Aryl acylsulfonamides as BLT1 antagonists
View Patent ↗Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are antagonists of leukotriene B 4 receptor 1 (BLT1) and may be useful in the treatment, prevention and suppression of diseases mediated by the leukotriene B 4 receptor 1 (BLT1). The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Non-alcoholic fatty liver disease/nonalcoholic steatohepatitis, metabolic syndrome, atherosclerosis, and cancer.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
A is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl and halogen;
B is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl and halogen;
X is selected from the group consisting of:
(1) —C(O)NHSO 2 CF 3 ,
(2) —C(O)NHSO 2 CH 2 CF 3 ,
(3) —C(O)NHSO 2 CHF 2 ,
(4) —C(O)NHSO 2 C 1-6 alkyl,
(5) —C(O)NHSO 2 CH 2 C 3-6 cycloalkyl, and
(6) —C(O)NHSO 2 C 3-6 cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl;
Z is selected from the group consisting of:
(1) heteroaryl,
(2) C 2-6 cycloheteroalkyl, and
(3) C 3-6 cycloalkyl,
wherein heteroaryl, cycloheteroalkyl and cycloalkyl are unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl;
R a is selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) C 1-6 alkyl; and
R b is selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) C 1-6 alkyl.
2. The compound according to claim 1 wherein Z is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 wherein Z is thiazole, wherein thiazole is unsubstituted or substituted with 1-2 substituents independently selected from C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 wherein X is selected from the group consisting of:
(1) —C(O)NHSO 2 C 1-6 alkyl, and
(2) —C(O)NHSO 2 C 3-6 cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein X is selected from the group consisting of:
(1) —C(O)NHSO 2 C(CH 3 ) 3 , and
(2) —C(O)NHSO 2 cyclopropyl,
wherein alkyl and cyclopropyl are unsubstituted or substituted with 1-3 substituents independently selected from CH 3 ; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 wherein A is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl and halogen; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 wherein A is pyridine, wherein pyridine is unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl and halogen; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 wherein B is aryl, wherein aryl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl and halogen; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 wherein B is phenyl, wherein phenyl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl and halogen; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 wherein R a and R b are each independently selected from the group consisting of: hydrogen, and C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 wherein R a and R b are each hydrogen; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 wherein
A is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl and halogen;
B is aryl, wherein aryl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl and halogen;
X is selected from the group consisting of:
(1) —C(O)NHSO 2 C 1-6 alkyl, and
(2) —C(O)NHSO 2 C 3-6 cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl;
Z is heteroaryl, wherein heteroaryl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl; and
R a and R b are each independently selected from the group consisting of: hydrogen, and C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 wherein
A is pyridine, wherein pyridine is unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl and halogen;
B is phenyl, wherein phenyl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl and halogen;
X is selected from the group consisting of:
(1) —C(O)NHSO 2 C(CH 3 ) 3 , and
(2) —C(O)NHSO 2 cyclopropyl,
wherein alkyl and cyclopropyl are unsubstituted or substituted with 1-3 substituents independently selected from CH 3 ;
Z is thiazole, wherein thiazole is unsubstituted or substituted with 1-2 substituents independently selected from C 1-6 alkyl; and
R a and R b are each hydrogen;
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 selected from:
(1) 2-((Rac-trans)-4-Hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)-N-((1-methylcyclopropyl)sulfonyl)benzamide;
(2) 2-((3S, 4R)-4-Hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)-N-((1-methylcyclopropyl)sulfonyl)benzamide;
(3) 2-((3R, 4S)-4-Hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)-N-((1-methylcyclopropyl)sulfonyl)benzamide;
(4) N-(tert-Butylsulfonyl)-2-((rac-trans)-4-hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
(5) N-(tert-Butylsulfonyl)-2-((3S, 4R)-4-hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
(6) N-(tert-Butylsulfonyl)-2-((3R, 4S)-4-hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
(7) N-(tert-Butylsulfonyl)-2-((rac-trans)-4-hydroxy-3-((5-(2-methylthiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
(8) N-(Cyclopropylsulfonyl)-2-((rac-trans)-4-hydroxy-3-((5-(thiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
(9) N-(Cyclopropylsulfonyl)-2-((rac-trans)-4-hydroxy-3-((5-(2-methylthiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
(10) N-(Cyclopropylsulfonyl)-2-((3S,4R)-4-hydroxy-3-((5-(2-methylthiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide; and
(11) N-(Cyclopropylsulfonyl)-2-((3R,4S)-4-hydroxy-3-((5-(2-methylthiazol-5-yl)pyridin-2-yl)methyl)chroman-7-yl)benzamide;
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.