Hsp90 inhibitors

Patent metadata

Field	Value
Publication number	US-9346808-B2
Application number	US-201214009976-A
Country	US
Kind code	B2
Filing date	Apr 5, 2012
Priority date	Apr 5, 2011
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

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.

First claim

What is claimed:

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, a

Assignees

• Sun Weilin
• Taldone Tony
• Patel Pallav
• Chiosis Gabriela
• Sloan Kettering Inst Cancer

Inventors

• Sun Weilin
• Taldone Tony
• Patel Pallav
• Chiosis Gabriela

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D473/40

  with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6 · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title