MH) ^- = 526.95. Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) -3-hydroxy- Carbonyl] amino} propanoic acid 0.03 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.07. (2-pyridinyl) -1,6-dihydro-5-pyrimidinyl] amino} carbonyl Yl) amino] -3- (4-methylphenyl) propanoic acid 0.025 Calculated (M + H) ^- = 498.22; Found (M + H) ^- = 498.10. (3S) -3 - {[({1 - [(5-amino-2- bromophenyl) methyl] -3- (4-methylphenyl) propanoic acid 0.08 Calculated (MH) ^- = 497.08; Found (MH) ^- = 497.02. (3S) -3 - {[({1 - [(2,5-dimethylphenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] (4-methylphenyl) propanoic acid 0.15 Calculated (MH) ^- = 432.19; Found (MH) ^- = 432.04.

compound IC ₅₀ (nM) Mass spectral data (m / z) Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) -3-hydroxy- Carbonyl] amino} propanoic acid 0.03 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.03. 3-pyridinyl} amino) carbonyl] amino} -3- (4-hydroxy-2- 3,4-dichlorophenyl) propanoic acid 0.04 Calculated (MH) ^- = 508.02; Found (MH) ^- = 507.97. (3S) -3 - ({[(1 - {[5- (acetylamino) -2-bromophenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] } Amino) -3- (4-methylphenyl) propanoic acid 0.2 Calculated (MH) ^- = 539.09; Found (MH) ^- = 539.02. (2-bromo-5 - [(methylsulfonyl) amino] phenyl} methyl) -2-oxo-1,2-dihydro-3-pyridinyl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid 0.25 Calculated (MH) ^- = 575.06; Found (MH) ^- = 575.01. 3-pyridinyl} amino) carbonyl] amino} -1H-pyrazolo [3,4-d] Propanoic acid 0.4 Calculated (MH) ^- = 458.07; Found (MH) ^- = 457.96. 3-pyridinyl} amino) carbonyl] amino} -2-oxo-1,2-dihydro-3-pyridinyl} Propanoic acid One Calculated (MH) ^- = 458.07; Found (MH) ^- = 457.93. 3-pyridinyl} amino) carbonyl] amino} -3- (3,4-dichloro-3,3-dihydro- Phenyl) propanoic acid One Calculated (MH) ^- = 492.03; Found (MH) ^- = 491.85. (2-bromo-4-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid One Calculated (MH) ^- = 516.03; Found (MH) ^- = 515.91. (3S) -3 - {[({1 - [(4-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] amino} -3- - methylphenyl) propanoic acid 2 Calculated (MH) ^- = 438.12; found (MH) ^- = 437.88.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [2,3-dimethyl-4- (methyloxy) phenyl] propanoic acid 0.035 Calculated (MH) ^- = 498.14; Found (MH) ^- = 498.05. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- {4 - [(trifluoromethyl) oxy] phenyl} propanoic acid 0.015 Calculated (MH) ^- = 524.08; Found (MH) ^- = 524.03. (3R) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (1,4- Pyridinyl] amino} carbonyl) amino] -5-methylhexanoic acid 0.1 Calculated (MH) ^- = 489.19; Found (MH) ^- = 489.13. (Phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] - 3- (4-methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 434.17; Found (MH) ^- = 434.08. (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -2-oxo-4 - [(propylsulfonyl) amino] -1,2-dihydro- ) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid 0.030 Calculated (MH) ^- = 559.14; Found (MH) ^- = 559.04. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (4-ethylphenyl) propanoic acid 0.025 Calculated (MH) ^- = 468.13; Found (MH) ^- = 468.06. (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [4- (ethyloxy) phenyl] propanoic acid 0.02 Calculated (MH) ^- = 484.13; Found (MH) ^- = 484.06. (4-hydroxy-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- - methylphenyl) propanoic acid 0.030 Calculated (MH) ^- = 420.16; Found (MH) ^- = 420.08.

All references cited are incorporated herein by reference.

The present invention is illustrated by the foregoing description and embodiments. Because numerous modifications will be apparent to those skilled in the art, the foregoing detailed description is considered as a non-limiting example. It is intended that all such variations within the scope and spirit of the appended claims be included in the scope of the claims.

Changes may be made in the structure, process and arrangement of the method of the invention described herein without departing from the concept and scope of the invention as defined in the following claims.

Claims (15)

A compound of formula I or a pharmaceutically acceptable salt thereof. Formula I In this formula, Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S; q is an integer from 3 to 10; A is selected from ^{O, S, C (R 16} ) (R 17) , and the group consisting of NR ^6; E is selected from the group consisting of CH ₂ , O, S and NR ⁷ ; J is selected from the group consisting of O, S, and NR ⁸ ; T is selected from the group consisting of C (O) and (CH _{2) b} (wherein, b is an integer from 0 to 3); M is selected from the group consisting of ^{C (R 9) (R 10} ) and (CH _{2) u} (wherein, u is an integer from 0 to 3); L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n wherein n is an integer of 0 or 1; X is _{CO 2 B, PO 3 H 2} , SO 3 H, SO 2 NH 2, SO 2 NHCOR 12, OPO 3 H 2, C (O) NHC (O) R 13, C (O) NHSO 2 R 14, Is selected from the group consisting of hydrogen, hydroxyl, tetrazolyl, and hydrogen; W is selected from the group consisting of C, CR &lt; ¹⁵ &gt; and N; ^{B, R 1, R 2,} R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16 , and R ¹⁷ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , nitro, , carboxy, -N (C ₁ -C _{3 alkyl) -C (O) (C 1} -C 3 alkyl), -NHC (O) N ( C 1 -C 3 alkyl) C (O) NH (C 1 - C ₃ alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkylamino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C (O) O- (C 1 -C 3 ) alkyl, -C (O) NH- (C 1 -C 3) alkyl, -C (O) N (C 1 -C 3 _{alkyl) 2, -CH = NOH, -PO} 3 H 2, -OPO 3 H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diaryl Amino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhetero Cycle reel, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and It is selected from the group consisting of a -C (O) NH ^{(benzyl), B, R 1, R} 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11 , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are unsubstituted or substituted with one or more electron-donating or electron-withdrawing groups, and when L is NR ¹¹ , R ⁴ and R ¹¹ together form a ring R ⁹ and R ¹⁰ may form a ring together, and when A is NR ⁶ and at least one Y is CR ¹ , R ¹ and R ⁶ may together form a ring; With the proviso that E is not NR ⁷ when A is C (R ¹⁶ ) (R ¹⁷ ). The method of claim 1 wherein A is NR ^6, and E is NR ^7, and J is O, M is a ^{C (R 9) (R 10} ), q is 4 or 5, T is (CH _{2) b} (wherein, b is 0) and, L is (CH _{2) n} (where, n is zero), X is a C ₂ OB, W is C or CR ^15, R ⁴ is aryl, alkylaryl, Wherein R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are independently selected from the group consisting of hydrogen and lower alkyl; and R is selected from the group consisting of hydrogen, lower alkyl, aralkyl, heterocyclyl, alkylheterocyclyl and heterocyclylalkyl, compound. 2. A compound according to claim 1 which is a derivative selected from the group consisting of esters, carbamates, amides, amides and prodrugs. A compound of formula (II) or a pharmaceutically acceptable salt thereof: (II) In this formula, Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S; q is an integer from 3 to 7; T is selected from the group consisting of C (O) and (CH _{2) b} (wherein, b is an integer from 0 to 3); L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n wherein n is an integer of 0 or 1; W is selected from the group consisting of C, CR &lt; ¹⁵ &gt; and N; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, (C ₁ -C ₃ alkyl) -C (O) R 2, wherein R ₁ , R 2, R ₃ , R 4 and R _{5 are the same or different} and are selected from the group consisting of hydrogen, alkyl, alkoxy, alkenoxy, alkoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, (C ₁ -C ₃ alkyl), -NHC (O) N ( C 1 -C 3 alkyl) C (O) NH (C 1 -C 3 alkyl), -NHC (O) NH ( C 1 -C 6 alkyl ), alkyl, alkenyl, amino, di (C ₁ -C ₃₎ amino, -C (O) O- (C 1 -C 3) alkyl, -C (O) NH- (C 1 -C 3) alkyl , -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH═NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, Cycloalkenyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheteroaryl, Cycloalkyl, heterocyclylalkyl, _{Sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH (benzyl R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are each independently selected from the group consisting of here, or is substituted with electron withdrawing group, L is NR ¹¹ be when, R ⁴ and R ¹¹ may form a ring together, and R ⁹ and R ¹⁰ taken together may form a ring, a is NR ⁶ and at least one Y that may form a ring with CR in case of ^1, R ¹ and R ^6. The method of claim 4 wherein q is 4 or 5 and W is C or CR ^15, T is (CH _{2) b} (wherein, b is zero) and, L is (CH _{2) n} (where, n is And R ⁴ is selected from the group consisting of aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl and heterocyclylalkyl, and R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ Is independently selected from the group consisting of hydrogen and lower alkyl. The compound according to claim 4, which is a derivative selected from the group consisting of ester, carbamate, aminal, amide and prodrug. A compound of formula (III) or a pharmaceutically acceptable salt thereof: (III) In this formula, Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S; q is an integer from 2 to 5; T is selected from the group consisting of C (O) and (CH _{2) b} (wherein, b is an integer from 0 to 3); L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n wherein n is an integer of 0 or 1; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), alkoxy, alkoxy, alkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , nitro, amino, cyano, carboxy, -C ₃ alkyl), -NHC (O) N ( C 1 -C 3 alkyl) C (O) NH (C 1 -C 3 alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkyl amino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C (O) O- (C 1 -C 3) alkyl, -C (O) NH- (C 1 -C 3) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, Cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, Heterocyclylalkyl, sulfo _{Carbonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH (benzyl) R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹¹ are unsubstituted or substituted with one or more electron- is substituted with, when L is NR ¹¹ il, R ⁴ and R ¹¹ may form a ring together, and R ⁹ and R ¹⁰ taken together may form a ring, a is NR ⁶ and at least one Y CR ¹ il , R &lt; ¹ &gt; and R &lt; ⁶ &gt; may form a ring together. The method of claim 7, wherein, R ⁵ is selected from hydrogen, alkyl, aryl, cycloalkyl, alkyl, heterocyclyl, heterocyclylalkyl and heterocyclyl reel consisting of a group, T is (CH _{2) b} (wherein, b is 0 And L is selected from the group consisting of (CH ₂ ) _n (wherein n is 0) and Y is CR ¹ and C (R ² ) (R ³ ), and q is 2 or 3. 8. A compound according to claim 7 which is a derivative selected from the group consisting of esters, carbamates, amides, amides, optical isomers and prodrugs. 8. The method of claim 7, Is selected from the group consisting of , And In the above formulas, R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, CF _3, nitro, amino, cyano, carboxy, -N (C ₁ -C _{3 alkyl) -C (O) (C 1} -C 3 alkyl), -NHC (O) N ( C 1 -C 3 alkyl) _{C (O) NH (C 1} -C 3 alkyl), -NHC (O) NH ( C 1 -C 6 alkyl), alkylamino, alkenyl amino, di (C ₁ -C ₃₎ amino, -C (O ) O- (C ₁ -C ₃₎ alkyl, -C (O) NH- (C 1 -C 3) alkyl, -C (O) N (C 1 -C 3 alkyl) _2, -CH = NOH, - _{PO 3 H 2, -OPO 3 H} 2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkyl, alkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino (C ₁ -C ₃ alkyl) alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO ₂ - (C ₁ -C ₃ alkyl) , -SO ₃ - (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH (benzyl) groups, c is an integer from 0 to 2 and d is E is an integer from 0 to 4, and f is 0 or 1. The method of claim 7, wherein, R is a ^5-alkyl aryl, and R ⁴ is aryl, T is (CH _{2) b} (wherein, b is zero) and, L is (CH _{2) n} (where, n is 0 And B, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are each independently hydrogen. (Phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({[2-oxo- 1- (phenylmethyl) -4- Pyridinyl] amino} carbonyl) amino] propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-ethyl- 3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({6-methyl-2-oxo-1- (phenylmethyl) -4 - [(phenylmethyl) oxy] -1,2-dihydro-3-pyridinyl} amino) Yl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2,4- dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({4-amino-1 - [(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methyloxy) phenyl) propanoic acid, (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (3,4-dimethylphenyl) propanoic acid, (3S) -3 - {[({4-amino-1 - [(2- chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (4-methylphenyl) propanoic acid, (3S) -3 - [({[1- [(2-chlorophenyl) methyl] -4- (1,4- Pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (Propylamino) -1,2-dihydro-3-pyridinyl] amino} carbonyl) -2,3- Amino] -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-bromophenyl) methyl] -4-methyl- -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -2-oxo- 3- (4-methylphenyl) propanoic acid, (2 - {[2- (methyloxy) ethyl] oxy} ethyl) oxy] -2-oxo-1, , 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1- [(2-chlorophenyl) methyl] -4-hydroxy- Yl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4 - [(1,1- dimethylethyl) amino] -2-oxo-1,2-dihydro- Decyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- 3-phenylpropanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4- [4-methyltetrahydro- -3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2- chlorophenyl) methyl] -4-hydroxy- -3- [4- (methyloxy) phenyl] propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3,5-dimethylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- (3-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3- (methyloxy) phenyl] propanoic acid, (3S) -3- [3,5-bis (methyloxy) phenyl] -3 - {[({1- [ Dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} amino} carbonyl) } -3- [4-methylphenyl] propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -4-hydroxy- -3- [3- (trifluoromethyl) phenyl] propanoic acid, (Ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1,2,3,4-tetrahydroisoquinoline; 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({4- (1-azetanyl) -1 - [(2- chlorophenyl) methyl] Carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (2 - {[2- (methyloxy) ethyl] oxy} ethyl) oxy] ethyl} -1,3- Oxy) -1,2-dihydro-3-pyridinyl} amino} carbonyl) amino] -3- (4- (3S) -3 - {[({1 - [(2- fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid, (2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- Carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 - {[({1 - [(2-chlorophenyl) methyl] -5- 3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2- - dihydro-3-pyridinyl) amino) carbonyl) amino) propanoic acid, (3S) -3 - ((((1 - ((2- chlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) -Methylphenyl) propanoic acid, (3S) -3 - ((((1 - ((2- fluorophenyl) methyl) -2-oxo-1,2-dihydro-3- pyridinyl) amino) carbonyl) 4-methylphenyl) propanoic acid, (3S) -3 - ((((1 - ((2-bromophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) 4-methylphenyl) propanoic acid, (3S) -3 - (((1 - ((2,4-dichlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) (4-methylphenyl) propanoic acid, (2-chloro-6-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 - ((((1 - ((2-chlorophenyl) methyl) -4-hydroxy- 3- (4-trifluoromethyl) oxy) phenyl) propanoic acid, and a pharmaceutically acceptable salt thereof. 12. A compound according to claim 11 wherein the derivative is selected from the group consisting of esters, carbamates, amides, amides, optical isomers and prodrugs. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A method of selectively inhibiting alpha ₄ beta ₁ integrin binding in a mammal, comprising administering to a mammal a therapeutic amount of a compound of claim 1.