Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9839639-B2
Application number	US-201715409976-A
Country	US
Kind code	B2
Filing date	Jan 19, 2017
Priority date	Jan 30, 2014
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

In one aspect, the invention relates to compounds having the formula I:

where R 1 , R 2a , R 2b , and R 3 -R 6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

First claim

What is claimed is:

1. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of a compound of formula I:

where:
R 1 is H, —C 1-8 alkyl, —CH(CH 3 )OC(O)—O-cyclohexyl, —(CH 2 ) 2 -morpholinyl, or —CH 2 -5-methy-[1,3]dioxol-2-one;
R 2a is —C 1-2 alkyl and R 2b is —C 0-2 alkylene-NH 2 , —C(O)NH 2 , —COOH, —CH 2 —O—C 1-6 alkyl, —CN, or pyridine; or R 2a is —CH 2 OH and R 2b is —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —C 1-2 alkylene-OH, —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 —NHC(O)CH 2 , or —CH 2 CH═CH 2 ; or R 2a and R 2b are taken together to form —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, —NH—(CH 2 ) 2 —, —(CH 2 )—NH—(CH 2 ) 2 —, or —(CH 2 )—N[C(O)CH 3 ]—(CH 2 ) 2 —;
R 3 , R 4 and R 5 are independently H or halo;
R 6 is a heterocycle selected from the group consisting of 3H-oxazol-2-one, [1,2,4]oxadiazol-5-one, [1,2,3,5]oxatriazole, [1,2,4]triazolo[1,5-α]pyridine, triazole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, pyridine, oxadiazole, and pyrimidine; the heterocycle is attached at a carbon atom; and each nitrogen atom in the heterocycle is unsubstituted or substituted with an R 60 group selected from the group consisting of —OH, —(CH 2 ) 2 OH, —C 0-2 alkylene-O—C 1-6 alkyl, —C 1-6 alkyl, —CHF 2 , and —CF 3 ; and each carbon atom in the heterocycle is unsubstituted or substituted with an R 61 group independently selected from the group consisting of halo, —OH, —C 1-6 alkyl, —C 0-2 alkylene-O—C 1-6 alkyl, —C(O)CH 3 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , —C 3-6 cycloalkyl, —CF 3 , —CH 2 SO 2 CH 3 , —NH 2 , —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , and phenyl substituted with methyl or halo;
with the proviso that when R 2a is —CH 3 and R 2b is —CH 2 —O—C 1-6 alkyl, then R 6 is not unsubstituted 3H-oxazol-2-one; unsubstituted [1,2,3]triazole; [1,2,3]triazole substituted with an R 60 group selected from the group consisting of —OH, —C 0-2 alkylene-O—C 1-6 alkyl, and —C 1-6 alkyl; [1,2,4]triazole substituted with an R 61 group selected from the group consisting of halo and —OH; pyrazole substituted with an R 60 group that is —C 1-6 alkyl; pyrazole substituted with an R 61 group selected from the group consisting of —OH, —C 1-6 alkyl, —C 0-2 alkylene-O—C 1-6 alkyl, and —C(O)CH 3 ; or isoxazole substituted with an R 61 group selected from the group consisting of —OH, —C 1-6 alkyl, and —C 0-2 alkylene-O—C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , where R 1 of the compound of Formula I is H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , or —(CH 2 ) 5 CH 3 .

3. The method of claim 1 , where R 1 of the compound of Formula I is H or —CH 2 CH 3 .

4. The method of claim 1 , where R 2a of the compound of Formula I is —C 1-2 alkyl and R 2b is —NH 2 , —CH 2 NH 2 , —C(O)NH 2 , —COOH, —CH 2 —O—CH 3 , —CH 2 —O—CH 2 CH 3 , or —CN; or R 2a is —CH 2 OH and R 2b is —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 2 —OH, —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 —NHC(O)CH 3 , or —CH 2 CH═CH 2 ; or R 2a and R 2b are taken together to form —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, —NH—(CH 2 ) 2 —, —(CH 2 )—NH—(CH 2 ) 2 —, or —(CH 2 )—N[C(O)CH 3 ]—(CH 2 ) 2 —.

5. The method of claim 1 , where R 2a of the compound of Formula I is —CH 3 and R 2b is —NH 2 , —CH 2 NH 2 , —C(O)NH 2 , —COOH, —CH 2 —O—CH 3 , —CH 2 —O—CH 2 CH 3 , or —CN; or R 2a is —CH 2 CH 3 and R 2b is —CN; or R 2a is —CH 2 OH and R 2b is —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 2 —OH, —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 —NHC(O)CH 3 , or —CH 2 CH═CH 2 ; or R 2a and R 2b are taken together to form —(CH 2 ) 2 —O—CH 2 —, —(CH 2 )—NH—(CH 2 ) 2 —, or —(CH 2 )—N[C(O)CH 3 ]—(CH 2 ) 2 —.

6. The method of claim 1 , where R 3 of the compound of Formula I is H.

7. The method of claim 1 , where R 4 of the compound of Formula I is F.

8. The method of claim 1 , where R 5 of the compound of Formula I is Cl.

9. The method of claim 1 , where R 3 of the compound of Formula I is H, R 4 is F, and R 5 is Cl; or R 3 and R 4 are H and R 5 is Br or Cl; or R 3 , R 4 , and R 5 are H; or R 3 is Cl, R 4 is F, and R 5 is Cl; or R 3 is H, R 4 is F, and R 5 is H.

10. The method of claim 1 , where R 3 of the compound of Formula I is H, R 4 is F, and R 5 is Cl; or R 3 and R 4 are H and R 5 is Cl.

11. The method of claim 1 , where R 6 of the compound of Formula I is 3H-oxazol-2-one, 4H-[1,2,4]oxadiazol-5-one, [1,2,3,5]oxatriazole, [1,2,4]triazolo[1,5-α]pyridine, [1,2,3]triazole, [1,2,4]triazole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, pyridine, oxadiazole, or pyrimidine.

12. The method of claim 11 , where R 6 is 4H-[1,2,4]oxadiazol-5-one, [1,2,3]triazole, [1,2,4]triazole, pyrazole, oxazole, pyridine, or pyrimidine.

13. The method of claim 1 , where the nitrogen atoms in the heterocycle of the compound of Formula I are unsubstituted.

14. The method of claim 1 , where R 60 of the compound of Formula I is —OH, —(CH 2 ) 2 OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CHF 2 , or —CF 3 .

15. The method of claim 14 , where R 60 is —(CH 2 ) 2 OH, —OCH 3 , —OCH 2 CH 3 , or —CHF 2 .

16. The method of claim 1 , where the carbon atoms in the heterocycle of the compound of Formula I are unsubstituted.

17. The method of claim 1 , where R 61 of the compound of Formula I is chloro, —OH, —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —CH 2 —OCH 3 , —C(O)CH 3 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , cyclopropyl, —CF 3 , —CH 2 SO 2 CH 3 , —NH 2 , —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , or phenyl substituted with methyl or halo.

18. The method of claim 17 , where R 61 is chloro, —CH 3 , —C(O)CH 3 , cyclopropyl, or —CF 3 .

19. The method of claim 1 , where a first carbon atom in the heterocycle is substituted with an R 61 group selected from the group consisting of fluoro, —OH, —CH 3 , —C 0-2 alkylene-O—C 1-6 alkyl, —C(O)CH 3 , —C 3-6 cycloalkyl, —CF 3 , —CH 2 SO 2 CH 3 , —NH 2 , and —CH 2 N(CH 3 ) 2 ; and a second carbon atom in the heterocycle is substituted with an R 61 group selected from the group consisting of halo, —OH, —C 1-6 alkyl, —O—CH 2 CH 3 , —C(O)CH 3 , cyclopropyl, —CF 3 , —CH 2 SO 2 CH 3 , —NH 2 , and —CH 2 N(CH 3 ) 2 .

20. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound formula I:

where:
R 1 is H, —C 1-8 alkyl, —CH(CH 3 )OC(O)—O-cyclohexyl, —(CH 2 ) 2 -morpholinyl, or —CH 2 -5-methyl-[1,3]dioxol-2-one;
R 2a is —C 1-2 alkyl and R 2b is —C 0-2 alkylene-NH 2 , —C(O)NH 2 , —COOH, —CH 2 —O—C 1-6 alkyl, —CN, or pyridine; or R 2a is —CH 2 OH and R 2b is —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —C 1-2 alkylene-OH, —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 —NHC(O)CH 3 , or —CH 2 CH═CH 2 ; or R 2a and R 2b are taken together to form —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, —NH—(CH 2 ) 2 —, —(CH 2 )—NH—(CH 2 ) 2 —, or —(CH 2 )—N[C(O)CH 3 ]—(CH 2 ) 2 —;
R 3 , R 4 and R 5 are independently H or halo;
R 6 is a heterocycle selected from the group consisting of 3H-oxazol-2-one, [1,2,4]oxadiazol-5-one, [1,2,3,5]oxatriazole, [1,2,4]triazolo[1,5-α]pyridine, triazole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, pyridine, oxadiazole, and

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Fleury Melissa
• Beausoliel Anne-Marie
• Hughes Adam D
• Long Daniel D
• Wilton Donna A A

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title