Pharmaceutical compositions containing anti-beta 1 integrin compounds and uses

A method for inhibiting activity of a plurality of integrins containing a φ1 subunit, the method comprising administering to a system containing said integrins, an effective amount of a pan-β1 integrin antagonist compound of Formula 1:

• 51
• or a pharmaceutically acceptable salt thereof wherein:
• R1 is
• 1) C1-10 alkyl,
• 2) C2-10alkenyl,
• 3) C2-10 alkynyl,
• 4) Cy,
• 5) Cy—C1-10 alkyl,
• 6) Cy—C2-10 alkenyl,
• 7) Cy—C2-C10 alkynyl,
• wherein alkyl, alkenyl, and alkynyl are 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;
• R2 is
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) aryl,
• 6) aryl-C1-10 alkyl,
• 7) heteroaryl,
• 8) 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
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) Cy, or
• 4) 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;
• R4 is
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) Cy,
• 6) Cy—C1-10 alkyl,
• 7) Cy—C2-10 alkenyl,
• 8) 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
• R3, R4 or R3, R5 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteroatoms selected from N, O, and S;
• R5 is
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) aryl,
• 6) aryl-C1-10 alkyl,
• 7) heteroaryl,
• 8) 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
• R4, R5 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;
• R6, R7, and R8 are each independently selected from the group consisting of
• 1) a group selected from Rd, and
• 2) a group selected from Rx;
• or
• two of R6, R7, and R8 and the atom to which both are attached, or two of R6, R7, and R8 and the two adjacent atoms to which they are attached, together form a 5-7 membered saturated or unsaturated monocyclic ring containing zero to three heteroatoms selected from N, O or S,
• R12 is
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) Cy,
• 6) Cy—C1-10 alkyl,
• 7) Cy—C2-10 alkenyl,
• 8) 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;
• R13 is
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) aryl,
• 6) aryl-C1-10 alkyl,
• 7) heteroaryl,
• 8) 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;
• Ra is
• 1) Cy, or
• 2) a group selected from Rx;
• wherein Cy is optionally subsituted with one to four substituents independently selected from Rc;
• Rb is
• 1) a group selected from Ra,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) aryl C1-10 alkyl,
• 6) heteroaryl C1-10 alkyl,
• wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc;
• Rc is
• 1) halogen,
• 2) NO2,
• 3) C(O)ORf
• 4) C1-4 alkyl,
• 5) C1-4 alkoxy,
• 6) aryl,
• 7) aryl C1-4 alkyl,
• 8) aryloxy,
• 9) heteroaryl,
• 10) NRfRg,
• 11) NRfC(O)Rg,
• 12 NRfC(O)NRfRg,
• 13) CN;
• 14) C(O)Cy;
• or
• 15) C(O)alkyl.
• Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10 alkyl, aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl, heteroaryl-substituted heteroaryl
• wherein alkyl, alkenyl, alkynyl, heteroaryl and Cy is optionally substituted with one to four substituents independently selected from Rc;
• 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, wherein the nitrogen is optionally substituted with C(O)Re, SO2Re;
• or SO2NRdRe;
• Rh is
• 1) hydrogen,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) cyano,
• 6) aryl,
• 7) aryl C1-10 alkyl,
• 8) heteroaryl,
• 9) heteroaryl C1-10 alkyl, or
• 10) —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 independently selected from Rb;
• Ri is
• 1) C1-10 alkyl,
• 2) C2-10 alkenyl,
• 3) C2-10 alkynyl, or
• 4) aryl;
• wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from Rc;
• Rj is selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Cy and Cy C1-10 alkyl, aryl, heteroaryl, aryl-substituted aryl, aryl substituted heteroaryl, heteroaryl-substituted heteroaryl
• wherein alkyl, alkenyl, alkynyl, heteroaryl, and Cy is optionally substituted with one to four substituents independently selected from Rc
• Rx is
• 1) —ORd,
• 2) —NO2,
• 3) halogen,
• 4) —S(O)mRd
• 5) —SRd,
• 6) —S(O)2ORd,
• 7) —S(O)mNRdRe,
• 8) —NRdRe,
• 9) —O(CRfRg)nNRdRe,
• 10) —C(O)Rd,
• 11) —CO2Rd,
• 12) —CO2(CRfRg)nCONRdRe,
• 13) —OC(O)Rd,
• 14) —CN,
• 15) —C(O)NRdRe,
• 16) —NRdC(O)Re,
• 17) —OC(O)NRdRe,
• 18) —NRdC(O)ORe,
• 19) —NRdC(O)NRdRe,
• 20) —CRd(N—ORe),
• 21) —CF3,
• 22) oxo,
• 23) NRdC(O)NRdSO2Ri,
• 24) NRdS(O)mRe,
• 25) —OS(O)2ORd,
• 26) —OP(O)(ORd)2;
• or
• 52
• Ry is
• 1) a group selected from Rx,
• 2) C1-10 alkyl,
• 3) C2-10 alkenyl,
• 4) C2-10 alkynyl,
• 5) aryl C1-10 alkyl,
• 6) heteroaryl C1-10 alkyl,
• 7) cycloalkyl,
• 8) heterocyclyl;
• 9) aryl;
• 10) heteroaryl
• wherein alkyl, alkenyl, alkynyl, heteroaryl and aryl are each optionally substituted with one to four substituents 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;
• X is
• 1) —C(O)ORd
• 2) -5-tetrazolyl;
• 3) —(CRfRg)COORd
• Y is
• 1) —S(O)2—;
• or
• 2) —S(O)2NRe
• Z and A are independently selected from —C— and —C—C—;
• B is selected from the group consisting of
• 1) a bond,
• 2) —C—,
• 3) —C—C—;
• 4) —C═C—,
• 5) a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur;
• and
• 5) —S(O)m—.