3,4-substituted piperidine derivatives as renin inhibitors
The present invention relates to 3,4-substituted piperidinyl-based renin inhibitor compounds bearing at 4-position oxopyridine and having the formula (I). The invention further relates to pharmaceutical compositions containing said compounds, as well as their use in treating cardiovascular events and renal insufficiency.
1. A compound of formula I, or a pharmaceutically acceptable salt thereof, having formula (I)
wherein:
R 1 is selected from the group consisting of: C 1 -C 6 -alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl and C 2 -C 6 alkynyl, wherein each of the foregoing is optionally substituted with 1-3 halogens and/or C 1 -C 5 alkoxy;
R 2 and R 3 are independently selected from the group consisting of: hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkenyl, C 3 -C 8 cycloalkenyl, C 2 -C 5 alkynyl, cyano, C 1 -C 5 alkoxy, aryl and hetetoaryl,
wherein said heteroaryl contains from 1 to 3 heteroatoms, independently selected from the group consisting of: N, O and S, wherein each N is optionally in the form of an oxide and each S is optionally in the form of an oxide selected from the group consisting of S(═O) and S(═O) 2 ,
wherein said aryl and heteroaryl are optionally substituted with 1-4 halogens,
wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and alkoxy are optionally substituted with 1-3 substituents, each of which is independently selected from the group consisting of: halogen, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, cyano and C 1 -C 5 alkoxy, wherein each of the foregoing alkyl, alkenyl and alkoxy substituents is optionally substituted with 1-3 halogens;
W is cyclopropyl, unsubstituted or mono-, di-, tri-, tetra- or penta-substituted with fluorine,
X is H;
Z is C 1 -C 2 alkylene optionally substituted with 1-2 substituents, independently selected from the group consisting of: halogen, C 1 -C 3 alkyl and C 3 cycloalkyl, wherein the foregoing alkyl and cycloalkyl substituents are optionally substituted with 1-3 halogens;
n1 is 0 or 1;
Y is phenyl, which is optionally mono-, di-, tri-, tetra-, or penta-substituted, each substituent of which is independently selected from the group consisting of:
(1) halogen,
(2) —OH,
(3) —NH(R 6 ),
(4) oxo,
(5) —C(═O)—R 6 ,
(6) —OC(═O)—R 6 ,
(7) C 1 -C 5 alkyl optionally substituted with 1-3 halogens,
(8) C 3 -C 8 cycloalkyl optionally substituted with 1-3 halogens,
(9) C 2 -C 5 alkenyl optionally substituted with 1-3 halogens,
(10) C 3 -C 8 cycloalkenyl optionally substituted with 1-3 halogens,
(11) C 2 -C 5 alkynyl optionally substituted with 1-3 halogens,
(12) C 1 -C 5 alkoxy optionally substituted with 1-3 halogens,
(13) cyano
(14) C 1 -C 5 -cyano optionally substituted with 1-3 halogens,
(15) —OCF 3 ,
(16) —C(R 7 ) 3 ,
(17) —(C 1 -C 5 alkylene)-OR 8 optionally substituted with 1-3 halogens,
(18) —N(R 6 )—(C 1 -C 5 alkylene)-OR 8 optionally substituted with 1-3 halogens,
19) —O—(C 1 -C 5 alkylene)-OR 8 optionally substituted with 1-3 halogens,
(20) —S—(C 1 -C 5 alkylene)-OR 8 optionally substituted with 1-3 halogens,
(21) —S(═O)—(C 1 -C 5 alkylene)-OR 8 optionally substituted with 1-3 halogens,
(22) —S(═O) 2 —(C 1 -C 5 alkylene)-OR 8 optionally substituted with 1-3 halogens,
(23) —(C 1 -C 5 alkylene)-N(R 6 )—C(═O)—(C 1 -C 5 alkylene)-R 8 optionally substituted with 1-3 halogens,
(24) —(C 1 -C 5 alkylene)-N(R 6 )—C(═O)—OR 8 optionally substituted with 1-3 halogens,
(25) —(C 1 -C 5 alkylene)-N(R 6 )(R 8 ) optionally substituted with 1-3 halogens,
(26) —O—(C 1 -C 5 alkylene)-C(R 6 ) 2 —C(═O)OR 8 optionally substituted with 1-3 halogens,
(27) —(C 1 -C 5 alkylene)-C(R 6 ) 2 —C(═O)OR 8 optionally substituted with 1-3 halogens,
(28) —O—(C 1 -C 5 alkylene)-morpholine optionally substituted with 1-3 halogens,
(29) —OC(═O)-morpholine,
(30) —SR 8 ,
(31) —S(═O)—R 8 ,
(32) —S(═O) 2 —R 8
(33) —N(R 6 )(R 8 ),
(34) —(C 1 -C 5 alkylene)-C(R 6 ) 2 —(R 8 ) optionally substituted with 1-3 halogens,
(35) —(R 9 ) 0-1 R 10 ,
(36) C 2 -C 5 alkenyl-OR 8 optionally substituted with 1-3 halogens,
(37) C 2 -C 5 alkynyl-OR 8 optionally-substituted with 1-3 halogens,
(38) —(C 1 -C 5 alkylene)-C(═O)—(C 1 -C 5 alkylene)-R 8 optionally substituted with 1-3 halogens,
(39) —(C 1 -C 5 alkylene)-O—C(═O)—(C 1 -C 5 alkylene)-R 8 optionally substituted with 1-3 halogens,
(40) —(C 1 -C 5 alkylene)-C(═O)—N(R 6 )(R 8 ) optionally substituted with 1-3 halogens,
(41) —(C 1 -C 5 alkylene)-O—C(═O)—N(R 6 )(R 8 ) optionally substituted with 1-3 halogens,
(42) —(C 1 -C 5 alkylene)-SR 8 optionally substituted with 1-3 halogens,
(43) —(C 1 -C 5 alkylene)-S(═O)—R 8 optionally substituted with 1-3 halogens, and
(44) —(C 1 -C 5 alkylene)-S(═O) 2 —R 8 optionally substituted with 1-3 halogens,
wherein R 6 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloakenyl and C 2 -C 6 alkynyl, wherein each of the foregoing alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally substituted with 1-3 halogens,
wherein R 7 is halogen,
wherein R 8 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkenyl and C 2 -C 6 alkynyl, wherein each of the foregoing alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally substituted with 1-3 halogens,
wherein R 9 is selected from the group consisting of: —C(H)(OH)—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—, —OC(═O)O—, C 1 -C 5 alkylene, C 1 -C 5 alkenylene, —N(R 6 )—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 6 )—C(═O)—, —C(═O)—N(R 6 )—, —OC(═O)—N(R 6 )—, —N(R 6 )—C(═O)O—, —N(R 6 )—S(═O) 2 —, —S(═O) 2 —N(R 6 )—, wherein each of the foregoing alkylene and alkenylene substituents is optionally substituted with 1-3 halogens, and wherein R 6 is defined above, and
wherein R 10 is a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring which is optionally mono-, di-, tri-, tetra- or penta-substituted, wherein each substituent is independently selected from the group consisting of: halogen, —OH, —SR 6 , —N(R 6 )(R 8 ), C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 5 alkynyl, C 1 -C 5 alkoxy, cyano and C 1 -C 5 -cyano, wherein said heterocyclic ring contains from 1 to 3 heteroatoms, independently selected from N, O and S, wherein, each N is optionally in the form of an oxide and each S is optionally is in the form of an oxide selected from the group consisting of: S(═O) or S(═O) 2 , and wherein R6 and R8 are defined above.
2. The compound of claim 1 wherein R 1 is —CH 3 or —CH 2 CH 3 .
3. The compound of claim 1 wherein R 2 and R 3 are independently selected from the group consisting of: H, —OCH 2 OCH 3 and —CH 3 .
4. The compound of claim 1 wherein (Z) n1 is —CH 2 — or a bond.
5. The compound of claim 1 wherein:
R 1 is C 1 -C 2 alkyl optionally substituted with 1-3 halogens,
R 2 and R 3 are independently selected from the group consisting of: hydrogen, halogen, C 1 -C 5 alkyl and C 1 -C 5 alkoxy wherein the alkyl and alkoxy are optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen, C 1 -C 5 alkyl optionally substituted with 1-3 halogens and C 1 -C 5 alkoxy optionally substituted with 1-3 halogens,
X is hydrogen,
and
Z is C 1 -C 2 alkylene.
6. The compound of claim 5 having formula (II)
wherein:
A is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1 -C 5 alkyl,
(4) C 1 -C 5 alkoxy, and
(5) —S—(CH 2 ) 0-3 —CH 3 ,
wherein (3) and (4) are optionally substituted with 1-3 halogens,
B is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1 -C 5 alkyl,
(4) C 1 -C 5 alkoxy,
(5) —OH,
(6) —CF 3 ,
(7) —C(═O)—CH 3 ,
(8) —O—(C 1 -C 5 alkylene)-O-cyclopropyl,
(9) —O—(C 1 -C 5 alkylene)-O—(CH 2 ) 0-2 —CH 3 ,
(10) —(C 1 -C 5 alkylene)-O—(CH 2 ) 0-2 —CH 3 ,
(11) —OC(═O)-morpholine,
(12) —O—(C 1 -C 5 alkylene)-morpholine,
(13) —O—(C 1 -C 5 alkylene)-C(CH 3 ) 2 —C(═O)OH.
(14) —O—(C 1 -C 5 alkylene)-C(CH 3 ) 2 —C(═O)OCH 3 ,
(15)
and
(16)
wherein (3), (4), (8), (9), (10), (12), (13), (14), (15) and (16) are optionally substituted with 1-3 halogens,
C is selected from the group consisting of:
(1) hydrogen,
(2) C 1 -C 5 alkyl optionally substituted with 1-3 halogens, and
(3) C 1 -C 5 alkoxy optionally substituted with 1-3 halogens, and
D is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1 -C 5 alkyl,
(4) C 1 -C 5 alkoxy,
(5) C 1 -C 5 -cyano,
(6) C 2 -C 5 alkenylene-O—(C 1-12 ) 0-2 —CH 3 ,
(7) —(C 1 -C 5 alkylene)-N(H)—C(═O)—O—(CH 2 ) 0-2 —CH 3 ,
(8) —(C 1 -C 5 alkylene)-N(H)—C(═O)—(CH 2 ) 0-2 —CH 3 ,
(9) —(C 1 -C 5 alkylene)-O—CHF 2 ,
(10) —(C 1 -C 5 alkylene)-O—(CH 2 ) 0-2 —CH 3 ,
(11) —O—(C 1 -C 5 alkylene)-O—(CH 2 ) 0-2 —CH 3 ,
(12) —(C 1 -C 5 alkylene)-OH,
(13) —S—(C 1 -C 5 alkylene)-OH,
(14) —SCF 3 ,
15) —N(H)—(C 1 -C 5 alkylene)-O—(CH 2 ) 0-2 —CH 3 , and
(16)
wherein F, G and H are independently selected from the group consisting of: hydrogen, halogen and C 1 -C 3 alkyl, and
wherein R 11 is selected from the group consisting of: —CH 2 —, —C(H)(OH)— and —C(═O)—, and
wherein (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13) and (15) are optionally substituted with 1-3 halogens, or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 wherein the compound is selected from the following:
TABLE
Ex. 105
Ex. 107
Ex. 106
Ex. 104
Ex. 103
Ex. 102
Ex. 4
Ex. 101
Ex. 96
Ex. 93
Ex. 90
Ex. 92
Ex. 94
Ex. 89
Ex. 88
Ex. 9
Ex. 16
Ex. 95
Ex. 91
Ex. 87
Ex. 86
Ex. 84
Ex. 85
Ex. 83
Ex. 11
Ex. 40
Ex. 81
Ex. 80
Ex. 98
Ex. 97
Ex. 34
Ex. 33
Ex. 35
Ex. 31
Ex. 30
Ex. 78
Ex. 28
Ex. 27
Ex. 19
Ex. 17
Ex. 15
Ex. 8
Ex. 7
Ex. 10
Ex. 6
Ex. 5
Ex. 32
Ex. 1
Ex. 3
Ex. 12
Ex. 14
and
Ex. 13
8. The compound of claim 7 which is
or a pharmaceutically acceptable salt thereof.
9. A compound which is
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 7 which is
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 7 which is
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 7 which is
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising an effective amount of a compound according to claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method for the treatment of hypertension or pulmonary hypertension, comprising the administration to a patient a pharmaceutically active amount of a compound according to claim 1 .