Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9688692-B2
Application number	US-201615173870-A
Country	US
Kind code	B2
Filing date	Jun 6, 2016
Priority date	Dec 15, 2010
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

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

where R 1 -R 6 , a, b, 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 formula:

or a salt thereof;
where
R 1 is selected from —OR 7 and —NR 8 R 9 ;
R 2 is H or —P(O)(OH) 2 or R 2 is taken together with R 7 to form —CR 18 R 19 — or is taken together with R 8 to form —C(O)—;
X is a —C 1-9 heteroaryl;
R 3 is absent or is selected from 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 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 4 is absent or is selected from 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 halo, —COOR 35 , —OCH 3 —OCF 3 , and —SCF 3 ; and R 4 , when present, is attached to a carbon or nitrogen atom;
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 halo, —CH 3 , —CF 3 , and —CN;
b is 0 or an integer from 1 to 3; each R 6 is independently selected from halo, —OH, —CH 3 , —OCH 3 , and —CF 3 ;
R 7 is selected from 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 —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 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 —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 H, —OH, —OC(O)R 14 , —CH 2 COOH, —O-benzyl, -pyridyl, and —OC(S)NR 15 R 16 ; R 14 is selected from 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 H and —C 1-4 alkyl;
R 9 is selected from H, —C 1-6 alkyl, and —C(O)—R 17 ; and R 17 is selected from 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 H, —C 1-6 alkyl, and —O—C 3-7 cycloalkyl, or R 18 and R 19 are taken together to form ═O;
R 20 is selected from H and —C 1-6 alkyl;
R 21 and R 35 are independently selected from 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 —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 ; R 27 and R 28 are independently selected from 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 —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 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 —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; and
R 36 is selected from 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;
where the methylene linker on the biphenyl is optionally substituted with one or two —C 1-6 alkyl groups or cyclopropyl;
R 1P is selected from —O—P 3 , —NHP 2 , and —NH(O—P 4 );
R 3P is selected from —C 0-5 alkylene-O—P 4 , —C 0-1 alkylene-COO—P 3 , and phenyl substituted with —O—P 4 ;
R 4P is selected from —O—P 4 ; —C 1-2 alkylene-COO—P 3 ; and phenyl or benzyl substituted with —COO—P 3 ;
P 2 is an amino-protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl;
P 3 is a carboxy-protecting group selected from methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl; and
P 4 is a hydroxyl-protecting group selected from —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 R 1 is selected from —OR 7 and —NR 8 R 9 , R 7 is H, R 8 is H or —OH, and R 9 is H.

3. The compound of claim 1 , where:
R 1 is —OR 7 ; and R 7 is selected from —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,

 or
R 1 is —NR 8 R 9 ; R 8 is selected from —OC(O)R 14 , —CH 2 COOH, —O-benzyl, pyridyl, and —OC(S)NR 15 R 16 ; and R 9 is H; or
R 1 is —NR 8 R 9 ; R 8 is selected from —OC(O)R 14 , —CH 2 COOH, —O-benzyl, pyridyl, and —OC(S)NR 15 R 16 ; and R 9 is —C 1-6 alkyl or —C(O)R 17 ;
R 1 is —NR 8 R 9 ; R 8 is selected from H or —OH; and R 9 is selected from —C 1-6 alkyl, and —C(O)R 17 ;
R 1 is —OR 7 and R 2 is taken together with R 7 to form —CR 18 R 19 —; or
R 1 is —NR 8 R 9 and R 2 is taken together with R 8 to form —C(O)—.

4. The compound of claim 1 , where R 1 is —OR 7 , and R 7 is selected from H, —C 1-8 alkyl, —C 1-6 alkylene-OC(O)R 10 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl, and

R 10 is —O—C 3-7 cycloalkyl; and R 32 is —CH 3 .

5. The compound of claim 1 , where R 1 is —NR 8 R 9 , where R 8 is H and R 9 is H.

6. The compound of claim 1 , where R 2 is H.

7. The compound of claim 1 , where a is 0; or a is 1 and R 5 is 3-chloro.

8. The compound of claim 1 , where b is 0; or b is 1 and R 6 is 3′-chloro, 3′-methyl, or 2′-methoxy; or b is 2 and R 6 is 2′-flu

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Gendron Roland
• Fleury Melissa
• Hughes Adam D

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title