Purine analogs having HSP90-inhibiting activity
Novel purine compounds of Formula I. and tautomers, pharmaceutically acceptable salts, and prodrugs thereof, wherein X is S, S(O), or S(O) 2 ; and O is selected from alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, and heterocyclic, all optionally substituted, are described, as are pharmaceutical compositions comprising the same, complexes comprising the same, e.g., HSP90 complexes, and methods of using the same.
1. A compound of formula:
wherein,
X is S;
A is NH 2 or CH 3 ;
Z is selected from the group of F, Cl, Br and CF 3 ;
Y is selected from the group of optionally substituted C 2 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, optionally substituted C 3 -C 8 alkynyl, optionally substituted C 6 -C 10 aryl, and optionally substituted C 3 -C 10 alicyclic;
Q is a member selected from the group of:
L is O, S or NR 1 ;
R 1 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R 2 , C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2 , and S(O) 2 R 2 ;
R 2 is independently selected from the group of C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, heterocyclic, heteroaryl, and aryl, all optionally substituted;
R 3 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR 4 2 ;
R 4 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclic; and
each R 6 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, lower cycloalkyl, OR 3 , SR 3 , NHR 3 , C(O)N(R 4 ) 2 , NO 2 , CN, halogen, and S(O) 2 R 2 ;
or a tautomer or a pharmaceutically acceptable salt or prodrug thereof.
2. A compound of formula:
wherein,
X is S;
A is NH 2 orCH 3 ;
Z is selected from the group of H, F, Cl, Br and CF 3 ;
Y is selected from the group of optionally substituted C 2 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, optionally substituted C 3 -C 8 alkynyl, optionally substituted C 6 -C 10 aryl, and optionally substituted C 3 -C 10 alicyclic;
Q is a member selected from the group of:
L is O, S or NR 1 ;
R 1 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R 2 , C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2 , and S(O) 2 R 2 ;
R 2 is independently selected from the group of C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, heterocyclic, heteroaryl, and aryl, all opiionally substituted;
R 3 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR 4 2 ;
R 4 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclic; and
each R 6 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, lower cycloalkyl, OR 3 , SR 3 , NHR 3 , C(O)N(R 4 ) 2 , NO 2 , CN, halogen, and S(O) 2 R 2 , provided that at least one R 6 is OMe or halogen;
or a tautomer or a pharmaceutically acceptable salt or prodrug thereof.
3. A compound according to claim 2 , wherein
A is NH 2 ;
Z is selected from the group of H, Cl and F;
Y is selected from the group of —(CH 2 ) 2 CH═C(CH 3 ) 2 , —(CH 2 ) 3 CCH; —(CH 2 ) 4 Br, —(CH 2 ) 4 Cl, —(CH 2 ) 4 OAc, —(CH 2 ) 4 NHEt, —(CH 2 ) 4 OH, —(CH 2 ) 5 Br, —(CH 2 ) 5 Cl, —(CH 2 ) 5 OAc, —(CH 2 ) 2 —O(CH)(CH 3 ) 2 , and —(CH 2 ) 5 OH; and
Q is selected from the group of 2,5-dimethoxyphenyl, 2-iodo-5-methoxyphenyl, 4-iodo-5-methoxyphenyl, 2-iodo-4-fluoro-5-methoxyphenyl, 2-bromo-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2,4-diiodo-5-methoxyphenyl, 2-iodo-4-bromo-5-methoxyphenyl, 2-iodo-4-chloro-5-methoxyphenyl, and 2-chloro-3,4,5-trimethoxyphenyl.
4. A compound selected from the group of:
wherein Me is a methyl group.
5. A compound of formula:
wherein,
X is S;
A is NH 2 or CH 3 ;
Z is selected from the group of H, F, Cl, Br and CF 3 ;
Y is selected from the group of optionally substituted C 2 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, optionally substituted C 3 -C 8 alkynyl, optionally substituted C 6 -C 10 aryl, and optionally substituted C 3 -C 10 alicyclic; wherein the optional substituent of Y is selected from alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylthio, oxo, carboxyester, carboxamido, acyloxy, halogen, CN, NO 2 , NH 2 , N 3 , NHCH 3 , N(CH 3 ) 2 , SH, SCH 3 , OH, OCH 3 , OCF 3 , CH 3, CF 3 , C(O)CH 3 , CO 2 CH 3 , CO 2 H, C(O)NH 2 ;
Q is a member selected from the group of:
L is O, S orNR 1 ;
R 1 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R 2 , C(O)OR 2 , C(O)NR 4 2 , C(S)OR 2 , C(S)NR 4 2 , and S(O) 2 R 2 ;
R 2 is independently selected from the group of C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, heterocyclic, heteroaryl, and aryl, all optionally substituted;
R 3 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR 4 2 ;
R 4 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclic; and
each R 6 is independently selected from the group of H, optionally substituted C 1 -C 6 alkyl, lower cycloalkyl, OR 3 , SR 3 . NHR 3 , C(O)N(R 4 ) 2 , NO 2 , CN, halogen, and S(O) 2 R 2 ;
or a tautomer or a pharmaceutically acceptable salt or prodrug thereof.