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;
(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;
(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds and a carbonyl group or —N(O)— group, wherein the point of attachment of A 1 to the attached phenyl ring is a carbon atom; and
(d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from O, N, and S, and optionally 1-2 double bonds, wherein the point of attachment of A 1 to the attached phenyl ring is a carbon atom;
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;
(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds and a carbonyl group or —N(O)— group;
(d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from O, N, and S, and optionally 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 ;
wherein at least one group A 1 or A 2 is a 5-6-membered heterocyclic ring or a benzoheterocyclic ring;
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 R a 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 allcyl 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 allcyl, 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 allcyl 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 allcylene(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;
(b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, and optionally also comprising 1-3 double bonds and a carbonyl group or —N(O)— group, wherein the point of attachment of A 1 to the attached phenyl ring is a carbon atom; and
(c) a bicyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-3 heteroatoms independently selected from O, N, and S, and optionally 1-2 double bonds, wherein the point of attachment of A 1 to the attached phenyl ring is a carbon atom;
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, —C 3 -C 6 cycloalkyl, and a heterocyclic 5-6 membered ring having 1-3 heteroatoms independently selected from O, N, and S, and optionally also comprising 1-3 double bonds and a carbonyl group or —N(O)— group, 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 selected from the group consisting of phenyl, thienyl, furyl, pyridyl, 1-oxidopyridinyl, quinolyl, isoquinolyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, oxazolyl, isoxazolyl, and oxadiazolyl; and
A 2 is selected from the group consisting of phenyl, thienyl, furyl, pyridyl, 1-oxidopyridinyl, quinolyl, isoquinolyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, oxazolyl, isoxazolyl, oxadiazolyl, 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 1 is selected from the group consisting of phenyl, thienyl, furyl, pyridyl, quinolyl, isoquinolyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, oxazolyl, and isoxazolyl; and
A 2 is selected from phenyl, pyridyl, thienyl, 1-oxidopyridinyl, and cyclohexyl;
wherein A1 and A2 are optionally substituted as in claim 4 , or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 , which is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
TABLE 1
Example
Structure
Ex. 47
Ex. 134
TABLE 2
Example
A 1
76
77
78
79
79a
80
81
83
84
85
86
87
88
89
90
92
93
94
95
98
99
100
101
101a
102
TABLE 4
EXAMPLE
Q
123
124
125
127
9. A method of treating atherosclerosis by inhibiting CETP in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient.
10. A method of raising HDL-C by inhibiting CETP in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient.
11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. 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.