Neprilysin inhibitors

1. A compound selected from the formula:

or a salt thereof;

where

R 1 is selected from —OR 7 and —NR 8 R 9 ;

R 2 is H or —P(O)(OH) 2 or R 2 is taken together with R 7 to form —CR 18 R 19 — or is taken together with R 8 to form —C(O)—;

X is a —C 1-9 heteroaryl;

R 3 is absent or is selected from H; halo; —C 0-5 alkylene-OH; —NH 2 ; —C 1-6 alkyl; —CF 3 ; —C 3-7 cycloalkyl; —C 0-2 alkylene-O—C 1-6 alkyl; —C(O)R 20 ; —C 0-1 alkylene-COOR 21 ; —C(O)NR 22 R 23 ; —NHC(O)R 24 ; ═O; —NO 2 ; —C(CH 3 )═N(OH); phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF 3 , —OCH 3 , —NHC(O)CH 3 , and phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl optionally substituted with methyl; thiophenyl optionally substituted with methyl or halo; furanyl; and —CH 2 -morpholinyl; and R 3 , when present, is attached to a carbon atom;

R 4 is absent or is selected from H; —OH; —C 1-6 alkyl; —C 1-2 alkylene-COOR 35 ; —CH 2 OC(O)CH(R 36 )NH 2 ; —OCH 2 OC(O)CH(R 36 )NH 2 ; —OCH 2 OC(O)CH 3 ; —CH 2 OP(O)(OH) 2 ; —CH 2 CH(OH)CH 2 OH; —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl; pyridinyl; and phenyl or benzyl optionally substituted with one or more groups selected from halo, —COOR 35 , —OCH 3 —OCF 3 , and —SCF 3 ; and R 4 , when present, is attached to a carbon or nitrogen atom;

or R 3 and R 4 are taken together to form -phenylene-O—(CH 2 ) 1-3 — or -phenylene-O—CH 2 —CHOH—CH 2 —;

a is 0 or 1; R 5 is selected from halo, —CH 3 , —CF 3 , and —CN;

b is 0 or an integer from 1 to 3; each R 6 is independently selected from halo, —OH, —CH 3 , —OCH 3 , and —CF 3 ;

R 7 is selected from H, —C 1-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-C 1-9 heteroaryl, —C 3-7 cycloalkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-OC(O)R 10 , —C 1-6 alkylene-NR 12 R 13 , —C 1-6 alkylene-C(O)R 31 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,

R 10 is selected from —C 1-6 alkyl, —O—C 1-6 alkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, phenyl, —O-phenyl, —NR 12 R 13 , —CH[CH(CH 3 ) 2 ]—NH 2 , —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl, and —CH(NH 2 )CH 2 COOCH 3 ; and R 12 and R 13 are independently selected from H, —C 1-6 alkyl, and benzyl; or R 12 and R 13 are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 31 is selected from —O—C 1-6 alkyl, —O-benzyl, and —NR 12 R 13 ; and R 32 is —C 1-6 alkyl or —C 0-6 alkylene-C 6-10 aryl;

R 8 is selected from H, —OH, —OC(O)R 14 , —CH 2 COOH, —O-benzyl, -pyridyl, and —OC(S)NR 15 R 16 ; R 14 is selected from H, —C 1-6 alkyl, —C 6-10 aryl, —OCH 2 —C 6-10 aryl, —CH 2 O—C 6-10 aryl, and —NR 15 R 16 ; and R 15 and R 16 are independently selected from H and —C 1-4 alkyl;

R 9 is selected from H, —C 1-6 alkyl, and —C(O)—R 17 ; and R 17 is selected from H, —C 1-6 alkyl, —C 3-7 cycloalkyl, —C 6-10 aryl, and —C 1-9 heteroaryl;

R 18 and R 19 are independently selected from H, —C 1-6 alkyl, and —O—C 3-7 cycloalkyl, or R 18 and R 19 are taken together to form ═O;

R 20 is selected from H and —C 1-6 alkyl;

R 21 and R 35 are independently selected from H, —C 1-6 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-C 1-9 heteroaryl, —C 3-7 cycloalkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-OC(O)R 25 , —C 1-6 alkylene-NR 27 R 28 , —C 1-6 alkylene-C(O)R 33 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,

R 25 is selected from —C 1-6 alkyl, —O—C 1-6 alkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, phenyl, —O-phenyl, —NR 27 R 28 , —CH[CH(CH 3 ) 2 ]NH 2 , —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl, and —CH(NH 2 )CH 2 COOCH 3 ; R 27 and R 28 are independently selected from H, —C 1-6 alkyl, and benzyl; or R 27 and R 28 are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 33 is selected from —O—C 1-6 alkyl, —O-benzyl, and —NR 27 R 28 ; and R 34 is —C 1-6 alkyl or —C 0-6 alkylene-C 6-10 aryl;

R 22 and R 23 are independently selected from H, —C 1-6 alkyl, —CH 2 COOH, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 SO 2 NH 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —C 0-1 alkylene-C 3-7 cycloalkyl, and —(CH 2 ) 2 -imidazolyl; or R 22 and R 23 are taken together to form a saturated or partially unsaturated —C 3-5 heterocycle optionally substituted with halo, —OH, —COOH, or —CONH 2 ; and optionally containing an oxygen atom in the ring;

R 24 is selected from —C 1-6 alkyl; —C 0-1 alkylene-O—C 1-6 alkyl; phenyl optionally substituted with halo or —OCH 3 ; and —C 1-9 heteroaryl; and

R 36 is selected from H, —CH(CH 3 ) 2 , phenyl, and benzyl;

where each alkyl group in R 1 , R 3 , and R 4 is optionally substituted with 1 to 8 fluoro atoms;

where the methylene linker on the biphenyl is optionally substituted with one or two —C 1-6 alkyl groups or cyclopropyl;

R 1P is selected from —O—P 3 , —NHP 2 , and —NH(O—P 4 );

R 3P is selected from —C 0-5 alkylene-O—P 4 , —C 0-1 alkylene-COO—P 3 , and phenyl substituted with —O—P 4 ;

R 4P is selected from —O—P 4 ; —C 1-2 alkylene-COO—P 3 ; and phenyl or benzyl substituted with —COO—P 3 ;

P 2 is an amino-protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl;

P 3 is a carboxy-protecting group selected from methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl; and

P 4 is a hydroxyl-protecting group selected from —C 1-6 alkyl, triC 1-6 alkylsilyl, —C 1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl.

2. The compound of claim 1 , where R 1 is selected from —OR 7 and —NR 8 R 9 , R 7 is H, R 8 is H or —OH, and R 9 is H.

3. The compound of claim 1 , where:

R 1 is —OR 7 ; and R 7 is selected from —C 1-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-C 1-9 heteroaryl, —C 3-7 cycloalkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-OC(O)R 10 , —C 1-6 alkylene-NR 12 R 13 , —C 1-6 alkylene-C(O)R 31 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,

 or

R 1 is —NR 8 R 9 ; R 8 is selected from —OC(O)R 14 , —CH 2 COOH, —O-benzyl, pyridyl, and —OC(S)NR 15 R 16 ; and R 9 is H; or

R 1 is —NR 8 R 9 ; R 8 is selected from —OC(O)R 14 , —CH 2 COOH, —O-benzyl, pyridyl, and —OC(S)NR 15 R 16 ; and R 9 is —C 1-6 alkyl or —C(O)R 17 ;

R 1 is —NR 8 R 9 ; R 8 is selected from H or —OH; and R 9 is selected from —C 1-6 alkyl, and —C(O)R 17 ;

R 1 is —OR 7 and R 2 is taken together with R 7 to form —CR 18 R 19 —; or

R 1 is —NR 8 R 9 and R 2 is taken together with R 8 to form —C(O)—.

4. The compound of claim 1 , where R 1 is —OR 7 , and R 7 is selected from H, —C 1-8 alkyl, —C 1-6 alkylene-OC(O)R 10 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl, and

R 10 is —O—C 3-7 cycloalkyl; and R 32 is —CH 3 .

5. The compound of claim 1 , where R 1 is —NR 8 R 9 , where R 8 is H and R 9 is H.

6. The compound of claim 1 , where R 2 is H.

7. The compound of claim 1 , where a is 0; or a is 1 and R 5 is 3-chloro.

8. The compound of claim 1 , where b is 0; or b is 1 and R 6 is 3′-chloro, 3′-methyl, or 2′-methoxy; or b is 2 and R 6 is 2′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy.

9. The compound of claim 1 , where the methylene linker on the biphenyl is substituted with 2 methyl groups.

10. The compound of claim 1 , where R 1 is —OR 7 ; R 7 is selected from H, —C 1-8 alkyl, —C 1-6 alkylene-OC(O)R 10 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl, and

R 10 is —O—C 3-7 cycloalkyl, R 32 is —CH 3 , R 8 is H; R 9 is H;

R 2 is H;

X is selected from pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and pyridyltriazole;

R 3 is absent or is selected from H; halo; —C 0-5 alkylene-OH; —NH 2 ; —C 1-6 alkyl; —CF 3 ; —C 3-7 cycloalkyl; —C 0-2 alkylene-O—C 1-6 alkyl; —C(O)R 20 ; —C 0-1 alkylene-COOR 21 ; —C(O)NR 22 R 23 ; —NHC(O)R 24 ; ═O; —C(CH 3 )═N(OH); phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF 3 , —OCH 3 , —NHC(O)CH 3 , and phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl substituted with methyl; thiophenyl substituted with methyl or halo; furanyl; and —CH 2 -morpholinyl;

R 4 is absent or is selected from H; —OH; —C 1-6 alkyl; —C 1-2 alkylene-COOR 35 ; —CH 2 OC(O)CH(R 36 )NH 2 ; —CH 2 CH(OH)CH 2 OH; pyridinyl; phenyl optionally substituted with one halo group; and benzyl optionally substituted with one or more groups selected from halo, —COOH, —OCH 3 , —OCF 3 , and —SCF 3 ;

or R 3 and R 4 are taken together to form -phenylene-O—(CH 2 ) 1-3 -or -phenylene-O—CH 2 —CHOH—CH 2 —;

a is 0; or a is 1 and R 5 is 3-chloro;

b is 0; or b is 1 and R 6 is 3′-chloro, 3′-methyl, or 2′-methoxy; or b is 2 and R 6 is 2′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy;

R 20 is —C 1-6 alkyl;

R 21 is selected from H and —C 1-6 alkyl;

R 22 is selected from H and —C 1-6 alkyl; and R 23 is selected from H, —C 1-6 alkyl, —CH 2 COOH, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 N(CH 3 ) 2 , —C 3-7 cycloalkyl, and —(CH 2 ) 2 -imidazolyl; or R 22 and R 23 are taken together to form azetidine, pyrrolidine, piperidine or morpholine, all optionally substituted with —OH or —CONH 2 ;

R 24 is selected from —C 1-6 alkyl; —O—C 1-6 alkyl; —CH 2 —O—C 1-6 alkyl; phenyl substituted with halo or —OCH 3 ; and pyridinyl;

R 35 is H;

R 36 is —CH(CH 3 ) 2 ; and

the methylene linker on the biphenyl is optionally substituted with 2 methyl groups.

11. The compound of claim 1 , where

R 1 is —OR 7 ;

R 2 is H;

X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole;

R 3 is selected from H; halo; —C 0-5 alkylene-OH; —C 1-6 alkyl; —CF 3 ; —C 3-7 cycloalkyl; —C 0-2 alkylene-O—C 1-6 alkyl; —C(O)R 20 ; —C 0-1 alkylene-COOR 21 ; —C(O)NR 22 R 23 ; —NHC(O)R 24 ; ═O; —C(CH 3 )═N(OH); phenyl optionally substituted with one or two groups independently selected from halo, —OH, and —OCH 3 ; pyridinyl; pyrazinyl; and thiophenyl substituted with methyl or halo;

R 4 is selected from H; —OH; —C 1-6 alkyl; —C 1-2 alkylene-COOR 35 ; —CH 2 CH(OH)CH 2 OH; pyridinyl; and phenyl optionally substituted with one halo group; or R 3 and R 4 are taken together to form -phenylene-O—(CH 2 ) 1-3 —;

a is 0; or a is 1 and R 5 is 3-chloro;

b is 0; or b is 1 and R 6 is 3′-chloro, 3′-methyl, or 2′-methoxy; or b is 2 and R 6 is 2′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy;

R 20 is —C 1-6 alkyl;

R 21 is H;

R 22 is selected from H and —C 1-6 alkyl; and R 23 is selected from —C 1-6 alkyl, —(CH 2 ) 2 OCH 3 , and —C 3-7 cycloalkyl; or R 22 and R 23 are taken together to form azetidine, pyrrolidine, or piperidine, all optionally substituted with —OH or —CONH 2 ;

R 24 is phenyl substituted with halo or —OCH 3 ;

R 35 is H; and

the methylene linker on the biphenyl is optionally substituted with 2 methyl groups.