Hydroxybenzamide derivatives and their use as inhibitors of HSP90

Patent metadata

Field	Value
Publication number	US-9914719-B2
Application number	US-201414467946-A
Country	US
Kind code	B2
Filing date	Aug 25, 2014
Priority date	Apr 13, 2005
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

The invention provides compounds of the formula (I):

or salts, tautomers, solvates and N-oxides thereof; wherein R 1 is hydroxy or hydrogen; R 2 is hydroxy; methoxy or hydrogen; provided that at least one of R 1 and R 2 is hydroxy; R 3 is selected from hydrogen; halogen; cyano; optionally substituted C 1-5 hydrocarbyl and optionally substituted C 1-5 hydrocarbyloxy; R 4 is selected from hydrogen; a group —(O) n —R 7 where n is 0 or 1 and R 7 is an optionally substituted acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C 1-5 hydrocarbyl-amino; or R 3 and R 4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR 5 R 6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur.

The compounds have activity as Hsp90 inhibitors.

First claim

We claim:

1. A method of inhibiting human Hsp90, which method comprises contacting the human Hsp90 with an Hsp90-inhibiting compound of the formula (VII):

or a salt or tautomer thereof;
wherein n is 1, 2, or 3;
R 1 and R 2a are both hydroxy;
R 3 is selected from isopropyl and tert-butyl;
R 4a is hydrogen;
R 8 is hydrogen; and
R 10b is selected from a group consisting of halogen, OH, NH 2 , CH 2 OH, CH 2 NH 2 , O—C 1-6 -alkyl, NH—C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, heterocyclyl, O-heteroaryl, O—C 3-7 cycloalkyl, O-heterocycloalkyl, C(═O)C 1-6 alkyl, C(═O)OC 1-6 alkyl, C(═O)NH 2 , C(═O)NHC 1-6 alkyl, C(═O)N(C 1-6 alkyl) 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHC(═O)C 1-6 alkyl, C 6 aryl, OC 6 aryl, C(═O)C 6 aryl, C(═O)OC 6 aryl, C(═O)NH 2 , C(═O)NHC 6 aryl, C(═O)N(C 6 aryl) 2 , NH(C 6 aryl), N(C 6 aryl) 2 , NHC(═O)C 6 aryl, C 5-6 heterocyclyl, OC 5-6 heterocyclyl, C(═O)C 5-6 heterocyclyl, C(═O)OC 5-6 heterocyclyl, C(═O)NHC 5-6 heterocyclyl, C(═O)N(C 5-6 heterocyclyl) 2 , NH(C 5-6 heterocyclyl), N(C 5-6 heterocyclyl) 2 , NHC(═O)C 5-6 heterocyclyl, C(═O)NHC 1-6 alkyl, C 5-6 aryl, S(═O)C 1-6 alkyl, S(═O)NH—C 1-6 alkyl and SO 2 N—C 1-6 alkyl; and a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from one of the following groups:

2. The method according to claim 1 wherein inhibiting human Hsp90 modulates a cellular process.

3. The method according to claim 2 wherein the cellular process is cell division.

4. The method according to claim 1 wherein R 10b is selected from a group R 10c wherein R 10c is a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from one of the following groups:

5. The method according to claim 1 wherein R 3 is isopropyl.

6. The method according to claim 1 wherein n is 1.

7. The method according to claim 1 wherein the compound of the formula (VII) is selected from:
2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-dimethylamino-ethoxy)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(1-methyl-piperidin-4-ylamino)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-(5-piperazin-1-yl-1,3-dihydro-isoindol-2-yl)-methanone; or
(2,4-dihydroxy-5-isopropyl-phenyl)-(5-dimethylaminomethyl-1,3-dihydroisoindol-2-yl)-methanone;
or salts or tautomers thereof.

8. The method according to claim 7 wherein the compound of formula (VII) is:
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone or a salt or tautomer thereof.

9. The method according to claim 8 wherein the compound of formula (VII) is in the form of a salt.

10. The method according to claim 8 wherein the compound of formula (VII) is in the form of a free base.

11. A method for the diagnosis and treatment of a disease state or condition regulated by human Hsp90 wherein said disease state or condition is a proliferative disorder, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against human Hsp90; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient an effective amount of a compound which is (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone or a salt or tautomer thereof.

12. A method for alleviating or reducing the incidence of a disease state or condition regulated by inhibiting human Hsp90 wherein said disease state or condition is a proliferative disorder, which method comprises administering to a subject in need thereof a therapeutically effective amount of a human Hsp90-inhibiting compound of the formula (VII):

or a salt or tautomer thereof;
wherein n is 1, 2, or 3;
R 1 and R 2a are both hydroxy;
R 3 is selected from isopropyl and tert-butyl;
R 4a is hydrogen;
R 8 is hydrogen; and
R 10b is selected from a group consisting of halogen, OH, NH 2 , CH 2 OH, CH 2 NH 2 , O—C 1-6 -alkyl, NH—C 1-6 alkyl, aryl, heteroaryl, C 3-7 cycloalkyl, heterocyclyl, O-heteroaryl, O—C 3-7 cycloalkyl, O-heterocycloalkyl, C(═O)C 1-6 alkyl, C(═O)OC 1-6 alkyl, C(═O)NH 2 , C(═O)NHC 1-6 alkyl, C(═O)N(C 1-6 alkyl) 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHC(═O)C 1-6 alkyl, C 6 aryl, OC 6 aryl, C(═O)C 6 aryl, C(═O)OC 6 aryl, C(═O)NH 2 , C(═O)NHC 6 aryl, C(═O)N(C 6 aryl) 2 , NH(C 6 aryl), N(C 6 aryl) 2 , NHC(═O)C 6 aryl, C 5-6 heterocyclyl, OC 5-6 heterocyclyl, C(═O)C 5-6 heterocyclyl, C(═O)OC 5-6 heterocyclyl, C(═O)NHC 5-6 heterocyclyl, C(═O)N(C 5-6 heterocyclyl) 2 , NH(C 5-6 heterocyclyl), N(C 5-6 heterocyclyl) 2 , NHC(═O)C 5-6 heterocyclyl, C(═O)NHC 1-6 alkyl, C 5-6 aryl, S(═O)C 1-6 alkyl, S(═O)NH—C 1-6 alkyl and SO 2 N—C 1-6 alkyl; and a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from one of the following groups:

13. The method according to claim 12 wherein R 10b is selected from a group R 10c wherein R 10c is a group [sol], CH 2 [sol] or OCH 2 CH 2 [sol] where [sol] is selected from one of the following groups:

14. The method according to claim 12 wherein R 3 is isopropyl.

15. The method according to claim 12 wherein n is 1.

16. The method according to claim 12 wherein the compound of the formula (VII) is selected from:
2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-dimethylamino-ethoxy)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(1-methyl-piperidin-4-ylamino)-1,3-dihydro-isoindol-2-yl]-methanone;
(2,4-dihydroxy-5-isopropyl-phenyl)-(5-piperazin-1-yl-1,3-dihydro-isoindol-2-yl)-methanone; or
(2,4-dihydroxy-5-isopropyl-phenyl)-(5-dimethylaminomethyl-1,3-dihydroisoindol-2-yl)-methanone;
or salts or tautomers thereof.

17. The method according to claim 12 wherein the compound of formula (VII) is:
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone or a salt or tautomer thereof.

18. The method according to claim 17 wherein the compound of formula (VII) is in the form of a salt.

19. Th

Assignees

• Astex Therapeutics Ltd

Inventors

• Chessari Gianni
• Congreve Miles Stuart
• Frederickson Martyn
• Murray Christopher William
• Navarro Eva Figueroa
• Woolford Alison Jo-Anne
• Carr Maria Grazia
• Downham Robert
• O'Brien Michael Alistair
• Phillips Theresa Rachel
• Woodhead Andrew James

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title