Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9555041-B2
Application number	US-201514804407-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Dec 15, 2010
Publication date	Jan 31, 2017
Grant date	Jan 31, 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 method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of formula I:

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; pyrazole 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 —; and R 31 is selected from —O—C 1-6 alkyl, —O-benzyl, and —NR 12 R 13 ; 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 )OH, —(CH 2 ) 2 OCH 3 , —(CH 2 )SO 2 NH 2 , —(CH 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; and
where the methylene linker on the biphenyl is optionally substituted with one or two —C 1-6 alkyl groups or cyclopropyl;
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , where X is selected from 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 method of claim 2 , where X is selected from pyrazole, triazole, benzotriazole, tetrazole, oxazole, isoxazole, thiazole, pyridazine, pyrimidine, and pyridyltriazole.

4. The method of claim 1 , where R 1 is selected from —OR 7 and —NR 8 R 9 , where R 7 is H, R 8 is H or —OH, and R 9 is H.

5. The method 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)—.

6. The method of claim 1 , where R 1 is —OR 7 , where R 7 is selected from H, —C l-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 0-6 alkylenemorpholinyl, and

where R 32 is —C 1-6 alkyl; and where each alkyl group is optionally substituted with 1 to 8 fluoro atoms.

7. The method of claim 1 , where R 2 is H.

8. The method of claim 1 , where 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; naphthalen

Assignees

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

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title