Substituted picolinamides as MAO-B inhibitors useful for treating obesity

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

• wherein:
• A is N;
• A1 and A3 are CH;
• A2 is CX;
• A4 is CY;
• R, at each occurrence, is independently selected from H and C1-6 alkyl;
• R1 is selected from H and C1-6 alkyl;
• R2 is selected from H and C1-6 alkyl;
• Q is C═O;
• X is selected from H, OR3, NR3Z, OZ, SZ, SO2OR3, SO2NR3R4, CO2R3, CONR3R4, PO(OR3)2, (CH2)mCO2R, (CH2)mCONR2, NR—C2-4 alkenyl, NRSO2CH3, NR(CH2)nCO2R, CH2-aryl, O(CH2)n-biphenyl, O(CH2)n-biphenyl-(CH2)mCO2R, O(CH2)n-biphenyl-(CH2)mCN, O(CH2)n-biphenyl-(CH2)mCON(R)2, NR(CH2)n-biphenyl-(CH2)mCO2R, NR(CH2)n-biphenyl-(CH2)mCN, NR(CH2)n-biphenyl, NR(CH2)n-biphenyl-(CH2)mCON(R)2, O(CH2)n-aryl, O(CH2)n-heteroaryl, NR(CH2)n-aryl, NR(CH2)n-heteroaryl, O(CH2)n-aryl(CH2)mCO2R, O(CH2)n-aryl-C2-6 alkenyl-CO2R, O(CH2)n-aryl(CH2)mCN, O(CH2)n-aryl(CH2)mCON(R)2, O(CH2)n-aryl(CH2)m—PO(OR)2, O(CH2)n-aryl-O(CH2)nCO2R, O(CH2)n-aryl-O—C2-6 alkenyl-CO2R, O(CH2)n-arylO(CH2)nCN, O(CH2)n-arylO(CH2)nCON(R)2, O(CH2)n-arylO(CH2)n—PO(OR)2, O(CH2)n-aryl-NR(CH2)nCO2R, O(CH2)n-aryl-NRC2-6 alkenyl-CO2R, O(CH2)n-aryl-NR(CH2)nCN, O(CH2)n-aryl-NR(CH2)nCON(R)2, O(CH2)n-aryl-NR(CH2)n—PO(OR)2, NR(CH2)n-aryl(CH2)mCO2R, NR(CH2)n-aryl-C2-6 alkenyl-CO2R, NR(CH2)n-aryl(CH2)mCN, NR(CH2)n-aryl(CH2)mCON(R)2, NR(CH2)n-aryl(CH2)m—PO(OR)2, NR(CH2)n-aryl-NR(CH2)nCO2R, NR(CH2)n-aryl-NR—C2-6 alkenyl-CO2R, NR(CH2)n-aryl-NR(CH2)nCN, NR(CH2)n-aryl-NR(CH2)nCON(R)2, NR(CH2)n-aryl-NR(CH2)nPO(OR)2, NR(CH2)n-arylO(CH2)nCO2R, NR(CH2)n-aryl-O—C2-6 alkenyl-CO2R, NR(CH2)n-arylO(CH2)nCN, NR(CH2)n-aryl-O(CH2)nCON(R)2, NR(CH2)n-arylO(CH2)nPO(OR)2, O(CH2)n-heteroaryl(CH2)mCO2R, O(CH2)n-heteroaryl-C2-6 alkenyl-CO2R, O(CH2)n-heteroaryl-(CH2)mCN, O(CH2)n-heteroaryl(CH2)mCON(R)2, O(CH2)n-heteroaryl(CH2)m—PO(OR)2, O(CH2)n-heteroaryl-O(CH2)nCO2R, O(CH2)n-heteroaryl-O—C2-6 alkenyl-CO2R, O(CH2)n-heteroaryl O(CH2)nCN, O(CH2)n-heteroarylO(CH2)nCON(R)2, O(CH2)n-heteroarylO(CH2)n—PO(OR)2, O(CH2)n-heteroaryl-NR(CH2)nCO2R, O(CH2)n-heteroaryl-NR—C2-6 alkenyl-CO2R, O(CH2)n-heteroaryl-NR(CH2)nCN, O(CH2)n-heteroaryl-NR(CH2)nCON(R)2, O(CH2)n-heteroaryl-NR(CH2)n—PO(OR)2, NR(CH2)n-heteroaryl(CH2)mCO2R, NR(CH2)n-heteroaryl-C2-6 alkenyl-CO2R, NR(CH2)n-heteroaryl, NR(CH2)n-heteroaryl(CH2)mCN, NR(CH2)n-heteroaryl(CH2)mCON(R)2, NR(CH2)n-heteroaryl(CH2)m—PO(OR)2, NR(CH2)n-heteroaryl-NR(CH2)nCO2R, NR(CH2)n-heteroaryl-NR—C2-6 alkenyl-CO2R, NR(CH2)nheteroaryl-NR(CH2)nCN, NR(CH2)n-heteroaryl-NR(CH2)nCON(R)2, NR(CH2)n-heteroaryl-NR(CH2)nPO(OR)2, NR(CH2)n-heteroaryl-O(CH2)nCO2R, NR(CH2)n-heteroaryl-O—C2-6 alkenyl-CO2R, NR(CH2)n-heteroaryl-O(CH2)nCN, NR(CH2)n-heteroaryl-O(CH2)nCON(R)2, NR(CH2)n-heteroarylO(CH2)nPO(OR)2, and O(CH2CH2O)pCH2CH2OR3, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl, heteroaryl, and biphenyl are substituted with 1-2 X2;
• X2, at each occurrence, is independently selected from H, OR, C1-4 alkyl, C1-4 alkyloxy, fluoro-C1-4 alkyloxy, C2-4 alkenyl, C2-4 alkynyl, halogen, CF3, nitro, —CN, CON(R)2, and SO2N(R)C1-4alkyl;
• Y is selected from H, OR3, NR3Z, OZ, SZ, SO2OR3, SO2NR3R4, CO2R3, CONR3R4, PO(OR3)2, CF3, CON(R)2, SO2N(R)C1-4alkyl and NHSO2R;
• provided that when Q is C═O and A, A1, A2, A3, and A4 are other than N+—O−, then at least one of X and Y is present and is other than H, OH, OC1-6 alkyl, OC2-6 alkenyl, and aryl-C1-6 alkyl-O—;
• Z, at each occurrence, is independently selected from (CH2)nCO2R3, CH2CH═CHCO2R3, (CH2)nCN, (CH2)nCONR3R4, CH2CH═CHCN, CH2CH═CHCON(R3)2, (CH2)nPO(OR3)2, (CH2)nSO3R3, and (CH2)nN+(R3)3G−;
• G− is a counterion;
• R3, at each occurrence, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and aryl-C1-6 alkyl-;
• R4, at each occurrence, is independently selected from H, C1-6 alkyl, phenyl, and CH(L)CO2R3;
• L is selected from H, C1-6 alkyl, —(CH2)m-phenyl, —(CH2)n—O—C1-6 alkyl, and —(CH2)n—S—C1-6 alkyl;
• m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
• n, at each occurrence, is independently selected from 1, 2, 3, and 4;
• and,
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11.