Hsp90 inhibitors
The disclosure relates to Compounds of Formulae (IA) and (IB): and pharmaceutically acceptable salts thereof wherein Z 1 , Z 2 , Z 3 , Xa, Xb, Xc, Xd, Y, X 2 , and X 4 are as defined herein, compositions comprising an effective amount of a Compound of Formula (IA) and/or (IB), and methods to treat or prevent a condition, such cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (IA) or (IB). The disclosure further relates to compounds of Formulae (IA) and IB) in which X 2 is a leaving for introducing a radiolabeled atom, such as 124 I or 131 I and to methods of using such compounds in the preparation of radiolabeled compounds, particularly for use in imaging.
1. A Compound of Formula (IA) or (IB):
or a pharmaceutically acceptable salt thereof, wherein:
(a) each of Z 1 , Z 2 and Z 3 is N;
(b) Y is S;
(c) Xa, Xb, Xc and Xd are O, O, CH 2 , and CH 2 , respectively;
(d) X 4 is hydrogen or halogen; and
(e) X 2 and R are a combination selected from the following:
(i) in formula (IA):
(a) X 2 is NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(b) X 2 is halogen, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, or —C(O)N(R A )— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(c) X 2 is halogen, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —NR A C(O)— groups, and/or terminated by an —NR A C(O)R B group, wherein each R A is independently selected from C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyland, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(d) X 2 is aryl or alkynyl, R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(e) X 2 is aryl or alkynyl, R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —NR A SO 2 — or —C(O)N(R A )— groups, and/or terminated by an —SO 2 NR A R B or —C(O)NR A R B group, wherein each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl;
(f) X 2 is halogen, aryl, alkynyl, or NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl; and R is straight-chain-substituted or unsubstituted alkyl, straight-chain-substituted or unsubstituted alkenyl, straight-chain-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is independently selected from hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and R B is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; and
(ii) in formula (IB):
(g) X 2 is halogen, aryl, alkynyl, or NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, or —SO 2 N(R A )— groups, and/or terminated by an —S(O)NR A R B or —NR A S(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(h) X 2 is halogen, aryl, alkynyl, or NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(j) X 2 is halogen, aryl, alkynyl, or NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl; and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and R B is independently selected from C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
2. The compound of claim 1 which is a Compound of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein Y is S.
3. The compound of claim 1 which is Compound of Formula (6):
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein in formula (IA):
(i)(b) X 2 is halogen, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, or —C(O)N(R A )— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(i)(c) X 2 is halogen, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —NR A C(O)— groups, and/or terminated by an —NR A C(O)R B group, wherein each R A is independently selected from C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyland, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
5. The compound of claim 1 , wherein in formula (IA):
(i)(d) X 2 is aryl or alkynyl, R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(i)(e) X 2 is aryl or alkynyl, R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —NR A SO 2 — or —C(O)N(R A )— groups, and/or terminated by an —SO 2 NR A R B or —C(O)NR A R B group, wherein each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
6. The compound of claim 1 , wherein in formula (IA),
(i)(f) X 2 is halogen, aryl, alkynyl, or NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl; and R is straight-chain-substituted or unsubstituted alkyl, straight-chain-substituted or unsubstituted alkenyl, straight-chain-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is independently selected from hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and R B is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
7. The compound of claim 1 , wherein R is cyclopropane carboxylic acid 3-propyl-amide, N-3-propyl 2,2-dimethyl-propionamide, N-propyl-2-methyl-propane-2-sulfinamide, t-butanesulfonic acid 3-propylamide, or cyclopropanesulfonic acid 3-propylamide.
8. The compound of claim 1 , wherein X 4 is H or F.
9. The compound of claim 1 , wherein X 2 is optionally substituted heteroaryl.
10. The compound of claim 9 , wherein X 2 is furan-2-yl, furan-3-yl, 5-methylfuran-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, thiazol-2-yl, 5-methylthiazol-2-yl, oxazol-2-yl, or 5-methyloxazol-2-yl.
11. The compound of claim 1 , wherein X 2 is alkynyl or NR 1 R 2 .
12. The compound of claim 11 , wherein X 2 is ethynyl or dimethylamino.
13. The compound of claim 1 , wherein X 2 is halo.
14. The compound of claim 13 , wherein X 2 is I.
15. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
16. A method for the inhibition of Hsp90, comprising contacting Hsp90 with an Hsp90 function inhibiting amount of a compound of claim 1 .
17. A Compound of Formula (IA) or (IB):
or a pharmaceutically acceptable salt thereof, wherein:
(a) each of Z 1 , Z 2 and Z 3 is N;
(b) Y is CH 2 ;
(c) Xa, Xb, Xc and Xd are O, O, CH 2 , and CH 2 , respectively;
(d) X 4 is hydrogen or halogen; and
(i) in formula (IA):
(a) X 2 is NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(b) X 2 is halogen, and R is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched- substituted or unsubstituted alkenyl, straight-chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(c) X 2 is halogen, and R is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched- substituted or unsubstituted alkenyl, straight-chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by a —SO 2 NR A R B group, wherein R A is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and R B is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(d) X 2 is aryl or alkynyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(e) X 2 is aryl or alkynyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by an —SO 2 NR A R B or —C(O)NR A R B group, wherein each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; and
(ii) in formula (IB),
(a) X 2 is NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(b) X 2 is halogen, aryl, or alkynyl, wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(c) X 2 is halogen, aryl, or alkynyl, wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by an —SO 2 N A R B or —C(O)NR A R B group, wherein each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
18. The compound of claim 17 which is a Compound of the following Formula:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 17 , wherein X 2 is optionally substituted heteroaryl, and wherein the optionally substituted heteroaryl comprises furan-2-yl, furan-3-yl, 5-methylfuran-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, thiazol-2-yl, 5-methylthiazol-2-yl, oxazol-2-yl, or 5-methyloxazol-2-yl.
20. The compound of claim 17 , wherein X 2 is ethynyl, I, or dimethylamino.
21. The compound of claim 17 , wherein in formula (IA), X 2 is NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
22. The compound of claim 17 , wherein in formula (IA):
(i)(d) X 2 is aryl or alkynyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(i)(e) X 2 is aryl or alkynyl, and R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by an —SO 2 NR A R B or —C(O)NR A R B group, wherein each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and each R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
23. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable carrier.
24. A Compound of Formula (IA) or (IB):
or a pharmaceutically acceptable salt thereof, wherein:
(a) each of Z 1 , Z 2 and Z 3 is N;
(b) Y is O;
(c) Xa, Xb, Xc and Xd are independently selected from CH, CH 2 , O, N, NH, S, carbonyl, fluoromethylene, and difluoromethylene selected so as to satisfy valence, wherein each bond to an X group is either a single bond or a double bond;
(d) X 2 is halogen, aryl, alkynyl, or NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl;
(e) X 4 is hydrogen or halogen; and
(f) R is straight-chain- or branched-substituted or unsubstituted alkyl, straight-chain- or branched-substituted or unsubstituted alkenyl, straight-chain- or branched-substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
25. The compound of claim 24 , wherein X 2 is optionally substituted heteroaryl, and wherein the optionally substituted heteroaryl comprises furan-2-yl, furan-3-yl, 5-methylfuran-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, thiazol-2-yl, 5-methylthiazol-2-yl, oxazol-2-yl, or 5-methyloxazol-2-yl.
26. The compound of claim 24 , wherein X 2 is ethynyl, I, or dimethylamino.
27. The compound of claim 24 , wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups.
28. The compound of claim 24 , wherein the R group is terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group.
29. A pharmaceutical composition comprising the compound of claim 24 and a pharmaceutically acceptable carrier.
30. The compound of claim 17 , wherein in formula (IA),
(b) X 2 is halogen, and R is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched- substituted or unsubstituted alkenyl, straight-chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; or
(c) X 2 is halogen, and R is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched- substituted or unsubstituted alkenyl, straight-chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is terminated by a —SO 2 NR A R B group, wherein R A is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl, and R B is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.
31. The compound of claim 30 , wherein R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen and C 1 -C 6 alkyl.
32. The compound of claim 31 , wherein X 2 is Iodo, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein R A is hydrogen, and R B is tert-butyl or cyclopropyl.
33. The compound of claim 32 , which is a compound of the formula:
34. The compound of claim 22 , wherein X 2 is alkynyl, and R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein each R A and R B is independently selected from hydrogen and C 1 -C 6 alkyl.
35. The compound of claim 34 , wherein X 2 is ethynyl, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a —NR A S(O)R B , —NR A SO 2 R B , or —NR A C(O)R B group, wherein R A is hydrogen, and R B is tert-butyl or cyclopropyl.
36. The compound of claim 35 , which is a compound of the formula:
37. A method for the inhibition of Hsp 9 O, comprising contacting Hsp 9 O with an Hsp 9 O function inhibiting amount of a compound of claim 17 .
38. A method for the inhibition of Hsp 9 O, comprising contacting Hsp 9 O with an Hsp 9 O function inhibiting amount of a compound of claim 24 .
39. The compound of claim 4 , wherein R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is interrupted by one or more —S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, or —C(O)N(R A )— groups, and/or terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B group, wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, and cycloalkyl.
40. The compound of claim 39 , wherein X 2 is Iodo, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by an —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B group, wherein R A is hydrogen, and R B is tert-butyl or cyclopropyl.
41. The compound of claim 6 , wherein X 2 is halogen, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is hydrogen, and each R B is independently selected from C 1 -C 6 alkyl and cycloalkyl.
42. The compound of claim 41 , wherein X 2 is Iodo, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a —S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is hydrogen, and RB is tert-butyl or cyclopropyl.
43. The compound of claim 6 , wherein X 2 is alkynyl, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a 13 S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is hydrogen, and each R B is independently selected from C 1 -C 6 alkyl and cycloalkyl.
44. The compound of claim 43 , wherein X 2 is ethynyl, R is straight-chain- unsubstituted C 1 -C 6 alkyl, which is terminated by a 13 S(O)NR A R B , —NR A S(O)R B , —SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B group, wherein R A is hydrogen, and R B is tert-butyl or cyclopropyl.