Compounds which inhibit leukocyte adhesion mediated by VLA-4

A compound of formula IA below:

• where
• R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl;
• R2 and R3 together with the nitrogen atom bound to R2 and the carbon atom bound to R3 form a heterocyclic or a substituted heterocyclic group selected from the group consisting of thiazolidinyl, piperidinyl and pyrrolidinyl wherein said substituted heterocyclic group consists of from 1 to 2 substituents selected from the group consisting of fluoro, methyl, hydroxyl, amino, phenyl, thiophenyl and thiobenzyl;
• R4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substitute aryl, heteroaryl, and substituted heteroaryl;
• R5 is selected from the group consisting of isopropyl, —CH2X and ═CH—X where X is selected from the group consisting of
• hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
• wherein substituted aryl refers to aryl groups substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, —S(O)2-alkyl, —S(O)2-substituted alkyl, —S(O)2-cycloalkyl, —S(O)2-substituted cycloalkyl, —S(O)2-alkenyl, —S(O)2-substituted alkenyl, —S(O)2-aryl, —S(O)2-substituted aryl, —S(O)2-heteroaryl, —S(O)2-substituted heteroaryl, —S(O)2-heterocyclic, —S(O)2-substituted heterocyclic, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2-NRR where R is hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2-NR-alkyl, —NRS(O)2-NR-substituted alkyl, —NRS(O)2-NR-aryl, —NRS(O)2-NR-substituted aryl, —NRS(O)2-NR-heteroaryl, —NRS(O)2-NR-substituted heteroaryl, —NRS(O)2-NR-heterocyclic, —NRS(O)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and disubstituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups selected from the group consisting of Boc, Cbz, and formyl or substituted with —SO2NRR where R is hydrogen or alkyl;
• and
• substituted heteroaryl refers to heteroaryl groups substituted with from 1 to 3 substituents selected from hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminocarbonylamino, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, —S(O)2-alkyl, —S(O)2-substituted alkyl, —S(O)2-cycloalkyl, —S(O)2-substituted cycloalkyl, —S(O)2-alkenyl, —S(O)2-substituted alkenyl —S(O)2-aryl, —S(O)2-substituted aryl, —S(O)2-heteroaryl, —S(O)2-substituted heteroaryl, —S(O)2-heterocyclic, —S(O)2-substituted heterocyclic, —OS(O)2-alkyl, —S(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2-NRR where R is hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2-NR-alkyl, —NRS(O)2-NR-substituted alkyl, NRS(O)2-NR-aryl, NRS(O)2-NR-substituted aryl, NRS(O)2-NR-heteroaryl, —NRS(O)2-NR-substituted heteroaryl, —NRS(O)2-NR-heterocyclic, —NRS(O)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups selected from the group consisting of Boc, Cbz, and formyl or substituted with —SO2NRR where R is hydrogen or alkyl;
• with the proviso that when R5 is ═CH—X then (H) is removed from the formula and X is not hydroxyl;
• R6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, —O-(N-succinimidyl), —NH-adamantyl, —O-cholest-5-en-3-β-yl, —NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, —NH(CH2)pCOOY where p is an integer of from 1 to 8 and Y is as defined above, —OCH2NR9R10 where R9 is selected from the group consisting of —C(O)-aryl and —C(O)-substituted aryl and R10 is selected from the group consisting of hydrogen and —CH2COOR11 where R11 is alkyl, and —NHSO2Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic;
• Q is —C(X′)NR7— wherein R7 is selected from the group consisting of hydrogen and alkyl;
• and X′ is selected from the group consisting of oxygen and sulfur;
• or pharmaceutically acceptable salts thereof
• with the proviso that
• when R1 is p-methylphenyl, R2 and R3 are joined together with the nitrogen atom pendent to R2 and the carbon atom pendent to R3 to form a pyrrolidinyl ring, R4 is methyl, R5 is p-hydroxybenzyl then R6 is not t-butoxy.

A compound selected from the group consisting of:

• N-(toluene-4-sulfonyl)-L-α-methylprolyl-L-phenylalanine;
• N-(toluene-4-sulfonyl)-L-α-methylprolyl-L-4-(isonicotinamido)phenylalanine methyl ester;
• N-(toluene-4-sulfonyl)-L-α-methylprolyl-L-4-(isonicotinamido)phenylalanine;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(1-methylpiperidin-4-oxy)phenylalanine ethyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(1-methylpiperidin-4-oxy)phenylalanine;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(4-methylpiperazin-1-carbonyloxy)phenylalanine tert-butyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(N,N-dimethylcarbamyloxy)phenyl-alanine tert-butyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(4-methylpiperazin-1-carbonyloxy)phenylalanine;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-tyrosine tert-butyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(morpholin-4-ylcarbonyloxy)phenyl-alanine tert-butyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(morpholin-4-ylcarbonyloxy)phenyl-alanine;
• N-(toluene-4-sulfonyl)-α-methylprolyl-D-tyrosine tert-butyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-(morpholin-4-ylcarbonyloxy)phenyl-alanine 1-(trimethyacetoxy)methyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-[N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamyloxy]phenylalanine tert-butyl ester;
• N-(toluene-4-sulfonyl)-α-methylprolyl-L-4-[N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamyloxy]phenylalanine;
• N-(4-fluorobenzenesulfonyl)-α-methylprolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester;
• N-(4-fluorobenzenesulfonyl)-α-methylprolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• or pharmaceutically acceptable salts thereof or any of the ester compounds recited above wherein one ester group is replaced with another ester group selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester.

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

• where
• R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
• R2 and R3 together with the nitrogen atom bound to R2 and the carbon atom bound to R3 form a heterocyclic or a substituted heterocyclic group selected from the group consisting of thiazolidinyl, piperidinyl and pyrrolidinyl wherein said substituted heterocyclic group consists of from 1 to 2 substituents selected from the group consisting of fluoro, methyl, hydroxyl, amino, phenyl, thiophenyl and thiobenzyl;
• R4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R5 is selected from the group consisting of isopropyl, —CH2X and ═CH—X where X is selected from the group consisting of:
• hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
• wherein substituted aryl refers to aryl groups substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, —S(O)2-alkyl, —S(O)2-substituted alkyl, —S(O)2-cycloalkyl, —S(O)2-substituted cycloalkyl, —S(O)2-alkenyl, —S(O)2-substituted alkenyl, —S(O)2-aryl, —S(O)2-substituted aryl, —S(O)2-heteroaryl, —S(O)2-substituted heteroaryl, —S(O)2-heterocyclic, —S(O)2-substituted heterocyclic, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2-NRR where R is hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2-NR-alkyl, —NRS(O)2-NR-substituted alkyl, —NRS(O)2-NR-aryl, —NRS(O)2-NR-substituted aryl, —NRS(O)2-NR-heteroaryl, —NRS(O)2-NR-substituted heteroaryl, —NRS(O)2-NR-heterocyclic, —NRS(O)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups selected from the group consisting of Boc, Cbz, and formyl or substituted with —SO2NRR where R is hydrogen or alkyl;
• and
• substituted heteroaryl refers to heteroaryl groups substituted with from 1 to 3 substituents selected from hydroxyl, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, —S(O)2-alkyl, —S(O)2-substituted alkyl, —S(O)2-cycloalkyl, —S(O)2-substituted cycloalkyl, —S(O)2-alkenyl, —S(O)2-substituted alkenyl —S(O)2-aryl, —S(O)2-substituted aryl, —S(O)2-heteroaryl, —S(O)2-substituted heteroaryl, —S(O)2-heterocyclic, —S(O)2-substituted heterocyclic, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2NRR where R is hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2-NR-alkyl, —NRS(O)2-NR-substituted alkyl, —NRS(O)2-NR-aryl, —NRS(O)2-NR-substituted aryl, —NRS(O)2-NR-heteroaryl, —NRS(O)2-NR-substituted heteroaryl, —NRS(O)2-NR-heterocyclic, —NRS(O)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups selected from the group consisting of Boc, Cbz, and formyl or substituted with —SO2NRR where R is hydrogen or alkyl;
• with the proviso that when R5 is ═CH—X then (H) is removed from the formula and X is not hydroxyl;
• R6′ is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), hydroxyl, amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, —O-(N-succinimidyl), —NH-adamantyl, —O-cholest-5-en-3-β-yl, —NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, —NH(CH2)pCOOY where p is an integer of from 1 to 8 and Y is as defined above, —OCH2NR9R10 where R9 is selected from the group consisting of —C(O)-aryl and —C(O)-substituted aryl and R10 is selected from the group consisting of hydrogen and —CH2COOR11 where R11 is alkyl, and —NHSO2Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic;
• Q is —C(X′)NR7— wherein R7 is selected from the group consisting of hydrogen and alkyl;
• and
• X is selected from the group consisting of oxygen and sulfur;
• or pharmaceutically acceptable salts thereof
• with the proviso that
• when R1 is p-methylphenyl, R2 and R3 are joined together with the nitrogen atom pendent to R2 and the carbon atom pendent to R3 to form a pyrrolidinyl ring, R4 is methyl, R5 is p-hydroxybenzyl then R6′ is not t-butoxy.