Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-10005740-B2
Application number	US-201715696713-A
Country	US
Kind code	B2
Filing date	Sep 6, 2017
Priority date	Jan 30, 2014
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

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

where R 1 -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 process for preparing a compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
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 2 is —C 0-3 alkylene-NR 22 R 23 ; R 22 is H or —C 1-6 alkyl R 23 is H, —C 1-6 alkyl, —C 1-6 alkyl substituted with 1 to 6 fluoro atoms, —SO 2 —C 1-6 alkyl, —CH 2 OC(O)—C 1-6 alkyl, —C 2-4 alkylene-OH, —C 2-4 alkylene-O—CH 3 , or cyclopropyl optionally substituted with one or two R 31 groups; or R 22 and R 23 are taken together to form —(CH 2 ) 2 —O—(CH 2 ) 2 —, a 2-oxa-6-aza-spiro[3.3]heptane ring, or an azetidine ring optionally substituted with one or two R 31 groups; and each R 31 is independently halo, —C 1-6 alkyl, —C 0-2 alkylene-OH, —C 0-2 alkylene-OC 1-6 alkyl, —CN, or —CONH 2 ;
R 3 , R 4 and R 5 are independently H or halo; and
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, dihydro-[1,2,4]triazol-3-one, [1,2,4]triazolo[1,5-α]pyridine, triazole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, pyridine, oxadiazole, and pyrimidine; wherein 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 , —CF 3 , and phenyl; 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 , pyrazine, and phenyl substituted with methyl or halo;

comprising the step of coupling a compound of formula 1 with a compound of formula 2:

to produce a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein P 1 is H or an amino-protecting group selected from the group consisting of t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl; and wherein the process further comprises deprotecting the compound of formula 1 when P 1 is an amino protecting group.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• C07D261/18

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07D213/81

  Amides; Imides · CPC title

• C07D263/34

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D231/14

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D249/04 Primary

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title