CETP inhibitors
View Patent ↗Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. In the compounds of Formula 1, A 1 and A2 are each an aromatic ring, a 5-6-membered heterocyclic ring, an aromatic ring fused to a heterocyclic ring, a phenyl ring fused to a heterocyclic ring, or a cycloalkyl ring.
1. A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein
A 1 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl; and
(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;
A 2 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl;
(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds; and
(e) a —C 3 -C 8 cycloalkyl ring optionally having 1-3 double bonds;
wherein A 1 and A 2 are each optionally substituted with 1-5 substituent groups independently selected from R a ;
Each R a is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8 cycloalkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —NR 10 R 11 , —C(═O)NR 10 R 11 , —NR 10 C(═O)OC 1 -C 6 alkyl, —NR 10 C(═O)NR 10 R 11 , —S(O) x C 1 -C 6 alkyl, —S(O) y NR 10 R 11 , —NR 10 S(O) y NR 10 R 11 , halogen, —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds,
wherein for compounds in which R a is selected from the group consisting of a heterocyclic ring, —C 3 -C 8 cycloalkyl, —OC 3 -C 8 cycloalkyl, and —C(═O)C 3 -C 8 cycloalkyl, the heterocyclic ring and —C 3 -C 8 cycloalkyl groups of R a are optionally substituted with 1-5 substituent groups independently selected from halogen, —C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens,
wherein for compounds in which R a is selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —C(═O)C 1 -C 6 alkyl, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —NR 10 C(═O)OC 1 -C 6 alkyl, and —S(O) x C 1 -C 6 alkyl, the alkyl, alkenyl, and alkynyl groups of Ra are optionally substituted with 1-15 halogens and are optionally also substituted with 1-3 substituent groups independently selected from (a) —OH, (b) —CN, (c) —NR 10 R 11 , (d) —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) —OC 1 -C 4 alkyl optionally substituted with 1-9 halogens and optionally also substituted with 1-2 substituent groups independently selected from —OC 1 -C 2 alkyl, (f) —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) —CO 2 H, (h) —C(═O)CH 3 , and (i) —CO 2 C 1 -C 4 alkyl which is optionally substituted with 1-9 halogens;
n is an integer selected from 0 and 1;
p is an integer from 0-4;
x is an integer selected from 0, 1, and 2;
y is an integer selected from 1 and 2;
Z is selected from the group consisting of —S(O) x C 1 -C 6 alkyl, —S(O) 2 NR 17 R 18 , —C(═S)OC 1 -C 6 alkyl, and —C(═O)X, wherein X is selected from the group consisting of H, —C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, —SC 1 -C 6 alkyl, and —NR 10 R 11 ; wherein —C 1 -C 6 alkyl in all instances is optionally substituted with 1-13 halogens and 1-2 substituents independently selected from —OC 1 -C 3 alkyl, —CN, and —NO 2 , wherein —OC 1 -C 3 alkyl is optionally substituted with 1-7 halogens and is optionally also substituted with 1-2—OC 1 -C 2 alkyl;
R 1 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from the group consisting of H, —OH, halogen, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —OC 1 -C 4 alkyl, and —NR 10 R 11 , wherein —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, and —OC 1 -C 4 alkyl are each optionally substituted with 1-9 halogens and are each optionally also substituted with 1-2 groups independently selected from —OH, —C(═O)CH 3 , —OC(═O)CH 3 , —OC 1 -C 2 alkyl, and —OC 1 -C 2 alkylene(OC 1 -C 2 alkyl);
R 10 and R 11 are each independently selected from H, —C 1 -C 5 alkyl, —C(═O)C 1 -C 5 alkyl and —S(O) y C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl in all instances is optionally substituted with 1-11 halogens; and
R 17 and R 18 are each independently selected from the group consisting of H, —C 1 -C 5 alkyl, and —C 3 -C 7 cycloalkyl, wherein —C 1 -C 5 alkyl, and —C 3 -C 7 cycloalkyl are optionally substituted with 1-13 halogens.
2. A compound of claim 1 having Formula Ia, or a pharmaceutically acceptable salt thereof, wherein
A 1 is selected from the group consisting of:
(a) an aromatic ring selected from phenyl and naphthyl;
wherein A 1 is optionally substituted with 1-4 substituent groups independently selected from —C 1 -C 5 alkyl, —OC 1 -C 3 alkyl, —CO 2 C 1 -C 3 alkyl, —CO 2 H, halogen, —NR 10 R 11 , —C(═O)C 1 -C 3 alkyl, —C(═O)H, —C(═O)NR 10 R 11 , —SC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —CN, —NO 2 , —C 3 -C 6 cycloalkyl, and a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds, wherein —C 1 -C 3 alkyl and —C 1 -C 5 alkyl in all occurrences are optionally substituted with 1-6 substituents independently selected from 1-5 halogens and one —OH group; and —C 3 -C 6 cycloalkyl and the 5-6-membered heterocyclic ring are optionally substituted with 1-3 substituents independently selected from halogen and —C 1 -C 3 alkyl; and —C 2 -C 3 alkenyl is optionally substituted with 1-3 halogens;
A 2 is selected from the group consisting of phenyl, naphthyl, and —C 3 -C 6 cycloalkyl, wherein A 2 is optionally substituted with 1-2 substituent groups independently selected from —C 1 -C 4 alkyl, —OC 1 -C 3 alkyl, —C(═O)C 1 -C 3 alkyl, —C(═O)H, —NO 2 , —CN, —S(O) x C 1 -C 3 alkyl, —NHS(O) 2 C 1 -C 3 alkyl, —NR 10 R 11 , —NR 10 C(═O)R 11 , —C 2 -C 3 alkenyl, —C(═O)NR 10 R 11 , halogen, —C 3 -C 6 cycloalkyl, and a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds, wherein C 1 -C 3 alkyl, C 1 -C 4 alkyl, and C 2 -C 3 alkenyl in all instances are optionally substituted with 1-3 halogens, and —C 3 -C 6 cycloalkyl and the 5-6-membered heterocyclic ring are optionally substituted with 1-3 substituents independently selected from halogen and —C 1 -C 3 alkyl;
x is an integer selected from 0, 1, and 2;
n is an integer selected from 0 and 1;
R 1 is selected from the group consisting of H, OH, C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl, wherein C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are each optionally substituted with 1-3 halogens and also are optionally substituted with one —OC 1 -C 2 alkyl;
R 2 and R 3 are each independently selected from the group consisting of H, halogen, —NR 10 R 11 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —C 3 -C 6 cycloalkyl optionally having a double bond, —OC 3 -C 6 cycloalkyl optionally having a double bond, —C(═O)C 1 -C 3 alkyl, —C(═O)C 3 -C 6 cycloalkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 3 alkyl, —C(═O)NR 10 R 11 , —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, and optionally 1-3 double bond, wherein C 1 -C 3 alkyl and —C 2 -C 3 alkenyl in all instances are optionally substituted with 1-5 halogens, and —C 3 -C 6 cycloalkyl and the 5-6-membered heterocyclic ring are in all occurrences optionally substituted with 1-3 substituents independently selected from halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CF 3 , and —OCF 3 ; and
R 10 and R 11 are each independently selected from H and —C 1 -C 3 alkyl.
3. The compound of claim 2 , wherein R 2 and R 3 are each independently selected from the group consisting of H, halogen, —NR 10 R 11 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CN, —NO 2 , and pyridyl, wherein C 1 -C 3 alkyl in all instances is optionally substituted with 1-3 halogens, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 having the formula Ib, or a pharmaceutically acceptable salt thereof:
5. The compound of claim 4 , wherein R 2 is selected from the group consisting of H, halogen, —NR 10 R 11 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CN, —NO 2 , and pyridyl, wherein C 1 -C 3 alkyl in all instances is optionally substituted with 1-3 halogens; and
R 3 is selected from the group consisting of H, halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 , or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4 , wherein A 1 is phenyl; and
A 2 is selected from the group consisting of phenyl, and C 3 -C 6 cycloalkyl;
wherein A1 and A2 are optionally substituted as in claim 4 , or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , wherein
A 2 is selected from phenyl, and cyclohexyl;
wherein A1 and A2 are optionally substituted as in claim 4 , or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 having formula II, or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H, halogen, and C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-3 halogens;
R 2 is selected from the group consisting of H, halogen, —NR 10 R 11 , —OC 1 -C 3 alkyl, C 1 -C 3 alkyl, —CN, —NO 2 , and pyridyl, wherein C 1 -C 3 alkyl in all occurrences is optionally substituted with 1-3 halogens;
R 4 is selected from the group consisting of H, halogen, —C 1 -C 3 alkyl, —OC 1 -C 2 alkyl, —SC 1 -C 2 alkyl and —CN, wherein —C 1 -C 3 alkyl, —SC 1 -C 3 alkyl, and —OC 1 -C 3 alkyl are optionally substituted with 1-3 F;
R 5 and R 6 are independently selected from the group consisting of H, halogen, —CH 3 and —OCH 3 , wherein —CH 3 and —OCH 3 are optionally substituted with 1-3 F;
R 7 is selected from the group consisting of H, —C 1 -C 5 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, halogen, —CN, —CO 2 H, —CO 2 C 1 -C 3 alkyl, —SC 1 -C 3 alkyl, —C(═O)NR 10 R 11 , —C(═O)H, —C(═O)C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and 5-(1,2,4-oxadiazolyl), wherein —C 1 -C 3 alkyl and —C 1 -C 5 alkyl in all occurrences is optionally substituted with 1-6 substituent groups independently selected from 1-5 halogens and one —OH, —C 2 -C 3 alkenyl is optionally substituted with 1-3 halogens, and 1,2,4-oxadiazolyl and C 3 -C 6 cycloalkyl are optionally substituted with 1-2 substituent groups independently selected from halogen and C 1 -C 3 alkyl;
R 8 and R 9 are each independently selected from the group consisting of H, —C 1 -C 3 alkyl, halogen, —S(O) x C 1 -C 3 alkyl, —NR 10 R 11 , —OC 1 -C 3 alkyl, C 2 -C 3 alkenyl, —NO 2 , —CN, —C(O)NR 10 R 11 , —C(═O)H, —NHC(═O)C 1 -C 3 alkyl, —NHS(O) 2 C 1 -C 3 alkyl, CO 2 H, CO 2 C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and pyridyl, wherein C 1 -C 3 alkyl in all occurrences is optionally substituted with 1-3 halogens, C 2 -C 3 alkenyl is optionally substituted with 1-3 halogens, and C 3 -C 6 cycloalkyl and pyridyl are optionally substituted with 1-2 substituent groups independently selected from halogen and C 1 -C 3 alkyl;
R 10 and R 11 are each H or C 1 -C 3 alkyl;
Z is selected from the group consisting of —C(═O)C 1 -C 3 alkyl, —C(═O)OC 1 -C 3 alkyl, —S(O) y C 1 -C 3 alkyl, —C(═O)H, —C(O)NR 10 R 11 , —C(═O)SC 1 -C 3 alkyl, and —C(═S)OC 1 -C 3 alkyl;
n is an integer selected from 0 and 1;
x is an integer selected from 0, 1 and 2; and
y is an integer selected from 0 and 1.
9. A compound of claim 8 , wherein
R 1 is H or CH 3 ;
R 2 is selected from the group consisting of H, —CF 3 , —OCH 3 , —NO 2 , —CN, halogen, —NH 2 and 3-pyridyl;
R 4 is selected from the group consisting of H, halogen, —CH 3 , —C 2 H 5 , —OCH 3 , —OC 2 H 5 , —SCH 3 , and —CN;
R 5 is selected from the group consisting of H and F;
R 6 is selected from the group consisting of H, F, —CH 3 , and —OCH 3 ;
R 7 is selected from the group consisting of H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)CH 3 , —CH═CH 2 , —CN, Cl, F, —CO 2 H, —CO 2 C 1 -C 3 alkyl, —OCH 3 , —SCH 3 , —C(═O)NR 10 R 11 , and 3-methyl-5-(1,2,4-oxadiazolyl), wherein C 1 -C 4 alkyl is optionally substituted with 1-6 substituents which are independently selected from 1-5 F and one —OH;
R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 2 alkyl, which is optionally substituted with 1-3 F; halogen; —CN; —NO 2 ; —S(O) x CH 3 , which is optionally substituted with 1-3F; —OCH 3 , which is optionally substituted with 1-3 F; —CH═CH 2 ; —C(═O)H; —C(═O)NR 10 R 11 ; —CO 2 H; —NR 10 R 11 ; —CO 2 C 1 -C 3 alkyl; —NHC(═O)CH 3 ; —NHS(O) 2 CH 3 ; and 4-pyridyl; and
R 10 and R 11 are each independently selected from H and CH 3 , or a pharmaceutically acceptable salt thereof.
10. A compound of claim 9 , wherein n is 0, or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 , which is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
TABLE 1
Example
Structure
Ex. 6
Ex. 7
Ex. 8
Ex. 9
Ex. 10
Ex. 11
Ex. 12
Ex. 13
Ex. 14
Ex. 19
Ex. 22
Ex. 28
Ex. 29
Ex. 30
Ex. 31
Ex. 32
Ex. 33
Ex. 34
Ex. 35
Ex. 36
Ex. 37
Ex. 38
Ex. 39
Ex. 40
Ex. 41
Ex. 42
Ex. 43
Ex. 44
Ex. 45
Ex. 46
Ex. 48
Ex. 135
Ex. 136
Ex. 137
Ex. 138
Ex. 139
Ex. 140
Ex. 141
Ex. 142
Ex. 143
Ex. 144
Ex. 145
Ex. 146
Ex. 147
Ex. 148
Ex. 149
Ex. 150
TABLE 2
Example
A′
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
82
91
96
97
TABLE 3
EXAMPLE
A 1
R 2
103
OMe
104
OMe
105
F
106
F
107
F
108
H
108a
Cl
109
H
110
Cl
TABLE 4
EXAMPLE
Q
111
112
113
114
115
116
117
118
119
120
121
122
126
128
129
130
TABLE 5
EXAMPLE
Z
131
132
133
12. A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient.
13. A method of raising HDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient.
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of atherosclerosis.
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more active ingredients selected from the group consisting of: (a) PPAR gamma agonists and partial agonists;
(b) biguanides;
(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,
(d) dipeptidyl peptidase IV (DP-IV) inhibitors;
(e) insulin or insulin mimetics;
(f) sulfonylureas;
(g) α-glucosidase inhibitors;
(h) one or more compounds selected from the group consisting of (a) HMG-CoA reductase inhibitors; (b) bile acid sequestrants; (c) niacin, nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof; (d) PPARα agonists; (e) cholesterol absorption inhibitors; (f) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors; (g) phenolic anti-oxidants, such as probucol, and (h) a microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor;
(i) PPARα/γdual agonists;
(j) PPARδ agonists;
(k) antiobesity compounds
(l) ileal bile acid transporter inhibitors;
(m) anti-inflammatory agents;
(n) glucagon receptor antagonists;
(o) GLP-1,
(p) GIP-1, and
(q) GLP-1 analogs.