Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

A compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

• wherein:
• X, Y, X′, and Y′, are independently selected from:
• H, C1-6 alkyl, halogen, CF3, O—C1-6 alkyl, NO2, NR2, —CN, O(CH2)nCO2R, O(CH2)nCN, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2R, NRaCO(CH2)nCO2R, NRaCO(CH2)nCONRa2, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONRa2, O(CH2)nC6H4 (CH2)nCONRa2, P(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4CONRa2, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4(CH2)nCO2R, NRa(CH2)nC6H4CONRa2, CH2NRa(CH2)nC6H4CONRa2, NRa(CH2)nC6H4(CH2)nCONRa2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, NRa(CH2)nC6H4(CH2)n-tetrazole, CONHOH, C(NH)NRa2, (CH2)nC(NH)NRa2, O(CH2)nCONRa2, O(CH2)nC(NH)NRa2, O(CH2)nC(NOH)NRa2, CH2O(CH2)nCONRa2, NRa(CH2)nCONRa2, OCH2CH═CHCONRa2, CH2OCH2CH═CHCONRa2, NRaCH2CH═CHCONRa2, (CH2)m-tetrazole, O(CH2)n-tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NHCH3;
• Z is selected from:
• H, C1-6 alkyl, OH, O—C1-6 alkyl, O(CH2CH2O)pR, OC(O)—C1-6 alkyl, O(CH2)nCO2R, OCH2CH═CHCO2R, O(CH2)nPO(OR)2, O(CH2)nCONRa2, O(CH2)nC(NH)NH2, O(CH2)nC(NOH)NRa2, OCH2CH═CHCONRa2, O(CH2)n-phenyl-(CH2)mCO2R, and O(CH2)n-phenyl-(CH2)m-tetrazole;
• Z′ is selected from H, CO2R, CONRa2, and CONRaCHACONRa2;
• Q is selected from:
• H, C1-6 alkyl, (CH2CH2O)pR, (CH2)n-aryl, (CH2)m-aryl-(CH2)mCO2R, (CH2)m-aryl-(CH2)mC(O)NRa2, (CH2)n-heteroaryl, (CH2)m heteroaryl-(CH2)mCO2R, (CH2)m-heteroaryl-(CH2)mC(O)NRa2, (CH2)mCHA(CH2)mC(O)NRa2, (CH2)mCAA″(CH2)mC(O)NRa2, (CH2)mCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCO2R, (CH2)mCHA(CH2)mSO2NRa2, (CH2)mCHA(CH2)mSO3R, (CH2)mCHA(CH2)mC(NH)NH2, (CH2)mCHA(CH2)mC(NOH)NH2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCHA(CH2)mCONHCHA(CH2)mSO2NRa2, (CH2)mCAA″(CH2)mCONHCHA(CH2)mSO2NRa2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa2, C3-C6-cyclic amino-(CH2)mCO2R, C3-C6-cyclic amino-(CH2)mCONRa2, C3-C6-cycloalkylene-(CH2)mCO2R, and C3-C6-cycloalkylene-(CH2)mCONRa2;
• A is selected from H, C1-6 alkyl, (CH2)mC3-6-cycloalkyl, OH, CH2OH, CH(CH3)OH, C(CH3)2OH, (CH2)nCO2Rb, (CH2)nC(O)NRb2, and (CH2)m-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C1-4 alkyl, halogen, CF3, OH, O—C1-4 alkyl, NO2, —CN, C(O)NH2, C(NH)NH2, and NHSO2CH3;
• A″ is C1-6 alkyl;
• alternatively, A and A″ form a C3-6 cycloalkyl group with the carbon to which they both are attached;
• R is independently selected from H, (CH2)m(CHRb)n(CH2)mOH, CH(CH2OH)2, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Ra is independently selected from H, (CH2)m(CHR)n(CH2)mOH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Rb is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Rc is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylidene-O—C1-2 alkyl, (CH2)mCHA(CH2)mC(O)NRa2, (CH2)mCAA″(CH2)mC(O)NRa2, (CH2)mCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCO2R, (CH2)mCHA(CH2)mSO2NRa2, (CH2)mCHA(CH2)mSO3R, (CH2)mCHA(CH2)mC(NH)NH2, (CH2)mCHA(CH2)mC(NOH)NH2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa2, C3-C6-cyclic amino-(CH2)mCO2R, C3-C6-cyclic amino-(CH2)mCONRa2, C3-C6-cycloalkylene-(CH2)mCO2R, and C3-C6-cycloalkylene-(CH2)mCONRa2;
• Rd is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OC3-4 alkenyl, OC3-4 alkynyl, and C1-6 alkylidene-O—C1-2 alkyl;
• alternatively, Rc and Rd taken together form —(CH2)n′—U—(CH2)n′—, and the ring formed by N(Rc)CH2Rd is substituted with 0-2 Re at other than group U;
• U is selected from O, S, SO, SO2, CHRe, and NRe;
• Re is selected from H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C2-6 alkylidene-O—C1-2 alkyl, (CH2)mCO2R, (CH2)mCONRa2, (CH2)mCONH(CH2)mCHA(CH2)mCONRa2, and (CH2)mCONH(CH2)mCHA(CH2)mCONRa2;
• p is independently selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
• m is independently selected from 0, 1, 2, 3, and 4;
• and,
• n is independently selected from 1, 2, 3, and 4;
• and
• n′ is independently selected from 1 and 2;
• provided that at least one of (a)-(f) is satisfied:
• a. at least one of X, Y, X′, and Y′ is other than H, C1-6 alkyl, halogen, CF3, O—C1-6 alkyl, NO2, NR2, and SO2NHCH3;
• b. Z is other than H, C1-6 alkyl, OH, O—C1-6 alkyl, and OC(O)—C1-6 alkyl;
• c. Z′ is other than H;
• d. Q is other than H, C1-6 alkyl, (CH2)n-aryl, and (CH2)n-heteroaryl;
• e. Rc is other than H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkylidene-O—C1-2 alkyl;
• and/or
• f. Re is present and is other than H, C1-6 alkyl, C3-6 alkenyl, and C3-6 alkynyl.