Neprilysin inhibitors
In one aspect, the invention relates to compounds having the formula: where R 1 -R 6 , a, b, and Z 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 I:
where:
R 1 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 11 R 12 , —C 1-6 alkylene-C(O)R 13 , —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 11 R 12 , —CH(R 15 )—NH 2 , —CH(R 15 )—NHC( O)O—C 1-6 alkyl, and —CH(NH 2 )CH 2 COOCH 3 ; and R 11 and R 12 are independently selected from H, —C 1-6 alkyl, and benzyl; or R 11 and R 12 are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 13 is selected from —O—C 1-6 alkyl, —O-benzyl, and —NR 11 R 12 ; and R 14 is —C 1-6 alkyl or —C 0-6 alkylene-C 6-10 aryl; R 15 is H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl;
R 2 is —CH 2 OR 21 ; and R 3 is —CH 3 ; where R 21 is H , —C(O)—C 1-6 alkyl, —C(O)—CH(R 22 )—NH 2 , —C(O)—CH(R 22 )—NHC(O)O—C 1-6 alkyl, or —P(O)(OR 23 ) 2 ; R 22 is H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl; R 23 is H, —C 1-6 alkyl, or phenyl; or
Z is selected from —CH— and —N—;
R 4 is selected from H, —C 1-8 alkyl, —C 1-3 alkylene-O—C 1-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-O—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 40 , —C 1-6 alkylene-NR 41 R 42 , —C 1-6 alkylene-C(O)R 43 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,
R 40 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 41 R 42 , —CH(R 45 )—NH 2 , —CH(R 45 )—NHC(O)O—C 1-6 alkyl, and —CH(NH 2 )CH 2 COOCH 3 ; and R 41 and R 42 are independently selected from H, —C 1-6 alkyl, and benzyl; or R 41 and R 42 are taken together as —(CH 2 ) 3-6 —,—C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 43 is selected from —O—C 1-6 alkyl, —O—benzyl, and —NR 41 R 42 ; and R 44 is —C 1-6 alkyl or —C 0-6 alkylene-C 6-10 aryl; R 45 is H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl;
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 , —CN, and —CF 3 ;
where each alkyl group in R 1 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 compound of claim 1 , where R 1 is H.
3. The compound of claim 1 , where R 1 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 11 R 12 , —C 1-6 alkylene-C(O)R 13 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,
4. The compound of claim 1 , where R 1 is selected from H, —C 1-8 alkyl, —C 1-6 alkylene-OC(O)R 10 , and
where R 10 is —C 1-6 alkyl, —O—C 1-6 alkyl, or —CH[R 15 ]—NHC(O)O—C 1-6 alkyl; R 1 is —C 1-6 alkyl; R 15 is —CH(CH 3 ) 2 ; and each alkyl group in R 1 is optionally substituted with 1 to 8 fluoro atoms.
5. The compound of claim 4 , where R 1 is selected from H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —(CH 2 ) 6 CH 3 ,—CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)CH 2 CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)—CH[CH(CH 3 ) 2 ]—NHC(O)O—CH 3 , and
where R 14 is —CH 3 .
6. The compound of claim 1 , where R 21 is H.
7. The compound of claim 1 , where R 4 is H.
8. The compound of claim 1 , where R 4 is selected from —C 1-8 alkyl, —C 1-3 alkylene-O—C 1-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene—O—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 40 , —C 1-6 alkylene-NR 41 R 42 , —C 1-6 alkylene-C(O)R 43 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,
9. The compound of claim 1 , where R 4 is selected from H, —C 1-8 alkyl, —C 1-3 alkylene-O—C 1-8 alkyl, —C 1-3 alkylene-O—C 6-10 aryl, —[(CH 2 ) 2 O] 1-3 CH 3 , and
where R 44 is —C 1-6 alkyl; and each alkyl group in R 4 is optionally substituted with 1 to 8 fluoro atoms.
10. The compound of claim 9 , where R 4 is selected from H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —C(CH 3 ) 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —(CH 2 ) 3 —O—CH 2 CH 3 , —(CH 2 ) 2 —O-phenyl, —(CH 2 ) 2 OCH 3 , and
where R 44 is —CH 3 .
11. The compound of claim 1 , where a is 0, or a is 1 and R 5 is halo.
12. The compound of claim 1 , where b is 0, or b is 1 and R 6 is halo, or b is 2 and each R 6 is independently selected from halo and —CH 3 .
13. The compound of claim 1 , where:
a is 0 and b is 0; or
a is 0, b is 1, and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro; or
a is 0, b is 2, and R 6 is 2′-fluoro, 5′-chloro or 2′-methyl, 5′-chloro or 2′,5′-dichloro; or
a is 1, R 5 is 3-chloro, and b is 0; or
a is 1, R 5 is 3-chloro, b is 1, and R 6 is 3′-chloro; or
a is 1, R 5 is 3-chloro, b is 2, and R 6 is 2′-fluoro, 5′-chloro.
14. The compound of claim 6 , where R 1 is H or —C 1-8 alkyl; Z is —CH—; R 4 is H or —C 1-8 alkyl; a is 0; and b is 0, or b is 1 and R 6 is halo.
15. The compound of claim 14 , where R 1 is H or —CH 2 CH 3 ; R 4 is H or —CH 2 CH(CH 3 ) 2 ; and b is 0, or b is 1 and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro.
16. The compound of claim 1 , where R 1 is selected from H, —C 1-8 alkyl, —C 1-6 alkylene-OC(O)R 10 , and
where R 10 is —C 1-6 alkyl, —O—C 1-6 alkyl, or —CH[R 15 ]—NHC(O)O—C 1-6 alkyl; R 14 is —C 1-6 alkyl; R 15 is —CH(CH 3 ) 2 ; and each alkyl group in R 1 is optionally substituted with 1 to 8 fluoro atoms;
R 4 is selected from H, —C 1-8 alkyl, —C 1-3 alkylene-O—C 1-8 alkyl, —C 1-3 alkylene-O—C 6-10 aryl, —[(CH 2 ) 2 O] 1-3 CH 3 , and
where R 44 is —C 1-6 alkyl; and each alkyl group in R 4 is optionally substituted with 1 to 8 fluoro atoms;
a is 0 and b is 0; or a is 0, b is 1, and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro; or a is 0, b is 2, and R 6 is 2′-fluoro, 5′-chloro or 2′-methyl, 5′-chloro or 2′,5′-dichloro; or a is 1, R 5 is 3-chloro, and b is 0; or a is 1, R 5 is 3-chloro, b is 1, and R 6 is 3′-chloro; or a is 1, R 5 is 3-chloro, b is 2, and R 6 is 2′-fluoro, 5′-chloro; and
where the methylene linker on the biphenyl is optionally substituted with two —CH 3 groups.
17. (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-4-(oxalyl-amino)pentanoic acid or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , where Z is —CH—.
19. The compound of claim 1 , where R 4 is —C 1-8 alkyl.
20. The compound of claim 1 , where R 4 is —CH 2 CH 3 .
21. The compound of claim 1 , where a is 0.
22. The compound of claim 1 , where b is 2.
23. The compound of claim 1 , where a is 0; b is 2; and R 6 is 2′-fluoro, 5′-chloro.
24. The compound of claim 16 , where Z is —CH—.
25. The compound of claim 16 , where R 4 is —C 1-8 alkyl.
26. The compound of claim 16 , where R 4 is —CH 2 CH 3 .
27. The compound of claim 16 , where a is 0.
28. The compound of claim 16 , where b is 2.
29. The compound of claim 16 , where a is 0; b is 2; and R 6 is 2′-fluoro, 5′-chloro.
30. A pharmaceutical composition comprising a compound of any one of claims 1 - 5 , 6 - 13 , 14 - 16 and 17 - 29 and a pharmaceutically acceptable carrier.
31. The pharmaceutical composition of claim 30 , wherein the pharmaceutical composition further comprises an AT 1 receptor antagonist.
32. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1 - 5 , 6 - 13 , 14 - 16 and 17 - 29 .