Dual-acting benzoimidazole antihypertensive agents

A compound, selected from the group consisting of:

• where Ar* is
• Ar is
• R1 is selected from —COOR1a, —NHSO2R1b—SO2NHR1d, —SO2OH, —C(O)NH—SO2R1c, —P(O)(OH)2, —CN, —OCH(R1e)—COOH, tetrazol-5-yl,
• R1a is H, —C1-6alkyl, —C1-3alkylenearyl, —C1-3alkyleneheteroaryl, —C3-7cycloalkyl, —CH(C1-4alkyl)OC(O)R1aa, —C0-6alkylenemorpholine,
• R1aa is —O—C1-6alkyl, —O—C3-7cycloalkyl, —NR1abR1ac, or —CH(NH2)CH2COOCH3;
• R1ab and R1ac are independently H, —C1-6alkyl, or benzyl, or are taken together as —(CH2)3-6—;
• R1b is R1c or —NHC(O)R1c;
• R1c is —C1-6alkyl, —C0-6alkylene-O—R1ca, —C1-5alkylene-NR1cbR1cc, —C0-4alkylenearyl, or —C0-4alkyleneheteroaryl;
• R1ca is H, —C1-6alkyl, or —C1-6alkylene-O—C1-6alkyl;
• R1cb and R1cc are independently H or —C1-6alkyl, or are taken together as —(CH2)2—O—(CH2)2— or —(CH2)2—N[C(O)CH3]—(CH2)2—;
• R1d is H, R1c, —C(O)R1c, or —C(O)NHR1c;
• R1e is —C1-4alkyl or aryl;
• R1* is selected from —C(O)O—P2, —SO2O—P5, —SO2NH—P6, —P(O)(O—P7)2, —OCH(CH3)—C(O)O—P2, —OCH(aryl)-C(O)O—P2, and tetrazol-5-yl-P4;
• n is 0, 1, or 2;
• each R2 is independently selected from halo, —NO2—C1-6alkyl, —C2-6alkenyl, —C3-7cycloalkyl, —CN, —C(O)R2a, —C0-5alkylene-OR2b, —C0-5alkylene-NR2cR2d;
• —C0-3alkylenearyl, and —C0-3alkyleneheteroaryl;
• R2a is H, —C3-7cycloalkyl, —OR2b, or —NR2cR2d;
• R2b is H, —C1-6alkyl, —C3-7cycloalkyl, or —C0-1alkylenearyl;
• and R2c and R2d are independently H, —C1-4alkyl, or —C0-1alkylenearyl;
• R2′ is selected from H and R2;
• R3 is selected from —C1-10alkyl, —C2-10alkenyl, —C3-10alkynyl, —C0-3alkylene-C3-7cycloalkyl, —C2-3alkenylene-C3-7cycloalkyl, —C2-3alkynylene-C3-7cycloalkyl, —C0-5alkylene-NR3a—C0-5alkylene-R3b, —C0-5alkylene-O—C0-5alkylene-R3b, —C1-5alkylene-S—C1-5alkylene-R3b, and —C0-3alkylenearyl;
• R3a is H, —C1-6alkyl, —C3-7cycloalkyl, or —C0-3alkylenearyl;
• and R3b is H, —C1-6alkyl, —C3-7cycloalkyl, —C2-4alkenyl, —C2-4alkynyl, or aryl;
• X is —C1-12alkylene-, where at least one —CH2— moiety in the alkylene is replaced with a —NR4a—C(O)— or —C(O)—NR4a— moiety, where R4a is H, —OH, or —C1-4alkyl;
• R5 is selected from —C0-3alkylene-SR5a, —C0-3alkylene-C(O)NR5bR5c, —C0-3alkylene-NR5b—C(O)R5d, —NH—C0-1alkylene-P(O)(OR5e)2, —C0-3alkylene-P(O)OR5eR5f, —C0-2alkylene-CHR5g—COOH, —C0-3alkylene-C(O)NR5h—CHR5i—COOH, and —C0-3alkylene-S—SR5j;
• R5a is H or —C(O)—R5aa;
• R5aa is —C1-6alkyl, —C0-6alkylene-C3-7cycloalkyl, —C0-6alkylenearyl, —C0-6alkyleneheteroaryl, —C0-6alkylenemorpholine, —C0-6alkylenepiperazine-CH3, —CH[N(R5ab)2]-aa where aa is an amino acid side chain, -2-pyrrolidine, —C0-6alkylene-OR5ab, —OC0-6alkylenearyl, —C1-2alkylene-OC(O)—C1-6alkyl, —C1-2alkylene-OC(O)—C0-6alkylenearyl, or —C1-2alkylene-OC(O)—OC1-6alkyl;
• R5ab is independently H or —C1-6alkyl;
• R5b is H, —OH, —OC(O)R5ba, —CH2COOH, —O-benzyl, -pyridyl, or —OC(S)NR5bbR5bc;
• R5ba is H, —C1-6alkyl, aryl, —OCH2-aryl, —CH2O-aryl, or —NR5bbR5bc;
• R5bb and R5bc are independently H or —C1-4alkyl;
• R5c is H, —C1-6alkyl, or —C(O)—R5ca;
• R5ca is H, —C1-6alkyl, —C3-7cycloalkyl, aryl, or heteroaryl;
• R5d is H, —C1-4alkyl, —C0-3alkylenearyl, —NR5daR5db, —CH2SH, or —O—C1-6alkyl;
• R5da and R5db are independently H or —C1-4alkyl;
• R5e is H, —C1-6alkyl, —C1-3alkylenearyl, —C1-3alkyleneheteroaryl, cycloalkyl, —CH(CH3)OC(O)R5ea,
• R5ea is —O—C1-6alkyl, —O—C3-7cycloalkyl, —NR5ebR5ec, or —CH(NH2)CH2COOCH3;
• R5eb and R5ec are independently H, —C1-4alkyl, or —C1-3alkylenearyl, or are taken together as —(CH2)3-6—;
• R5f is H, —C1-4alkyl, —C0-3alkylenearyl, —C1-3alkylene-NR5faR5fb, or —C1-3alkylene(aryl)-C0-3alkylene-NR5faR5fb;
• R5fa and R5fb are independently H or —C1-4alkyl;
• R5g is H, —C1-6alkyl, —C1-3alkylenearyl, or —CH2—O—(CH2)2—OCH3;
• R5h is H or —C1-4alkyl;
• and R5i is H, —C1-4alkyl, or —C0-3alkylenearyl;
• and R5j is —C1-6alkyl, aryl, or —CH2CH(NH2)COOH;
• R5* is selected from —C0-3alkylene-S—P3, —C0-3alkylene-C(O)NH(O—P5), —C0-3alkylene-N(O—P5)—C(O)R5d, —C0-1alkylene-NHC(O)CH2S—P3, —NH—C0-1alkylene-P(O)(O—P7)2, —C0-3alkylene-P(O)(O—P7)—R5f, —C0-2alkylene-CHR5g—C(O)O—P2, —C0-3alkylene-C(O)NR5h—CHR5i— C(O)O—P2, and —C0-3alkylene-S—S—P3;
• R6 is selected from —C1-6alkyl, —CH2O—(CH2)2OCH3, —C1-6alkylene-O—C1-6alkyl, —C0-3alkylenearyl, —C0-3alkyleneheteroaryl, and —C0-3alkylene-C3-7cycloalkyl;
• and
• R7 is H or is taken together with R6 to form —C3-8cycloalkyl;
• wherein each —CH2— group in —(CH2)r— is optionally substituted with 1 or 2 substituents independently selected from —C1-4alkyl and fluoro;
• each carbon atom in the alkylene moiety in X is optionally substituted with one or more R4b groups and one —CH2— moiety in X may be replaced with a group selected from —C4-8cycloalkylene-, —CR4d═CH—, and —CH═CR4d—;
• R4b is —C0-5alkylene-COOR4c, —C1-6alkyl, —C0-1alkylene-CONH2, —C1-2alkylene-OH, —C0-3alkylene-C3-7cycloalkyl, 1H-indol-3-yl, benzyl, or hydroxybenzyl;
• R4c is H or —C1-4alkyl;
• and R4d is —CH2-thiophene or phenyl;
• each alkyl and each aryl in R1, R2, R2′, R3, R4a-4d, and R5-6 is optionally substituted with 1 to 7 fluoro atoms;
• the ring in Ar and each aryl and heteroaryl in R1, R2, R2′, R3, and R5-6 is optionally substituted with 1 to 3 substituents independently selected from —OH, —C1-6alkyl, —C2-4alkenyl, —C2-4alkynyl, —CN, halo, —O—C1-6alkyl, —S—C1-6alkyl, —S(O)—C1-6alkyl, —S(O)2—C1-4alkyl, -phenyl, —NO2, —NH, —NH—C1-6alkyl, and —N(C1-6alkyl)2, wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1 to 5 fluoro atoms;
• P2 is a carboxy-protecting group;
• P3 is a thiol-protecting group;
• P4 is a tetrazole-protecting group;
• P5 is a hydroxyl-protecting group;
• P6 is a sulfonamide-protecting group;
• and P7 is a phosphate-protecting group or phosphinate-protecting group;
• or a salt thereof.