Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9487514-B2
Application number	US-201414460567-A
Country	US
Kind code	B2
Filing date	Aug 15, 2014
Priority date	Feb 17, 2011
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

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

where R 1 , R 2a , R 2b , R 3 —R 6 , a, b, Z, and X 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 such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

First claim

What is claimed is:

1. A compound selected from the group consisting of:

or a salt thereof; where
R 1 is selected from the group consisting of —OR 7 and —NR 8 R 9 ;
R 1P is selected from the group consisting of —O—P 3 , —NHP 2 , and —NH(O—P 4 );
R 2a is selected from the group consisting of —OH, —OP(O)(OH) 2 , and —OC(O)CH(R 37 )NH 2 , and R 2b is —CH 3 ; or R 2a and R 2b are taken together to form —CH 2 —CH 2 —; or R 2a is taken together with R 7 to form —OCR 18 R 19 — or is taken together with R 8 to form —OC(O)—;
Z is selected from the group consisting of —CH— and —N—;
X is a —C 1-9 heteroaryl;
R 3 is absent or is selected from the group consisting of H; halo; —C 0-5 alkylene-OH; —NH 2 ; —C 1-6 alkyl; —CF 3 ; —C 3-7 cycloalkyl; —C 0-2 alkylene-O—C 1-6 alkyl; —C(O)R 20 ; —C 0-1 alkylene-COOR 21 ; —C(O)NR 22 R 23 ; —NHC(O)R 24 ;═O; —NO 2 ; —C(CH 3 )═N(OH); phenyl optionally substituted with one or two groups independently selected from the group consisting of halo, —OH, —CF 3 , —OCH 3 , —NHC(O)CH 3 , and phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl optionally substituted with methyl; thiophenyl optionally substituted with methyl or halo; furanyl; and —CH 2 -morpholinyl; and R 3 , when present, is attached to a carbon atom;
R 3P is selected from the group consisting of —C 0-5 alkylene-O—P 4 , —C 0-1 alkylene-COO—P 3 , and phenyl substituted with —O—P 4 ;
R 4 is absent or is selected from the group consisting of H; —OH; —C 1-6 alkyl; —C 1-2 alkylene-COOR 35 ; —CH 2 OC(O)CH(R 36 )NH 2 ; —OCH 2 OC(O)CH(R 36 )NH 2 ; —OCH 2 OC(O)CH 3 ;
—CH 2 OP(O)(OH) 2 ; —CH 2 CH(OH)CH 2 OH; —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl; pyridinyl; and phenyl or benzyl optionally substituted with one or more groups selected from the group consisting of halo, —COOR 35 , —OCH 3 , —OCF 3 , and —SCF 3 ; and R 4 , when present, is attached to a carbon or nitrogen atom;
R 4P is selected from the group consisting of —O—P 4 ; —C 1-2 alkylene-COO—P 3 ; and phenyl or benzyl substituted with —COO—P 3 ;
or R 3 and R 4 are taken together to form -phenylene-O—(CH 2 ) 1-3 - or -phenylene-O—CH 2 —CHOH—CH 2 —;
a is 0 or 1; R 5 is selected from the group consisting of halo, —CH 3 , —CF 3 , and —CN;
b is 0 or an integer from 1 to 3; each R 6 is independently selected from the group consisting of halo, —OH, —CH 3 , —OCH 3 , and —CF 3 ;
R 7 is selected from the group consisting of H; —C 1-8 alkyl; —C 1-3 alkylene-C 6-10 aryl; —C 1-3 alkylene-C 1-9 heteroaryl; —C 3-7 cycloalkyl; —[(CH 2 ) 2 O] 1-3 CH 3 ;—C 1-6 alkylene-OC(O)R 10 ; —C 1-6 alkylene-NR 12 R 13 ; —C 1-6 alkylene-C(O)R 31 ; —C 0-6 alkylenemorpholinyl; —C 1-6 alkylene-SO 2 —C 1-6 alkyl;

R 10 is selected from the group consisting of —C 1-6 alkyl, —O—C 1-6 alkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, phenyl, —O-phenyl, —NR 12 R 13 , —CH[CH(CH 3 ) 2 ]—NH 2 , —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl, and —CH(NH 2 )CH 2 COOCH 3 ; and R 12 and R 13 are independently selected from the group consisting of H, —C 1-6 alkyl, and benzyl, or R 12 and R 13 are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 31 is selected from the group consisting of —O—C 1-6 alkyl, —O-benzyl, and —NR 12 R 13; and R 32 is —C 1-6 alkyl or —C 0-6 alkylene-C 6-10 aryl;
R 8 is selected from the group consisting of H, —OH, —OC(O)R 14 , —CH 2 COOH, —O-benzyl, pyridyl, and —OC(S)NR 15 R 16 ; R 14 is selected from the group consisting of H, —C 1-6 alkyl, —C 6-10 aryl, —OCH 2 —C 6-10 aryl, —CH 2 O—C 6-10 aryl, and —NR 15 R 16 ; and R 15 and R 16 are independently selected from the group consisting of H and —C 1-4 alkyl;
R 9 is selected from the group consisting of H, —C 1-6 alkyl, and —C(O)R 17 ; and R 17 is selected from the group consisting of H,—C 1-6 alkyl, —C 3-7 cycloalkyl, —C 6-10 aryl, and —C 1-9 heteroaryl;
R 18 and R 19 are independently selected from the group consisting of H, —C 1-6 alkyl, and —O—C 3-7 cycloalkyl, or R 18 and are taken together to form ═O;
R 20 is selected from the group consisting of H and —C 1-6 alkyl;
R 21 and R 35 are independently selected from the group consisting of H, —C 1-6 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-C 1-9 heteroaryl, —C 3-7 cycloalkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-OC(O)R 25 , —C 1-6 alkylene-NR 27 R 28 , —C 1-6 alkylene-C(O)R 33 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,

R 25 is selected from the group consisting of —C 1-6 alkyl,—O—C 1-6 alkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, phenyl, —O-phenyl, —NR 27 R 28 , —CH[CH(CH 3 ) 2 ]—NH 2 , —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl, and —CH(NH 2 )CH 2 COOCH 3 ; and R 27 and R 28 are independently selected from the group consisting of H, —C 1-6 alkyl, and benzyl, or R 27 and R 28 are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 33 is selected from the group consisting of —O—C 1-6 alkyl, —O-benzyl, and —NR 27 R 28; and R 34 is —C 1-6 alkyl or —C 0-6 alkylene-C 6-10 aryl;
R 22 and R 23 are independently selected from the group consisting of H, —C 1-6 alkyl, —CH 2 COOH, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 SO 2 NH 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —C 0-1 alkylene-C 3-7 cycloalkyl, and —(CH 2 ) 2 -imidazolyl; or R 22 and R 23 are taken together to form a saturated or partially unsaturated —C 3-5 heterocycle optionally substituted with halo, —OH, —COOH, or —CONH 2 ; and optionally containing an oxygen atom in the ring;
R 24 is selected from the group consisting of —C 1-6 alkyl; —C 0-1 alkylene-O—C 1-6 alkyl; phenyl optionally substituted with halo or —OCH 3 ; and —C 1-9 heteroaryl;
R 36 is selected from the group consisting of H, —CH(CH 3 ) 2 , phenyl, and benzyl; and
R 37 is selected from the group consisting of H, —CH(CH 3 ) 2 , phenyl, and benzyl;
where each alkyl group in R 1 , R 3 , and R 4 is optionally substituted with 1 to 8 fluoro atoms; and;
where the methylene linker on the biphenyl is optionally substituted with one or two —C 1-6 alkyl groups or cyclopropyl;
P 2 is an amino-protecting group selected from the group consisting of t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl; P 3 is a carboxy-protecting group selected from the group consisting of methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl; and P 4 is a hydroxyl-protecting group selected from the group consisting of —C 1-6 alkyl, triC 1-6 alkylsilyl, —C 1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl.

2. The compound of claim 1 , where X is selected from the group consisting of pyrazole, imidazole, triazole, benzotriazole, furan, pyrrole, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridazine, pyridine, pyrimidine, pyran, benzimidazole, benzoxazole, benzothiazole, pyridylimidazole, and pyridyltriazole.

3. The compound of claim 2 , wherein X is selected from the group consisting of pyrazole, triazole, benzotriazole, tetrazole, oxazole, isoxazole, pyrimidine, and pyridyltriazole.

4. The compound of claim 1 , where R 1 is selected from the group consisting of —OR 7 and —NR 8 R 9 ; R 7 is H; R 8 is H or —OH; and R 9 is H.

5. The compound of claim 1 , where:
R 1 is —OR 7 ; and R 7 is selected from the group consisting of —C 1-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-C 1-9 heteroaryl, —C 3-7 cycloalk

Assignees

• Fleury Melissa
• Gendron Roland
• Hughes Adam D
• Smith Cameron
• Theravance Biopharma R&D Ip Llc

Inventors

• Fleury Melissa
• Gendron Roland
• Hughes Adam D
• Smith Cameron

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title