Heterocyclic compounds as inhibitors of 17beta-HSD3
View Patent ↗There is provided a compound having Formula (I) wherein each of rings A and B is selected from five or six membered carbon rings optionally containing one or more hetero atoms selected from N, S, and O and optionally having fused thereto a further ring; X is an optional group selected from O, S, —S═O, —S(═O) 2 , —C═O, —S(═O) 2 NR 8 , —C═ONR 9 , and —NR 10 , wherein n and p are independently selected from 0 and 1; Y is (R 11 ) 1-3 wherein each R 11 is independently selected from —NR 12 , —CR 13 R 14 , —S(═O) 2 and —C═O; Z is selected from (i) six or seven membered ring containing carbon and at least one nitrogen, which may be optionally substituted wherein the substituents may together form further ring fused thereto; and (ii) a —R 15 —NR 16 — group.
1. A compound having Formula VI
wherein
each of R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are independently selected from
(a) H,
(b) R 17 , —OC(R 17 ) 3 , —OCH(R 17 ) 2 , or —OCH 2 R 17 , wherein R 17 is a halogen;
(c) —CN;
(d) optionally substituted alkyl,
(e) optionally substituted heteroalkyl;
(f) optionally substituted aryl;
(g) optionally substituted heteroaryl;
(h) optionally substituted arylalkyl;
(i) optionally substituted heteroarylalkyl;
(j) hydroxy;
(k) alkoxy;
(l) aryloxy;
(m) —SO 2 -alkyl; and
(n) —N(R 11 )C(O)R 13 ,
wherein the optional substituents of (d) (e) (h) and (i) are selected from the group consisting of: C 1-6 alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl;
A optionally has fused thereto a further ring independently selected from five or six membered carbon rings optionally containing one or more hetero atoms selected from N, S, and O;
X is O,
wherein n and p are 0;
Y is (R 11 ) 1-3 wherein each R 11 is independently selected from —NR 12 , —CR 13 R 14 , —S(═O) 2 and —C═O, wherein R 12 , R 13 and R 14 are independently selected from H and hydrocarbyl;
Z is
which may be optionally substituted; and
R 3 is selected from
2. A compound according to claim 1 wherein R 17 is Cl or F.
3. A compound according to claim 1 wherein (b) is Cl, —OCF 3 , —OCHF 2 , —OCH 2 F, —CF 3 , —CHF 2 , or —CH 2 F.
4. A compound according to claim 1 wherein (b) is C 1 , CF 3 , OCF 3 , or —OCHF 2 .
5. A compound according to claim 1 wherein R 1 is selected from (b) R 17 , —OC(R 17 ) 3 , —OCH(R 17 ) 2 , or —OCH 2 R 17 , wherein R 17 is a halogen; (c) —CN; (d) optionally substituted alkyl, (e) optionally substituted heteroalkyl; (f) optionally substituted aryl; (g) optionally substituted heteroaryl; (h) optionally substituted arylalkyl; (i) optionally substituted heteroarylalkyl; (j) hydroxy; (k) alkoxy; (l) aryloxy; (m) —SO 2 -alkyl; and (n) —N(R 11 )C(O)R 13 , wherein the optional substituents of (d) (e) (f) (h) and (i) are selected from the group consisting of: C 1-6 alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl.
6. A compound according to claim 1 wherein R 1 is C 1 , CF 3 , OCF 3 , or —OCHF 2 .
7. A compound according to claim 1 wherein R 2 is selected from (a) H, (b) R 17 , —OC(R 17 ) 3 , —OCH(R 17 ) 2 , or —OCH 2 R 17 , wherein R 17 is a halogen; (c) —CN; (d) optionally substituted alkyl, (e) optionally substituted heteroalkyl; and (k) alkoxy;
wherein the optional substituents of (d) and (e) are selected from the group consisting of: C 1-6 alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl.
8. A compound according to claim 1 wherein R 2 is H or Me.
9. A compound according to claim 1 wherein R 2 is Me.
10. A compound according to claim 1 wherein R 2 is H.
11. A compound according to claim 1 wherein each of R 4 , R 5 , R 6 and R 7 is H.
12. A compound according to claim 1 wherein when A is a single ring each of R 4 and R 5 is H.
13. A compound according to claim 1 wherein each of R 6 and R 7 is H.
14. A compound according to claim 1 wherein each of R 2 , R 6 and R 7 is H.
15. A compound according to claim 1 wherein ring A has fused thereto a further ring (ring A′) and ring A together with ring A′ contains more than six members.
16. A compound according to claim 1 wherein Y is R 11 .
17. A compound according to claim 1 wherein Y is (R 11 ) 2 .
18. A compound according to claim 1 wherein Y is (R 11 ) 3 .
19. A compound according to claim 1 wherein R 12 , R 13 and R 14 are independently selected from H and C 1-6 alkyl.
20. A compound according to claim 1 wherein Y is selected from —NR 12 , —NR 12 —CR 13 R 14 , —NR 12 C═O, —CR 13 R 14 —CR 13 R 14 , —CR 13 R 14 —NR 12 —CR 13 R 14 , and —NR 12 —S(═O) 2 .
21. A compound according to claim 1 wherein Y is selected from —NR 12 , —NR 12 —CR 13 R 14 , and —NR 12 C═O.
22. A pharmaceutical composition comprising a compound according to claim 1 optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
23. A compound according to claim 1 wherein (d) optionally substituted alkyl is —C(R 17 ) 3 , —CH(R 17 ) 2 , or —CH 2 R 17 , wherein R 17 is a halogen.
24. A compound according to claim 5 wherein (d) optionally substituted alkyl is —C(R 17 ) 3 , —CH(R 17 ) 2 , or —CH 2 R 17 , wherein R 17 is a halogen.
25. A compound according to claim 7 wherein (d) optionally substituted alkyl is —C(R 17 ) 3 , —CH(R 17 ) 2 , or —CH 2 R 17 , wherein R 17 is a halogen.
26. A compound according to claim 1 , of the general formula