Substituted quinoxalines as inhibitors of fatty acid binding protein
View Patent ↗The present invention relates to novel quinoxaline compounds of Formula I: as Fatty Acid Binding Protein (“FABP”) inhibitors, pharmaceutical compositions comprising the quinoxaline compounds and the use of the quinoxaline compounds for treating or preventing a cardiovascular disease, a metabolic disorder, obesity or an obesity-related disorder, diabetes, dyslipidemia, a diabetic complication, impaired glucose tolerance or impaired fasting glucose.
1. A compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
wherein X and Y represent carbon atoms and Z represents a nitrogen atom;
each R 1 is H or is selected from the group consisting of:
halo, CN, OH, C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 haloalkyl, S(O) x C 1-6 alkyl, and S(O) x C 1-6 haloalkyl, wherein x is 0, 1 or 2;
R 2 represents OH, halo, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 haloalkyl, NH 2 , NHC 1-6 alkyl and N(C 1-6 alkyl) 2 , the alkyl portions of NHC 1-6 alkyl and N(C 1-6 alkyl) 2 being optionally substituted with 1-3 halo atoms;
R 3 and R 4 taken together with the N atom to which they are attached represent a 4-7 membered ring consisting of carbon atoms and 1 N atom, wherein the 4-7 membered ring is substituted with 1-3 groups selected from R b ;
each R b is selected from the group consisting of:
a) C 1-6 alkyl optionally substituted with 1-2 Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-6 Alkyl, O-Aryl, O-Heteroaryl, NH—C 1-6 Alkyl, NH-Aryl, and NH-Heteroaryl groups, the Aryl, Heteroaryl, Heterocyclyl and Alkyl portions being further optionally substituted with 1-3 C 1-3 alkyl, halo, OC 1-6 alkyl, C 1-6 haloalkyl and OC 1-6 haloalkyl groups;
b) CO 2 C 1-6 Alkyl, CO 2 -Aryl, CO 2 -Heteroaryl, and CO 2 C 3-6 Cycloalkyl, each being optionally substituted with 1-2 C 1-3 alkyl, halo, Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-6 Alkyl, NH—C 1-6 Alkyl, and NH-Aryl groups, the Aryl, Heteroaryl, and Heterocyclyl portions, and the alkyl portions of O—C 1-6 Alkyl and NH—C 1-6 Alkyl being further optionally substituted with 1-3 C 1-6 alkyl, halo, OC 1-6 alkyl, haloC 1-6 alkyl and OC 1-6 haloalkyl groups;
c) Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-6 Alkyl, NH—C 1-6 Alkyl, and NH-Aryl, each being optionally substituted with 1-3 alkyl, halo, OC 1-6 alkyl, haloC 1-6 alkyl and OC 1-6 haloalkyl groups;
or 2 R b groups are taken together and represent a fused phenyl ring, optionally substituted with 1-3 halo atoms or C 1-6 alkyl groups.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein each R 1 is selected from H, F, Cl and I.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein 1-2 R 1 groups are selected from F and Cl, and the remainder of the R 1 groups are selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, haloC 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, SC 1-3 alkyl, SC 1-3 haloalkyl, SO 2 C 1-3 alkyl and SO 2 C 1-3 haloalkyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from OH, NH 2 , C 1 , C 1-3 alkyl and C 1-3 haloalkyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together with the N atom to which they are attached represent a 4, 5, or 6 membered ring consisting of carbon atoms and 1 N atom, wherein the 4, 5 or 6 membered ring is substituted with 1-2 groups selected from R b ;
and each R b is selected from the group consisting of:
a) C 1-3 alkyl optionally substituted with 1 Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, NH—C 1-3 Alkyl, NH-Aryl, or NH-Heteroaryl groups, the Aryl, Heteroaryl, Heterocyclyl and Alkyl portions being further optionally substituted with 1-3 C 1-3 alkyl, halo, OC 1-3 alkyl, C 1-3 haloalkyl and OC 1- 3haloalkyl groups;
b) CO 2 C 1-3 Alkyl, CO 2 -Aryl, CO 2 -Heteroaryl, and CO 2 C 3-6 Cycloalkyl, each being optionally substituted with 1 C 1-3 Alkyl, halo, Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-3 Alkyl, NH—C 1-3 Alkyl, and NH-Aryl group, the Aryl, Heteroaryl, and Heterocyclyl portions, and the Alkyl portions of O—C 1-3 Alkyl and NH—C 1-3 Alkyl being further optionally substituted with 1-3 C 1-3 alkyl, halo, OC 1-3 alkyl, haloC 1-3 alkyl and OC 1-3 haloalkyl groups;
and
c) Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-3 Alkyl, NH—C 1-3 Alkyl, and NH-Aryl, each being optionally substituted with 1-3 alkyl, halo, OC 1-3 alkyl, haloC 1-3 alkyl and OC 1-3 haloalkyl groups;
or 2 R b groups are taken together and represent a fused phenyl ring, optionally substituted with 1-3 halo atoms.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:
each R 1 is selected from H, F, Cl and I, or 1-2 R 1 groups are selected from F and Cl, and the remainder of the R 1 groups are selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, haloC 1-3 alkyl, OC 1-3 alkyl, OC 1-3 haloalkyl, SC 1-3 alkyl, SC 1-3 haloalkyl, SO 2 C 1-3 alkyl and SO 2 C 1-3 haloalkyl;
R 2 is selected from OH, NH 2 , C 1 , C 1-3 alkyl and C 1-3 haloalkyl;
R 3 and R 4 considered together with the N atom to which they are attached represent a 4, 5, or 6 membered ring consisting of carbon atoms and 1 N atom, wherein the 4, 5 or 6 membered ring is substituted with 1-2 groups selected from R b ;
each R b is selected from the group consisting of:
a) C 1-3 alkyl optionally substituted with 1 Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, NH—C 1-3 Alkyl, NH-Aryl, or NH-Heteroaryl groups, the Aryl, Heteroaryl, Heterocyclyl and Alkyl portions being further optionally substituted with 1-3 C 1-3 alkyl, halo, OC 1-3 alkyl, C 1-3 haloalkyl and OC 1-3 haloalkyl groups;
b) CO 2 C 1-3 Alkyl, CO 2 -Aryl, CO 2 -Heteroaryl, and CO 2 C 3-6 Cycloalkyl, each being optionally substituted with 1 C 1-3 Alkyl, halo, Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-3 Alkyl, NH—C 1-3 Alkyl, and NH-Aryl group, the Aryl, Heteroaryl, and Heterocyclyl portions, and the Alkyl portions of O—C 1-3 Alkyl and NH—C 1-3 Alkyl being further optionally substituted with 1-3 C 1-3 alkyl, halo, OC 1-3 alkyl, haloC 1-3 alkyl and OC 1-3 haloalkyl groups;
and
c) Aryl, Heteroaryl, Heterocyclyl, Cycloalkyl, O—C 1-3 Alkyl, NH—C 1-3 Alkyl, and NH-Aryl, each being optionally substituted with 1-3 alkyl, halo, OC 1-3 alkyl, haloC 1-3 alkyl and OC 1-3 haloalkyl groups;
or 2 R b groups are taken together and represent a fused phenyl ring, optionally substituted with 1-3 halo atoms.
7. The compound of claim 1 selected from the compounds in Table A, Table B and Table C:
TABLE A
1-2
1-3
1-4
1-5
1-6
1-7
1-8
1-9
1-10
1-11
1-12
1-13
1-14
1-15
1-16
1-17
1-18
1-19
1-20
1-21
1-22
1-23
1-24
1-25
1-26
1-27
1-28
1-29
1-30
1-31
1-34
1-35
1-36
1-37
1-38
1-39
1-40
1-42
1-43
1-44
1-45
1-46
1-47
1-48
1-49
1-51
1-52
1-53
1-54
1-55
1-56
1-57
1-58
1-59
1-60
1-61
1-62
1-63
1-64
1-65
1-66
1-67
1-68
1-69
1-70
1-71
1-72
1-73
1-74
1-75
1-76
1-77
1-78
1-79
1-80
1-81
1-83
1-84
1-85
1-86
1-87
1-88
1-89
1-91
1-92
1-93
1-94
1-95
1-96
TABLE B
1-99
1-100
1-101
1-102
1-107
1-111
1-115
1-116
1-117
1-118
1-134
1-153
1-158
1-161
1-162
1-163
1-164
1-165
TABLE C
5-2
6-4
6-5
7-7
7-8
8-6
8-7
8-8
8-9
8-10
8-11
8-12
8-13
8-14
8-15
8-17
8-18
9-16
9-18
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 which is:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.