Substituted Aminobutyric Derivatives as Neprilysin Inhibitors

A compound of the formula (I′):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is C1-7alkyl;
• for each occurrence, R2 is independently C1-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, C1-7alkoxy, halo-C1-7alkyl, NRbRc, C6-10aryl, heteroaryl or heterocyclyl;
• wherein Rb and Rc for each occurrence, are independently H or C1-7alkyl;
• R3 is A1C(O)X1 or A2-R4;
• R4 is C6-10aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from hydroxy, hydroxy-C1-7alkyl, NRbRc, nitro, C1-7alkoxy, halo, C1-7alkyl, halo-C1-7alkyl, C2-7alkenyl, C6-10aryl, heteroaryl, —C(O)C1-7alkyl, —NHS(O)2-C1-7alkyl, —SO2C1-7alkyl and benzyl;
• R5 is H, halo, hydroxy, C1-7alkoxy, halo, C1-7alkyl or halo-C1-7alkyl;
• and
• X and X1 are independently OH, —O—C1-7alkyl, —NRbRc, —NHS(O)2—C1-7alkyl, —NHS(O)2-benzyl or —O—C6-10aryl;
• wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, —C(O)NH2, —C(O)NH—C1-6alkyl, and —C(O)N(C1-6alkyl)2;
• A1 is a bond or a linear C1-4alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, C1-7 alkyl and C3-7cycloalkyl;
• in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl;
• or
• A1 is a linear or branched C2-6alkenylene;
• or
• A1 is a linear C1-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa;
• and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and C1-7alkyl;
• in which Ra for each occurrence, is independently H, C1-7alkyl or CH2C(O)OH;
• or
• A1 is a C3-7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of C1-7alkyl, C3-7cycloalkyl, halo-C1-7alkyl, hydroxy, C1-7alkoxy, halo, NRbRc, OCH2CO2H, and OCH2C(O)NH2;
• or
• A1 is —C1-4alkylene-C6-10-aryl-, —C1-4alkylene-heteroaryl- or —C1-4alkylene-heterocyclyl-, wherein
• A1 may be in either direction;
• and
• A2 is a bond or a linear or branched C1-7alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-7alkoxy, hydroxy, O-Acetate and C3-7cycloalkyl;
• n is 0, 1, 2, 3, 4 or 5;
• wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and
• each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.