Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
Heteroaromatic compounds of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; and liver steatosis.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
A is selected from the group consisting of:
wherein r is 0 or 1; and s is 0 or 1;
B is selected from the group consisting of:
each R 1 is independently selected from the group consisting of: hydrogen, halogen, and C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy;
each R2 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6 alkyl,
(4) (CH 2 )nOR e ,
(5) (CH 2 )nN(R e )2,
(6) (CH 2 )nCN,
(7) (CH 2 )nCOR e , and
(8) (CH 2 )nS(O)qR e ,
wherein alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and
wherein any CH 2 in R 2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —C 1-6 alkenyl,
(5) —OC 1-6 alkyl,
(6) (CH 2 ) n OR e ,
(7) (CH 2 ) n N(R e ) 2 ,
(8) (CH 2 ) n C≡N,
(9) (CH 2 ) n COR e , and
(10) (CH 2 ) n S(O) q R e ,
wherein alkyl is unsubstituted or substituted with one to three substituents selected from: hydroxy, halogen, and C 1-4 alkyl wherein alkyl are unsubstituted or substituted with one to three substituents selected from: halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines, and wherein any CH 2 in R 3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;
R 4 is
each R a is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) cyano,
(4) C 1-4 alkyl, unsubstituted or substituted with one to five fluorines,
(5) C 1-4 alkoxy, unsubstituted or substituted with one to five fluorines,
(6) C 1-4 alkylthio, unsubstituted or substituted with one to five fluorines,
(7) C 1-4 alkylsulfonyl,
(8) —CO 2 H,
(9) C 1-4 alkyloxycarbonyl, and
(10) C 1-4 alkylcarbonyl;
each R e is independently selected from the group consisting of:
(1) hydrogen, and
(2) C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, —C 1-4 alkoxy, —C 1-4 alkylthio, —C 1-4 alkylsulfonyl, —C 2 H, and —CO 2 C 1-4 alkyl;
n is an integer from 0 to 3;
q is an integer from 1 to 2;
t is an integer from 0 to 8;
d is an integer from 0 to 2; and
e is an integer from 0 to 2,
provided that d+e is 2.
2. The compound of claim 1 wherein t is 0, d is 1, and e is 1; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein r is 1 or 0; s is 0 or 1; R2 is hydrogen; and R 3 is independently selected from the group consisting of: hydrogen, halogen, and —OCH 3 ; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein:
A is selected from the group consisting of:
B is selected from the group consisting of:
R 4 is
R 3 is independently selected from the group consisting of: hydrogen, halogen, —OH, and —OC 1-6 alkyl; and
s is 0 or 1;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 3 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 wherein:
A is:
B—R 4 is selected from the group consisting of:
each R 3 is independently selected from the group consisting of: Cl, Br, —CH 3 , —CF 3 , and —OCF 3 ;
R 4 is:
and
s is 1; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
9. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein B—R 4 is
10. The compound of claim 9 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A compound that is
or a pharmaceutically acceptable salt thereof.
12. A compound that is
13. A pharmaceutical composition comprised of the compound of claim 11 in combination with a pharmaceutically acceptable carrier.