US 11,851,443 B2
Neprilysin inhibitors
Roland Gendron, El Verano, CA (US); Melissa Fleury, Brisbane, CA (US); and Adam D. Hughes, Half Moon Bay, CA (US)
Assigned to Theravance Biopharma R&D IP, LLC, South San Francisco, CA (US)
Filed by THERAVANCE BIOPHARMA R&D IP, LLC, South San Francisco, CA (US)
Filed on Jan. 19, 2022, as Appl. No. 17/579,457.
Application 16/410,361 is a division of application No. 15/806,680, filed on Nov. 8, 2017, granted, now 10,336,773, issued on Jul. 2, 2019.
Application 15/173,870 is a division of application No. 14/800,966, filed on Jul. 16, 2015, granted, now 9,388,145, issued on Jul. 12, 2016.
Application 14/050,733 is a division of application No. 13/325,425, filed on Dec. 14, 2011, granted, now 8,586,536, issued on Nov. 19, 2013.
Application 17/579,457 is a continuation of application No. 16/947,214, filed on Jul. 23, 2020, granted, now 11,261,197.
Application 16/947,214 is a continuation of application No. 16/410,361, filed on May 13, 2019, granted, now 10,759,813, issued on Sep. 1, 2020.
Application 15/806,680 is a continuation of application No. 15/599,769, filed on May 19, 2017, granted, now 9,845,332, issued on Dec. 19, 2017.
Application 15/599,769 is a continuation of application No. 15/173,870, filed on Jun. 6, 2016, granted, now 9,688,692, issued on Jun. 27, 2017.
Application 14/800,966 is a continuation of application No. 14/050,733, filed on Oct. 10, 2013, granted, now 9,120,747, issued on Sep. 1, 2015.
Claims priority of provisional application 61/423,180, filed on Dec. 15, 2010.
Prior Publication US 2022/0298173 A1, Sep. 22, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 498/08 (2006.01); C07D 213/81 (2006.01); C07D 231/14 (2006.01); C07D 233/26 (2006.01); C07D 233/90 (2006.01); C07D 237/24 (2006.01); C07D 239/34 (2006.01); C07D 241/24 (2006.01); C07D 249/04 (2006.01); C07D 249/10 (2006.01); C07D 249/18 (2006.01); C07D 257/04 (2006.01); C07D 261/20 (2006.01); C07D 263/34 (2006.01); C07D 271/06 (2006.01); C07D 277/56 (2006.01); C07D 307/68 (2006.01); C07D 333/70 (2006.01); C07D 401/04 (2006.01); C07D 401/06 (2006.01); C07D 403/04 (2006.01); C07D 403/06 (2006.01); C07D 405/12 (2006.01); C07D 409/06 (2006.01); C07D 471/04 (2006.01); C07D 498/04 (2006.01); C07D 261/18 (2006.01); C07D 207/34 (2006.01); C07D 239/36 (2006.01); C07D 413/06 (2006.01); A61K 31/42 (2006.01); A61K 31/422 (2006.01); A61K 31/5377 (2006.01); A61K 45/06 (2006.01); C07D 413/04 (2006.01); C07D 413/12 (2006.01); C07D 213/79 (2006.01); C07D 213/80 (2006.01); C07D 237/04 (2006.01); C07D 249/08 (2006.01); C07D 249/12 (2006.01); C07D 261/12 (2006.01); C07D 263/56 (2006.01); C07D 277/46 (2006.01); C07D 333/40 (2006.01)
CPC C07D 498/08 (2013.01) [A61K 31/42 (2013.01); A61K 31/422 (2013.01); A61K 31/5377 (2013.01); A61K 45/06 (2013.01); C07D 207/34 (2013.01); C07D 213/79 (2013.01); C07D 213/80 (2013.01); C07D 213/81 (2013.01); C07D 231/14 (2013.01); C07D 233/26 (2013.01); C07D 233/90 (2013.01); C07D 237/04 (2013.01); C07D 237/24 (2013.01); C07D 239/34 (2013.01); C07D 239/36 (2013.01); C07D 241/24 (2013.01); C07D 249/04 (2013.01); C07D 249/08 (2013.01); C07D 249/10 (2013.01); C07D 249/12 (2013.01); C07D 249/18 (2013.01); C07D 257/04 (2013.01); C07D 261/12 (2013.01); C07D 261/18 (2013.01); C07D 261/20 (2013.01); C07D 263/34 (2013.01); C07D 263/56 (2013.01); C07D 271/06 (2013.01); C07D 277/46 (2013.01); C07D 277/56 (2013.01); C07D 307/68 (2013.01); C07D 333/40 (2013.01); C07D 333/70 (2013.01); C07D 401/04 (2013.01); C07D 401/06 (2013.01); C07D 403/04 (2013.01); C07D 403/06 (2013.01); C07D 405/12 (2013.01); C07D 409/06 (2013.01); C07D 413/04 (2013.01); C07D 413/06 (2013.01); C07D 413/12 (2013.01); C07D 471/04 (2013.01); C07D 498/04 (2013.01)] 19 Claims
 
1. A method of treating a disease mediated, at least in part by, neprilysin in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from:
(a) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl)amino]pentanoic acid ethyl ester;
(b) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl)amino]pentanoic acid;
(c) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl)amino]pentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
(d) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(3-methoxyisoxazole-5-carbonyl)amino]-pentanoic acid;
(e) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(4-chlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(f) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[3-(2-methoxy-benzoylamino)-isoxazole-5-carbonyl]-amino}-pentanoic acid;
(g) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(2-chlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(h) (2R,4R)-5-Biphenyl-4-yl-4-[(3-cyclohexyl-isoxazole-5-carbonyl)-amino]-2-hydroxy-pentanoic acid;
(i) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(3-fluorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(j) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(2-fluorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(k) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[3-(1-methyl-1H-pyrazol-4-yl)-isoxazole-5-carbonyl]-amino}-pentanoic acid;
(l) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(2,5-dichlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(m) (2R,4R)-5-Biphenyl-4-yl-4-{[3-(3,4-dichlorophenyl)-isoxazole-5-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(n) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[3-(2-methoxy-phenyl)-isoxazole-5-carbonyl]-amino}-pentanoic acid;
(o) 5-((1R,3R)-1-Biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl)-isoxazole-3-carboxylic acid;
(p) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[5-(2-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-pentanoic acid;
(q) (2R,4R)-5-Biphenyl-4-yl-4-{[5-(2-chlorophenyl)-isoxazole-3-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(r) (2R,4R)-5-Biphenyl-4-yl-4-{[5-(4-chlorophenyl)-isoxazole-3-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(s) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[5-(3-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-pentanoic acid;
(t) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(5-morpholin-4-ylmethyl-isoxazole-3-carbonyl)-amino]-pentanoic acid;
(u) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[5-(4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-pentanoic acid;
(v) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-{[5-(2-hydroxy-phenyl)-isoxazole-3-carbonyl]-amino}-pentanoic acid;
(w) (2R,4R)-5-Biphenyl-4-yl-4-{[5-(2-chlorobenzoylamino)-isoxazole-3-carbonyl]-amino}-2-hydroxy-pentanoic acid;
(x) (2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(2-phenyl-oxazole-5-carbonyl)-amino]-pentanoic acid;
(y) (2R,4R)-4-[(3-Acetyl-isoxazole-5-carbonyl)-amino]-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid;
(z) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-methoxy-isoxazole-5-carbonyl)-amino]-pentanoic acid;
(aa) (2R,4R)-5-(3′-Chloro-biphenyl-4-yl)-4-[(3-chloro-isoxazole-5-carbonyl)-amino]-2-hydroxy-pentanoic acid;
(bb)(2R,4R)-5-(3′-Chloro-biphenyl-4-yl)-2-hydroxy-4-[(3-isopropyl-isoxazole-5-carbonyl)-amino]-pentanoic acid;
(cc) (2R,4R)-5-(3′-Chloro-biphenyl-4-yl)-2-hydroxy-4-[(3-propyl-isoxazole-5-carbonyl)-amino]-pentanoic acid;
(dd)(2R,4R)-5-(3′-Chloro-biphenyl-4-yl)-2-hydroxy-4-[(3-isobutyl-isoxazole-5-carbonyl)-amino]-pentanoic acid;
(ee) (2R,4R)-5-(3′-Chloro-biphenyl-4-yl)-2-hydroxy-4-{[3-(1-hydroxy-1-methyl-ethyl)-isoxazole-5-carbonyl]-amino}-pentanoic acid;
(ff) (2R,4R)-4-[(3-tert-Butyl-isoxazole-5-carbonyl)-amino]-5-(3′-chloro-biphenyl-4-yl)-2-hydroxy-pentanoic acid;
(gg) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-4-{[5-(2-chlorophenyl)-isoxazole-3-carbonyl]-amino}-2-hydroxy-pentanoic acid; and
(hh) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-{[5-(2-hydroxyphenyl)-isoxazole-3-carbonyl]-amino}-pentanoic acid;
or a pharmaceutically acceptable salt thereof.