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USOO8871792B2 (12) United States Patent (10) Patent No.: US 8,871,792 B2 Hughes et al. (45) Date of Patent: Oct. 28, 2014 (54) NEPRILYSIN INHIBITORS C07D 231/14 (2013.01); C07F 9/65312 (2013.01); C07F 9/653 (2013.01) (71) Applicants: Adam D. Hughes, Belmont, CA (US); USPC ........... 514/369; 514/380: 514/381: 514/406; Melissa Fleury, San Francisco, CA (US) 514/378: 514/384: 514/383: 548/266.8; 548/263.2: 548/188: 548/248: 548/243: (72) Inventors: Adam D. Hughes, Belmont, CA (US); 548/374.1: 548/253 Melissa Fleury, San Francisco, CA (US) (ss) Field of classification search (73) Assignee: Theravance Biopharma R&D IP, LLC, None South San Francisco, CA (US) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. U.S. PATENT DOCUMENTS (21) Appl. No.: 13/911,552 4,189.604 A 2/1980 Umezawa et al. 4,206,232 A 6, 1980 Ondetti et al. (22) Filed: Jun. 6, 2013 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2013/033O365A1 Dec. 12, 2013 WO WO 2011/O887.97 A1 T 2011 OTHER PUBLICATIONS Related U.S. Application Data The International Search Report for PCT/US2013/044485 dated (60) Provisional application No. 61/774,148, filed on Mar. Aug. 27, 2013. 7, 2013, provisional application No. 61/657,220, filed U.S. Appl. No. 13/905,338, Mammen et al. on Jun. 8, 2012. (Continued) (51) Int. Cl. CO7D 26L/2 (2006.01) Primary Examiner — Michael Barker CO7D 249/04249/2 (2006.01) Eberle(74) Attorney, ey, Agent, or Firm — Jeffreyy A. Hagenah;Flagenan, Shelley CO7D 26L/08 (2006.01) C07D 277/34 (2006.01) CO7D 23L/2 (2006.01) (57) ABSTRACT C07D 257/04 (2006.01) A6 IK3 L/45 (2006.01) In one aspect, the invention relates to compounds having the A6 IK3I/492 (2006.01) formula X: A6 IK3I/42 (2006.01) A6 IK3I/426 (2006.01) A6 IK3I/4I (2006.01) O X (X) CO7D 413/2 (2006.01) O N A6 IK3I/496 (2006.01) CO7D 26L/8 (2006.01) RN NH A 6LX3/5377 (2006.01) O N CO7D 405/2 (2006.01) O C07D 277/56 (2006.01) R21 A6 IK3I/675 (2006.01) O A6 IK 45/06 (2006.01) Rb CO7D 319/06 (2006.01) CO7D 231/4 (2006.01) C07F 9/653 (2006.01) Ra (52) U.S. Cl. CPC ............ C07D 249/12 (2013.01); C07D 413/12 where R,R,R,R, and Xareas defined in the specification, (2013.01); A61 K3I/4 196 (2013.01); C07D or a pharmaceutically acceptable salt thereof. The com 249/04 (2013.01); C07D 261/18 (2013.01); pounds described herein are prodrugs of compounds having A61 K3I/5377 (2013.01); C07D405/12 neprilysin inhibition activity. In another aspect, the invention (2013.01); C07D 277/56 (2013.01); A6IK relates to pharmaceutical compositions comprising these 31/426 (2013.01); A61 K3I/675 (2013.01); compounds; methods of using these compounds; and pro A61K 45/06 (2013.01); A61 K3I/42 (2013.01); cesses and intermediates for preparing these compounds. A6 IK3I/415 (2013.01); A61 K3I/41 (2013.01); C07D 319/06 (2013.01); A61 K 31/4192 (2013.01); C07D 257/04 (2013.01); 24 Claims, No Drawings US 8,871,792 B2 Page 2 (56) References Cited 2010/0305131 A1 12/2010 Coppola et al. 2010/0305145 A1 12/2010 Coppola et al. U.S. PATENT DOCUMENTS 2011, 0046397 A1 2/2011 Hook et al. 2011/O124695 A1 5, 2011 Iwaki et al. 4,374,829 2, 1983 Harris et al. 2012/O122844 A1 5, 2012 Foo 4.513,009 4, 1985 Roques et al. 2012/O122977 A1 5/2012 Coppola et al. 4,722,810 2, 1988 Delaney et al. 2012. O157383 A1 6/2012 Gendron et al. 4,906,615 3, 1990 Berger et al. 2012. O157386 A1 6, 2012 Smith et al. 4,929,641 5, 1990 Haslanger et al. 2012fO213806 A1 8/2012 Fleury et al. 4,939,261 7, 1990 Ksander 2012fO213807 A1 8/2012 Fleury et al. 4,975.444 12, 1990 Danilewicz et al. 2012/0308587 A1 12/2012 Gendron et al. 5,021,430 6, 1991 Ksander 2012/0308588 Al 12/2012 Fleury et al. 5,030,654 7, 1991 Barnish et al. 2012/0309724 A1 12/2012 Fleury et al. 5,155,100 10, 1992 Erion et al. 2013,0109639 A1 5/2013 Hughes et al. 5,208,255 5, 1993 Duhamel et al. 5,217,996 6, 1993 Ksander OTHER PUBLICATIONS 5,294,632 3, 1994 Erion et al. 5,508,272 4, 1996 Robl Ksander et al., “Dicarboxylic acid dipeptide neutral endopeptidase 5,599.951 2, 1997 Plaquevent et al. 5,677,297 10, 1997 Waldeck et al. inhibitors”, Journal of Medicinal Chemistry, 38(10): 1689-1700 5,977.075 11, 1999 Ksander et al. (1995). 6,602,866 8, 2003 Flynn et al. Misawa et al., “Structure-based design of dipeptide derivatives for 6,660,756 12, 2003 Challenger et al. the human neutral endopeptidase'. Bioorganic & Medicinal Chem 2010.0113801 A1 5, 2010 Hook et al. istry, 19: 5935-5947 (2011). US 8,871,792 B2 1. NEPRLYSIN INHIBITORS O X (X) CROSS-REFERENCE TO RELATED APPLICATIONS O n RN O N NH This application claims the benefit of U.S. Provisional O Application No. 61/657,220, filed on Jun. 8, 2012 and U.S. R21 Provisional Application No. 61/774,148, filed on Mar. 7, 2013; the entire disclosures of which are incorporated herein 10 Rb by reference. Ra BACKGROUND OF THE INVENTION where: 15 (i) R' is F: R is Cl; X is 1. Field of the Invention The present invention relates to novel compounds which are metabolized in vivo to compounds having activity as neprilysin inhibitors. The invention also relates to pharma ceutical compositions comprising these compounds, pro N cesses and intermediates for preparing these compounds and methods of using these compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension, and ( NO O 25 renal disease. 2. State of the Art Commonly-assigned U.S. Patent Publication No. 2012/ N O 0157386, filed on Dec. 14, 2011 to Smith et al., describes novel compounds that have activity as neprilysin inhibitors, 30 als the disclosure of which is incorporated herein by reference. In - particular, compounds of the genus: 35 40 N O ( NO 45 R’ is H and R7 is selected from CHCH, -CHCH (CH), —CHCF. —(CH2)CF, —CHCFCH. —CHCFCF, —C(CH) (CF), —CH(CH2CH)CF, are described. Depending upon the variables, compounds —CH(CH)CFCF, -(CH), OH, -CH-CH(NH) 50 COOCH, -(CH)OCH, -CHROC(O) Calkyl, within this genus can be referred to as being in the active form - CHROC(O)O Calkyl, -CHROC(O)O-cyclohexyl, or as being a prodrug, which is metabolized in Vivo to gener —Calkylene-N(CH), -CHOC(O)CHR NH, ate the active form of the compound. —CHOC(O)CHR NHC(O)C Calkyl, benzyl, and In spite of these compounds however, there remains a need for compounds and prodrugs within this genus that have 55 different metabolic and cleavage properties. For example, there remains a need for active compounds and/or prodrug compounds having improved oral absorption and for prodrug compounds that undergo rapid cleavage to form the active 60 compound. This invention is directed to that need. SUMMARY OF THE INVENTION 65 or R is selected from C(O) Coalkyl, -C(O)CHR One aspect of the invention relates to a compound of the NH, -C(O)CHR NHC(O)C Calkyl, and -P(O) formula X: (OR), and R is H; and US 8,871,792 B2 7 8 COOCH, -(CH)OCH, -CHROC(O) Calkyl, DETAILED DESCRIPTION OF THE INVENTION —CHROC(O)C) Calkyl, -CHROC(O)C)-cyclohexyl, —Calkylene-N(CH), CHOC(O)CHR NH, When describing the compounds, compositions, methods —CHOC(O)CHR NHC(O)C Calkyl, and and processes of the invention, the following terms have the following meanings unless otherwise indicated. Additionally, as used herein, the singular forms “a” “an and “the' include the corresponding plural forms unless the context of use clearly dictates otherwise. The terms “comprising”, “includ ing.” and "having are intended to be inclusive and mean that 10 there may be additional elements other than the listed ele ments. All numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used herein are to be understood as being modified in all instances by the term “about unless otherwise indicated. Accordingly, the numbers set forth hereinare approximations or R is selected from C(O) Calkyl, -C(O)CHR 15 that may vary depending upon the desired properties sought NH, -C(O)CHR NHC(O)C Calkyl, and -P(O) to be obtained by the present invention. At least, and not as an (OR), R is -OH, and R7 is H; or R is H, R is selected attempt to limit the application of the doctrine of equivalents from —OCHROC(O) Calkyl, OCHOC(O)CHCH to the scope of the claims, each number should at least be (CH), NH –OCHOC(O)CHCH(CH), NHC(O) construed in light of the reported significant digits and by OCH and applying ordinary rounding techniques. The term “alkyl means a monovalent saturated hydrocar bon group which may be linear or branched. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 ? CH3, carbonatoms and include, for example, —Calkyl, meaning A Yo o 25 an alkyl group having from 1 to 6 carbon atoms where the carbon atoms are in any acceptable configuration.
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