RENIN INHIBITORS
The present invention relates to biaryl piperidine-based renin inhibitor compounds, and their use in treating cardiovascular events and renal insufficiency.
1 - 20 . (canceled)
21 . A compound of Formula III, or a pharmaceutically acceptable salt thereof, having the formula
wherein:
Ar 1 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heteroaryl ring containing 1 to 3 heteroatoms independently selected from O, S and N, wherein the substituents on the substituted aryl ring and substituted heteroaryl ring consist of one, two or three substituents independently selected from the group consisting of:
1) oxo,
2) OH,
3) CN,
4) halogen,
5) NH 2 ,
6) COOH,
7) OCF 2 H,
8) OCF 3 ,
9) CF 3 ,
10) C 1 -C 6 alkyl,
11) OC 1 -C 6 alkyl,
12) C 3 -C 6 cycloalkyl,
13) C 3 -C 6 cycloalkyl,
14) C 2 -C 6 alkenyl,
15) C 1 -C 6 alkoxy,
16) (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl,
17) O(CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl,
18) (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 3 -C 6 cycloalkyl,
19) C(O)NHC 1 -C 6 alkyl,
20) NHC(O)C 1 -C 6 alkyl,
21) S(O) 0-2 C 1 -C 6 alkyl,
22) O(CH 2 ) 1-4 OAr 4 , and
23) (CH 2 ) 1-5 OAr 4 ,
wherein Ar 4 is as described herein and wherein substituents (10)-(21) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) S(O) 0-2 C 1 -C 6 alkyl,
Ar 2 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heteroaryl ring containing 1 to 3 heteroatoms independently selected from O, S and N, wherein the substituents on the substituted aryl ring and substituted heteroaryl ring consist of one, two or three substituents independently selected from the group consisting of:
1) OH,
2) CN,
3) halogen,
4) COOH,
5) OCF 2 H,
6) OCF 3 ,
7) CF 3 ,
8) C 1 -C 6 alkyl,
9) C 3 -C 6 cycloalkyl,
10) C 2 -C 6 alkenyl,
11) C 1 -C 6 alkoxy,
12) C(O)C 1 -C 6 alkyl,
13) NHC(O)C 1 -C 6 alkyl, and
14) S(O) 0-2 C 1 -C 6 alkyl,
15) R 2
16) R 3
wherein substituents (8)-(14) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) S(O) 0-2 C 1 -C 6 alkyl,
wherein R 2 is selected from the group consisting of
a) H,
b) C 1 -C 6 alkyl,
c) C 3 -C 6 cycloalkyl,
d) C 0 -C 3 alkyleneC(O)C 1 -C 6 alkyl,
e) C 0 -C 3 alkyleneC(O)OR 1 , and
f) C 0 -C 3 alkyleneCONHR 1 ,
wherein R 3 is selected from the group consisting of:
1) halogen as long as it is not attached to a N atom directly,
2) hydrogen,
3) CF 3 ,
4) C 1 -C 6 alkyl,
5) C 3 -C 6 cycloalkyl,
6) CH(OH),
7) C(O)C 1 -C 6 alkyl, and
8) CH(OH)C 1 -C 6 alkyl;
unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of: OH, halogen, CF 3 , and C 1 -C 3 alkyl,
Ar 3 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heteroaryl ring containing 1 to 3 heteroatoms independently selected from O, S and N, wherein the substituents on the substituted aryl ring and substituted heteroaryl ring consist of one, two or three substituents independently selected from the group consisting of:
1) OH,
2) CN,
3) halogen,
4) COOH,
5) OCF 2 H,
6) OCF 3 ,
7) CF 3 ,
8) C 1 -C 6 alkyl,
9) C 3 -C 6 cycloalkyl,
10) C 2 -C 6 alkenyl,
11) C 1 -C 6 alkoxy,
12) C 1 -C 3 alkyleneNH 2 ,
13) C 1 -C 3 alkyleneNHC(O)NH 2 ,
14) C 1 -C 3 alkyleneOC 1 -C 6 alkyl,
15) OC 1 -C 3 alkyleneOC 1 -C 6 alkyl,
16) C 1 -C 3 alkyleneNHC(O)C 1 -C 6 alkyl,
17) C 1 -C 3 alkyleneNHC(O)OC 1 -C 6 alkyl,
18) C 1 -C 3 alkyleneNHC(O)NR 1 C 1 -C 6 alkyl,
19) C 1 -C 3 alkyleneNHC(O)C 3 -C 6 cycloalkyl,
20) C 1 -C 3 alkyleneNHC(O)OC 3 -C 6 cycloalkyl,
21) C 1 -C 3 alkyleneNHC(O)NR 1 C 3 -C 6 cycloalkyl,
22) C 1 -C 3 alkyleneNHS(O) 2 C 1 -C 6 alkyl,
23) C 0 -C 3 alkyleneC(O)NR 1 C 1 -C 6 alkyl,
24) C 0 -C 3 alkyleneS(O) 0-2 C 1 -C 6 alkyl,
25) C 1 -C 3 alkyleneNHC(O)Ar 5 ,
26) C 0 -C 3 alkyleneO(CH 2 ) 0-3 Ar 5 ,
27) C 1 -C 3 alkyleneNHC(O)O(CH 2 ) 0-3 Ar 5 , and
28) C 0 -C 3 alkyleneHet,
wherein Het, Ar 5 , and R 1 are as described herein, wherein substituents (8)-(22) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy,
i) C 1 -C 3 alkyleneOC 1 -C 6 alkyl, and
j) S(O) 0-2 C 1 -C 6 alkyl, and
wherein substituents (23)-(26) are unsubstituted or substituted with 1-3 halogens,
Ar 4 is an unsubstituted or substituted 5- or 6-membered aryl ring, or an unsubstituted or substituted 5 or 6-membered heteroaryl ring containing 1 to 2 heteroatoms independently selected from O, S and N, wherein the substituents on the substituted aryl ring or substituted heteroaryl ring consist of one, two or three substituents independently selected from the group consisting of:
1) CN,
2) halogen,
3) OCF 2 H,
4) OCF 3 ,
5) CF 3 ,
6) C 1 -C 6 alkyl,
7) C 3 -C 6 cycloalkyl,
8) C 1 -C 6 alkoxy, and
9) S(O) 0-2 C 1 -C 6 alkyl,
wherein substituents (6)-(9) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) COOH,
c) CN,
d) CF 3 ,
e) C 1 -C 6 alkoxy, and
f) S(O) 0-2 C 1 -C 6 alkyl,
Ar 5 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heteroaryl ring containing 1 to 4 heteroatoms independently selected from O, S and N, wherein the substituents on the substituted aryl ring and substituted heteroaryl ring consist of one, two or three substituents independently selected from the group consisting of:
1) OH,
2) CN,
3) halogen,
4) COOH,
5) OCF 2 H,
6) OCF 3 ,
7) CF 3 ,
8) C 1 -C 6 alkyl,
9) C 3 -C 6 cycloalkyl,
10) C 2 -C 6 alkenyl, and
11) C 1 -C 6 alkoxy,
wherein substituents (8)-(11) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 1 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) S(O) 0-2 C 1 -C 6 alkyl,
R is selected from the group consisting of:
1) hydrogen,
2) halogen,
3) OH,
4) COOH,
5) COOC 1 -C 6 alkyl,
6) CF 3 ,
7) CN,
8) C 1 -C 6 alkyl,
9) C 3 -C 6 cycloalkyl,
10) (CH 2 ) 1-3 OC 1 -C 6 alkyl,
11) OC 1 -C 6 alkyl, and
12) CONHC 1 -C 6 alkyl,
wherein substituents (8)-(12) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) S(O) 0-2 C 1 -C 6 alkyl,
R 1 is selected from the group consisting of:
1) hydrogen,
2) C 1 -C 6 alkyl, and
3) C 3 -C 6 cycloalkyl,
wherein substituents (2)-(3) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 1 -C 6 alkoxy, and
h) S(O) 0-2 C 1 -C 6 alkyl,
W is selected from the group consisting of:
1) hydrogen,
2) CN,
3) COOR 1 ,
4) C 1 -C 6 alkyl, and
5) C 3 -C 6 cycloalkyl;
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substitutents selected from the group consisting of:
a) halogen,
b) OR 1
c) COOR 1 ,
d) CN,
e) CONHR 1 ,
f) CON(R 1 )R 4 ,
g) OC(O)N(R 1 )R 4 ,
h) NHC(O)N(R 1 )R 4
i) NHC(O)R 1 , and
j) NHC(O)Ar 4 ;
wherein R 4 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and Ar 4 ;
X is selected from the group consisting of:
1) hydrogen,
2) OH,
3) CN,
4) halogen,
5) COOH,
6) CF 3 ,
7) COOC 1 -C 6 alkyl,
8) OC 1 -C 6 alkyl,
9) OC(O)NH 2
10) O(CH 2 ) 1-3 Ar 5 , and
11) O(CH 2 ) 1-3 Het,
wherein substituents (7)-(8) and (10)-(11) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) OC 1 -C 6 alkyl, and
h) S(O) 0-2 C 1 -C 6 alkyl,
Het is a 5-7-membered substituted or unsubstituted heterocyclic ring containing 1-4 heteroatoms independently selected from O, N and S; and
Q is absent or selected from the group consisting of:
1) a bond,
2) CH 2 ,
3) CH 2 CH 2 ,
4) CH 2 OCH 2 ,
5) CH 2 S(O) 0-2 CH 2 ,
6) CH 2 NR 2 CH 2 , and
7) CONR 2 CH 2 ,
wherein R 2 is as defined above for Ar 2 .
22 . The compound of claim 21 wherein Ar 1 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heteroaryl ring containing 1-3 N heteroatoms, wherein the substituents on the substituted aryl ring and substituted heteroaryl ring consist of one, two or three substituents independently selected from the group consisting of: oxo, halogen, C 1 -C 6 alkyl, OC 1 -C 6 alkyl, NH 2 , (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl, O(CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl, and (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 3 -C 6 cycloalkyl, wherein the alkyl substituents are unsubstituted or substituted with 1-3 halogen or C 1 -C 6 alkyl substituents, or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 21 wherein Ar 1 is selected from the group consisting of:
unsubstituted or substituted at any carbon atom with one, two or three substituents independently from the group consisting of:
1) oxo,
2) OH,
3) CN,
4) halogen,
5) NH 2 ,
6) COOH,
7) OCF 2 H,
8) OCF 3 ,
9) CF 3 ,
10) C 1 -C 6 alkyl,
11) OC 1 -C 6 alkyl,
12) C 3 -C 6 cycloalkyl,
13) C 3 -C 6 cycloalkyl,
14) C 2 -C 6 alkenyl,
15) C 1 -C 6 alkoxy,
16) (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl,
17) O(CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl,
18) (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 3 -C 6 cycloalkyl,
19) C(O)NHC 1 -C 6 alkyl,
20) NHC(O)C 1 -C 6 alkyl,
21) S(O) 0-2 C 1 -C 6 alkyl,
22) O(CH 2 ) 1-4 OAr 4 , and
23) (CH 2 ) 1-5 OAr 4 ,
wherein Ar 4 is described in claim 21 and wherein substituents (10)-(21) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) S(O) 0-2 C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 21 wherein Ar 1 is selected from the group consisting of:
unsubstituted or substituted at any carbon atom with one, two or three substituents independently selected from the group consisting of: OH, NH 2 , CN, halogen, C 1 -C 6 alkyl, C 3 -C6cycloalkyl, OC 1 -C 6 alkyl, OC 3 -C 6 cycloalkyl, (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl, (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 3 -C 6 cycloalkyl, O(CH 2 ) 1-4 OAr 4 and (CH 2 ) 1-5 OAr 4 ; said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OC 1 -C 6 alkyl, OC 3 -C 6 cycloalkyl, (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl, O(CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 1 -C 6 alkyl, (CH 2 ) 1-3 OC 1 -C 3 alkyleneOC 3 -C 6 cycloalkyl, O(CH 2 ) 1-4 OAr 4 and (CH 2 ) 1-5 OAr 4 substituents unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) S(O) 0-2 C 1 -C 6 alkyl,
wherein Ar 4 is described in claim 21 , or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 21 wherein Ar 1 is selected from the group consisting of:
unsubstituted or substituted at any carbon atom with one, two, three or four substituents independently selected from the group consisting of: halogen, CF 3 and methyl, where Ar 4 is described in claim 21 , or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 21 wherein Ar 1 is selected from the group consisting of:
unsubstituted or substituted at any carbon atom with one, two, three or four substituents independently selected from the group consisting of: halogen, CF 3 and methyl, or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 21 wherein Ar 2 -Ar 3 is selected from the group consisting of:
wherein R 2 , R 3 , and Ar 3 are described in claim 21 , or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 21 wherein Ar 2 -Ar 3 is selected from the group consisting of:
wherein R 2 , R 3 , and Ar 3 are described in claim 21 , or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 21 wherein Ar 2 -Ar 3 is selected from the group consisting of:
wherein Ar 3 is described in claim 21 , wherein R 3 is selected from the group consisting of: hydrogen, halogen, Me, Et, isopropyl, cyclopropyl, CF 3 , CH 3 C(O), CH 3 CH 2 C(O), CH 3 CH(OH) and CH 3 CH 2 CH(OH); said isopropyl, cyclopropyl, CH 3 C(O), CH 3 CH 2 C(O), CH 3 CH(OH) and CH 3 CH 2 CH(OH) unsubstituted or substituted with 1-3 halogens, or a pharmaceutically acceptable salt thereof.
30 . The compound of claim 21 wherein Ar 3 is selected from the group consisting of:
unsubstituted or substituted at any carbon atom with one, two or three substituents independently selected from the group consisting of:
1) OH,
2) CN,
3) halogen,
4) COOH,
5) OCF 2 H,
6) OCF 3 ,
7) CF 3 ,
8) C 1 -C 6 alkyl,
9) C 3 -C 6 cycloalkyl,
10) C 2 -C 6 alkenyl,
11) C 1 -C 6 alkoxy,
12) C 1 -C 3 alkyleneNH 2 ,
13) C 1 -C 3 alkyleneNHC(O)NH 2 ,
14) C 1 -C 3 alkyleneOC 1 -C 6 alkyl,
15) C 1 -C 3 alkyleneNHC(O)C 1 -C 6 alkyl,
16) C 1 -C 3 alkyleneNHC(O)OC 1 -C 6 alkyl,
17) C 1 -C 3 alkyleneNHC(O)NR 1 C 1 -C 6 alkyl,
18) C 1 -C 3 alkyleneNHC(O)C 3 -C 6 cycloalkyl,
19) C 1 -C 3 alkyleneNHC(O)OC 3 -C 6 cycloalkyl,
20) C 1 -C 3 alkyleneNHC(O)NR 1 C 3 -C 6 cycloalkyl,
21) C 1 -C 3 alkyleneNHS(O) 2 C 1 -C 6 alkyl,
22) C 0 -C 3 alkyleneC(O)NR 1 C 1 -C 6 alkyl,
23) C 0 -C 3 alkyleneS(O) 0-2 C 1 -C 6 alkyl,
24) C 1 -C 3 alkyleneNHC(O)Ar 5 ,
25) C 0 -C 3 alkyleneO(CH 2 ) 0-3 Ar 5 ,
26) C 1 -C 3 alkyleneNHC(O)O(CH 2 ) 0-3 Ar 5 , and
27) C 0 -C 3 alkyleneHet,
wherein Het, Ar 5 , and R 1 are described in claim 21 , wherein substituents (8)-(21) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of:
a) OH,
b) halogen,
c) COOH,
d) CN,
e) CF 3 ,
f) C 1 -C 6 alkyl,
g) C 3 -C 6 cycloalkyl,
h) C 1 -C 6 alkoxy, and
i) C 1 -C 3 alkyleneOC 1 -C 6 alkyl, and
j) S(O) 0-2 C 1 -C 6 alkyl,
and substituents (20)-(23) are unsubstituted or substituted with 1-3 halogens, or a pharmaceutically acceptable salt thereof.
31 . The compound of claim 21 wherein Ar 3 is selected from the group consisting of:
unsubstituted or substituted at any carbon atom with 1-2 groups independently selected from the group consisting of: halogen, CF 3 and Me, wherein R and X are independently selected from the group consisting of: H and OH, or a pharmaceutically acceptable salt thereof.
32 . The compound of claim 21 wherein R is selected from the group consisting of:
1) H,
2) halogen,
3) OH,
4) OC 1 -C 6 alkyl,
5) COOC 1 -C 6 alkyl, and
6) CONHC 1 -C 6 alkyl,
wherein 4)-6) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of: OH, halogen, CF 3 , and C 1 -C 3 alkyl, or a pharmaceutically acceptable salt thereof.
33 . The compound of claim 21 wherein R is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.
34 . The compound of claim 21 wherein W is selected from the group consisting of: hydrogen and C 1 -C 6 alkyl, unsubstituted or substituted with 1-3 halogen substitutents, or a pharmaceutically acceptable salt thereof.
35 . The compound of claim 21 wherein X is selected from the group consisting of:
1) H,
2) halogen,
3) OH,
4) OC(O)NH 2 ,
5) OC 1 -C 6 alkyl, and
6) O(CH 2 ) 1-3 Het,
wherein Het is defined in claim 21 and wherein 5)-6) are unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of: OH, halogen, CF 3 , and C 1 -C 3 alkyl, or a pharmaceutically acceptable salt thereof.
36 . A compound from the following table:
Structure 1
Structure 2
Structure 3
Structure 4
Structure 5
Structure 6
Structure 7
Structure 8
Structure 9
Structure 10
Structure 11
Structure 12
Structure 13
Structure 14
Structure 15
Structure 16
Structure 17
Structure 18
Structure 19
Structure 20
Structure 21
Structure 22
Structure 23
Structure 24
Structure 25
Structure 26
Structure 27
Structure 28
Structure 29
Structure 30
Structure 31
Structure 32
Structure 33
Structure 34
Structure 35
Structure 36
Structure 37
Structure 38
Structure 39
Structure 40
Structure 41
Structure 42
Structure 43
Structure 44
Structure 45
Structure 46
Structure 47
Structure 48
Structure 49
Structure 50
Structure 51
Structure 52
Structure 53
Structure 54
Structure 55
Structure 56
Structure 57
Structure 58
Structure 59
Structure 60
Structure 61
Structure 62
Structure 63
Structure 64
Structure 65
Structure 66
Structure 67
Structure 68
Structure 69
Structure 70
Structure 71
Structure 72
Structure 73
Structure 74
Structure 75
Structure 76
Structure 77
Structure 78
Structure 79
Structure 80
Structure 81
Structure 82
Structure 83
Structure 84
Structure 85
Structure 86
Structure 87
Structure 88
Structure 89
Structure 90
Structure 91
Structure 92
Structure 93
Structure 94
Structure 95
Structure 96
Structure 97
Structure 98
Structure 99
Structure 100
Structure 101
Structure 102
Structure 103
Structure 104
Structure 105
Structure 106
Structure 107
Structure 108
Structure 109
Structure 110
Structure 111
Structure 112
Structure 113
Structure 114
Structure 115
Structure 116
Structure 117
Structure 118
Structure 119
Structure 120
Structure 121
Structure 122
Structure 123
Structure 124
Structure 125
Structure 126
Structure 127
Structure 128
Structure 129
Structure 130
Structure 131
Structure 132
or a pharmaceutically acceptable salt thereof.
37 . A compound from the following table:
Structure 54
Structure 55
Structure 59
Structure 76
Structure 80
Structure 89
Structure 93
Structure 94
Structure 95
Structure 96
Structure 107
Structure 112
Structure 113
Structure 114
Structure 121
Structure 122
Structure 126
Structure 129
or a pharmaceutically acceptable salt thereof.
38 . A pharmaceutical composition comprising an effective amount of a compound according to claim 21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
39 . A method for the treatment or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system, comprising the administration to a patient of a pharmaceutically active amount of a compound according to claim 21 , or a pharmaceutically acceptable salt thereof.