Neprilysin inhibitors

A compound of formula XII:

• where:
• (i) Ra is H;
• Rb is Cl;
• X is
• and
• R2 is H, R4 is —OH, and R7 is selected from —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is H, R4 is selected from —O-benzyl, —OCHRcOC(O)—C1-4alkyl, —OCH2OC(O)CHRd—NH2, and —OCH2OC(O)CHRd—NHC(O)O—C1-6alkyl, and R7 is selected from H and —CH2OC(O)CH3;
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, R4 is —OH, and R7 is H;
• or
• (ii) Ra is H;
• Rb is Cl;
• X is
• and
• R2 is H, R3 is —OH and R7 is selected from —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R3 is selected from —OC(O)CH2CH3, —OC(O)CH2CH(CH3)2, —OC(O)-phenyl, —OCH2OC(O)CHRd—NH2, and —OCH2OC(O)CHRd—NHC(O)O—C1-6alkyl, and R7 is H;
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, R3 is —OH, and R7 is H;
• or
• (iii) Ra is H;
• Rb is Cl;
• X is
• and
• R2 is H, R3 is —OH and R7 is selected from —CH2CH3, —CH2CH(CH3)2, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is H, R3 is selected from —OC(O)CH2CH3, —OC(O)CH2CH(CH3)2, —OC(O)-phenyl, —OCH2OC(O)CHRd—NH2, and —OCH2OC(O)CHRd—NHC(O)O—C1-6alkyl, and R7 is H;
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, R3 is —OH, and R7 is H;
• or
• (iv) Ra is F;
• Rb is Cl;
• X is
• and
• R2 is H and R7 is selected from H, —CH2CH3, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, and R7 is H;
• or
• (v) Ra is H;
• Rb is Cl;
• X is
• and
• R2 is H and R7 is selected from H, —CH2CH3, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, and R7 is H;
• or
• (vi) Ra is H;
• Rb is Cl;
• X is
• and
• R2 is H and R7 is selected from H, —CH2CH3, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, and R7 is H;
• or
• (vii) Ra is H;
• Rb is Cl;
• X is
• R is H or —CH3;
• and
• R2 is H and R7 is selected from —CH2CH3, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, and R7 is H;
• or
• (viii) Ra is F;
• Rb is Cl;
• X is
• and
• R2 is H, R4 is —OH, and R7 is selected from —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is H, R4 is selected from —O-benzyl, —OCHRcOC(O)—C1-4alkyl, —OCH2OC(O)CH[CH(CH3)2]NH2, —OCH2OC(O)CH[CH(CH3)2]—NHC(O)OCH3 and
• and R7 is H;
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, R4 is —OH, and R7 is H;
• or
• (ix) Ra is H;
• Rb is Cl;
• X is
• and
• R2 is H and R7 is selected from —CH2CH3, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, benzyl, and
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, and R7 is H;
• or
• (x) Ra is H;
• Rb is H;
• X is
• and
• R2 and R4 are H, and R7 is selected from —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —CHRcOC(O)—C1-4alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, and benzyl;
• or R2 is H, R4 is selected from —CH2OC(O)CH[CH(CH3)2]-NHC(O)OCH3 and —CH2OC(O)CH[CH(CH3)2]NH2, and R7 is H;
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, R4 is H, and R7 is H;
• or R2 is H, R4 is —CH2OP(O)(ORe)2 or —CH2OC(O)CH[CH(CH3)2]NH2, and R7 is —CH2CH3;
• or R2 is —C(O)CH[CH(CH3)2]NH2, R4 is H, and R7 is —CH2CH3;
• or
• (xi) Ra is H;
• Rb is Cl;
• X is
• and
• R2 and R4 are H, and R7 is selected from H, —CH2CH3, —CH2CF3, —(CH2)2CF3, —CH2CF2CH3, —CH2CF2CF3, —C(CH3)(CF3)2, —CH(CH2CH3)CF3, —CH(CH3)CF2CF3, —(CH2)2-3OH, —CH2CH(NH2)COOCH3, —(CH2)2OCH3, —CH2OC(O)CH3, —CH2OC(O)(CH2)2CH3, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —C2-4alkylene-N(CH3)2, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, and benzyl;
• or R2 is H, R4 is selected from —CH2OC(O)CH[CH(CH3)2]—NHC(O)OCH3 and —CH2OC(O)CH[CH(CH3)2]NH2, and R7 is H;
• or R2 is selected from —C(O)—C1-6alkyl, —C(O)CHRd—NH2, —C(O)CHRd—NHC(O)O—C1-6alkyl, and —P(O)(ORe)2, R4 is H, and R7 is H;
• or R2 is H, R4 is —CH2OP(O)(ORe)2 or —CH2OC(O)CH[CH(CH3)2]NH2, and R7 is —CH2CH3;
• or R2 is —C(O)CH[CH(CH3)2]NH2, R4 is H, and R7 is —CH2CH3;
• where each Re is independently H or —C1-3alkyl;
• each Rd is independently H, —CH3, —CH(CH3)2, phenyl, or benzyl;
• and each Re is independently H, —C1-6alkyl, or phenyl;
• or a pharmaceutically acceptable salt thereof.