Neprilysin inhibitors
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.
1. A compound of formula 1:
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)—;
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 , —O 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—NH 2 , —CH—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 —O 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;
where each alkyl group in R 1 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;
P 1 is H or an amino-protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl;
or a salt thereof.
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 —O 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′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy.
9. The compound of claim 1 , where the methylene linker on the biphenyl is substituted with 2 methyl groups.
10. The compound of claim 1 , where
R 1 is —O 7 ; 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, R 32 is —CH 3 , R 8 is H; R 9 is H;
R 2 is H;
a is 0; or a is 1 and R 5 is 3-chloro;
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′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy; and
the methylene linker on the biphenyl is optionally substituted with 2 methyl groups.
11. The compound of claim 1 , where
R 1 is —O 7 ;
R 2 is H;
a is 0; or a is 1 and R 5 is 3-chloro;
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′-fluoro-5′-chloro, 2′,5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy; and
the methylene linker on the biphenyl is optionally substituted with 2 methyl groups.
12. The compound of claim 11 , wherein R 7 is H.
13. The compound of claim 11 , wherein R 7 is —C 1-8 alkyl.
14. The compound of claim 11 , wherein a is 0.
15. The compound of claim 11 , wherein b is 2 and R 6 is 2′-fluoro-5′-chloro.
16. The compound of claim 11 , wherein P 1 is H.