Sulfonyl compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1

1. A compound represented by structural formula I

or a pharmaceutically acceptable salt thereof; wherein:

Q represents NR 2 R 3 or a group selected from the following:

wherein said group may be optionally substituted with from one to five substituents selected from the group consisting of halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and hydroxyl;

L represents the linking group —(CH 2 ) a —X—(CH 2 ) b —, wherein:

X represents a bond or is selected from the group consisting of: O, S, NH, N(C 1-3 alkyl), C(O)NH, NHC(O), vinyl, Aryl, Aryloxy and HAR,

when L is other than a bond, said group L is optionally substituted with 1-5 groups selected from: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

said Aryl, Aryloxy and HAR groups being optionally substituted with 1-5 groups selected from halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

when X is O, S, NH or N(C 1-3 alkyl), a represents an integer of from 2-6 and b represents an integer of from 0-4, such that the sum of a and b is from 2-6;

and when X is a bond, C(O)NH, NHC(O), vinyl, Aryl, Aryloxy or HAR, a and b each represent integers of from 0-6, such that the sum of a and b is 0 to 6;

R 1 selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, Aryl or HAR, optionally substituted with one to five of the following groups: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino, Aryl and HAR, said Aryl and HAR being further optionally substituted with one to three substituents independently selected from cyano, halo, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;

R 2 is H or C 1-3 alkyl; and

R3 is a bicyclic or tricyclic alkyl moiety having 6-12 carbon atoms, optionally substituted with 1-4 substituents selected from the group consisting of C 1-4 alkyl, halo, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, OH, C 1-6 alkyl-SO 2 — and phenyl-SO 2 —, the alkyl and phenyl portions of C 1-6 alkyl-SO 2 — and phenyl-SO 2 — being optionally substituted with 1-3 halo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups.

2. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein:

Q represents NR 2 R 3 or a group selected from the following:

wherein said group may be optionally substituted with from one to five substituents selected from the group consisting of halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and hydroxyl;

L represents the linking group —(CH 2 ) a —X—(CH 2 ) b —, wherein:

X represents a bond or is selected from the group consisting of: O, S, NH, N(C 1-3 alkyl), C(O)NH, NHC(O), vinyl, Aryl, Aryloxy and HAR,

when L is other than a bond, said group L is optionally substituted with 1-5 groups selected from: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

said Aryl, Aryloxy and HAR groups being further optionally substituted with one to five of the following groups: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

when X is O, S, NH or N(C 1-3 alkyl), a represents an integer of from 2-6 and b represents an integer of from 0-4, such that the sum of a and b is from 2-6;

and when X is a bond, C(O)NH, NHC(O), vinyl, Aryl, Aryloxy or HAR, a and b each represent integers of from 0-6, such that the sum of a and b is 0 to 6;

R 1 represents a member selected from the group consisting of: C 1-6 alkyl or C 2-6 alkenyl, optionally substituted with one to five of the following groups: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino, Aryl and HAR, said Aryl and HAR being further optionally substituted with one to three substituents independently selected from cyano, halo, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;

R 2 is H or C 1-3 alkyl; and

R 3 is a bicyclic or tricyclic alkyl moiety having 6-12 carbon atoms, optionally substituted with 1-4 substituents selected from the group consisting of C 1-4 alkyl, halo, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, OH, C 1-6 alkyl-SO 2 — and phenyl-SO 2 —, the alkyl and phenyl portions of C 1-6 alkyl-SO 2 — and phenyl-SO 2 — being optionally substituted with 1-3 halo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups.

3. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein:

Q represents NR 2 R 3 or a group selected from the following:

wherein said group may be optionally substituted with from one to five substituents selected from the group consisting of halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and hydroxyl;

L represents the linking group —(CH 2 ) a —X—(CH 2 ) b —, wherein:

X represents a bond or is selected from the group consisting of: O, S, NH, N(C 1-3 alkyl), C(O)NH, NHC(O), vinyl, Aryl, Aryloxy and HAR,

when L is other than a bond, said group L is optionally substituted with 1-5 groups selected from: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

said Aryl, Aryloxy and HAR groups being further optionally substituted with one to five of the following groups: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

when X is O, S, NH or N(C 1-3 alkyl), a represents an integer of from 2-6 and b represents an integer of from 0-4, such that the sum of a and b is from 2-6;

and when X is a bond, C(O)NH, NHC(O), vinyl, Aryl, Aryloxy or HAR, a and b each represent integers of from 0-6, such that the sum of a and b is 0 to 6;

R 1 represents a member selected from the group consisting of: Aryl or HAR, optionally substituted with one to five of the following groups: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino, Aryl and HAR, said Aryl and HAR each being further optionally substituted with one to three substituents independently selected from cyano, halo, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;

R 2 is H or C 1-3 alkyl; and

R 3 is a bicyclic or tricyclic alkyl moiety having 6-12 carbon atoms, optionally substituted with 1-4 substituents selected from the group consisting of C 1-4 alkyl, halo, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, OH, C 1-6 alkyl-SO 2 — and phenyl-SO 2 —, the alkyl and phenyl portions of C 1-6 alkyl-SO 2 — and phenyl-SO 2 — being optionally substituted with 1-3 halo, C 13 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups.

4. A compound represented by structural formula I

or a pharmaceutically acceptable salt thereof; wherein:

Q represents NR 2 R 3 or a group selected from the following:

wherein said group may be optionally substituted with from one to five substituents selected from the group consisting of halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and hydroxyl;

L represents the linking group —(CH 2 ) a —X—(CH 2 ) b —, wherein:

X represents a bond or is selected from the group consisting of: O, S, NH, N(C 1-3 alkyl), C(O)NH, NHC(O), vinyl, Aryl, Aryloxy and HAR,

when L is other than a bond, said group L is optionally substituted with 1-5 groups selected from: halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

said Aryl, Aryloxy and HAR groups being optionally substituted with 1-5 groups selected from halo, cyano, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and amino;

when X is O, S, NH or N(C 1-3 alkyl), a represents an integer of from 2-6 and b represents an integer of from 0-4, such that the sum of a and b is from 2-6;

and when X is a bond, C(O)NH, NHC(O), vinyl, Aryl, Aryloxy or HAR, a and b each represent integers of from 0-6, such that the sum of a and b is 0 to 6;

wherein R 1 represents a C 1-4 alkyl group optionally substituted with 1-3 fluoro groups, or a phenyl group optionally substituted with 1-2 halo, C 1-3 alkyl, mono-, di- or tri-fluoroC 1-3 alkyl or mono-, di- or tri-fluoroC 1-3 alkoxy groups;

R 2 is H or C 1-3 alkyl; and

R 3 is a bicyclic or tricyclic alkyl moiety having 6-12 carbon atoms, optionally substituted with 1-4 substituents selected from the group consisting of C 1-4 alkyl, halo, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, OH, C 1-6 alkyl-SO 2 — and phenyl- SO 2 — the alkyl and phenyl portions of C 1-6 alkyl-SO 2 — and phenyl-SO 2 — being optionally substituted with 1-3 halo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy and haloC 1-3 alkoxy groups.

5. A compound in accordance with claim 4 wherein R 1 represents methyl, ethyl, trifluoromethyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl or phenyl optionally substituted with halo, methyl, trifluoromethyl or trifluoromethoxy.

6. A compound in accordance with claim 1 wherein:

L represents —(CH 2 ) a —X—(CH 2 ) b —,

X represents a bond, O, S, Aryl, Aryloxy or HAR;

when X represents O or S, a represents an integer having the value of either 2, 3 or 4, and b represents an integer from 0-4 such that the sum of a plus b represents an integer from 2-6, and

when X is a bond, Aryl, Aryloxy or HAR, a and b each represent an integer from 0-6 such that the sum of a plus b represents an integer from 0 to 6.

7. A compound in accordance with claim 6 wherein L is selected from the group consisting of: methylene, ethylene, propylene, butylene and 1,4-phenylene.

8. A compound in accordance with claim 1 wherein:

Q represents a member selected from the group consisting of:

9. A compound in accordance with claim 1 wherein: Q represents NR 2 R 3 .

10. A compound in accordance with claim 9 wherein:

Q represents NR 2 R 3 ,

R 2 represents H and

R 3 represents a bicyclic or tricyclic alkyl moiety having 6-12 carbon atoms, optionally substituted with 1-3 members selected from the group consisting of: CH 3 , fluoro, chloro, CF 3 , OCH 3 , OCF 3 , and CH 3 SO 2 .

11. A compound in accordance with claim 10 wherein R 3 represents 2-adamantyl optionally substituted with 1-3 members selected from the group consisting of: CH 3 , fluoro, chloro, CF 3 , OCH 3 , OCF 3 , and CH 3 SO 2 .

12. A compound in accordance with claim 10 wherein R 3 represents exo-bornyl optionally substituted with 1-3 members selected from the group consisting of: CH 3 , fluoro, chloro, CF 3 , OCH 3 , OCF 3 , and CH 3 SO 2 .

13. A compound in accordance with claim 4 wherein:

R l represents a C 1-4 alkyl group optionally substituted with 1-3 fluoro groups, or a phenyl group optionally substituted with 1-2 halo, C 1-3 alkyl, mono-, di- or tri-fluoroC 1 - 3 alkyl or mono-, di- or tri-fluoroC 1-3 alkoxy groups;

L represents —(CH 2 ) a —X—(CH 2 ) b —,

X represents a bond, O, S, Aryl, Aryloxy or HAR;

when X represents O or S, a represents an integer having the value of either 2, 3 or 4, and b equals represents an integer from 0-4 such that the sum of a plus b represents an integer from 2-6, and

when X is a bond, Aryl, Aryloxy or HAR, a and b each represent an integer from 0-6 such that the sum of a plus b represents an integer from 0 to 6;

Q represents NR 2 R 3 or is selected from the group consisting of:

R 2 represents H and R 3 represents a bicyclic or tricyclic alkyl moiety having 6- 12 carbon atoms, optionally substituted with 1-3 members selected from the group consisting of: CH 3 , fluoro, chloro, CF 3 , OCH 3 , OCF 3 , and CH 3 SO 2 .

14. A compound in accordance with claim 13 wherein:

R 1 represents methyl or ethyl, trifluoromethyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl or phenyl optionally substituted with halo, methyl, trifluoromethyl or trifluoromethoxy;

L is selected from the group consisting of: methylene, ethylene, propylene, butylene and 1,4-phenylene,

Q represents NR 2 R 3 ;

R 2 represents H and R 3 represents a bicyclic or tricyclic alkyl moiety having 6-12 carbon atoms, optionally substituted with 1-3 members selected from the group consisting of: CH 3 , fluoro, chloro, CF 3 , OCH 3 , OCF 3 , and CH 3 SO 2 .

15. A compound in accordance with claim 1 selected from the group consisting of:

R 1

L

Q

ethyl

ethylene

ethyl

ethylene

ethyl

ethylene

ethyl

ethylene

ethyl

ethylene

ethyl

ethylene

ethyl

ethylene

ethyl

propylene

ethyl

methylene

ethyl

methylene

ethyl

methylene

methyl

CF 3

ethylene

CF 3

propylene

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.