Multicyclic compounds which inhibit leukocyte adhesion mediated by VLA-4

A compound of the formula:

• where R is quinuclidinyl;
• R1 is selected from the group consisting of:
• (a) —(CH2)x—Ar—R5 where R5 is selected from the group consisting of —O-Z-NR6R6′ and —O-Z-R7 wherein R6 and R6′ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R6 and R6′ are joined to form a heterocycle or a substituted heterocycle, R7 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —S(O)2—,
• Ar is aryl, heteroaryl, substituted aryl and substituted heteroaryl,
• x is an integer from 1 to 4;
• (b) Ar1—Ar2—C1-10 alkyl-, Ar1—Ar2—C2-10 alkenyl- and Ar1—Ar2—C2-10 alkynyl-, wherein Ar1 and Ar2 are independently azyl 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;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10 alkyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb;
• R3 is selected from the group consisting of hydrogen, C1-10alkyl optionally substituted with one to four substituents independently selected from Ra and Cy 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)nNRdRe, —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 Re;
• Rb is selected from the group consisting of Ra, C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl, aryl, aryl C1-10alkyl, beteroaryl C1-10alkyl, wherein alkyl, alkenyl, aryl and alkynyl are optionally substituted with a group independently selected from Re,
• Rc is selected from the group consisting of halogen, amino, carboxy, C1-4 alkyl, C1-4 alkoxy, aryl, aryl C1-4 alkyl, hydroxyl, CF3 and aryloxy;
• Rd and Re are independently selected from hydrogen, C1-10 alkyl, C1-10 alkenyl, C2-10 alkynyl, 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 heteroatoins 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 atom 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, heteroeryl, heteroaryl C1-10 alkyl, and —SO2Ri, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
• and aryl and heteroaryl are each optionally substituted with one to four substituents indepedently 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 aryi are each optionally substituted with one to four substituents independently selected ftom Rc;
• Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl;
• X1 is selected from the group consisting of —C(O)ORd, —P(O)(ORd)(ORe), —P(O)(Rd)(ORe), —S(O)mRd, —C(O)NRdRh, and 5-tetrazolyl;
• m is an integer from 1 to 2;
• n is an integer from1 to 10;
• or pharmaceutically acceptable salts thereof.