KR100853950B1 - Carboxylic acid derivatives that inhibit the binding of integrins to their receptors - Google Patents

Abstract

The present invention provides a method for inhibiting α ₄ β ₁ integrins from binding to their receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; Compounds which inhibit this binding; Pharmaceutically active compositions comprising such compounds; And the use as such forms or formulations of such compounds for the inhibition or prevention of disease states involving α ₄ β ₁ .

α4β1 integrin, receptor of α4β1 integrin, VCAM-1, fibronectin, carboxylic acid derivative

Description

Carboxylic acid derivatives that inhibit the binding of integrins to their receptors             

The present invention generally relates to inhibiting the α ₄ β ₁ integrins from binding to their receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The present invention also relates to compounds which inhibit such binding, pharmaceutically active compositions containing these compounds, and the use of such compounds as such forms or formulations for controlling or preventing disease conditions involving α ₄ β _1. will be.

If tissue is infected or damaged by microorganisms, white blood cells play a major role in the inflammatory response. One of the most important aspects of the inflammatory response relates to cell adhesion. In general, white blood cells have been found to circulate through the bloodstream. However, when tissue is infected or damaged, white blood cells recognize the infected or damaged tissue, bind to the capillary wall, and then migrate through the capillary to the infected or damaged tissue. This phenomenon is mediated by a class of proteins called cell adhesion molecules.

White blood cells fall into three categories: granulocytes, monocytes and lymphocytes. Integrin α ₄ β ₁ (also called VLA-4 (very late antigen-4)) is expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes (eosinophils and basophils). Is a heterodimeric protein. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin (proteins that bind to endothelial cells that form the inner wall of the capillary).

Following infection or injury of pericapillary tissue, endothelial cells express a series of adhesion molecules, including VCAM-1, which are important for binding to the white blood cells needed to combat infection. Leukocytes first bind to specific adhesion molecules before binding to VCMA-1 or fibronectin to slow the flow and cause the cells to roll along the activated endothelial. Monocytes, lymphocytes, basophils and eosinophils can bind strongly to VCAM-1 or fibronectin on the vessel wall via α ₄ β ₁ integrin. There is evidence that this interaction is related to the initial rolling phenomenon itself as well as the migration of these white blood cells to damaged tissues.

Although leukocyte migration to the wound site may help fight infection and destroy foreign material, in many cases this migration is uncontrollable and leukocytes rush to these sites and cause extensive tissue damage. Thus, compounds that can block this process may be useful as therapeutic agents. In this regard, it may be beneficial to develop inhibitors that inhibit the binding of white blood cells to VCAM-1 and fibronectin.

Some of the diseases that can be treated by inhibition of α ₄ β ₁ binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergies, multiple sclerosis, lupus, inflammatory bowel disease, transplant rejection, contact hypersensitivity, and Type I diabetes is included. In addition to being found in some leukocytes, α ₄ β ₁ is also found in several cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that α ₄ β ₁ related cell adhesion has been implicated in the metastasis of certain cancers. Thus, inhibitors of α ₄ β ₁ binding may be useful for the treatment of some cancer types.

Isolation and purification of peptides that inhibit the binding of α ₄ β ₁ to proteins is described in US Pat. 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 adhesion and cell adhesion-mediated pathology are described in WO 96/22966, WO 98/04247 and WO 98/04913.

Accordingly, it is an object of the present invention to provide novel compounds that are inhibitors of α ₄ β ₁ binding and pharmaceutical compositions containing these new compounds.

Summary of the Invention

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:                 

In the above formula,

Y is independently at each occurrence 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 the group consisting of O, S, C (R ¹⁶ ) (R ¹⁷ ) and 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 , where 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 , Selected from the group consisting of 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 independently in each occurrence is 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, alkenylamino, 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 , Diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, Kill 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) group; 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 unsubstituted or substituted with one or more electron donating or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ together may form a ring; 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 include 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 (where b Is 0), L is (CH ₂ ) _n (where 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 , R ¹⁰ and R ¹⁵ are independently hydrogen or lower alkyl.

More specifically, the compound of the present invention may be a compound of formula (II) or a pharmaceutically acceptable salt thereof:

In the above formula,                 

Y is independently at each occurrence 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 , where 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 hydrogen, halogen, hydroxyl, alkyl, alkenyl, alky Nyl, 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, alkenylamino, 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 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 ( Benzyl) group; 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 unsubstituted or substituted with one or more electron donating or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ together may form a ring; When A is NR ⁶ and at least one Y is CR ¹ , R ¹ and R ⁶ may form a ring together.

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 where n is 0), R ⁴ is aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl, and R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are independently hydrogen or It is a compound that is lower alkyl.

More specifically, the compound of the present invention may be a compound of formula III or a pharmaceutically acceptable salt thereof:

In the above formula,

Y is independently at each occurrence 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 , where 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 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, alkenylamino, 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, cyclo Alkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl , Heterocyclylalkyl, sulf _{Carbonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) NH (benzyl) Is selected from the group consisting of groups; B, 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 donor or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ together may form a ring; When A is NR ⁶ and at least one Y is CR ¹ , R ¹ and R ⁶ may form a ring together.

Preferred compounds of formula III are those in which R ⁵ is hydrogen, alkyl, aryl, cycloalkyl, alkylheterocyclyl, heterocyclylalkyl or heterocyclyl, T is (CH ₂ ) _b , where b is 0, L is (CH ₂ ) _n where n is 0, Y is CR ¹ and C (R ² ) (R ³ ), and q is 2 or 3;

는 하기의 분자일 수 있다:In Formula III, a portion of the molecule

Can be a molecule of

,

및

.

,

And

.

In the above formula,

R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are independently at each occurrence 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, alkenylamino, 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, aryl Oxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C _1- C ₃ Alkyl), -SO ₃ - is selected from (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C (O) group consisting of a NH (benzyl); 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 where n is 0 And each of B, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ is independently hydrogen.

Preferred compounds are as follows:

(3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (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-propyl-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] propanoic acid,

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

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

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

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

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

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

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

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

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

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

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

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

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

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3- pyridinyl} amino) carbonyl] amino} -3- (3,5-dimethylphenyl] propanoic acid,

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

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

(3S) -3- [3,5-bis (methyloxy) phenyl] -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2- 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) amino } -3- [4-methylphenyl] propanoic acid,

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

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

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

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

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

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

(3S) -3- (1,3-benzodioxol-5-yl) -3-((((2-oxo-1-((4- (trifluoromethyl) phenyl) methyl) -1,2 -Dihydro-3-pyridinyl) amino) carbonyl) amino) propanoic acid,

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

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

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

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

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

(3S) -3-((((1-1-((2-chlorophenyl) methyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-trifluoromethyl) oxy) phenyl) propanoic acid and salts thereof.                 

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

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

In addition, the present invention inhibits the binding of α ₄ β ₁ integrins to VCAM-1, including exposing α ₄ β ₁ integrin expressing cells to VCAM-1 expressing cells in the presence of an inhibitory effective amount of a compound of the present invention. It is about how to. 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 .

Term Definition

As used herein, alone or in combination, the term “alkyl” refers to a C ₁ -C ₁₂ straight or branched chain, substituted or derived from a saturated hydrocarbon by the removal of one hydrogen atom unless specifically indicated as C _x -C _y . It refers to an unsubstituted, saturated chain radical. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary-butyl, iso-butyl and t-butyl.

As used herein, alone or in combination, the term “alkenyl” refers to a substituted or unsubstituted straight or substituted or unsubstituted 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.

As used herein, alone or in combination, the term “alkynyl” refers to a substituted or unsubstituted straight or substituted or unsubstituted branched alkynyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decinyl, and the like.

The term "lower" used before "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a C ₁ -C ₆ unit for each functional group. For example, lower alkyl means C ₁ -C ₆ alkyl.

As used herein, alone or in combination, the term "aliphatic acyl" refers to the formulas alkyl-C (O)-, alkenyl-C (O)-and alkynyl-C (O) derived from alkanes, alkenes, or alkyncarboxylic acids. ), Wherein "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 3 to 10 carbon atoms and 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl and adamman Teal is included. Cycloalkyl groups are groups consisting of lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide It may be substituted or unsubstituted with one, two or three substituents independently selected from among.

"Cycloalkyl" includes cis or trans forms. In addition, the substituent may be at the endo or exo position of the crosslinked bicyclic system.

As used herein, alone or in combination, the term “cycloalkenyl” refers to a cyclic carbocycle containing 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

As used herein, the term “cycloalkylalkyl” refers to a cycloalkyl group bonded to a lower alkyl radical and includes, but is not limited to, cyclohexylmethyl.

As used herein, the term "halo" or "halogen" refers to I, Br, Cl or F.

The term "haloalkyl" as used herein refers to a lower alkyl radical 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, t-butoxy and the like. Included.

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

As used herein, alone or in combination, the term "alkynoxy" refers to a radical of the formula alkynyl-O-, provided that the radical is not -inol ether. Examples of suitable alkynoxy include, but are not limited to, propargyloxy, 2-butynyloxy, and the like.

The term "carboxyl" as used herein 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.

As used herein, the term “carboxaldehyde” refers to —C (O) R, wherein R is hydrogen.

As used herein, the term “carboxamide” or “amide” refers to —C (O) NR _a R _b where 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 and R _d is alkylene-(CH ₂ ) _{n '} -(where n' is 1 to 6). Is an integer). Representative examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy.

The term "alkylamino" as used herein refers to R _c NH where R _c is a lower alkyl group and examples include ethylamino, butylamino.

As used herein, alone or in combination, the term "alkenylamino" refers to the formula alkenyl-NH- or (alkenyl) ₂ N-, wherein the term "alkenyl" is as defined above, provided that the radical It is not an enamine. Examples of such alkenylamino radicals include allylamino radicals.

The term "alkynylamino" as used herein refers to the formula alkynyl-NH- or (alkynyl) ₂ N-, wherein the term "alkynyl" is as defined above, provided 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, and examples include diethylamino and methyl propylamino. .

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

The term "alkoxycarbonyl" as used herein refers to an alkoxy group as defined above which is attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl.

As used herein, alone or in combination, the term “aryl” or “aromatic” refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms (eg, phenyl, naphthyl, indenyl, indanyl) , Azulenyl, fluorenyl and anthracenyl) or heterocyclic aromatic groups 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, 1,3 , 4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-tritianyl, indolinyl, indolyl, isoindoleyl, 3H- Indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, furinyl, 4H-qui Teasing Neil, Isoquinolinyl, Cinolinyl, Phthalaginyl, Quinazolinyl, Quinoxalinyl, 1,8-naphthridinyl, Pterridinyl, Carbazolyl, Acridinyl, Phenazinyl, Phenothiazinyl, Phenoxy Cyazinyl, pyrazolo [1,5-c] triazinyl, etc.). "Aralkyl" and "alkylaryl" use the term "alkyl" as defined above. The ring may be substituted in plural.

As used herein, alone or in combination, the term "aralkyl" refers to an aryl substituted alkyl radical, wherein the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl, and the like. This includes.

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

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

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

As used herein, alone or in combination, the term "thioaryl" refers to a radical of the formula aryl-S-, where aryl is as defined above. Examples of thioaryl radicals include thiophenyl radicals.

As used herein, alone or in combination, the term “aroyl” refers to a radical of the formula aryl-CO—, where 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.

As used herein, alone or in combination, the term “heterocyclyl” refers to a nonaromatic 3- to 10-membered ring containing one or more endocyclic N, O or S atoms. In addition, heterocycles are optionally hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl It may be substituted with one or more substituents selected from the group consisting of, oxo, arylsulfonyl and aralkylaminocarbonyl.

As used herein, the term "alkylheterocyclyl" refers to an alkyl group as defined above attached to the parent moiety through a heterocyclyl group, examples of which are 2-methyl-5-thiazolyl, 2-methyl-1-pyrrolyl and 5-ethyl-2-thienyl is included.

As used herein, the term “heterocyclylalkyl” refers to the heterocyclyl group bonded to the parent molecular moiety through an alkyl group, examples of which are 2-thienylmethyl, 2-pyridinylmethyl and 2- (1-piperididi). Nil) ethyl.

As used herein, the term "amino" refers to hemi acetals of the formula R _h C (NR _i R _j ) (NR _k R _l )-wherein R _h , R _i , R _j , R _k and R _l are independently Hydrogen, alkyl or other suitable substituent).

As used herein, the term "ester" 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 based on carbamic acid NH ₂ C (O) OH.

Use of the term includes substituted and unsubstituted residues. Substituents include alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyls, nitros, cyanos, carboxys, amines, heteroatoms, lower alkyls, lower alkoxys, lower alkoxycarbonyls, alkoxyalkoxy, acyloxy, halogen, trifluoro Methoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocycle It may be one or more groups such as arylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents described in the paragraphs above or any of the substituents directly connected or connected by a suitable linker. Linkers are typically of -C-, -C (O)-, -NH-, -S-, -S (O)-, -O-, -C (O) O- or -S (O) O-. It is a short chain of 1 to 3 atoms, in which any combination is included. The ring may be substituted in plural.

The term “electron attraction” or “electron donation” refers to the ability of a substituent to attract or donate an electron as compared to hydrogen when hydrogen is present at the same position in the molecule. These terms are well understood by those skilled in the art and are described 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 donating groups include hydroxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, aryloxy, mercapto, lower alkylthio, lower alkyl mercapto and disulfide. Those skilled in the art will appreciate that such substituents may have electron donating or electron withdrawing properties under different chemical conditions. In addition, the present invention includes any combination of substituents selected from the groups identified above.

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

The term "composition," as used herein, encompasses products that contain certain components in specific amounts, as well as products formed by combining certain components directly or indirectly in specific amounts.

Rings designated Y in Formulas (I), (II) and (III) may be mono-cyclic heterocycle or aromatic rings or bicyclic rings.

Dotted lines used in formulas (I), (II) and (III) indicate that the bond between atoms Y and W may be a double bond or a single bond if W and / or Y is a substituent such as N, C or CH. Thus, the ring denoted Y in the formula may be saturated or unsaturated depending on the selected substituents of W and / or Y.

Suitable substituents for the aryl, alkyl, cycloalkyl, heterocyclyl groups or suitable substituents for the rings represented by Y and W in Formulas I and II above are alcohols, amines or heteros which, when present, are bonded directly or via suitable linkers Or combinations of aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or heterocyclyl groups. The linker is typically 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, in Formulas I, II, and III, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ^7, and R ⁸ are not limited to, but independently hydrogen, alkyl, phenyl, thienylmethyl , Isobutyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzothiophen-2- Yl, allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfanylmethyl, benzylsulfonylmethyl, phenylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl , 4-((2-toluidinocarbonyl) amino) benzyl, 2-pyridinylethyl, 2- (1H-indol-3-yl) ethyl, 1H-benzylimidazol-2-yl, 4-pipe Ridinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenethyl, 4-aminobenzyl, phenylsulfonylmethyl, 4- (acetylamino) phenyl, 4-methoxyphenyl, 4-aminophenyl , 4-chlorophenyl, (4- (benzylsulfonyl) amino) phenyl, 4- (methylsulfonyl) amino) phenyl, 2-aminophenyl, 2 -Methylphenyl, isopropyl, 2-oxo-1-pyrrolidinyl, 3- (methylsulfanyl) propyl, (propylsulfanyl) methyl, octylsulfanylmethyl, 3-aminophenyl, 4-((2-tolui Dinocarbonyl) amino) phenyl, 2-((methylbenzyl) amino) benzyl, methylsulfanylethyl, hydroxy, chloro, fluoro, bromo, ureido, amino, methanesulfonylamino, acetylamino or ethylsulpa Nylmethyl.

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-dimethylphenyl, Allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl, methylsulfanyl, phenylsulfanyl, phenethylsulfanyl , 4-bromo-2-thienyl, 3-methyl-2-thienyl, 4- methylphenyl, 3,5-bis (methoxyoxy) phenyl, 4- (methoxyoxy) phenyl, 4-fluorophenyl , 3- (methoxyoxy) phenyl, 3,4,5-tris (methoxyoxy) phenyl, 2,3-dihydro-1-benzofuran-5-yl, 3-fluorophenyl, 4- (tri Fluoromethyl) phenyl, 4-fluoro-3- (trifluoromethyl) phenyl, 4- (1,1-dimethylethyl) phenyl, 3,5-dimethylphenyl, 4-hydroxyphenyl, 3,4- Dimethylphenyl, 3-methyl-4- (methyloxy) phenyl, 4-hydroxy-3-methylphenyl, 3-methylphenyl, 2,3-dihydro-inden-5-yl, 2-methylphenyl, 2,6-bis (Methyloxy) phenyl, 2,6-diha Drophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-((trifluoromethyl) oxy) phenyl, 4-ethylphenyl, 4- (ethyloxy) phenyl, methyl, 2- Propyl or 4,5-dihydro-1,3-oxazol-2-yl.

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

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

R ⁹ and R ¹⁰ may be linked to form rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Abbreviation

The meanings of the abbreviations used in the following 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 is 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. The abbreviations for amino acids are as follows: 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.

Examples of procedures that can be used to synthesize the compounds of the formulas described above can be shown in the following schemes. Details of representative compounds according to the invention are 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:                 

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

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:                 

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

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

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

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

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

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

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

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

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

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:

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 that are suitable for use in contact with human and lower animal tissues without reasonable toxicity, irritation, allergic reactions, etc., and that have a reasonable benefit / risk ratio under 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 can be prepared in situ during the final separation and purification of the compounds of the invention or separately by reacting the free base functional groups 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, glycerol Lophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate , Nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate , Phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate Included. Basic nitrogen-containing groups also include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; Quaternized with agents such as arylalkyl halides such as benzyl and phenethyl bromide. This gives a water soluble or fat soluble or dispersible product. Examples of acids that 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 may be used to convert the carboxylic acid containing moiety in situ during the final separation and purification of a compound of the invention into a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or ammonia or organic 1 It can be prepared by reaction with a secondary, 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 nontoxic 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, ethanoldiamine, diethanolamine, piperidine, piperazine, and the like.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and other necessary preservatives, propellants or buffers. Eye drops, eye ointments, powders and solutions also fall within the scope of the present invention.

The actual dosage of the active ingredient contained in the pharmaceutical composition of the present invention may vary depending on the amount of the active compound, the composition, and the mode of administration effective to achieve the desired therapeutic response in a particular patient. The dose level chosen depends on the activity of the particular compound, the route of administration, the severity of the disease condition and the condition and history of the patient. However, it is common in the art to establish a dose of a compound at a level lower than necessary to achieve the desired therapeutic effect and then slowly increase until the desired effect is achieved.

The therapeutically effective amounts of the compounds according to the invention for use in these and other therapies can be used in pure form or when present in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound may be administered as a pharmaceutical composition containing the compound together with one or more pharmaceutically acceptable excipients. The term "therapeutically effective amount" of a compound of the present invention means an amount of the compound sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment. However, it will be understood by those skilled in the art that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician under reasonable medical judgment. The specific therapeutically effective dose level for a particular patient may include the disease to be treated and its severity; The activity of the specific compound employed; The specific composition used; The age, body weight, health, sex and diet of the patient; The time of administration, route of administration, and rate of excretion of the specific compound employed; Duration of treatment; It will depend on factors including drugs used in combination or coincidental with the specific compound employed and factors well known in the medical arts. For example, it is common in the art to establish a dose of a compound at a level lower than necessary to achieve the desired therapeutic effect and then slowly increase until the desired effect is achieved.

The total daily dose of a compound according to the invention administered to a human or lower animal is from about 0.0001 to about 1000 mg / kg / day. More preferred doses for the purpose of oral administration are from about 0.001 to about 5 mg / kg / day. If necessary, the 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 divided doses that make up the daily dose.

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

The pharmaceutical compositions of the present invention may be administered to humans or other mammals by oral, rectal, parenteral, subretinal alveolar, intravaginal, intraperitoneal, topical (powder, ointment or dropping), oral, oral or nasal sprays. Can be. As used herein, the term “parenteral” means a mode of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically acceptable diluent. The present invention relates to compositions with one or more physiologically acceptable nontoxic diluents, carriers, adjuvants or vehicles (collectively referred to as diluents) for parenteral injection, intranasal delivery, oral administration in solid or liquid form, rectal or topical administration. At least one compound formulated into.                 

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

Compositions suitable for parenteral injection may include sterile powders for redissolution into physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile injection solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (olive oils), injectable organic esters (e.g. ethyl oleate) and these Suitable mixtures of are included.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents (eg, parabens, chlorobutanol, phenol, sorbic acid, etc.) can inhibit the action of microorganisms. It may also be desirable to include osmotic pressure regulators such as sugars, sodium chloride, and the like. Absorption delaying agents (eg, aluminum monostearate and gelatin) may be used to delay absorption of the injectable drug.

Suspending agents in addition to the active compounds, suspending agents (e.g., ethoxyl ring isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof And the like).

In some cases it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection to sustain the effect of the drug. This can be achieved by using liquid suspensions of low water soluble or amorphous materials. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, will depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are prepared by forming the 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). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-capturing filter or by incorporation of the sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is one or more inert pharmaceutically acceptable excipients or carriers (eg sodium citrate or dicalcium phosphate) and / or a) fillers or extenders (eg starch, lactose, sucrose, Glucose, mannitol and silicic acid), b) binders (e.g. carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia), c) humectants (e.g. glycerol), d) disintegrants (e.g. Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate), e) liquid retardants (e.g. paraffin), f) absorption accelerators (e.g. quaternary ammonium compounds), g) wetting agents (e.g. Cetyl alcohol and glycerol monostearate), h) absorbents (e.g. kaolin and bentonite clay) and i) lubricants (e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and their Mixture). In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

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 from shells and of such objects as coatings well known in enteric skin and other pharmaceutical fields. They may optionally contain a clouding agent and may also be formulated to release only the active ingredient or preferentially release the active ingredient in a randomly delayed manner at certain sites of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes.

The active compound may also be present in microcapsule form with one or more of the aforementioned excipients as required.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms are water or other solvents, solubilizers and emulsifiers, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene Such as glycols, dimethyl formamide, oils (especially cottonseed oil, peanut oil, corn, seeds, olives, castor and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan and mixtures thereof It may contain an inert diluent commonly used in.

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

Compositions for rectal or vaginal administration are preferably suitable non-irritating adjuvants or carriers (e.g., cocoa butter, polyethylene glycol or suppositories) which release the active compound by dissolving the compound of the invention in solid or body temperature liquid at room temperature and thus in the rectum or vagina. And a suppository that can be mixed with a wax.

The compounds of the present invention can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellae hydrated liquid crystals dispersed in an aqueous medium. Any physiologically acceptable, non-toxic and acid-degradable lipid capable of forming liposomes can be used. 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 natural and synthetic phospholipids and phosphatidyl choline (lecithin) used separately or together.

Methods for forming liposomes 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 prodrug” is suitable for use in contact with tissues of humans and lower animals, without causing excessive toxicity, irritation and allergic reactions, under reasonable medical judgment, and with a reasonable benefit / risk ratio. And prodrugs of the compounds of the invention that are effective for the intended use, as well as the zwitterionic forms of the compounds of the invention where possible. The prodrugs of the present invention can be rapidly converted to the parent compound of the above formula in vivo, for example by hydrolysis in the blood. For details, see T. Higuchi and V. Stella, Pro-drugs 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 a mammal are also within the scope of the invention.

The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. These stereoisomers are R or S depending on the arrangement of the peripheral substituents of chiral carbon atoms. The present invention includes several stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers and diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared by synthesis from commercially available starting materials with 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) separation of the resulting mixture of diastereomers by linking, recrystallization or chromatography of a mixture of enantiomers and free of optically pure product from the auxiliary or (2) chiral chromatography There is a direct separation of the mixture of optical enantiomers in the chromatography column.

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

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

Cells expressing α ₄ β ₁ integrins are natural leukocytes, mast cells or other cell types that naturally express α ₄ β ₁ integrins on the cell surface, or polynucleotides encoding α ₄ β ₁ integrins (eg, genomic DNA Or cells transfected with an expression vector containing cDNA). In a particularly preferred embodiment, α ₄ β ₁ integrin is present on the surface of leukocytes such as monocytes, lymphocytes or granulocytes (eg basophils or eosinophils).

Cells expressing VCAM-1 may be natural cells (eg endothelial cells) or cells transfected with an expression vector containing polynucleotides encoding VCAM-1. Methods of preparing transfected cells expressing VCAM-1 are well known in the art.

When VCAM-1 is present on the cell surface, expression of that VCAM-1 is preferably induced by inflammatory cytokines such as tumor necrosis factor-α, interleukin-4 and interleukin-1β.

When cells expressing α ₄ β ₁ integrin and VCAM-1 are present in a living organism, the compounds of the present 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 methods of the invention are particularly useful for treating diseases associated with unregulated migration of white blood cells to 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 α ₄ β ₁ integrin in the presence of the compounds of the invention of an effective inhibiting amount of a protein. In a preferred embodiment, α ₄ β ₁ integrins are expressed on the surface of natural cells or cells transformed to express α ₄ β ₁ integrins.

The protein to which the α ₄ β ₁ integrin binds may be expressed on the cell surface or part of an extracellular matrix. Particularly preferred proteins are fibronectin or invacin.

The ability of the compounds of the invention to inhibit binding is described in detail in the Examples below. These examples are presented to describe preferred embodiments and usefulness 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 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 type E101 NE / W, about 50% water content, 5.75 g, 2.7 mmol Pd) Was added. The atmosphere was replaced with hydrogen (repeated hydrogen in vacuum and balloon five times) and the mixture was stirred overnight and then filtered. The filtrate was concentrated in vacuo and the residue was taken 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 ° 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 rt for 6 h 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 compound 3 (3.33 g, 75%).

Step 3 : Compound 3 (0.50 g, 2.4 mmol) was dissolved in dry THF (9.6 mL) and TMEDA (1.1 mL, 7.2 mmol) under anhydrous nitrogen atmosphere. The resulting solution was cooled to −20 to −10 ° C. and n-butyllithium (1.6M in hexanes, 2.25 mL) and t-butyllithium (1.7M in pentane, 2.1 mL) were added dropwise successively by syringe. After 30 minutes the bath temperature was raised to -5 to 0 ° C. and ethyl iodide (0.77 mL, 9.6 mmol) was treated with a syringe. The solution was stirred at 0 ° C. for 2 hours and then at room temperature overnight. The mixture was quenched with methanol and concentrated to dryness. The residue was purified by filtration through silica gel, eluting with 3: 1 hexanes: ethyl acetate, and recrystallized from 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 for 1.0 h in an oil bath adjusted to 115 ° C. The mixture was cooled, diluted with water and then adjusted to pH 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-chlorobenzylbromide (0.16 mL, 1.2 mmol) and the solution was warmed 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 , hexane: ethyl acetate from elution gradient 4: 1 to 2: 1) to afford compound 6 (0.16 g, 41%).

Step 6 : Compound 6 (0.16 g, 0.46 mmol) was suspended in 1: 1 water: concentrated HCl (4.6 mL). The suspension was refluxed for 4 hours to dissolve the compound. The mixture was cooled down, diluted with water and then extracted with diethyl ether. The aqueous layer was basified with excess 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 ° C. The cold solution was quickly treated with a phosgene solution (1.93 M 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 quickly added by syringe. The resulting mixture was heated to 55 ° 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 magnesium sulfate 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-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid (10, 0.095 g, 92%) was obtained.

Example 2

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

Step 1 : Benzyl bromide (2.31 g, 13.5 mmol) was added to a suspension of compound 11 (1.0 g, 5.9 mmol) and K ₂ CO ₃ (2.40 g, 17.6 mmol) in acetone (50 mL). After refluxing overnight the reaction was cooled and the mixture was 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 for 1 h at rt before further zinc (0.30 g, 4.6 mmol) was added. The resulting heterogeneous 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 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. To this solution was added dropwise phosgene (1.9 M in toluene, 0.55 ml, 1.0 mmol). The reaction mixture was stirred at 0 ° C. for 15 min and then compound 8 (0.19 g, 0.94 mmol) in CH ₂ Cl ₂ (2 mL) was added. The resulting solution was stirred at rt overnight then poured into ethyl acetate and washed with saturated aqueous NaHCO ₃ , 1N HCl and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with hexanes: ethyl acetate, increasing from 1: 1 to 1: 2 to give compound 14 (0.33 g, 64%).

Step 4 : A solution of compound 14 (0.33 g, 0.6 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). MeOH was added until a homogeneous solution was obtained. The reaction mixture was stirred for 30 min at room temperature 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 (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-{[({6-methyl-2-oxo-1- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3- Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid (15, 0.26 g, 90%) was obtained as a gray solid. Melting point: 124-126 ° C.

Example 3

(3S) -3-{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Synthesis of 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 ° C. was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol). The mixture was stirred at 0 ° C. for 15 minutes before 2-chlorobenzylchloride (12.3 g, 76.4 mmol) was added. After stirring at 55 ° 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 yield compound 16 (14.7 g, 85%).

Step 2 : In a flask containing Compound 16 (8.00 g, 28.6 mmol) sealed with a rubber stopper, POCl ₃ (30.0 ml, 322 mmol) was added by syringe at room temperature under anhydrous nitrogen atmosphere. The nitrogen line was removed and the reaction mixture was stirred at 70 ° C. overnight, then poured onto ice (300 ml) and stirred for 30 minutes. 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) was added to a 250 ml flask equipped with a rubber stopper with a balloon and a condenser. Was added. The reaction mixture was heated to 65 [deg.] C. for 60 hours only by opening the balloon. 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 saturated aqueous ammonium chloride (2 ml) and zinc dust (0.30 g, 4.6 mmol) successively. After stirring for 30 minutes at room temperature 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 extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 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 ° C. overnight. The mixture was cooled and diluted with ethyl acetate (60 mL). The organic layer was washed with 0.5N NaOH (3 × 30 mL) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with CHCl ₃ : MeOH, increasing from 9: 1 to 17: 3 to give compound 21 (0.120 g, 65%) as 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 rt for 30 min 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 (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-oxo-1,2-dihydro-3-pyridinyl} Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid (22, 0.100 g, 89%) was obtained as a gray solid. Melting point: 145-147 ° C.

Example 4

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

Step 1 : To a solution of compound 23 (10.00 g, 64.0 mmol) in dry DMF (130 mL) at 0 ° C. was added NaH (60% dispersion in mineral oil, 5.90 g, 147 mmol). The mixture was stirred at 0 ° C. for 15 minutes before 2-chlorobenzylchloride (13.4 g, 83.3 mmol) was added. After stirring at 55 ° C. overnight, the mixture was poured into ice water and washed with ethanol (twice). The aqueous layer was acidified and the resulting precipitate was filtered to give compound 24 (13.5 g, 75%).

Step 2 : A suspension of compound 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, 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-1,2-di from Compound 25 according to the procedure described in Example 3 Hydro-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was prepared. MS: calculated: (M + H) ⁺ = 469.93; Found: (M + H) ⁺ = 470.01.

Example 5

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-fluoro-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 dry THF (12.4 mL) and TMEDA (0.90 mL, 6 mmol) under anhydrous nitrogen atmosphere. The resulting solution was cooled to −15 to −10 ° C. and n-butyllithium (1.6M in hexanes, 7.75 mL, 12.4 mmol) was added dropwise by syringe. After 1.5 h, a solution of N-fluorobenzenesulfonimide (1.07 g, 3.4 mmol) in THF (5 mL) was added dropwise to the cooling solution by syringe. The solution was stirred at 0 ° C. for 1 hour and then at room temperature for 3 hours. The mixture was quenched with water 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 (SiO ₂ , plug gel, 4: 1 to 3: 1 hexanes: ethyl acetate) to give compound 26 (0.177 g, 25%).

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-fluoro-2-oxo-1,2-dihydro- from Compound 26 according to the procedure described in Example 1 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared. MS: calculated: (M + H) ⁺ = 458.12; Found: (M + H) ⁺ = 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 ° C. The solution was treated with n-butyllithium (1.6 M in hexanes, 4.8 mL, 7.8 mmol). The mixture was kept between -20 and -10 ° C for 1 hour and cooled to -78 ° C. The instrument was placed under a positive outflow 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 quenched with water 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 compound 27 (0.25 g, 33%).

(3S) -4-chloro-3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 from Compound 27 according to the procedure described in Example 1 -Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared.

Example 7

(3S) -4-bromo-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 (2.00 g, 9.6 mmol) was dissolved in dry THF (32 mL) and TMEDA (2.20 mL, 14.4 mmol) under anhydrous nitrogen atmosphere. The resulting solution was cooled to −20 to −10 ° C. and n-butyl lithium (1.60 M in hexanes, 18.0 mL, 28.8 mmol) was added dropwise by syringe. After the addition was complete, the solution was cooled to -78 ° C and bromine (0.49 mL, 10.5 mmol) was added dropwise by syringe. The solution was slowly warmed to room temperature overnight, then quenched with water and extracted with chloroform. The organic layer was dried over MgSO ₄ , 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- from compound 28 according to the procedure described in Example 1 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared.

Example 8

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Synthesis of 3- (4-methylphenyl) propanoic acid (32)

Step 1 : A saturated ammonium chloride (1.5 mL) and zinc dust (1.5 g, 23 mmol) were added successively to a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 mL) at room temperature. After stirring for 30 minutes at room temperature 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 (IN) was added to the resulting residue until the pH became about 4, and the resulting precipitate was collected by filtration to obtain Compound 29 (0.80 g, 57%) as a brown solid.

Step 2 : A solution of compound 29 (0.26 g, 1.0 mmol) and CDI (0.25 g, 1.6 mmol) in DMF (10 mL) was heated to 70 ° 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 afford 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 ° C. overnight. The mixture was cooled, 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. The residue was purified by flash chromatography (SiO ₂ ), eluting with 9: 1 CHCl ₃ : MeOH to give compound 31 (0.17 g, 97%).

Step 4 : A solution of compound 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 for 30 minutes at room temperature and poured into H ₂ O (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 (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino ) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid (32, 0.150 g, 94%) was obtained as a gray solid. Melting point: 113-115 ° C.

Example 9

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

Step 1 : Compound 33 (prepared from Compound 28 according to the procedure described in Example 1, 0.20 g, 0.50 mmol) was dissolved in DMF (1.8 mL) and water (0.7 mL) and K ₃ PO ₄ (0.39 g, 1.86 mmol) and phenyl boronic acid (0.113 g, 0.93 mmol). The resulting mixture was deoxygenated (5 conversions between vacuum and nitrogen) and then tetrakis (triphenylphosphine) palladium (0) (8.7 mg, 0.050 mmol) was added. The mixture was deoxygenated as before and heated to 90 ° C. overnight. The mixture was cooled down, diluted with water and then 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 cooled, then partitioned between ethyl acetate and saturated aqueous NaHCO ₃ . The ethyl acetate layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 3: 1 hexanes / ethyl acetate) to give compound 34 (0.115 g, 94%). This material was used without further purification.

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3 from compound 34 according to the procedure described in Example 1 -Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared.                 

¹ H NMR (400 MHz, CD ₃ OD): δ 2.25 (s, 3H), 2.50 (m, 2H), 4.89 (t, J = 5.9 Hz, 1H), 5.34 (s, 2H), 6.40 (d, J = 7.0Hz, 1H), 7.0 (d, J = 8.0Hz, 2H), 7.10 (d, J = 8.0Hz, 2H), 7.18 (m, 1H), 7.28 (m, 2H), 7.35 (m, 3H ), 7.43 (m, 1 H), 7.49 (m, 3 H).

Example 10

(3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Synthesis of Nyl) amino] -3- (4-methylphenyl) propanoic acid (43)

Step 1 : Compound 35 (2.00 g, 18.2 mmol) was dissolved in 30 mL of absolute methanol. To this solution benzylamine (1.97 g, 18.2 mmol) and triethylamine (2.0 g, 20.0 mmol) were added. The reaction mixture was stirred at 50 ° 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), isovaleraldehyde (2.8 mL, 27 mmol) and piperidine (1 mL) were added. The reaction mixture was heated to 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 hexanes: ethyl acetate to give 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 vigorously heated to reflux for 3 hours, cooled, and then concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 2: 1 hexanes: ethyl acetate, to afford 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) in a solution of compound 39 (2.5 g, 7.9 mmol) in CCl ₄ (15 mL) ) Was added. The reaction mixture was heated to reflux for 1 hour, cooled to room temperature, 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 hexanes: ethyl acetate to afford 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 rt for 2 h, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 41 (560 mg, 98%).

Step 6 : To a solution of compound 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 ° C. for 1 h and then a solution of compound 8 (0.39 g, 1.9 mmol) in benzene (2 mL) was added. The reaction was further stirred at 90 ° C. for 1 h, cooled to rt, 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 afford compound 42 (0.38 g, 40%).

Step 7 : 2N NaOH (8 mL) was added to a solution of compound 42 (0.35 g, 0.7 mmol) in a 1: 1 mixture of THF: MeOH (8 mL). The reaction was stirred at rt 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, filtered and the filtrate was concentrated under reduced pressure to give (3S) -3-[({[2-methyl-4- (2-methylpropyl-6-oxo-1- (phenylmethyl)- 1,6-dihydro-5-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid (43, 250 mg, 75%) was obtained MS: Calculated: (M + H) ^- = 477.25 m / z; found: (M + H) ^- = 477.17 m / z

Example 11

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

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

(3S) -3-{[({[2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl from Compound 45 according to the procedure described in Example 10 ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was obtained.

¹ H NMR (400 MHz, 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, 1H).

Example 12

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

Step 1 : A solution of Compound 46 (0.50 g, 1.8 mmol, prepared according to the procedure described in Example 3) in THF (10 mL) at 0 ° C. was added NaH (60% dispersion in mineral oil, 0.23 g, 5.1 mmol). Added. The mixture was stirred at 0 ° C. for 10 minutes and then ethyl isocyanate (0.65 g, 9.15 mmol) was added. The mixture was stirred at rt over the weekend, quenched with 1N HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 47 (0.60 g). This material was used without purification.

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylamino) carbonyl] amino} from Compound 47 according to the procedure described in Example 3 Carbonyl) amino] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared. Melting point: 128-130 ° C.

Example 13

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

Step 1 : To a solution of Compound 48 (2.00 g, 9.70 mmol) in dry 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 ° C. for 15 minutes before 2-chlorobenzylchloride (2.03 g, 12.6 mmol) was added. After stirring at 55 ° C. overnight, the mixture was poured into ice water and washed with Et ₂ O (twice). The aqueous layer was acidified and the resulting precipitate was filtered to yield 49 (3.45 g). This material was used without further purification.

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- from compound 49 according to the procedure described in Example 8 3-quinolinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared. Melting point: 134-136 ° C.

Example 14

(3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- Synthesis of 3- (4-methylphenyl) propanoic acid (56)

Step 1 : 2-chlorobenzylamine (1.30 mL, 10.8 mmol) and EDCl (2.35 g, 12.3 mmol) in a suspension of compound 51 (1.67 g, 9.81 mmol) in DMF (33 mL) at room temperature under anhydrous nitrogen atmosphere Added. The resulting mixture was stirred vigorously at room temperature 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 compound 52 (2.55 g, 100%) as a pale yellow solid.

Step 2 : A solution of compound 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 rt, 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 eluted with increasing hexane: ethyl acetate ratio from 7: 3 to 1: 1 and finally chromatographed on silica gel eluting with 19: 19: 2 hexane: ethyl acetate: methanol to give compound 53 (182 mg, 27%) was obtained as a yellow oil.

Step 3 : To a solution of compound 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 minutes, diluted with water and 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 yield compound 54 (139 mg, 91%) as a white solid.

Step 4 : DPPA (0.29 mL, 1.34 mmol) was added by 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 anhydrous nitrogen atmosphere. The resulting mixture was stirred at rt for 15 min and then heated to reflux for 3.5 h. The mixture was cooled to room temperature and a solution of compound 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 at rt overnight, diluted with ethyl acetate and washed with 2N HCl (twice), saturated aqueous NaHCO ₃ and brine. 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 hexanes: ethyl acetate of 7: 3, 3: 2 and 1: 1 in order to afford compound 55 (60 mg, 20%) as colorless oil.

Step 5 : 0.192 N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL) were added to a solution of compound 55 (60 mg, 0.12 mmol) in THF (3 mL). The resulting mixture was stirred at rt for 24 h 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 afford (3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl as gray solid. } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, sodium salt (56, 56 mg, 95%) was obtained. _{MS: (C 24 H 23 ClN} 3 O 4) - Calcd: 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-3-pyri Synthesis of diyl] amino} carbonyl) amino] propanoic acid (62)

Step 1 : Triethylamine (2.98 ml, 21.4 mmol) and methanesulfonyl in a solution of 2-thiophenmethanol (1.015 g, 8.89 mmol) in CH ₂ Cl ₂ (17.8 ml) cooled to 0 ° C. under anhydrous nitrogen atmosphere. Chloride (0.69 ml, 8.9 mmol) was added continuously by syringe. The resulting mixture was stirred at 0 ° C. for 15 minutes, 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 compound 58 (395 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 anhydrous nitrogen atmosphere. The resulting solution was heated at 60 ° C. for 20 minutes with vigorous stirring in an oil bath. The mixture was cooled to rt, 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. The residue was filtered through silica gel, eluting with hexanes: ethyl acetate, increasing from 1: 1 to 1: 3 ratio to give compound 59 (188 mg, 12% for two steps) as a green solid.

Step 3 : N, N-diisopropylethylamine (0.23 ml, 1.30 mmol) and phosgene in a solution of compound 59 (111 mg, 0.54 mmol) in CH ₂ Cl ₂ (2.7 ml) cooled to 0 ° C. under anhydrous nitrogen atmosphere. (0.31 ml, 1.9 M in toluene, 0.59 mmol) were added continuously by syringe. The resulting mixture was stirred at 0 ° C. for 15 minutes and a solution of β-amino ester 60 (167 mg, 0.70 mmol) in CH ₂ Cl ₂ (2.7 ml) was passed through the cannula with CH ₂ Cl ₂ rinse (1.0 ml). Added. The resulting mixture was allowed to warm to rt and stirred for 2 h then diluted with ethyl acetate 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 hexanes: ethyl acetate to give 61 (231 mg, 91%) as a purple foam.

Step 4 : To a solution of ester 61 (227 mg, 0.48 mmol) in THF (6 ml) at room temperature was added NaOH (2 ml, 2N in water, 4 mmol) and methanol (a sufficient amount to make a clear solution, about 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 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 (400 MHz, CD ₃ SOCD ₃ ) δ 2.63 (d, J = 7.3 Hz, 2H), 4.99 (dt, J = 8.4, 7.3 Hz, 1H), 5.30 (s, 2H), 5.98 (m, 2H ), 6.21 (dd, J = 7.5, 7.0 Hz, 1H), 6.78 (dd, J = 8.1, 1.6 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 1.6 Hz , 1H), 6.97 (dd, J = 5.1, 3.5Hz, 1H), 7.17 (dd, J = 3.5, 1.1Hz, 1H), 7.35 (dd, J = 7.0, 1.8Hz, 1H), 7.44 (dd, 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-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid (68)

Step 1 : 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) at room temperature under anhydrous nitrogen atmosphere To the solution of iodomethane (0.22 ml, 3.3 mmol) was added by syringe. The resulting mixture was stirred at rt 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 : Palladium on charcoal (300 mg, 10% Pd, degussa type E101 NE) in a solution of Compound 64 (0.86 g crude, theoretically 1.94 mmol) in methanol (10 ml) at 0 ° C. under anhydrous nitrogen atmosphere. / W, wet, 50% by weight of water) was added. Replace the nitrogen atmosphere with hydrogen (5 times repeated hydrogen supply to vacuum and balloon) and stir the mixture at 0 ° C. for 30 minutes and then into a flask containing 2-thiophenecarboxaldehyde (177 mg, 1.58 mmol). It was filtered directly. 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 hours, 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 hexanes: ethyl acetate to give lactam 65 (75 mg, 12% in two steps) as a colorless oil.

Step 3 : HCl (7.2 ml, 4.0 M in dioxane, 28.8 mmol) was added by syringe to a flask containing Compound 65 (89 mg, 0.29 mmol) sealed with a rubber stopper at room temperature under anhydrous nitrogen atmosphere. The nitrogen needle was removed and the mixture in the 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 over 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 anhydrous 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 a CH ₂ Cl ₂ (0.2 ml) rinse. The resulting mixture was stirred for 3 days at room temperature, diluted with ethyl acetate and washed with 2N NCl (twice), 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 hexanes: 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, 2N in water, 2 mmol) and methanol (a sufficient amount to make a clear solution, about 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 (400 MHz, 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 (m, 1H), 5.97 (s, 2H), 6.24 (d, J = 6.6 Hz, 1H ), 6.71 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.1, 1.5 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 1.5 Hz, 1H ), 6.97 (dd, 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 (br.s, 1H).

Example 17

(3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) tetrahydro-1H-pyrrole- Synthesis of 3-yl] amino} carbonyl) amino] propanoic acid (74)

Step 1 : To a solution of Nt-butoxycarbonyl-L-aspartic acid α-benzyl ester (2.10 g, 6.5 mmol) in dimethoxyethane (15 ml) cooled to −15 ° C. (bath temperature) under anhydrous nitrogen atmosphere. 4-methylmorpholine (0.71 ml, 6.5 mmol) and isobutyl chloroformate (0.84 ml, 6.5 mmol) were added sequentially 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 ° C. (bath temperature) and a solution of sodium borohydride (370 mg, 9.7 mmol) in water (3 ml) was added immediately followed by water (100 ml). The mixture was extracted with ethyl acetate (3 times) and the organic layers combined and washed with cold (0 ° C) HCl (0.2N), 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 : A solution of oxalyl chloride (2.4 ml, 2.0 M in CH ₂ Cl ₂ , 4.8 mmol) in CH ₂ Cl ₂ (30 ml) cooled to −65 ° C. under anhydrous nitrogen atmosphere in CH ₂ Cl ₂ (8 ml) 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 ° C for 3 hours and then warmed to -20 ° 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 : Sodium triacetoxyborohydride (959 mg, 4.5) in a solution of crude aldehyde 70 (3.2 mmol in theory) and 2-aminomethylthiophene (402 mg, 3.55 mmol) in dichloroethane (13 ml) at room temperature under anhydrous nitrogen atmosphere. mmol) was added. The resulting mixture was stirred at rt overnight, 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 hexanes: ethyl acetate to give lactam 71 (220 mg, 23% for three steps) as a white solid.

Step 4 : HCl (1.50 ml, 4.0 M in dioxane, 6.0 mmol) in compound 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml) sealed with a rubber stopper at room temperature under anhydrous nitrogen atmosphere was added by syringe. The nitrogen needle was removed and the mixture in the 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 anhydrous nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of β-amino ester 60 (164 mg, 0.69 mmol) in CH ₂ Cl ₂ (0.8 ml) was added via cannula with a CH ₂ Cl ₂ (0.2 ml) rinse. . The resulting mixture was stirred at rt overnight, diluted with ethyl acetate and washed with 2N NCl (twice), 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. This oil solidified slowly upon 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 and 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 , 1H), 4.56 (s, 2H), 4.96 (m, 1H), 5.97 (s, 2H), 6.30 (d, J = 7.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.77 (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.s, 1H).

Example 18

Synthesis of (3S) -3-[({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid

Step 1 : KNO ₃ (2.30 g, 22.9 mmol) and NaNO ₂ (20 mg, catalyst) in a mixture of 2-phenylmethyl-3-chlorophenol (5.00 g, 22.9 mmol) in ethanol (20 mL) and 6N HCl (50 mL). Was added continuously. 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 heterogeneous 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 : To a solution of compound 25 (0.20 g, 0.96 mmol) in CH ₂ Cl ₂ at 0 ° C. was added successively DIPEA (0.40 mL, 2.4 mmol) and phosgene (1.93 M in toluene, 0.60 mL, 1.2 mmol). It was. The resulting mixture was allowed to warm to room temperature, stirred for 20 minutes and then recooled to 0 ° C. To this mixture was added dropwise a solution of compound 100 (0.25 g, 1.1 mmol) in CH ₂ Cl ₂ . The resulting mixture was warmed to rt 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 hexanes: ethyl acetate, increasing from 9: 1 to 5: 1 to give compound 101 (60 mg, 12%).

(3S) -3-[({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino} carbonyl) amino] -3- (from Compound 101 according to the procedure described in Example 1). 4-Methylphenyl) propanoic acid was prepared.

¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ 2.26 (s, 3H), 2.58 (dd, J = 15.8, 6.6 Hz, 1H), 2.67 (dd, J = 15.8, 8.4 Hz, 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-1H-pyrrol-3-yl ] Amino} carbonyl) amino] propanoic acid

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 rt overnight and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes: 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- (phenyl) from Compound 102 according to the procedure described in Example 1 Methyl) tetrahydro-1H-pyrrole-3-yl] amino} carbonyl) amino] propanoic acid was prepared: melting point 80-85 ° C.

Example 20

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

Step 1 : Cyclopentanmethanol (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) at 0 ° C. under nitrogen atmosphere, followed by triphenyl Phosphine (551 mg, 2.1 mmol) was added. The solution was stirred at 0 ° C. for 15 minutes and diethyl azodicarboxylate (366 mg, 2.1 mmol) was added dropwise by syringe. The reaction was stirred for 1 h at 0 ° C. and then overnight at rt. The mixture was quenched with methanol (20 mL) and washed with water (twice). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 1: 1 hexanes: ethyl acetate to afford compound 103 (299 mg, 96% yield) as a yellow solid.

(3S) -3- (1,3-benzodioxol-5-yl) -3-[({[1- (cyclopentylmethyl) -2-oxo- from compound 103 according to the procedure described in Example 1 1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid was prepared.

¹ H NMR (400 MHz, 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 (d, J = 7.7 Hz, 1H), 8.89 (s, 1H).

Example 21

(3S) -3- (1,3-benzodioxol-5-yl) -3-{[({3-[(2-thiophenylmethyl) amino] phenyl} amino) carbonyl] amino} propanoic acid

Step 1 : 3-nitroaniline (0.51 g, 3.7 mmol) was added to a solution of 2-thiophenecarboxaldehyde (0.48 g, 4.0 mmol) in dichloromethane. The solution was concentrated to dryness and placed in 1,2-dichloroethane (16 mL). Molecular sieves (3x, 1.1 g) were added followed by NaBH (OAc) ₃ (1.01 g, 4.8 mmol). The solution was stirred at rt overnight, diluted with chloroform and 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 : Trifluoroacetic anhydride (0.193 mL, 1.4 mmol) in 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. The solution was stirred at 0 ° 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 yield compound 105 (0.38 g, 100%) as a yellow solid.

Step 3 : Add Fe powder (0.36 g, 6.5 mmol) to a solution of compound 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL) and acetic acid (2.6 mL) at room temperature and TLC to indicate complete disappearance of compound 105 The suspension was stirred vigorously at 40 ° C. until. The mixture was filtered through celite and washed with chloroform. The filtrate was diluted with saturated sodium bicarbonate and 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 (elute gradient 6: 1 to 4: 1 hexanes: ethyl acetate) to give compound 106 (0.102 g, 25%).

(3S) -3- (1,3-benzodioxol-5-yl) -3-{[({3-[(2-thiophenylmethyl) amino] from Compound 106 according to the procedure described in Example 1 Phenyl} amino) carbonyl] amino} propanoic acid.

¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ 2.50 (m, 2H overlapping DMSO), 4.37 (d, J = 5.9 Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06 (t, J = 5.8 Hz, 1H), 6.16 (m, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.78 (m, 3H), 6.85 (dd, J = 8.8, 7.7 Hz, 1H ), 6.90 (s, 1H), 6.94 (dd, J = 5.2, 3.7 Hz, 1H), 7.00 (d, J = 3.3 Hz, 1H), 7.33 (dd, J = 5.1, 1.1 Hz, 1H), 8.5 (s, 1 H).

Example 22

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

Step 1 : Lithium bis () in a solution of (1S, 2R, 5S)-(+)-mentyl (R) -p-toluenesulfinate (3.00 g, 10.2 mmol) in THF (25.5 mL) cooled to -78 ° C. Trimethylsilyl) amide (1.0 M in THF, 15.3 mL) was added dropwise over 15 minutes. The resulting mixture was stirred at rt for 6 h and then cooled to 0 ° C. Piperonal (3.06 g, 20.4 mmol) and CsF (3.10 g, 20.4 mmol) were added dropwise quickly and the suspension was stirred at rt for 36 h. The reaction was quenched with saturated NH ₄ Cl 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 compound 108 (1.36 g, 46%).

Step 2 : Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to a suspension of Zn dust (2.00 g, 30.5 mmol) in THF (20.2 mL) and refluxed for 15 minutes. The suspension was cooled to 0 ° C. and compound 108 (0.87 g, 3.0 mmol) was added. The suspension was warmed to rt and stirred overnight. The mixture was quenched with minimal amount of saturated NH ₄ Cl 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 chromatographed on silica gel (elute gradient 6: 1 to 4: 1 hexanes: ethyl acetate) to afford compound 109 (0.607 g, 61% to 80% conversion).

Step 3 : To a solution of compound 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 maintaining the external temperature below 30 ° C. The residue was taken up in diethyl ether and washed with 2N HCl (twice). The combined aqueous layers were carefully basified with excess saturated NaHCO ₃ and extracted with diethyl ether. The ether layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 110 (0.326 g, 80%).

3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3-[({[2-oxo-1- (2) from Compound 110 following the procedure described in Example 1 -Thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid was prepared. MS: calcd (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 Synthesis of -1H-pyrido [3,4-b] azin-1-yl] carbonyl} amino) propanoic acid

Step 1 : n-butyllithium (1.6M in hexane, 3.4 mL, 5.4 mmol) in a solution of compound 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) and TMEDA (1.60 mL, 10.8 mmol) at −20 ° C. ) And t-butyllithium (1.7 M in pentane, 2.5 mL, 4.3 mmol) were added dropwise successively by syringe. The temperature was warmed to −10 to 0 ° C. and maintained for 2 hours. 1,4-Dibromobutane (1.75 mL, 14.7 mmol) was added quickly to the resulting mixture and the solution was allowed to warm to room temperature and stirred for 4 days. The reaction was quenched 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 hexanes: ethyl acetate to afford 111 (0.41 g, 44%). (3S) -3- (1,3-benzodioxol-5-yl) -3-({[9-oxo-8- (phenylmethyl) -2, from Compound 111 according to the procedure described in Example 4 3,4,5,8,9-hexahydro-1H-pyrido [3,4-b] azin-1-yl] carbonyl} amino) propanoic acid was prepared. MS: calcd (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- (4 Synthesis of -hydroxyphenyl) propanoic acid

Step 1 : In a solution of compound 112 (0.19 g, 0.39 mmol, prepared according to the procedure described in Example 15, in CH ₂ Cl ₂ at 0 ° C. under nitrogen), BBr ₃ (1.0 M in CH ₂ Cl ₂ , 1.2 mL, 1.2 mmol) was added by 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 further diluted with saturated aqueous NaHCO ₃ . The organic layer was washed with water, 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 afford (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2 -Dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-hydroxyphenyl) propanoic acid (113, 120 mg, 70%) was obtained.

¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ 2.95 (d, J = 5.2 Hz, 2H), 5.28 (s, 2H), 5.35 (ddd, J = 9.2, 4.8, 4.4 Hz, 1H), 6.33 (t, J = 7.1Hz, 1H), 6.60 (d, J = 8.8Hz, 2H), 7.04 (m, 5H), 7.22 (m, 3H), 7.37 (dd, J = 7.7, 1.5Hz, 1H) , 8.35 (dd, J = 7.6, 1.5 Hz, 1 H), 8.80 (s, 1 H).

Synthetic procedures similar to those described above can be used to obtain the compounds of Tables 1, 2 and 3.

Example 25

The efficacy of the synthesized compound can be determined using the procedure of linking a 26-amino acid peptide (CDELPQLVTLPHPNLHGPEILDVPST) containing the CS1 sequence of fibronectin with N-terminal Cys to maleimide activated egg albumin. Bovine serum albumin (BSA) and CS1 linked egg albumin were coated on 96-well polystyrene plates with 0.5 3 g / ml in TBS (50 mM TRIS, pH 7.5; 150 mM NaCl) at 4 ° C. for 16 hours. Plates were washed three times with TBS and blocked with TBS containing 3% BSA for 4 hours at room temperature. Blocked plates were washed three times with binding buffer (TBS; 1 mM MgCl ₂ ; 1 mM CaCl ₂ ; 1 mM MnCl ₂ ) before assay. Ramos cells fluorescently labeled with calcein AM were resuspended in binding buffer (10 ⁷ cells / ml) and diluted 1: 2 with the same buffer with or without compound. 100 ③M of compound was added. Immediately cells were added to wells (2.5 × 10 ⁵ cells / well) and incubated at 37 ° C. for 30 minutes. After washing three times with binding buffer, adherent cells were lysed and quantified by fluorimeter. The results are listed in Tables 1-3. 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 higher the inhibition rate, the higher the efficiency of the compound for the inhibition of cell adhesion.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) hexahydro-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid 0.2 Calculated (MH) ^- = 444.12; Found (MH) ^- = 444.08. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) tetrahydro-1H-pyrrole- 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-3-pyridinyl ] 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-3-pyri Diyl] amino} carbonyl) amino] propanoic acid 0.9 Calculated (MH) ^- = 440.09; Found (MH) ^- = 439.98. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[((3S) -2-oxo-1- {4-[(2-toluidinocarbonyl) amino ] 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} -1 , 2-dihydro-3-pyridinyl] amino} carbonyl} amino) propanoic acid 0.001 Calculated (MH) ^- = 582.20; Found (MH) ^- = 582.20. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[((3S) -1- {4-[(2-methylbenzyl) amino] benzyl} -2-oxo Hexahydro-pyridinyl] amino] carbonyl) amino) propanoic acid none none (3S) -3- (1,3-benzodioxol-5-yl) -3-[({butyl [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) azpanyl] amino} carbonyl ) Amino] propanoic acid 0.015 Calculated (MH) ^- = 458.13; Found (MH) ^- = 458.09.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (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-propyl-1,2-dihydro-3-pyri Diyl] 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 -1H-pyrido [3,4-b] azin-1-yl] carbonyl} amino) propanoic acid 4000 Calculated (MH) ⁻ = 488.18; Found (MH) ^- = 488.19. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 466.15; Found (MH) ^- = 465.95. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-propyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 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] -1,2-dihydro-3-pyridinyl} amino) carbonyl] 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -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) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 15 Calculated (MH) ^- = 456.12; Found (MH) ^- = 455.94.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (phenylamino) -1,2-dihydro-3-pyridinyl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 529.16; Found (MH) ^- = 529.02. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (2-pyridinylamino) -1,2-dihydro-3-pyridinyl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid 15 Calculated (MH) ^- = 530.16; Found (MH) ^- = 529.99. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-3-pyridinyl } 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-3-pyridinyl } 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-oxazinan-4-yl) -2-oxo-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid One Calculated (MH) ^- = 523.17; Found (MH) ^- = 523.02. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (propylamino) -1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ⁻ = 495.18; Found (MH) ^- = 495.04. (3S) -3-{[({1-[(2-fluorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 20 Calculated (MH) ^- = 436.17; Found (MH) ^- = 435.99. (3S) -3-{[({1-[(2,6-dichlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} moiety Carbonic acid 30 Calculated (MH) ^- = 376.11; Found (MH) ^- = 376.00. (3S) -3-{[({1-[(2-bromophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 496.09; Found (MH) ^- = 495.87. (3S) -3-[({[4-methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4- Methylphenyl) propanoic acid 30 Calculated (MH) ^- = 418.17; Found (MH) ^- = 417.96. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-4-phenyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 514.15; Found (MH) ^- = 514.00. (3S) -3-{[({4-bromo-1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-2-oxo-1,2 -Dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid 20 Calculated (MH) ^- = 484.09; Found (MH) ^- = 484.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(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-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] 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-3-pyri Diyl} 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3-phenylpropanoic acid 10 Calculated (MH) ^- = 440.10; Found (MH) ^- = 440.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- [4-methyltetrahydro-1 (2H) -pyrazinyl] -2-oxo-1,2-dihydro -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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (methyloxy) phenyl] propanoic acid 5 Calculated (MH) ^- = 470.11; Found (MH) ^- = 470.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,5-dimethylphenyl) propanoic acid 15 Calculated (MH) ^- = 468.13; Found (MH) ^- = 468.08. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-methylphenyl] propanoic acid 20 Calculated (MH) ^- = 454.17; Found (MH) ^- = 454.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2- 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (trifluoromethyl) phenyl] propanoic acid 20 Calculated (MH) ^- = 508.04; Found (MH) ^- = 508.09. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1, 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-azanthyl) -1-[(2-chlorophenyl) methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4-methylphenyl) propanoic acid 5 Calculated (MH) ^- = 493.16; Found (MH) ^- = 493.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-fluorophenyl) propanoic acid 30 Calculated (MH) ^- = 458.09; Found (MH) ^- = 458.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-fluorophenyl) propanoic acid 40 Calculated (MH) ^- = 458.09; Found (MH) ^- = 458.06. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4-({2-[(2-{[2- (methyloxy) ethyl] oxy} ethyl) oxy] ethyl} Oxy) -2-oxo-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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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. (3S) -3-{[({1-[(2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid 10 Calculated (MH) ^- = 472.11; Found (MH) ^- = 472.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (1,1-dimethylethyl) phenyl] propanoic acid 400 Calculated (MH) ⁻ = 496.16; Found (MH) ^- = 496.11. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- [4- (methylphenyl) propanoic acid 70 Calculated (MH) ^- = 452.14; Found (MH) ^- = 451.99. 3- (4-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) 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-dihydro-5-pyrimidinyl ] Amino} carbonyl) amino] -3- [4- (methylphenyl) propanoic acid 25 Calculated (M + H) ⁺ = 498.22; Found (M + H) ⁺ = 498.10. 3- (3-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid 30 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.03. 3-{[({1-[(2-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,4-dichlorophenyl) propanoic acid 40 Calculated (MH) ^- = 508.02; Found (MH) ^- = 507.97.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[2-oxo-1- (phenylmethyl) -3-azpanyl] amino} carbonyl) amino] propane mountain 0.015 Calculated (MH) ^- = 452.18; Found (MH) ^- = 452.10. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(3-cyanophenyl) methyl] -2-oxo-3-azpanyl} amino) Carbonyl] amino} propanoic acid 0.04 Calculated (MH) ^- = 477.18; Found (MH) ^- = 477.14. (3S) -3- (4-methylphenyl) -3-[({[2-oxo-1- (2-thiophenylmethyl) -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-3-pyridinyl] amino } 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-1,2-dihydro-3- 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-oxo-1,2-di 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-1,2-dihydro-3- 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-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid 0.7 Calculated (MH) ^- = 456.12; Found (MH) ^- = 456.00.

compound IC ₅₀ (nM) Mass spectral data (m / z) (3S) -3- [4- (methyloxy) phenyl] -3-[({[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- [3- ( Trifluoromethyl) phenyl] propanoic acid 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. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({3-[(2-thiophenylmethyl) amino] phenyl} amino) carbonyl] amino} propanoic acid 5 Calculated (MH) ^- = 438.11; Found (MH) ^- = 438.00. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(3-chlorophenyl) methyl] -2-oxo-1,2-dihydro-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] methyl} -1,2 -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] methyl} -1,2 -Dihydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid 1.6 Calculated (MH) ^- = 502.12; Found (MH) ^- = 502.01. (3S) -3- (4-fluorophenyl) -3-[({[2-oxo-1- (2-thiophenylmethyl) -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-{[({1-[(4-chlorophenyl) methyl] -2-oxo-1,2-dihydro-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-oxo-1,2-di Hydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid 0.5 Calculated (MH) ^- = 464.14; Found (MH) ^- = 464.04. (3S) -3- [3- (methyloxy) phenyl] -3-[({[2-oxo-1- (2-thiophenylmethyl) -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] -3-phenylpropanoic acid 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- [3,4 , 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-1,2-dihydro-3 -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-oxo-1,2-dihydro- 3-pyridinyl} amino) carbonyl] amino} propanoic acid 2 Calculated (MH) ^- = 452.12; Found (MH) ^- = 452.00. 3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro -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-3 -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-oxo-1,2-dihydro -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-oxo-1,2-dihydro -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-1,2-dihydro-3-pyridinyl] 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] -1,2-dihydro -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- (4 -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) -1,2-dihydro -3-pyridinyl] amino} carbonyl) amino] propanoic acid 0.14 Calculated (MH) ^- = 438.11; Found (MH) ^- = 437.99. (3S) -3- (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) amino] -3- [4- ( Trifluoromethyl) phenyl] propanoic acid 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-3-pyridinyl] amino } Carbonyl) amino] propanoic acid 0.5 Calculated (MH) ^- = 434.13; Found (MH) ^- = 434.02. (3S) -3- [4-fluoro-3- (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-3-pyridinyl ] 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-1H-pyrrol-3-yl ] 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] amino} -3- [3 , 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-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (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] amino} -3- [4 -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] amino} -3- ( 4-methylphenyl) propanoic acid 0.1 Calculated (MH) ^- = 422.15; Found (MH) ^- = 422.01. (3S) -3- (4-methylphenyl) -3-{[({1-[(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] amino} -3- ( 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] amino} -3- (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] amino} -3- [2 , 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-1,2-dihydro-3 -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) phenyl] methyl} 1,2-dihydro-3-pyridinyl) 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] amino} -3- (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] amino} -3-phenylpropane 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} -3-phenyl 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- (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} -3-phenylpropane 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] amino} -3- [4 -(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- (4 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} amino) -3 -(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] amino} -3- [ 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- (3 , 4-dimethylphenyl) propanoic acid 0.09 Calculated (M + H) ^- = 454.15; Found (M + H) ^- = 454.07. (3S) -3-[({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino) carbonyl) amino] -3- (4-methylphenyl) propanoic acid 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] amino} -3- [3 -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- (4 -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] amino} -3- (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- (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- (2 -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- (2 , 3-dihydro-1H-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] amino} -3- ( 4-methylphenyl) propanoic acid 0.1 Calculated (M + H) ^- = 431.18; Found (M + H) ^- = 431.09. (3S) -3- [2,6-bis (methyloxy) phenyl] -3-{[({1-[(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] amino} -3- ( 4-methylphenyl) propanoic acid 0.2 Calculated (M + H) ^- = 420.18; Found (M + H) ⁻ = 422.05. (3S) -3-[({[2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyridinyl] amino} carbonyl) amino] -3- (4- 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- (4 -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. (3S) -3- (4-methylphenyl) -3-{[({1-[(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- (2 , 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. (3S) -3-{[({1-[(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. (3S) -3-{[({1-[(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. (3S) -3-{[({1-[(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) (3S) -3-{[({1-[(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] amino} -3- [ 3-methyl-4- (methyloxy) phenyl] propanoic acid 0.2 Calculated (MH) ^- = 512.08 found (MH) ^- = 511.96. (3S) -3-{[({1-[(3,5-dimethyl-4-isoxazole) 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. (3S) -3- (4-methylphenyl) -3-{[({2-oxo-1-[(2,4,6-trimethylphenyl) methyl] -1,2-dihydro-3-pyridinyl} Amino) carbonyl] amino} propanoic acid 2.5 Calculated (MH) ^- = 446.21; Found (MH) ^- = 446.08. (3S) -3- (4-methylphenyl) -3-{[({1-[(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. (3S) -3-({[(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. (3S) -3-({[(1- {2-[(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. (3S) -3-{[({1-[(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-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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. (3S) -3-({[(1-{[2-fluoro-4- (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-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid 1.3 Calculated (MH) ^- = 440.08; Found (MH) ^- = 443.97. (3S) -3-{[({1-[(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. 3- (4-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid 0.03 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.07. (3S) -3-[({[2-methyl-6-oxo-1- (phenylmethyl) -4- (2-pyridinyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo 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] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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] amino} -3- (4-methylphenyl) propanoic acid 0.15 Calculated (MH) ^- = 432.19; Found (MH) ^- = 432.04.

compound IC ₅₀ (nM) Mass spectral data (m / z) 3- (3-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid 0.03 Calculated (MH) ^- = 474.06; Found (MH) ^- = 474.03. 3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 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] carbonyl } Amino) -3- (4-methylphenyl) propanoic acid 0.2 Calculated (MH) ^- = 539.09; Found (MH) ^- = 539.02. (3S) -3-[({[1-({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- (4-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Propanoic acid 0.4 Calculated (MH) ^- = 458.07; Found (MH) ^- = 457.96. 3- (3-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Propanoic acid One Calculated (MH) ^- = 458.07; Found (MH) ^- = 457.93. 3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,4-dichloro Phenyl) propanoic acid One Calculated (MH) ^- = 492.03; Found (MH) ^- = 491.85. (3S) -3-{[({1-[(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- (4 -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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -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-oxazinan-4-yl) -2-oxo-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] -5-methylhexanoic acid 0.1 Calculated (MH) ⁻ = 489.19; Found (MH) ^- = 489.13. (3S) -3-[({[4-hydroxy-6-methyl-2-oxo-1- (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-3-pyridinyl} amino ) 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-ethylphenyl) propanoic acid 0.025 Calculated (MH) ^- = 468.13; Found (MH) ^- = 468.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (ethyloxy) phenyl] propanoic acid 0.02 Calculated (MH) ^- = 484.13; Found (MH) ^- = 484.06. (3S) -3-[({[4-hydroxy-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4 -Methylphenyl) propanoic acid 0.030 Calculated (MH) ^- = 420.16; Found (MH) ^- = 420.08.

All references cited are incorporated herein by reference.

The invention is illustrated by the foregoing description and examples. As many variations are apparent to those skilled in the art, the foregoing detailed description is considered as non-limiting examples. All such modifications within the scope and spirit of the appended claims are considered to be included in the claims.

Changes may be made in the construction, processes and arrangements of the methods of the invention described herein without departing from the spirit and scope of the invention as defined in the claims that follow.

<110> Texas Biotechnology Corporation <120> Carboxylic acid derivatives that inhibit the binding of integrins          to their receptors <130> TEX4542P0401KR; Cyclic 1 <150> US 60 / 132,197 <151> 1999-05-07 <160> 1 <170> KopatentIn 1.71 <210> 1 <211> 26 <212> PRT <213> Unknown <220> <223> single, linear <400> 1 Cys Asp Glu Leu Pro Gln Leu Val Thr Leu Pro His Pro Asn Leu His   1 5 10 15 Gly Pro Glu Ile Leu Asp Val Pro Ser Thr              20 25

Claims (18)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I

In the above formula, Y in each occurrence is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ and CH; q is an integer from 4 to 6; A is NR ⁶ ; E is NR ⁷ ; J is O; T is (CH ₂ ) _b , where b is 0; 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 1; L is (CH ₂ ) _n where n is 0; X is CO ₂ B; W is selected from the group consisting of C and CR ¹⁵ ; R ¹ and R ⁵ are independently at each occurrence hydrogen, halogen, hydroxyl, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, amino, —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) , C ₁ -C ₁₂ alkoxy C ₁ -C ₁₂ alkoxy, C ₆ -C ₁₂ aryl, (C ₆ -C ₁₂ ) arylamino and sulfonamido; Wherein R ¹ and R ⁵ are unsubstituted or halo, nitro, carboxyl, trifluoromethyl, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ aryloxy, hydroxy, C ₁ -C ₁₂ alkyl, C _1- Is substituted with at least one electron donor group or electron withdrawing group selected from the group consisting of C ₁₂ alkoxy and amino; B, R ² , R ³ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are hydrogen; R ⁶ is selected from the group consisting of hydrogen and C ₁ -C ₁₂ alkyl; R ⁴ is C ₁ -C ₁₂ alkyl, C ₆ -C ₁₂ aryl, C ₁ -C ₁₂ alkyl (C ₆ -C ₁₂ ) aryl, C ₆ -C ₁₂ ar (C ₁ -C ₁₂ ) alkyl and is unfused C ₆ -C ₁₂ aryl fused, selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings containing one or more endocyclic N, O or S atoms, wherein R ⁴ is unsubstituted or halo, And at least one electron donor or electron withdrawing group selected from the group consisting of trifluoromethyl, C ₆ -C ₁₂ aryl, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy and amino. The compound of claim 1, wherein A is NR ⁶ , E is NR ⁷ , J is O, M is C (R ⁹ ) (R ¹⁰ ), q is 4 or 5, and T is (CH ₂ ) _b Where b is 0, L is (CH ₂ ) _n (where n is 0), X is CO ₂ B, W is C or CR ¹⁵ , and R ⁴ is C ₆ -C ₁₂ Aryl, (C ₁ -C ₁₂ ) alkyl (C ₆ -C ₁₂ ) aryl, (C ₆ -C ₁₂ ) ar (C ₁ -C ₁₂ ) alkyl, containing one or more endocyclic N, O or S atoms , Unfused or C ₆ -C ₁₂ aryl fused, selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings, R ⁶ is selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl, R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are hydrogen. delete Compound of Formula (II) or a pharmaceutically acceptable salt thereof: Formula II

In the above formula, Y in each occurrence is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ and CH; q is an integer from 4 to 6; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; W is selected from the group consisting of C and CR ¹⁵ ; R ¹ and R ⁵ are independently at each occurrence hydrogen, halogen, hydroxyl, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, amino, —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) , C ₁ -C ₁₂ alkoxy C ₁ -C ₁₂ alkoxy, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ arylamino and sulfonamido; Wherein R ¹ and R ⁵ are unsubstituted, halo, nitro, carboxyl, trifluoromethyl, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ aryloxy, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ is substituted with one or more electron donor or electron withdrawing groups selected from the group consisting of alkoxy and amino; B, R ² , R ³ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are hydrogen; R ⁶ is selected from the group consisting of hydrogen and C ₁ -C ₁₂ alkyl; R ⁴ is C ₁ -C ₁₂ alkyl, C ₆ -C ₁₂ aryl, C ₁ -C ₁₂ alkyl (C ₆ -C ₁₂ ) aryl, C ₆ -C ₁₂ ar (C ₁ -C ₁₂ ) alkyl and is unfused C ₆ -C ₁₂ aryl fused, selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings containing one or more endocyclic N, O or S atoms, wherein R ⁴ is unsubstituted or halo, And at least one electron donor or electron withdrawing group selected from the group consisting of trifluoromethyl, C ₆ -C ₁₂ aryl, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy and amino. The compound of claim 4, 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 where n is 0) and R ⁴ is C ₆ -C ₁₂ aryl, C ₁ -C ₁₂ alkyl (C ₆ -C ₁₂ ) aryl, C ₆ -C ₁₂ ar (C ₁ -C ₁₂ ) alkyl and unfused or C ₆ -C ₁₂ aryl is selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings containing one or more endocyclic N, O or S atoms, R ⁶ is hydrogen and C ₁ -C ₆ alkyl And R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are each hydrogen. delete Compound of Formula III or a pharmaceutically acceptable salt thereof: Formula III

In the above formula, Y in each occurrence is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ and CH; q is an integer from 2 to 4; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; R ¹ and R ⁵ are independently at each occurrence hydrogen, halogen, hydroxyl, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, amino, —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) One or more endo, C ₁ -C ₁₂ alkoxy C ₁ -C ₁₂ alkoxy, C ₆ -C ₁₂ aryl, (C ₆ -C ₁₂ ) arylamino, sulfonamido and unfused or C ₆ -C ₁₂ aryl fused Is selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings containing cyclic N, O or S atoms; Wherein R ¹ and R ⁵ are unsubstituted or halo, nitro, carboxyl, trifluoromethyl, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ aryloxy, hydroxy, C ₁ -C ₁₂ alkyl, C _1- Is substituted with at least one electron donor group or electron withdrawing group selected from the group consisting of C ₁₂ alkoxy and amino; B, R ² , R ³ , R ⁷ , R ⁹ and R ¹⁰ are hydrogen; R ⁶ is selected from the group consisting of hydrogen and C ₁ -C ₁₂ alkyl; R ⁴ is C ₁ -C ₁₂ alkyl, C ₆ -C ₁₂ aryl, C ₁ -C ₁₂ alkyl (C ₆ -C ₁₂ ) aryl, C ₆ -C ₁₂ ar (C ₁ -C ₁₂ ) alkyl and is unfused C ₆ -C ₁₂ aryl fused, selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings containing one or more endocyclic N, O or S atoms, wherein R ⁴ is unsubstituted or halo, And at least one electron donor or electron withdrawing group selected from the group consisting of trifluoromethyl, C ₆ -C ₁₂ aryl, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy and amino. 8. Unfused or C ₆ -C ₁₂ aryl fused according to claim 7, wherein R ⁵ contains hydrogen, C ₁ -C ₁₂ alkyl, C ₆ -C ₁₂ aryl and at least one endocyclic N, O or S atom. Selected from the group consisting of 3 to 10 membered heterocyclic non-aromatic rings, wherein T is (CH ₂ ) _b where b is 0 and L is (CH ₂ ) _n where n is 0 ), Y is selected from the group consisting of CR ¹ and C (R ² ) (R ³ ), and q is 2 or 3. delete The method of claim 7, wherein

Is selected from the group consisting of:

,

And

In the above formula, R ¹⁹ , R ²⁰ and R ²¹ are independently at each occurrence hydrogen, halogen, hydroxyl, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, amino, -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), C ₁ -C ₁₂ alkoxy (C ₁ -C ₁₂ ) alkoxy, C ₆ -C ₁₂ aryl, (C ₆ -C ₁₂ ) arylamino, sulfonamido and one or more endocyclic N, O or S Is selected from the group consisting of unfused or C ₆ -C ₁₂ aryl fused 3 to 10 membered heterocyclic non-aromatic rings containing atoms, R ¹⁸ is an unfused or C ₆ -C ₁₂ aryl fused 3 to 10 membered heterocyclic non-aromatic ring containing hydrogen, C ₁ -C ₁₂ alkyl and one or more endocyclic N, O or S atoms Selected from the group consisting of; c is an integer of 1-2, d is an integer of 0-2, e is an integer of 0-4. 8. The compound of claim 7 wherein R ⁵ is C ₆ -C ₁₂ ar (C ₁ -C ₁₂ ) alkyl, R ⁴ is C ₆ -C ₁₂ aryl, and T is (CH ₂ ) _b , wherein b is 0 ), L is (CH ₂ ) _n (where n is 0), and B, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are each independently hydrogen. (3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (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-propyl-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-propyl-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-methylphenyl) propanoic acid, (3S) -3-{[({6-methyl-2-oxo-1- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3-pyridinyl} amino) carbo Nil] 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-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4- (1,4-oxazinan-4-yl) -2-oxo-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (propylamino) -1,2-dihydro-3-pyridinyl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-bromophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(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-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(1,1-dimethylethyl) amino] -2-oxo-1,2-dihydro-3-pyri Diyl} amino) carbonyl] amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3-phenylpropanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- [4-methyltetrahydro-1 (2H) -pyrazinyl] -2-oxo-1,2-dihydro -3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino} carbonyl] amino} -3- [4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,5-dimethylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (methyloxy) phenyl] propanoic acid, (3S) -3- [3,5-bis (methyloxy) phenyl] -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2- 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) amino } -3- [4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (trifluoromethyl) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1, 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({4- (1-azanthyl) -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-({2-[(2-{[2- (methyloxy) ethyl] oxy} ethyl) oxy] ethyl} Oxy) -2-oxo-1,2-dihydro-3-pyridinyl} amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3-((((2-oxo-1-((4- (trifluoromethyl) phenyl) methyl) -1,2 -Dihydro-3-pyridinyl) amino) carbonyl) amino) propanoic acid, (3S) -3-((((1-((2-chlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4 -Methylphenyl) propanoic acid, (3S) -3-((((1-((2-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- ( 4-methylphenyl) propanoic acid, (3S) -3-((((1-((2-bromophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- ( 4-methylphenyl) propanoic acid, (3S) -3-((((1-((2,4-dichlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-((((1-((2-chloro-6-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-((((1-1-((2-chlorophenyl) methyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) A compound selected from the group consisting of -3- (4-trifluoromethyl) oxy) phenyl) propanoic acid and a pharmaceutically acceptable salt thereof. delete Asthma, Atherosclerosis, Rheumatoid Arthritis, Allergy, Multiple Sclerosis, Lupus, Inflammatory Bowel Disease, Graft Rejection, Contact Hypersensitivity, Type I Diabetes, Leukemia and Brain Cancer, comprising the compound of claim 1 and a pharmaceutically acceptable carrier Pharmaceutical compositions for the treatment of delete (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid and pharmaceutically acceptable salts thereof. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid and pharmaceutically acceptable salts thereof. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (diethylamino) phenyl] propanoic acid and pharmaceutically acceptable salts thereof.