Neprilysin inhibitors

A compound of formula I:

• where:
• (i) X is
• and
• (a) Ra and Rb are H;
• R2 is H;
• and R7 is selected from —CH2CF2CH3, —CH2CF2CF3, —(CH2)5CH3, —(CH2)6CH3, and
• or R2 is —C1-6alkyl or —C(O)—C1-6alkyl, and R7 is H;
• or
• (b) Ra is selected from —CH3, —OCH3, and Cl and Rb is H;
• or Ra is selected from H, —CH3, Cl, and F, and Rb is Cl;
• or Ra is H and Rb is selected from —CH3 and —CN;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (c) Ra is H and Rb is F;
• or Ra is F and Rb is H;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• and R7 is selected from —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (ii) X is
• and
• (a) Ra is Cl and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• R4 is selected from —OH, —OCH3, —OCH2CH3, and —C1-4alkyl;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (b) Ra is F and Rb is H;
• R2 is H;
• R4 is —OH;
• and R7 is selected from —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (iii) X is
• and
• (a) Ra is Cl and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O— cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (b) Ra is F and Rb is H;
• R2 is H;
• and R7 is selected from —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (iv) X is
• (a) Ra and Rb are H;
• R2 is selected from —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• R3 is selected from —OH, —OCH3, —OCH2CH3, and C1-4alkyl;
• and R7 is H;
• or
• (b) Ra is selected from Cl and F and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• R3 is selected from —OH, —OCH3, —OCH2CH3, and —C1-4alkyl;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (v) X is
• Ra is selected from Cl and F and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• R3 is selected from —OH, —OCH3, —OCH2CH3, and C1-4alkyl;
• R4 is selected from H, —C1-6alkyl, and phenyl;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (vi) X is
• Ra is selected from Cl and F and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• R4 is selected from H, —C1-6alkyl, and phenyl;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (vii) X is
• Ra is selected from Cl and F and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• or
• (viii) X is
• Ra is selected from Cl and F and Rb is H;
• or Ra is H and Rb is selected from Cl, F, —CH3, and —CN;
• or Ra is F and Rb is Cl;
• R2 is selected from H, —C1-6alkyl, —(CH2)2-3ORe, and —(CH2)2-3NReRe;
• and R7 is selected from H, —C1-6alkyl, —[(CH2)2O]1-3CH3, —CHRcOC(O)—C1-4alkyl, —CH2OC(O)CHRd—NH2, —CH2OC(O)CHRd—NHC(O)O—C1-6alkyl, —CHRcOC(O)O—C2-4alkyl, —CHRcOC(O)O-cyclohexyl, —CH2CH(NH2)C(O)OCH3, —C2-4alkylene-N(CH3)2, —C0-6alkylenemorpholinyl, and
• where each Rc is independently H or —C1-3alkyl;
• each Rd is independently H, —CH3, —CH(CH3)2, phenyl, or benzyl;
• and each Re is independently H or —CH3;
• or a pharmaceutically acceptable salt thereof.