CETP inhibitors derived from benzoxazole arylamides
View Patent ↗Compounds having the structure of Formula I1 including pharmaceutically acceptable salts of the compounds, are potent CETP (cholesterol ester transfer protein) inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and penpheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world In formula I, A-B is an arylamide moiety.
1. A compound having Formula 1a, 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 ;
B is selected from the group consisting of:
(a) —C(═O)N(R 3 )(CR 4 R 5 ) x (CR 6 R 7 ) y D 2 ,
(b) —C(═O)N(R 3 )(CR 4 R 5 ) p (CR 6 R 7 ) q D 3 , and
(c) —C(═O)D 3 ;
R 3 is selected from the group consisting of H and CH 3 ;
R 4 is selected from the group consisting of H, CH 3 , —C(═O)OH, and —C(═O)OCH 3 ;
R 5 is H;
R 6 is H;
R 7 is selected from the group consisting of H 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;
p is 1;
q is 0 or 1;
D 2 is a cyclic group selected from (a) 4-membered and 6-8 membered saturated and partly unsaturated heterocyclic groups, and (b) a spirocyclic group having two rings joined by a spirocyclic linkage through a carbon atom wherein each ring is a 5-7-membered ring, 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 or a ring of 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 ;
D 3 is a heterocyclic group selected from (a) a saturated or partly unsaturated 4-8 membered monocyclic heterocyclic group, (b) a saturated or partly unsaturated bicyclic heterocyclic group wherein each ring is a 5-8-membered ring, and (c) a spirocyclic group having two rings joined by a spirocyclic linkage through a carbon atom wherein each ring is a 5-7-membered ring, wherein D 3 comprises one N atom which is connected to the right hand side of the structure represented by Formula I, and D 3 optionally comprises (a) 1-2 heteroatoms independently selected from O and S, (b) optionally one group —N(R 8 )—, (c) optionally 1-2 double bonds, and (d) optionally one carbonyl group, wherein D 3 or a ring of D 3 is optionally fused to a phenyl group, and D 3 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 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 one 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, and (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;
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(═O)CH═CH—, —CH 2 C(═O)—, C 2 -C 3 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 1-3 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, 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 , L 6 has the same selections as L 4 , and D 6 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, —C(═O)OC 1 -C 7 alkyl, and optionally one phenoxy, 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:
D 2 is selected from the group consisting of azetidine, piperidine, morpholine, a saturated 7-membered heterocyclic ring which comprises one —O— and one —N— in the ring, and a spirocyclic group comprising a cyclopentane ring and a piperidine ring joined by a spirocyclic linkage through a commonly shared carbon atom, wherein D 2 is connected to the right hand side of the structure of Formula Ia through a carbon atom of D 2 , wherein said carbon atom of D 2 that is connected to the right hand side of Formula Ia is optionally substituted with one group selected from phenyl, pyridyl, and C 1 -C 3 alkyl optionally substituted with 1-3F, wherein the phenyl and pyridyl groups are optionally substituted with one group selected from CH 3 , CF 3 , —OCH 3 , —OCF 3 , and halogen, and D 2 is optionally also substituted on another carbon atom of the ring with one substitutent selected from CH 3 , CF 3 , —OCH 3 , —OCF 3 and halogen, and the nitrogen atom in the ring of D 2 is attached to the group R 8 .
3. The compound of claim 1 having formula Ia, or a pharmaceutically acceptable salt thereof, wherein:
D 3 is selected from the group consisting of (a) a 5-7-membered saturated cyclic amine; (b) a 6-7 membered saturated cyclic diamine; and (c) a 5-6 membered saturated cyclic amine connected by a spirocyclic linkage through a shared carbon atom to a 5-6 membered cyclic ether, a 5-6 membered cycloalkyl, or a second 5-6 membered saturated cyclic amine, wherein one N atom of D 3 is connected to the right hand side of the structure of Formula Ia, and the second N atom of D 3 , if present, is connected to the group R 8 , wherein D 3 is optionally substituted with one substitutent group selected from CH 3 , CF 3 , —OCH 3 , —OCF 3 , halogen, phenyl, and —(CH 2 ) 1-3 -phenyl, wherein phenyl and the phenyl group of (CH 2 ) 1-3 phenyl are optionally substituted with one group selected from F, Cl, CH 3 , CF 3 , —OCH 3 and —OCF 3 .
4. The compound of claim 1 having formula Ia, or a pharmaceutically acceptable salt thereof, wherein:
R 8 is selected from the group consisting of C 1 -C 8 alkyl, optionally substituted with 1-7F, —C(═O)C 1 -C 8 alkyl, —C(═O)OC 1 -C 5 alkyl, and a cyclic group D 4 which is bonded directly to the N to which R 8 is connected or is bonded to a difunctional linking group L 4 which is bonded to the N to which R 8 is connected;
D 4 is selected from the group consisting of pyrimidinyl, pyridyl, phenyl, C 3 -C 6 cycloalkyl, naphthyl, and quinolyl, and is optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, CF 3 , —OC 1 -C 4 alkyl, —OCF 3 , —CO 2 H, —CO 2 C 1 -C 3 alkyl, —N(CH 3 ) 2 , —NO 2 , —CN, and optionally one cyclic group D 6 which is bonded directly to D 4 or is bonded to a difunctional linking group L 6 which is bonded to D 4 ; and
L 4 is selected from the group consisting of —(CH 2 ) 1-3 —, —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —C(═O)CH(C 2 H 5 )—, —C(═O)CH═CH—, —C(═O)OCH 2 —, —C(═O)NHCH 2 —, —C(═O)(CH 2 ) 1-2 NH—, —CH 2 C(═O)—, —SO 2 —, and —S(O) 2 (CH 2 ) 3 —.
5. The compound of claim 4 , having formula Ia, or a pharmaceutically acceptable salt thereof, wherein:
D 6 is selected from the group consisting of piperidinyl, phenyl, cyclopropyl, cyclohexyl, cyclohexenyl, and pyrazolyl, and is optionally substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl optionally substituted with 1-3F, —OC 1 -C 4 alkyl optionally substituted with 1-3F, halogen, and optionally one phenoxy;
and L 6 is optionally C 2 -C 3 alkenylene.
6. The compound of claim 1 having Formula Ia, or a pharmaceutically acceptable salt thereof, wherein:
D 2 is selected from the group consisting of azetidine, piperidine, morpholine, a saturated 7-membered heterocyclic ring which comprises one —O— and one —N— in the ring, and a spirocyclic group comprising a cyclopentane ring and a piperidine ring joined by a spirocyclic linkage through a commonly shared carbon atom, wherein D 2 is connected to the right hand side of the structure of Formula Ia through a carbon atom of D 2 , wherein said carbon atom of D 2 that is connected to the right hand side of Formula Ia is optionally substituted with one group selected from phenyl, pyridyl, and C 1 -C 3 alkyl optionally substituted with 1-3F, wherein the phenyl and pyridyl groups are optionally substituted with one group selected from CH 3 , CF 3 , —OCH 3 , —OCF 3 , and halogen, and D 2 is optionally also substituted on another carbon atom of the ring with one substitutent selected from CH 3 , CF 3 , —OCH 3 , —OCF 3 and halogen, and the nitrogen atom in the ring of D 2 is attached to the group R 8 ;
D 3 is selected from the group consisting of (a) a 5-7-membered saturated cyclic amine; (b) a 6-7 membered saturated cyclic diamine; and (c) a 5-6 membered saturated cyclic amine connected by a spirocyclic linkage through a shared carbon atom to a 5-6 membered cyclic ether, a 5-6 membered cycloalkyl, or a second 5-6 membered saturated cyclic amine, wherein one N atom of D 3 is connected to the right hand side of the structure of Formula Ia, and the second N atom of D 3 , if present, is connected to the group R 8 , wherein D 3 is optionally substituted with one substitutent group selected from CH 3 , CF 3 , —OCH 3 , —OCF 3 , halogen, phenyl, and —(CH 2 ) 1-3 -phenyl, wherein phenyl and the phenyl group of (CH 2 ) 1-3 phenyl are optionally substituted with one group selected from F, Cl, CH 3 , CF 3 , —OCH 3 and —OCF 3 ;
R 8 is selected from the group consisting of C 1 -C 8 alkyl, optionally substituted with 1-7F, —C(═O)C 1 -C 8 alkyl, —C(═O)OC 1 -C 5 alkyl, and a cyclic group D 4 which is bonded directly to the N to which R 8 is connected or is bonded to a difunctional linking group L 4 which is bonded to the N to which R 8 is connected;
D 4 is selected from the group consisting of pyrimidinyl, pyridyl, phenyl, C 3 -C 6 cycloalkyl, naphthyl, and quinolyl, and is optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, CF 3 , —OC 1 -C 4 alkyl, —OCF 3 , —CO 2 H, —CO 2 C 1 -C 3 alkyl, —N(CH 3 ) 2 , —NO 2 , —CN, and optionally one cyclic group D 6 which is bonded directly to D 4 or is bonded to a difunctional linking group L 6 which is bonded to D 4 ;
L 4 is selected from the group consisting of —(CH 2 ) 1-3 —, —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —C(═O)CH(C 2 H 5 )—, —C(═O)CH═CH—, —C(═O)OCH 2 —, —C(═O)NHCH 2 —, —C(═O)(CH 2 ) 1-2 NH—, —CH 2 C(═O)—, —SO 2 —, and —S(O) 2 (CH 2 ) 3 —;
D 6 is selected from the group consisting of piperidinyl, phenyl, cyclopropyl, cyclohexyl, cyclohexenyl, and pyrazolyl, and is optionally substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl optionally substituted with 1-3F, —OC 1 -C 4 alkyl optionally substituted with 1-3F, halogen, and optionally one phenoxy;
and L 6 is optionally C 2 -C 3 alkenylene.
7. The compound of claim 1 , wherein R W is isopropyl.
8. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
Ex.
Structures
1
7
8
9
10
11
12
13
14
15
16
25
26
35
36
37
38
39
40
41
42
65
66
67
68
69
70
79
80
81
99
100
101
102
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
9. 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
2
3
4
5
6
(b)
EXAMPLE
wherein R is
17
18
19
20
21
22
23
24
(c)
EXAMPLE
wherein R is
27
28
29
30
31
32
33
34
(d)
EXAMPLE
wherein R is
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
(e)
EXAMPLE
wherein R is
71
72
73
74
75
76
77
78
(f)
EXAMPLE
wherein R is
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
(g)
wherein R1, R2, and N form a
EXAMPLE
cyclic amine
124
125
126
127
128
129
130
(h)
EXAMPLE
wherein R is
131
132
133
wherein the symbol “X1” represents the point of attachment of the R substituent.
10. 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.
11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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, or a pharmaceutically acceptable salt thereof.
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, or a pharmaceutically acceptable salt thereof.
14. 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.