Fused ring heteroaryl and heterocyclic compounds which inhibit leukocyte adhesion mediated by VLA-4

A compound of formula IIIa:

• wherein
• R3 is selected from the group consisting of:
• (a) —(CH2)x—Ar—R35, where R35 is selected from the group consisting of —O—Z—NR∓R36 ′and —O—Z—R37 wherein R36 and R36′are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, or R36 and R36′are joined to form a heterocycle or a substituted heterocycle, R37 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)—and—SO2—, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4;
• and
• (b) Ar1—Ar2—C1-10alkynyl-, Ar1—Ar2—C2-10alkynyl-, Ar1—Ar2C2-10 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;
• R3′is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkynyl, aryl, aryl C1-10 alkyl, 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)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, 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, C2-10alkynyl, aryl C1-10 alkyl, heteroaryl, C1-10 alkyl, 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, C2-10 alkyl, C2-10 alkenyl, C2-10alkynyl, Cy and Cy—C1-10 alkyl, 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;
• Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• m is an integer from 1 to 2;
• n is an integer from 10;
• R4 ′is selected from the group consisting of hydrogen and alkyl;
• R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidirx, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl -substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, 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)2substituted 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)22—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, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted alkylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsynunetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups selected from t -butoxycarbonyl, benzyloxycarbonyl, and formyl or alkyl/substituted alkyl groups substituted with —SO2 -alkyl, —SO2-substituted alkyl, —SO2-alkenyl, —SO2-substituted alkenyl, —SO2-cycloalkyl, —SO2-substituted cycloalkyl, —SO2-aryl, —SO2-substituted aryl, —SO2-heteroaryl, —SO2-substituted heteroaryl, —SO2-heterocyclic, —SO2-substituted heterocyclic and —SO2 NRR where R is hydrogen or alkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl;
• 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
• or a pharmaceutically acceptable salt thereof.