Vascular adhesion protein-1 (vap-1) modulators and therapeutic uses thereof

A compound having the structure of the formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• A1 is selected from the group consisting of —(CH2)n—, —S—, —S(═O)—, —SO2—, —O—, —C(═S)—, —C(═O)—, —NR5—, —C(O)NR5—, —S(CH2)n—, —O(CH2)n—, —NR5(CH2)n—, —OC(O)NR5—, —NHC(O)NH— —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, —NR5SO2—, and a bond;
• when A1 is —S(═O)—, —SO2—, —C(═S)—, —C(═O)—, —NR5—, —C(O)NR5—, —S(CH2)n—, —O(CH2)n—, —NR5(CH2)n—, —OC(O)NR5—, —NHC(O)NH— —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, or —NR5SO2—, A2 is selected from the group consisting of 3-10 membered heterocyclyl optionally substituted with one or more R4, C6-10 aryl optionally substituted with one or more R4, 5-10 membered heteroaryl optionally substituted with one or more R4, C3-10 carbocyclyl optionally substituted with one or more R4, and C6-10 aryl(C1-C6)alkyl optionally substituted with one or more R4;
• when A1 is a bond, A2 is selected from the group consisting of —SO2NR5R6, —(CH2)nSO2NR5R6, —(CH2)nNR5SO2R6, —NRSO2R6, C6-10 aryl substituted with one or more R3, 3-10 membered heterocyclyl optionally substituted with one or more R4, C3-10 carbocyclyl optionally substituted with one or more R3a, and —NR1R2 wherein R1 and R2 together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl optionally substituted with one or more R4, or a 5-10 membered heteroaryl optionally substituted with one or more R4;
• when A1 is —O—, A2 is selected from the group consisting of 3-10 membered heterocyclyl optionally substituted with one or more R4, C6-10 aryl substituted with one or more R3a, 5-10 membered heteroaryl optionally substituted with one or more R7, C3-10 carbocyclyl optionally substituted with one or more R4, and C6-10 aryl(C1-C6)alkyl optionally substituted with one or more R4;
• when A1 is —(CH2)n—, A2 is selected from the group consisting of 3-10 membered heterocyclyl optionally substituted with one or more R4, C6-10 aryl substituted with one or more R3a, 5-10 membered heteroaryl optionally substituted with one or more R7, C3-10 carbocyclyl optionally substituted with one or more R4, and C6-10 aryl(C2-C6)alkyl optionally substituted with one or more R4;
• and
• when A1 is —S—, A2 is selected from the group consisting of 3-10 membered heterocyclyl optionally substituted with one or more R4, C6-10 aryl substituted with one or more R3a, 5-10 membered heteroaryl optionally substituted with one or more R4, C3-10 carbocyclyl optionally substituted with one or more R4, and C6-10 aryl(C1-C6)alkyl optionally substituted with one or more R4;
• each R3 is independently selected from 5-10 membered heterocyclyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), —NR5COOR6, —NR5COR6, —NR5CONR5R6, —NR5CSNR5R6, —O(CO)NR5R6, and C3-7 carbocyclyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy);
• each R3a is independently selected from 5-10 membered heterocyclyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), —NR5COOR6, —NR5COR6, —NR5CONR5R6, —NR5CSNR5R6, —O(CO)NR5R6, and C3-7 carbocyclyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy);
• each R4 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C6-10 aryl(C1-C6)alkyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with —OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl), —NR5COOR6, —NR5COR6, —NR5CONR5R6, —NR5CSNR5R6, —O(CO)NR5R6, —NR5R6, —SO2NR5R6, —C(O)NR5R6, —NSO2R6, —OCF3, —CF3, —OH, and —SR5;
• each R5 and R6 are independently selected from the group consisting of —H, optionally substituted C1-4 alkyl, —CO-(optionally substituted C1-4 alkyl), —CO-(optionally substituted C6-10 aryl), optionally substituted C1-8 alkoxyalkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C6-10 aryl(C1-C6)alkyl, and optionally substituted 5-10 membered heteroaryl;
• and
• R7 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C6-10 aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl), —NR5COOR6, —NR5CONR5R6, —O(CO)NR5R6, —NR5R6, —SO2NR5R6, —C(O)NR5R6, —NSO2R6, —OCF3, CF3, —OH, and —SR5;
• and
• n is selected to be an integer from 1 to 2.