CETP inhibitors derived from benzoxazole arylamides
View Patent ↗Compounds having the structure of Formula I, including pharmaceutically acceptable salts of the compounds, are potent CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. In formula I, A-B is an arylamide moiety.
1. A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein
Q is selected from the group consisting of O, S, and —N(R 2 )—;
A is 1,4-phenylene, wherein A is optionally substituted with 1-3 substituent groups R 1 ;
Each R 1 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, and —OC 1 -C 3 alkyl, wherein each alkyl, alkenyl, and alkynyl substituent is optionally substituted with 1-5 halogens;
Each R 2 is independently selected from the group consisting of H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl, wherein each alkyl, alkenyl, and alkynyl substituent is optionally substituted with 1-5 halogens;
R W is selected from the group consisting of (a) C 1 -C 5 alkyl which is optionally substituted with 1-5 halogens, (b) C 2-5 alkenyl which is optionally substituted with 1-5 halogens; (c) —OC 1 -C 5 alkyl which is optionally substituted with 1-5 halogens, (d) —SC 1 -C 5 alkyl which is optionally substituted with 1-5 halogens, (e) —OC 2-5 alkenyl which is optionally substituted with 1-5 halogens, (f) C 3 -C 6 cycloalkyl, (g) phenyl, (h) a 5-6 membered saturated or partly unsaturated heterocyclic group having 1-3 heteroatoms independently selected from N, S and O, (i) a 5-7 membered heteroaromatic group having 1-3 heteroatoms independently selected from N, S, and O, (j) —C(═O)OC 1-3 alkyl which is optionally substituted with 1-5 halogens, and (k) —C(═O)OH, wherein said C 3 -C 6 cycloalkyl, phenyl, 5-6 membered saturated or partly unsaturated heterocyclic group, and 5-7 membered heteroaromatic group are optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
R Y is selected from the group consisting of halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , —CN, phenyl, and a 6-membered heteroaroaromatic group having 1-2 N, wherein phenyl and the 6-membered heteroaroaromatic group are optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
R X and R Z are each selected from the group consisting of H, halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
B is —C(═O)N(R 3 )(CR 4 R 5 ) x (CR 6 R 7 ) y D 2 ;
R 3 is selected from the group consisting of H and C 1 -C 3 alkyl;
R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, CF 3 , —C(═O)OH, and —C(═O)OC 1 -C 3 alkyl;
R 5 is selected from the group consisting of H, C 1 -C 3 alkyl, and CF 3 ;
R 6 is selected from the group consisting of H, C 1 -C 3 alkyl, CF 3 , —C(═O)OH, and —C(═O)OC 1 -C 3 alkyl;
R 7 is selected from the group consisting of H, C 1 -C 3 alkyl, CF 3 , and phenyl, which is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
x is 0 or 1;
y is 0, 1, or 2;
D 2 is a cyclic group selected from 5-membered saturated and partly unsaturated heterocyclic groups, wherein D 2 comprises one ring member —N(R 8 )—, optionally 1-2 ring members independently selected from —O— and —S—, optionally one carbonyl group, and optionally 1-2 double bonds, wherein D 2 is optionally fused to a phenyl ring or to a C 5 -C 7 Cycloalkyl, wherein D 2 is connected to the right hand side of the structure represented by Formula I through a carbon atom of D 2 , wherein D 2 is optionally substituted with 1-3 substituents independently selected from halogen, —CN, —NO 2 , —N(R 3 ) 2 —, C 1 -C 3 alkyl, CF 3 , —OCH 3 , phenyl, pyridyl, and —OCF 3 , and optionally with 1 group C 1 -C 5 alkylene-phenyl, wherein phenyl and pyridyl in all uses are optionally substituted with 1-3 substituent groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
R 8 is selected from the group consisting of H, C 1 -C 9 alkyl, —C(═O)OC 1 -C 9 alkyl, —C(═O)C 1 -C 9 alkyl, —S(O) 1-2 C 1 -C 9 alkyl, —C(═O)N(R 9 ) 2 , —C 1 -C 3 alkylene-C(═O)OC 1 -C 6 alkyl, —C 1 -C 5 alkylene-OC 1 -C 9 alkyl, and a cyclic group D 4 bonded to the N to which R 8 is connected or to a difunctional linking group L 4 which is bonded to the N to which R 8 is connected, wherein the C 1 -C 9 alkyl and C 1 -C 6 alkyl groups in all uses are optionally substituted with 1-9 halogens;
Wherein D 4 is selected from the group consisting of (a) phenyl, (b) naphthyl, (c) C 3 -C 8 cycloalkyl optionally having 1-2 double bonds, (d) a saturated or partially unsaturated monocyclic or bicyclic 4-10 membered heterocycle having 1-3 heteroatoms independently selected from N, O, and S and optionally one —C(═O)— group, said heterocycle optionally having 1-2 double bonds, (e) a monocyclic or bicyclic 5-12 membered heteroaromatic group having 1-3 heteroatoms independently selected from N, S, and O and optionally having one —C(═O)— group, (f) tetralin, and (g) anthraquinone;
L 4 is selected from the group consisting of —C(═O)—, —C(═O)O—, —S(O) 2 —, —C(═O)N(R 3 )—, —S(O) 2 N(R 3 )—, —C 1 -C 7 alkylene-, —C(═O)C 1 -C 7 alkylene-, —C 2 -C 4 alkenylene-, —C(═O)C 1 -C 7 alkylene-N(R 3 )—, —C(═O)OC 1 -C 7 alkylene-, —S(O) 2 C 1 -C 7 alkylene-, —C(═O)N(R 3 )C 1 -C 7 alkylene-, —S(O) 2 N(R 3 )C 1 -C 7 alkylene-, —C 1 -C 7 alkylene-N(R 3 )S(O) 2 —, —C 1 -C 7 alkylene-S(O) 2 N(R 3 )—, —C 1 -C 7 alkylene-N(R 3 )C(═O)—, and —C 1 -C 7 alkylene-C(═O)N(R 3 )—, wherein —C 1 -C 7 alkylene- optionally comprises a double bond between two adjacent carbons and optionally comprises a difunctional group selected from O, S, —S(O) 2 —, —NR 3 —, —C(═O)—, —N(R 3 )C(═O)—, and —N(R 3 )S(O) 2 — between two adjacent carbons, wherein D 4 is optionally substituted with 1-4 substituents independently selected from halogen, —CN, —NO 2 , —OH, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, CF 3 , —OC 1 -C 5 alkyl, —C 1 -C 5 alkylene-OC 1 -C 5 alkyl, —OCF 3 , —NHC(═O)C 1 -C 5 alkyl, NHC(═O)CH 2 CO 2 C 1 -C 3 alkyl, —N(R 3 ) 2 —, —C(═O)OH, and —C(═)OC 1 -C 7 alkyl, and is optionally substituted with one cyclic group D 6 bonded directly to D 4 or connected to D 4 through a linking group L 6 , wherein D 6 has the same selections as D 4 , and L 6 has the same selections as L 4 , and D6 is optionally substituted with 1-3 substituents independently selected from halogen, —CN, —NO 2 , —OH, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, CF 3 , —OC 1 -C 5 alkyl, —C 1 -C 5 alkylene-OC 1 -C 5 alkyl, —OCF 3 , —N(R 3 ) 2 —, —C(═O)OH, and —C(═O)OC 1 -C 7 alkyl, wherein the C 1 -C 7 alkyl, C 2 -C 7 alkenyl, and —OC 1 -C 5 alkyl groups in all uses in substituents on D4 and D6 are optionally substituted with 1-5 halogens; and
Each R 9 is independently selected from the group consisting of H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, and C 2 -C 7 alkynyl, wherein said C 1 -C 7 alkyl, C 2 -C 7 alkenyl, and C 2 -C 7 alkynyl are optionally substituted with 1-9 halogens.
2. The compound of claim 1 having Formula Ia, or a pharmaceutically acceptable salt thereof:
wherein R W is selected from the group consisting of (a) C 1 -C 5 alkyl which is optionally substituted with 1-5 F, (b) C 2-3 alkenyl which is optionally substituted with 1-3 F, (c) —OC 1 -C 3 alkyl which is optionally substituted with 1-3 F, (d) —SC 1 -C 3 alkyl which is optionally substituted with 1-3 F, (e) —OC 2-3 alkenyl which is optionally substituted with 1-3 F, (f) C 3 -C 6 cycloalkyl, (g) phenyl, (h) pyridyl, (i) —C(═O)OC 1-3 alkyl which is optionally substituted with 1-3 F, and (k) —C(═O)OH, wherein said C 3 -C 6 cycloalkyl, phenyl, and pyridinyl substituents are optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
R Y is selected from the group consisting of halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , and —CN; and
R X and R Z are each selected the group consisting of H, halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 .
3. The compound of claim 1 having Formula Ib, or a pharmaceutically acceptable salt thereof:
wherein R W is selected from the group consisting of C 1 -C 4 alkyl which is optionally substituted with 1-3 F, C 2-3 alkenyl, —OCH 3 , —OCF 3 , —SCH 3 , —SCF 3 , cyclopropyl, —C(═O)OC 1-3 alkyl, and phenyl which is optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
D 2 is a cyclic group selected from 1,3-oxazolidin-2-one and pyrrolidine;
R 3 is selected from H and CH 3 ;
R 4 and R 5 are H;
x is 1; and
y is 0.
4. The compound of claim 3 , wherein
R W is isopropyl;
D 2 is selected from 1,3-oxazolidin-2-one and pyrrolidine, and is optionally substituted with 1-2 CH 3 groups and optionally one phenyl group, wherein phenyl is optionally substituted with 1-3 groups independently selected from F, Cl, CH 3 , CF 3 , —OCH 3 and —OCF 3 , and R 8 is attached to the N of D 2 ;
R 8 is selected from the group consisting of H, C 1 -C 3 alkyl, pyridyl, pyrimidinyl, —CH 2 -phenyl, —CH 2 -anthraquinone, and —CH 2 -tetralin, wherein the non-aromatic portion of the tetralin ring is optionally substituted with 1-4 CH 3 groups, wherein the pyridyl, pyrimidinyl, and phenyl rings of R 8 are optionally substituted with 1-2 substituents independently selected from F, Cl, Br, C 1 -C 4 alkyl, CF 3 , —OC 1 -C 4 alkyl, —OCF 3 , C 2 -C 5 alkenyl, —NO 2 , —NHC(═O)C 1 -C 5 alkyl, and —NHC(═O)CH 2 CO 2 C 1 -C 3 alkyl, and are optionally substituted with one cyclic group D 6 , which is connected directly to the aromatic ring of R 8 or is connected to the aromatic ring of R 8 through a linking group L 6 ;
with the proviso that if R 8 is H or C 1 -C 3 alkyl, then D 2 is substituted with one phenyl group which is optionally substituted with 1-3 groups independently selected from F, Cl, CH 3 , CF 3 , —OCH 3 and —OCF 3 , and D 2 is optionally also substituted with one CH 3 group;
D 6 is selected from the group consisting of phenyl, pyridyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, thienyl, pyrazolyl, oxazolyl, and isoxazolyl, wherein D 6 is optionally substituted with 1-3 substituent groups independently selected from halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, CF 3 , —OCF 3 , —CO 2 H, —C(═O)NH 2 , —NHC(═O)C 1 -C 5 alkyl, —CO 2 C 1 -C 3 alkyl, —CN, —OH, —NO 2 , —CH 2 OC 1 -C 2 alkyl, and optionally one cyclic group selected from 1,3-dioxolanyl, thienyl, pyrazolyl, isoxazolyl, and phenyl, wherein the cyclic group is optionally substituted with 1-2 groups independently selected from CH 3 , —OCH 3 , CF 3 , —OCF 3 , and halogen; and
the optional linking group L 6 is selected from the difunctional groups —C 2 -C 4 alkenylene- and —NHC(═O)—.
5. The compound of claim 4 , having Formula Ic, or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 9 are independently selected from H and CH 3 ;
R 8 is H or CH 3 ; and
R 10 is phenyl, which is optionally substituted with 1-2 groups independently selected from F, Cl, CH 3 , CF 3 , —OCH 3 , and —OCF 3 —.
6. The compound of claim 4 , having Formula Ic, or a pharmaceutically acceptable salt thereof:
wherein R 3 and R 9 are independently selected from H and CH 3 ;
R 10 is H;
R 8 is selected from the group consisting of pyridyl, pyrimidinyl, and —CH 2 -phenyl, wherein the pyridyl, pyrimidinyl, and phenyl rings of R 8 are optionally substituted with 1-2 substituents independently selected from F, Cl, Br, C 1 -C 4 alkyl, CF 3 , —OC 1 -C 4 alkyl, —OCF 3 , C 2 -C 5 alkenyl, —NO 2 , —NHC(═O)C 1 -C 5 alkyl, and —NHC(═O)CH 2 CO 2 C 1 -C 3 alkyl, and are optionally substituted with one cyclic group D 6 , which is connected directly to the pyridyl, pyrimidinyl or phenyl ring of R 8 or is connected to the pyridyl, pyrimidinyl or phenyl ring of R 8 through a linking group L 6 ;
wherein D 6 is selected from the group consisting of phenyl, pyridyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, thienyl, pyrazolyl, oxazolyl, and isoxazolyl, wherein D 6 is optionally substituted with 1-3 substituent groups independently selected from halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, CF 3 , —OCF 3 , —CO 2 H, —C(═O)NH 2 , —NHC(═O)C 1 -C 5 alkyl, —CO 2 C 1 -C 3 alkyl, —CN, —OH, —NO 2 , —CH 2 OC 1 -C 2 alkyl, and optionally one cyclic group selected from 1,3-dioxolanyl, thienyl, pyrazolyl, isoxazolyl, and phenyl, wherein the cyclic group is optionally substituted with 1-2 groups independently selected from CH 3 , —OCH 3 , CF 3 , —OCF 3 , and halogen; and
wherein the optional linking group L 6 is selected from the difunctional groups —C 2 -C 4 alkenylene- and —NHC(═O)—.
7. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
Ex.
Structure
1
2
27
28
29
40
49
50
51
57
58
64
65
66
67
79
84
85
86
87
88
89
90
8. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
(a)
EXAMPLE
wherein R is
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(b)
EXAMPLE
wherein R is
30
31
32
33
34
35
36
37
38
39
(c)
EXAMPLE
wherein R is
41
42
43
44
45
46
47
48
(d)
EXAMPLE
wherein R is
52
53
54
55
56
(e)
EXAMPLE
wherein R is
59
60
61
62
63
(f)
EXAMPLE
wherein R is
68
69
70
71
72
73
74
75
76
77
78
(g)
EXAMPLE
wherein R is
80
81
82
83
9. 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, or a pharmaceutically acceptable salt thereof.
10. 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, or a pharmaceutically acceptable salt thereof.
11. A method of lowering LDL-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, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:
(i) HMG-CoA reductase inhibitors;
(ii) bile acid sequestrants;
(iii) niacin and related compounds;
(iv) PPARα agonists;
(v) cholesterol absorption inhibitors;
(vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors;
(vii) phenolic anti-oxidants;
(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors;
(ix) anti-oxidant vitamins;
(x) thyromimetics;
(xi) LDL (low density lipoprotein) receptor inducers;
(xii) platelet aggregation inhibitors;
(xiii) vitamin B12 (also known as cyanocobalamin);
(xiv) folic acid or a pharmaceutically acceptable salt or ester thereof;
(xv) FXR and LXR ligands;
(xvi) agents that enhance ABCA1 gene expression; and
(xvii) ileal bile acid transporters.
13. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.