Neprilysin inhibitors

1. A compound of formula I:

where:

(i) X is

 and

(a) R a and R b are H; R 2 is H; and R 7 is selected from —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 6 CH 3 , and

or R 2 is —C 1-6 alkyl or —C(O)—C 1-6 alkyl, and R 7 is H; or

(b) R a is selected from —CH 3 , —OCH 3 , and Cl and R b is H; or R a is selected from H, —CH 3 , Cl, and F, and R b is Cl; or R a is H and R b is selected from —CH 3 and —CN; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(c) R a is H and R b is F; or R a is F and R b is H; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(ii) X is

 and

(a) R a is Cl and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 4 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and —C 1-4 alkyl; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(b) R a is F and R b is H; R 2 is H; R 4 is —OH; and R 7 is selected from —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(iii) X is

 and

(a) R a is Cl and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O— cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(b) R a is F and R b is H; R 2 is H; and R 7 is selected from —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(iv) X is

(a) R a and R b are H; R 2 is selected from —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 3 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and C 1-4 alkyl; and R 7 is H; or

(b) R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 3 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and —C 1-4 alkyl; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(v) X is

R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 3 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and C 1-4 alkyl; R 4 is selected from H, —C 1-6 alkyl, and phenyl; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(vi) X is

R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 4 is selected from H, —C 1-6 alkyl, and phenyl; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(vii) X is

R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

 or

(viii) X is

R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

where each R c is independently H or —C 1-3 alkyl; each R d is independently H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl; and each R e is independently H or —CH 3 ; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , of the formula IIa or IIb:

3. The compound of claim 2 , where R a and R b are H; and R 2 is H; and R 7 is selected from —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 6 CH 3 , and

or R 2 is —C 1-6 alkyl or —C(O)—C 1-6 alkyl, and R 7 is H.

4. The compound of claim 3 , where R 2 is H and R 7 is selected from —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 6 CH 3 , and

or

R 2 is selected from —CH 3 , —CH 2 CH 3 , —C(O)CH 3 , —C(O)CH(CH 3 ) 2 , and —C(O)CH 2 CH(CH 3 ) 2 ; and

R 7 is H.

5. The compound of claim 2 , where R a is selected from —CH 3 , —OCH 3 , and Cl and R b is H; or R a is selected from H, —CH 3 , Cl, and F, and R b is Cl; or R a is H and R b is selected from —CH 3 and —CN; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

6. The compound of claim 5 , where R a is selected from —CH 3 , —OCH 3 , and Cl and R b is H; or R a is selected from H, —CH 3 , Cl, and F, and R b is Cl; or R a is H and R b is selected from —CH 3 and —CN; R 2 is selected from H, —C 1-6 alkyl, and —(CH 2 ) 2-3 OR e where R e is H or —CH 3 ; and R 7 is H.

7. The compound of claim 2 , where R a is H and R b is F; or R a is F and R b is H; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

8. The compound of claim 1 , of the formula III:

9. The compound of claim 8 , where R a is Cl and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 4 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and —C 1-4 alkyl; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

10. The compound of claim 9 , where R a is F, R b is Cl, R 2 is H, R 4 is —OCH 3 or —OCH 2 CH 3 , and R 7 is H.

11. The compound of claim 8 , where R a is F and R b is H; R 2 is H; R 4 is —OH; and R 7 is selected from —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O— cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

12. The compound of claim 1 , of the formula IVa or IVb:

13. The compound of claim 12 , where R a is Cl and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

14. The compound of claim 13 , where R a is F, R b is Cl, R 2 is H, and R 7 is H.

15. The compound of claim 12 , where R a is F and R b is H; R 2 is H; and R 7 is selected from —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

16. The compound of claim 1 , of the formula V:

17. The compound of claim 16 , where R a and R b are H; R 2 is selected from —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 3 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and —C 1-4 alkyl; and R 7 is H.

18. The compound of claim 17 , where R a and R b are H, R 2 is —CH 3 , R 3 is —OH or —OCH 3 , and R 7 is H.

19. The compound of claim 16 , where R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl, F, —CH 3 , and —CN; or R a is F and R b is Cl; R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ; R 3 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and —C 1-4 alkyl; and R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

20. The compound of claim 19 , where R a is H, R b is Cl, R 2 is H, —CH 3 , —CH 2 CH 3 or —(CH 2 ) 2 OH, R 3 is —OH or —OCH 3 , and R 7 is H; or R a is F, R b is Cl, R 2 is H or —C 1-6 alkyl, R 3 is —OH, —OCH 3 or —C 1-4 alkyl, and R 7 is H.

21. The compound of claim 1 , of the formula VIa or VIb:

22. The compound of claim 21 , where R a is H or F; R b is Cl; R 2 is H or —C 1-6 alkyl; R 3 is —OCH 3 , —OCH 2 CH 3 , or —C 1-4 alkyl; R 4 , if present, is H; and R 7 is H.

23. The compound of claim 1 , of the formula VIIa or VIIb:

24. The compound of claim 23 , where R a is F, R b is Cl, R 2 is H or —C 1-6 alkyl, R 4 , if present, is H, and R 7 is H.

25. The compound of claim 1 , of the formula VIII:

26. The compound of claim 1 , of the formula IX:

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .

28. The pharmaceutical composition of claim 27 , further comprising a therapeutic agent selected from adenosine receptor antagonists, α-adrenergic receptor antagonists, β 1 -adrenergic receptor antagonists, β 2 -adrenergic receptor agonists, dual-acting β-adrenergic receptor antagonist/α 1 -receptor antagonists, advanced glycation end product breakers, aldosterone antagonists, aldosterone synthase inhibitors, aminopeptidase N inhibitors, androgens, angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzyme/neprilysin inhibitors, angiotensin-converting enzyme 2 activators and stimulators, angiotensin-II vaccines, anticoagulants, anti-diabetic agents, antidiarrheal agents, anti-glaucoma agents, anti-lipid agents, antinociceptive agents, anti-thrombotic agents, AT 1 receptor antagonists and dual-acting AT 1 receptor antagonist/neprilysin inhibitors and multifunctional angiotensin receptor blockers, bradykinin receptor antagonists, calcium channel blockers, chymase inhibitors, digoxin, diuretics, dopamine agonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, HMG-CoA reductase inhibitors, estrogens, estrogen receptor agonists and/or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and their analogs, natriuretic peptide clearance receptor antagonists, neprilysin inhibitors, nitric oxide donors, non-steroidal anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterase inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blocker, soluble guanylate cyclase stimulators and activators, tricyclic antidepressants, vasopressin receptor antagonists, and combinations thereof.

29. The pharmaceutical composition of claim 28 , wherein the therapeutic agent is an AT 1 receptor antagonist.

30. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of claim 1 .

31. The compound of claim 16 , wherein R 2 is —C 1-6 alkyl.

32. The compound of claim 16 , wherein R 3 is —OH.

33. The compound of claim 16 , wherein R 7 is —C 1-6 alkyl.

34. The compound of claim 16 , wherein R 7 is H.

35. The compound of claim 16 , wherein R a is F and R b is Cl.

36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 16 .

37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of claim 16 , and an AT 1 receptor antagonist.

38. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of claim 16 .

39. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

40. (2S,4R)-5-(5′-Chloro-2′-fluorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid.

41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 39 .

42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of claim 39 , and an AT 1 receptor antagonist.

43. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of claim 39 .