Nitric oxide donor neprilysin inhibitors

A compound of formula I:

• where:
• R1 is selected from —C1-10alkyl substituted with 1 or 2 —ONO2 groups, —CH2O—R10, —C1-6alkylene-O—CH2—CH(ONO2)—C1-6alkyl, -phenylene-R10, —C1-6alkylene-SO2NH(OH),
• R10 is —C2-10alkyl substituted with 1 or 2 —ONO2 groups;
• and
• a is an integer from 2-5;
• R2 is selected from —OH, —CH2OH, —OP(O)(OH)2, and —CH2OP(O)(OH)2;
• and R3 is selected from H and —CH3;
• or
• R2 is taken together with R3 to form —CH2—O—CH2— or —CH2—CH2—;
• or
• R2 and R3 are both —CH3;
• Z is —CH— or —N—;
• X is selected from —COOR4 , pyran, and —C1-9heteroaryl substituted with R5 and R6;
• R5 is absent or is selected from H;
• halo;
• —C0-5alkylene-OH;
• —NH2;
• —C1-6alkyl;
• —CF3;
• —C3-7cycloalkyl;
• —C0-2alkylene-O—C1-6alkyl;
• —C(O)H;
• —C(O)—C1-6alkyl;
• —C0-1alkylene—COOR50;
• —C(O)NR51R52;
• —NHC(O)R53;
• ═O;
• —NO2;
• —C(CH3)═N(OH);
• phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF3, —OCH3, —NHC(O)CH3, and phenyl;
• naphthalenyl;
• pyridinyl;
• pyrazinyl;
• pyrazolyl optionally substituted with methyl;
• thiophenyl optionally substituted with methyl or halo;
• furanyl;
• and —CH2-morpholinyl;
• and R5, when present, is attached to a carbon atom;
• where R51 and R52 are independently selected from H, —C1-6alkyl, —CH2COOH, —(CH2)2OH, —(CH2)2OCH3, —(CH2)2SO2NH2, —(CH2)2N(CH3)2, —C0-1alkylene-C3-7cycloalkyl, and —(CH2)2-imidazolyl;
• or R51 and R52 are taken together to form a saturated or partially unsaturated —C3-5heterocycle optionally substituted with halo, —OH, —COOH, or —CONH2;
• and optionally containing an oxygen atom in the ring;
• and R53 is selected from —C1-6alkyl;
• —C0-1alkylene-O—C1-6alkyl;
• phenyl optionally substituted with halo or —OCH3;
• and —C1-9heteroaryl;
• R6 is absent or is selected from H;
• —OH;
• —C1-6alkyl;
• —C1-2alkylene—COOR60;
• —CH2OC(O)CH(R61)NH2;
• —OCH2OC(O)CH(R61)NH2;
• —OCH2OC(O)CH3;
• —CH2OP(O)(OH)2;
• —CH2CH(OH)CH2OH;
• —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl;
• pyridinyl;
• and phenyl or benzyl optionally substituted with one or more groups selected from halo, —COOR60, —OCH3, —OCF3, and —SCF3;
• and R6, when present, is attached to a carbon or nitrogen atom;
• where R61 is selected from H, —CH(CH3)2, phenyl, and benzyl;
• R4, R50, and R60 are independently selected from H, —C1-8alkyl, —C1-3alkylene-C6-10aryl, —C1-3alkylene-C1-9heteroaryl, —C3-7cycloalkyl, —[(CH2)2O]1-3CH3, —C1-6alkylene-OC(O)R40, —C1-6alkylene-NR41R42, —C1-6alkylene-C(O)R43, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,
• where R40 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR41R42, —CH[CH(CH3)2]—NH2, —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3;
• R41 and R42 are independently selected from H, —C1-6alkyl,and benzyl;
• or R41 and R42 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2O(CH2)2—;
• and R43 is selected from —O—C1-6alkyl, —O-benzyl, and —NR41R42;
• b is 0 or 1;
• R7 is selected from halo, —CH3, —CF3, and —CN;
• c is 0 or an integer from 1 to 3;
• each R8 is independently selected from halo, —OH, —CH3, —OCH3, and —CF3;
• and
• where each alkyl group in X is optionally substituted with 1 to 8 fluoro atoms;
• or a pharmaceutically acceptable salt thereof.