Substituted bisphenyl butanoic ester derivatives as nep inhibitors

Patent metadata

Field	Value
Publication number	US-2020246295-A1
Application number	US-202016854355-A
Country	US
Kind code	A1
Filing date	Apr 21, 2020
Priority date	Feb 7, 2018
Publication date	Aug 6, 2020
Grant date	—

Abstract

or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined herein. The disclosure also relates to a method for manufacturing the compounds of the disclosure, and its therapeutic uses. The present disclosure further provides pharmaceutical composition of the compounds of the disclosure and a combination of pharmacologically active agents and a compound of the disclosure.

First claim

What is claimed is:

1 . A method of inhibiting neutral endopeptidase activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of the Formula (I):

wherein:
R 1 is H or (C 1 -C 4 )alkyl;
R 2 is H, (C 1 -C 4 )alkyl, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the alkyl is optionally substituted with one or more R 3 , and wherein the aryl and heteroaryl are optionally substituted with one or more R 4 ;
each R 3 is independently at each occurrence —NH 2 , (C 1 -C 4 )alkylamino, (C 1 -C 4 )dialkylamino, —OH, —SH, —S(C 1 -C 4 )alkyl, —CO 2 H, —CONH 2 , —NHC(NH)NH 2 , (C 6 -C 10 ) aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 5 ;
each R 4 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN; and
each R 5 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN;

or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered together, concomitantly or sequentially with an Angiotensin Receptor Blocker selected from candesartan, losartan, irbesartan, telmisartan, olmesartan, eprosartan, fimasartan, and azilsartan, or a pharmaceutically acceptable salt thereof.

2 . The method according to claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

3 . The method according to claim 1 , wherein R 1 is H, ethyl, or t-butyl.

4 . The method according to claim 1 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with one to two R 3 .

5 . The method according to claim 1 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with —NH 2 .

6 . The method according to claim 1 , wherein R 1 is H, ethyl, or t-butyl, and R 2 is H or (C 4 )alkyl optionally substituted with —NH 2 .

7 . The method according to claim 1 , wherein the compound is selected from:
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-leucine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysine; and tert-butyl (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysinate; ethyl (2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-(4-(((S)-1-ethoxy-4-methyl-1-oxopentan-2-yl)amino)-4-oxobutanamido)-2-methylpentanoate; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-arginine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-histidine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)glycine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-alanine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-valine; (4-(((2S, 4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-phenylalanine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-tryptophan; and (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-isoleucine; or a pharmaceutically acceptable salt thereof.

8 . The method according to claim 1 , wherein the compound is (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-leucine or a pharmaceutically acceptable salt thereof.

9 . The method according to claim 1 , wherein the compound is (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-histidine or a pharmaceutically acceptable salt thereof.

10 . A method of treating a disorder or a disease associated with neutral endopeptidase activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of the Formula (I):

wherein:
R 1 is H or (C 1 -C 4 )alkyl;
R 2 is H, (C 1 -C 4 )alkyl, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the alkyl is optionally substituted with one or more R 3 , and wherein the aryl and heteroaryl are optionally substituted with one or more R 4 ;
each R 3 is independently at each occurrence —NH 2 , (C 1 -C 4 )alkylamino, (C 1 -C 4 )dialkylamino, —OH, —SH, —S(C 1 -C 4 )alkyl, —CO 2 H, —CONH 2 , —NHC(NH)NH 2 , (C 6 -C 10 ) aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 5 ;
each R 4 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN; and
each R 5 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN;

or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered together, concomitantly or sequentially with an Angiotensin Receptor Blocker selected from candesartan, losartan, irbesartan, telmisartan, olmesartan, eprosartan, fimasartan, and azilsartan, or a pharmaceutically acceptable salt thereof.

11 . The method according to claim 10 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

12 . The method according to claim 10 , wherein R 1 is H, ethyl, or t-butyl.

13 . The method according to claim 10 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with one to two R 3 .

14 . The method according to claim 10 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with —NH 2 .

15 . The method according to claim 10 , wherein R 1 is H, ethyl, or t-butyl, and R 2 is H or (C 4 )alkyl optionally substituted with —NH 2 .

16 . The method according to claim 10 , wherein the compound is selected from:
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-leucine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysine; and tert-butyl (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysinate; ethyl (2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-(4-(((S)-1-ethoxy-4-methyl-1-oxopentan-2-yl)amino)-4-oxobutanamido)-2-methylpentanoate; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-arginine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-histidine; (4-(((2S,4R)-1-([1,1′-biphenyl]-4

Assignees

• Novartis Ag

Inventors

• Chai Yongshuai
• Godtfredsen Sven Erik
• Kagan Mark
• Liu Yugang
• Prashad Mahavir
• Wang Zhaoyin
• Zhu Saijie

Classifications

• C07C279/14 Primary

  being further substituted by carboxyl groups · CPC title

• A61P43/00

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title