Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4

A method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IVa and/or IVb:

• 31
• wherein, in formula IVa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
• in formula IVb, R1 and R2, together with the carbon atom and W′ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
• and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula IVa or IVb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl;
• substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently 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, —N[S(O)—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R13 is selected from the group consisting of hydrogen, C1-10alkyl, Cy, and Cy-C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from Ra;
• and Cy is optionally substituted with one to four substituents independently selected from Rb;
• R14 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy, Cy-C1-10 alkyl, Cy-C2-10 alkenyl and Cy-C2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from Ry;
• or R13, R14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S;
• R15 is selected from the group consisting of C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Ry;
• or R14, R15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
• Ra is selected from the group consisting of Cy and a group selected from Rx, wherein Cy is optionally substituted with one to four substituents independently selected from Rc,
• Rb is selected from the group consisting of Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
• Rc is selected from the group consisting of halogen, NO2, C(O)ORf, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, aryloxy, heteroaryl, NRfRg, RfC(O)Rg, NRfC(O)NRfRg, and CN;
• Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Re;
• or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl wherein Cy is optionally substituted with C1-10 alkyl;
• or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rh is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10 alkyl, and —SO2Rl;
• wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from Ra;
• and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb;
• Rl is selected from the group consisting of C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, and aryl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
• Rx is selected from the group consisting of —ORd, —NO2, halogen, —S(O)mRd, —SRd, —S(O)2ORd, —S(O)mNRdRe, —NRdRe, —O(CRfRg)nNRdRe, —C(O)Rd, —CO2Rd, —CO2(CRfRg)nCONRdRe, OC(O)Rd, —CN, C(O)NRdRe, —NRdC(O)Re, —OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CRd(N—ORe), CF3, oxo, NRdC(O)NRdSO2 μl, NRdS(O)nRe, —OS(O)2ORd, and —OP(O)(ORd)2;
• Ry is selected from the group consisting of Rx, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, cycloalkyl, heterocyclyl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substitutents independently selected from Rx;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• m is an integer from 1 to 2;
• n is an integer from 1 to 10;
• W is selected from the group consisting of carbon and nitrogen;
• W′ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O)2;
• X′ is selected from the group consisting of —C(O)ORd, —P(O)(ORd)(ORe), —P(O)(Rd)(ORe), —S(O)mORd, —C(O)NRdRh, and -5-tetrazolyl;
• and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.

A method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula VIa and/or VIb:

• 33
• wherein, in formula VIa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
• in formula VIb, R1 and R2, together with the carbon atom and W′ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
• and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently hydrogen or alkyl, —NRS(O)-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, —N[S(O)—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R23 is selected from the group consisting of hydrogen, C1-10 alkyl optionally substituted with one to four substituents independently selected from Ra′ and Cy optionally substituted with one to four substituents independently selected from Rb′;
• R24 is selected from the group consisting of Ar1—Ar2—C1-10 alkyl, Ar1—Ar2—C2-10 alkenyl, Ar1—Ar2—C2-10 alkynyl, wherein Ar1 and Ar1 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb′;
• alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra′;
• R25 is selected from the group consisting of hydrogen, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra′, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb′;
• Ra′ is selected from the group consisting of Cy, ORd′, —NO2, halogen —S(O)mRd′, —SRd′, —S(O)2ORd′, —S(O)mNRd′Re′, —C(O)Rd′, —CO2Rd′, —CO2(CRf′Rg′)CONRd′Re′, —OC(O)Rd′, —CN, —C(O)NRd′Re′, —NRd′C(O)Re′, —OC(O)NRd′Re′, —NRd′C(O)ORe′, —NRd′C(O)NRd′Re′, —C Rd′ (N—ORc′), CF3, and —OCF3;
• wherein Cy is optionally substituted with one to four substituents independently selected from Rc′;
• Rb′ is selected from the group consisting of Ra′, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl C1-10alkyl,
• wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc′;
• Rc′ is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, hydroxy, CF3, and aryloxy;
• Rd′ and Re′ are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc′;
• or Rd′ and Re′ together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rf′ and Rg′0 are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl;
• or Rf′ and Rg′ together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rh′ is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, or —SO2Rl′;
• wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Ra′;
• and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb′;
• Rl′ is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc′;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• X″ is selected from the group consisting of —C(O)ORd′, —P(O)(ORd′)(ORe′), —P(O)(Rd′)(ORe′), —S(O)mORd′, —C(O)NRd′Rh′, and -5-tetrazolyl;
• m is an integer from 1 to 2;
• n is an integer from 1 to 10;
• and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.

A compound of formula Ia and/or Ib:

• 35
• wherein, in formula Ia, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
• in formula Ib, R1 and R2, together with the carbon atom and W′ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
• and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently hydrogen or alkyl, —NRS(O)-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, —N[S(O)—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R3 is —(CH2)x—Ar—R9, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl;
• and x is an integer from 0 to 4;
• R3′ is selected from the group consisting of hydrogen, isopropyl, —CH2Z where Z 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;
• Q is selected from the group consisting of —O—, —S—, —S(O)—, —S(O), and —NR4—;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R4 and R1 or R4 and R2, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
• W is selected from the group consisting of nitrogen and carbon;
• and
• W′ is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O)2;
• X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″ where each R″ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• and enantiomers, diasteromers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.

A compound of formula IVa:

• 39
• wherein R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl group having two nitrogen atoms in the heteroaryl ring;
• and further wherein said-heteroaryl group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently hydrogen or alkyl, —NRS(O)-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, —N[S(O)2—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R13 is selected from the group consisting of hydrogen, C1-10 alkyl, Cy, and Cy-C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from Ra;
• and Cy is optionally substituted with one to four substituents independently selected from Rb;
• R14 is selected from the group consisting of hydrogen, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, Cy, Cy-C1-10 alkyl, Cy-C2-10 alkenyl and Cy-C2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from Ry;
• or R13, R14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S;
• R15 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Ry;
• or R14, R15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
• Ra is selected from the group consisting of Cy and a group selected from Rx, wherein Cy is optionally substituted with one to four substituents independently selected from Rc,
• Rb is selected from the group consisting of Ra, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, wherein alkyl, alkenyl, alkynyl, aryl heteroaryl are optionally substituted with a group independently selected from Rc;
• Rc is selected from the group consisting of halogen, NO2, C(O)ORf, C1-4alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, aryloxy, heteroaryl, NRfRg, RfC(O)Rg, NRfC(O)NRfRg, and CN;
• Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc;
• or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl wherein Cy is optionally substituted with C1-10 alkyl;
• or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rh is selected from the group consisting of hydrogen, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, and —SO2Rl;
• wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from Ra;
• and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb;
• Rl is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
• wherein alkyl alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
• Rx is selected from the group consisting of —ORd, —NO2, halogen, S(O)mRd, —SRd, —S(O)2ORd, —S(O)mNRdRe, —NRdRe, —O(CRf)nNRdRe, —C(O)Rd, —CO2Rd, —CO2(CRfRg)nCONRdRe, —OC(O)Rd, —CN, —C(O)NRdRe, —NRdC(O)Re, —OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CRd(N—ORe), CF3, oxo, NRdC(O)NRdSO2Rl, NRdS(O)mRe, —OS(O)2ORd, and —OP(O)(ORd)2;
• Ry is selected from the group consisting of Rx, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, cycloalkyl, heterocyclyl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substitutents independently selected from Rx;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• m is an integer from 1 to 2;
• n is an integer from 1 to 10;
• W is selected from the group consisting of carbon and nitrogen;
• W′ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O)2;
• X′ is selected from the group consisting of —C(O)ORd, —P(O)(ORd)(ORe), —P(O)(Rd)(ORe), —S(O)mORd, —C(O)NRdRh, and -5-tetrazolyl;
• and enatiomers, diastereomers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of formula IV has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less;
• and provided that when R1 and R2, together with the carbon atom and W to Which they are bound respectively, are joined to form a 2-arylpyrimidin-4-yl group and R14 is hydrogen, then R15 is not alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl;
• and when R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a 5-arylpyrazin-2-yl group and R14 is hydrogen, then R15 is not 4-hydroxybenzyl.

A compound of formula VIa and/or VIb:

• 41
• wherein, in formula VIa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
• in formula VIb, R1 and R2, together with the carbon atom and W′ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
• and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently 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, —N[S(O—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R23 is selected from the group consisting of hydrogen, C1-10 alkyl optionally substituted with one to four substituents independently selected from Ra′ and Cy optionally substituted with one to four substituents independently selected from Rb′;
• R24 is selected from the group consisting of Ar1—Ar2—C1-10 alkyl, Ar1—Ar2—C2-10 alkenyl, Ar1—Ar2—C2-10 alkynyl, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb;
• alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
• R25 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb′;
• Ra is selected from the group consisting of Cy, —ORd′, —NO2, halogen —S(O)mRd′, —SRd′, —S(O)2ORd′, —S(O)mNRd′Re′, —NRd′Re′, —O(CRf′Rg′)nNRd′Re′, —C(O)Rd′, —CO2Rd′, —CO2(CRf′Rg′)nCONRd′Re′, —OC(O)Rd′, —CN, —C(O)NRd′Re′, —NRd′C(O)Re′, —OC(O)NRd′Re′, —NRd′C(O)ORe′, —Nrd′C(O)NRd′Re′, —CRd′(N—ORe′), CF3, and —OCF3;
• wherein Cy is optionally substituted with one to four substituents independently selected from Rc′;
• Rb′ is selected from the group consisting of Ra′, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl C1-10alkyl,
• wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc′;
• Rc′ is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4alkyl, hydroxy, CF3, and aryloxy;
• Rd′ and Re′ are independently selected from hydrogen, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc′;
• or Rd′ and Re′ together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rf′ and Rg′ are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl;
• or Rf′ and Rg′ together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rh′ is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, or —SO2Rl′;
• wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Ra′;
• and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb′;
• Rl′ is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• X″ is selected from the group consisting of —C(O)ORd′, —P(O)(ORd′)(ORe′), —P(O)(Rd′)(ORe′), —S(O)mORd′, —C(O)NRd′Rh′, and -5-tetrazolyl;
• m is an integer from 1 to 2;
• n is an integer from 1 to 10;
• and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
• and further wherein the compounds of formula VIa and/or VIb have a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.

A compound selected from the group consisting of:

• N-(2-chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-[5-(N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
• N-[5-(N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
• N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-[5-(N,N-di-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-[5-[N-(1-N′-methylpyrazol-4-ylsulfonyl)-N-methylamino]pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
• N-[5-(N-methyl-N-3-pyridylsulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
• N-(5-(N-methyl-N-(1-butylpyrazol-4-yl)sulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2,4-dimethoxypyrimidin-5-yl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2,6-difluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-ethyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2,4-6-trimethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-isopropylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-butylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-ethyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N,N-diethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-ethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-benzyloxypyrimidin-4-yl)-L-phenylalanine,
• N-(5-benzyloxypyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine,
• N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-phenylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(3-(N-methyl —N-4-toluenesulfonylamino)pyrazin-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenyl alanine,
• N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine isopropyl ester,
• N-(5-benzylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-butyl ester,
• N-(5-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-N,N-dimethylcarbamylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-3-(1-methylpyrazole)sulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
• N-(6-phenylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(6-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(6-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-cyclohexylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-2-furanmethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(3-thienyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-thienyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl —N-2-hydroxyethylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(piperidin-1-yl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(1-propylbutyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-cyclobutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-cyclobutylamino)-5-ethylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N,N-bis-(2-hydroxyethyl)amino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-phenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(isopropoxy)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-3-methylbutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-N-methylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(2-tolyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-2-hydroxyethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-2-methylpropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N,N-dimethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-phenyl-2,2-difluoroethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-phenyl-2,2-difluoroethyl)-6-chloropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-propylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-methoxyphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-Methyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
• N-(3-(N-methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L-phenylalanine isopropyl ester,
• N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-phenylalanine isopropyl ester,
• N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4 (N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
• N-(5-(3-nitrophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(3-pyridyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-N,N-dimethylamino-5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine,
• N-(5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2-methoxyphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2-methoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-difluorophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine,
• N-(2-(N methyl-N-cyclohexylamino)-5-(3-thienyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2-thienyl)pyrimidin-4-yl)-L-4-(4-trifluoromethylphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(3-nitrophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-dichlorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(4-pyridyl)pyrimidin-4-yl)-L-4-(3-hydroxymethylphenyl)phenylalanine,
• N-(2-(N-ethyl-N-isopropylamino)-5-(2,6-dimethoxyphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-(2,3-dichlorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-ethylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine,
• N-(2-(N-methyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(3-pyridyl)phenylalanine,
• N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine,
• N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2-cyanophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine,
• N-(2-(N-ethyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(o-tolyl)phenylalanine,
• N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-yl)-L-4-(4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-cyclohexylamino)-5-ethylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine,
• N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,
• N-(4-(N,N-dimethylamino)-1-oxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester,
• N-[4-(2-(3-methylphenylaminocarbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine,
• N-(5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-cyclohexyl-N-methyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(2-(N-methyl-N-propyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,
• N-(3-chloropyrazin-2-yl)-L-4-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonylamino]phenylalanine ethyl ester,
• and pharmaceutically acceptable salts thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Ia and/or Ib:

• 43
• wherein, in formula Ia, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
• in formula Ib, R1 and R2, together with the carbon atom and W′ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
• and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently 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, —N[S(O—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R3 is —(CH2)x—Ar—R9, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl, and x is an integer from 0 to 4;
• R3′ is selected from the group consisting of hydrogen, isopropyl, —CH2Z where Z 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;
• Q is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)2, and —NR4—;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R4 and R1 or R4 and R2, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
• W is selected from the group consisting of nitrogen and carbon;
• and
• W′ is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O)2;
• X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″ where each R″ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• and enantiomers, diasteromers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.

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

• 47
• wherein R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl group having two nitrogen atoms;
• and further wherein said heteroaryl group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently hydrogen or alkyl, —NRS(O)-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, —N[S(O)2—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R13 is selected from the group consisting of hydrogen, C1-10 alkyl, Cy, and Cy-C1-10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from Ra;
• and Cy is optionally substituted with one to four substituents independently selected from Rb;
• R14 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy, Cy-C1-10 alkyl, Cy-C2-10 alkenyl and Cy-C2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and Rx, and Cy is optionally substituted with one to four substituents independently selected from Ry;
• or R13, R14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S;
• R15 is selected from the group consisting of C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Ry;
• or R14, R15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
• Ra is selected from the group consisting of Cy and a group selected from Rx, wherein Cy is optionally substituted with one to four substituents independently selected from Rc;
• Rb is selected from the group consisting of Ra, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl wherein alkyl alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
• Rc is selected from the group consisting of halogen, NO2, C(O)ORf, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, aryloxy, heteroaryl, NRfRg, RfC(O)Rg, NRfC(O)NRfRg, and CN;
• Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc;
• or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rf and Rg are independently selected from hydrogen, C1-10 alkyl, Cy and Cy-C1-10 alkyl wherein Cy is optionally substituted with C1-10 alkyl or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rh is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10 alkyl, and —SO2Rl;
• wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from Rb;
• and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb;
• Rl is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
• Rx is selected from the group consisting of —ORd, —NO2, halogen, —S(O)mRd, —SRd, —S(O)2ORd, —S(O)mNRdRe, —NRdRe, O(CRfRg)nNRdRe, —C(O)Rd, —CO2Rd, —CO2(CRfRg)nCONRdRe, —OC(O)Rd, —CN, —C(O)NRdRe, NRdC(O)Re, OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CRd(N—ORe), CF3, oxo, NRdC(O)NRdSO2Rl, NRdS(O)mRl, —OS(O)2ORd, and —OP(O)(ORd)2;
• Ry is selected from the group consisting of Rx, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, aryl C1-10alkyl, heteroaryl C1-10 alkyl, cycloalkyl, heterocyclyl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substitutents independently selected from Rx;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• m is an integer from 1 to 2;
• n is an integer from 1 to 10;
• W is selected from the group consisting of carbon and nitrogen;
• W′ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O)2;
• X′ is selected from the group consisting of —C(O)ORd, —P(O)(ORd)(ORe), —P(O)(Rd)(ORe), —S(O)mORd, —C(O)NRdRh, and -5-tetrazolyl;
• and enatiomers, diastereomers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of formula IV has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less;
• and provided that when R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a 2-arylpyrimidin-4-yl group and R14 is hydrogen, then R15 is not alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl;
• and when R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form a 5-arylpyrazin-2-yl group and R14 is hydrogen, then R15 is not 4-hydroxybenzyl.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula VIa and/or VIb:

• 49
• wherein, in formula VIa, R1 and R2, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
• in formula VIb, R1 and R2, together with the carbon atom and W′ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
• and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently 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, —N[S(O)—R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R23 is selected from the group consisting of hydrogen, C1-10 alkyl optionally substituted with one to four substituents independently selected from Ra′ and Cy optionally substituted with one to four substituents independently selected from Rb′;
• R24 is selected from the group consisting of Ar1—Ar2—C1-10 alkyl, Ar1—Ar2—C2-10 alkenyl, Ar1—Ar2—C2-10 alkynyl, wherein Ar1 and Ar1 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb′;
• alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra′;
• R25 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, and heteroaryl C1-10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra′, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb′;
• Ra′ is selected from the group consisting of Cy, —ORd′, —NO2, halogen —S(O)mRd′, —SRd′, —S(O)2ORd, —S(O)mNRd′Re′, —NRd′Re′, —O(CRf′Rg′)nNRd′Re′, —C(O)Rd′, —CO2Rd′, —CO2(CRf′Rg′)nCONRd′Re′, —OC(O)Rd′, —CN, —C(O)NRd′Re′, —NRd′C(O)Re′, —OC(O)NRd′Re′, —NRd′C(O)ORe′, —Nrd′C(O)NRd′Re′, —CRd′(N—ORe′), CF3, and —OCF3;
• wherein Cy is optionally substituted with one to four substituents independently selected from Rc′;
• Rb′ is selected from the group consisting of Ra′, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, aryl C1-10 alkyl, heteroaryl C1-10alkyl,
• wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc′;
• Rc′ is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4alkyl, hydroxy, CF3, and aryloxy;
• Rd′ and Re′ are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc′;
• or Rd′ and Re′ together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rf′ and Rg′ are independently selected from hydrogen, C1-10 alkyl Cy and Cy-C1-10 alkyl;
• or Rf′ and Rg′ together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
• Rh′ is selected from the group consisting of hydrogen, C1-10 alkyl C2-10 alkenyl, C2-10 alkynyl, cyano, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl or —SO2Rl′;
• wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from Ra′;
• and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb′;
• Ri′ is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and aryl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc′;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• X″ is selected from the group consisting of —C(O)ORd′, P(O)(ORd′)(ORe′), P(O)(Rd′)(ORe′), —S(O)mORd′, C(O)NRd′Rh′, and -5-tetrazolyl;
• m is an integer from 1 to 2;
• n is an integer from 1 to 10;
• and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
• and further wherein the compounds of formula VIa and/or VIb have a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.