Isoxazole compounds as inhibitors of heat shock proteins

1. A compound of formula (A) or (B) or a salt or N-oxide thereof:

wherein

R 1 is a group of formula (IB)

wherein in any compatible combination

R represents one or more optional substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, halo, trifluoromethyl, trifluoromethoxy, oxo, phenyl, —COOH, —COOR A , —COR A —, wherein R A is a (C 1 -C 6 )alkyl group,

Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 6 alkylene or C 2 -C 6 alkenylene radicals,

p, r and s are independently 0 or 1,

Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO 2 —, —C(═O)O—, —C(═O)NR A —, —C(═S)NR A —, —SO 2 NR A —, —NR A C(═O)—, —NR A SO 2 — or —NR A — wherein R A is hydrogen or C 1 -C 6 alkyl, and

Q is hydrogen or an optionally substituted phenyl or pyridinyl radical;

R 2 is (i) a group of formula (IA):

—Ar 1 -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q  (IA)

wherein in any compatible combination

Ar 1 is an optionally substituted aryl or heteroaryl radical, and

Alk 1 , Alk 2 , p, r, s, Z , R A and Q are as defined in relation to R 1 ;

(ii) a carboxamide radical; or

(iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula-(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q wherein Q, Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group (IA); and

R 3 is a carboxyl, carboxamide, or carboxyl ester group,

wherein the term optionally substituted means substituted with up to four substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 ) alkyl, (C 1 -C 6 )alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —NH 2 , —NHR A , —NR A R B , —OCONH 2 , —OCONHR A , —OCONR A R B , —NHCOR A , —NHCOOR A , —NR B COOR A , —NHSO 2 OR A , —NR B SO 2 OH, —NR B SO 2 OR A , —NHCONH 2 , —NR A CONH 2 , —NHCONHR B , —NR A CONHR B , —NHCONR A R B or —NR A CONR A R B wherein R A and R B are independently a (C 1 -C 6 )alkyl group.

2. A compound as claimed in claim 1 wherein R 3 is a carboxamide group.

3. A compound as claimed in claim 1 wherein the compound is one of formula (A).

4. A compound as claimed in claim 1 wherein the ring carbon atom adjacent the hydroxyl group in radical (IB) is unsubstituted.

5. A compound as claimed in claim 1 wherein, in R 1 , each of p, r and s is 0, and Q is hydrogen.

6. A compound as claimed in claim 2 wherein R 1 is optionally substituted phenyl.

7. A compound as claimed in claim 5 wherein R 1 is 2-hydroxyphenyl, optionally further substituted by one or more of hydroxy, methyl, ethyl, methoxy, ethoxy, chloro, or bromo.

8. A compound as claimed in claim 5 wherein R 1 is 2,4-dihydroxyphenyl, substituted in the 5-position by a methyl, ethyl, isopropyl, isobutyl, tert-butyl, chloro, or bromo.

9. A compound as claimed in claim 8 wherein the hydroxyl groups in R1 are protected by groups which are cleaved in the body to release the hydroxyl groups.

10. A compound as claimed in claim 9 wherein the protecting groups are alkylcarbonyloxy or alkylaminocarbonyloxy groups.

11. A compound as claimed in claim 9 wherein the protecting groups are methylcarbonyloxy, or isopropylamino-carbonyloxy.

12. A compound as claimed in claim 1 wherein, in R 1 , p, r and s are each 0, and Q is an optionally substituted phenyl or pyridyl ring.

13. A compound as claimed in claim 12 wherein Q is an optionally substituted phenyl ring.

14. A compound as claimed in claim 1 wherein, in R 1 , p and/or s are each 1 and r is 0.

15. A compound as claimed in claim 1 wherein, in R 1 , each of p, r, and s is 1.

16. A compound as claimed in claim 1 wherein, in R 1 , p and s are each 0 and r is 1.

17. A compound as claimed in claim 1 wherein R 2 is optionally substituted 2-, 3-, or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl, or thiazolyl.

18. A compound as claimed in claim 17 wherein optional substituents present in R 2 are selected from methoxy, ethoxy, methylenedioxy, ethylenedioxy, fluoro, chloro, bromo, and trifluoromethyl.

19. A compound as claimed in claim 1 wherein R 2 is phenyl substituted in the 4 position by methoxy, ethoxy, fluoro, chloro, bromo, piperazinyl, N-methylpiperazinyl, or piperidinyl.

20. A compound as claimed in claim 1 wherein R 2 has the partial structure:

wherein the substituted amino group —NR 10 R 11 is selected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, piperidin-4-yl, N-acetylpiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide, 4-hydroxyethylpiperidinyl, and 4-hydroxypiperidinyl.

21. A compound as claimed in claim 1 wherein R 2 is a carboxamide group of formula —CONR B (Alk) n R A wherein

Alk is an optionally substituted divalent alkylene, alkenylene or alkynylene radical,

n is 0 or 1,

R B is hydrogen or a C 1 -C 6 alkyl or C 2 -C 6 alkenyl group,

R A is hydroxy or optionally substituted carbocyclic,

or R A and R B taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms.

22. A compound as claimed in claim 1 wherein R 3 is a carboxamide group —CONR B (Alk) n R A as defined in claim 21 .

23. A compound as claimed in claim 1 wherein R 3 is ethylaminocarbonyl or isopropylaminocarbonyl.

24. A compound as claimed in claim 1 having formula (ID) or the formula B regioisomer (ID1) thereof having the formula (ID1)

wherein each R independently represents an optional substituent and R 3 represents a carboxamide group.

25. A compound as claimed in claim 1 having formula (IE)

or the formula B regioisomer thereof having the formula (IE1)

wherein R 3 represents a carboxamide group; R 9 represents —CH 2 NR 10 R 11 or

—NR 10 R 11 wherein the substituted amino group —NR 10 R 11 is selected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, piperidin-4-yl, N-acetylpiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide, 4-hydroxyethylpiperidinyl, and 4-hydroxypiperidinyl; and R 8 represents an optional substituent.

26. A compound as claimed in claim 25 wherein R 3 is ethylaminocarbonyl CH 3 CH 2 NHC(═O)—, or isopropylaminocarbonyl (CH 3 ) 2 CHNHC(═O)—; the substituted amino group —NR 10 R 11 in R 9 is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, piperidin-4-yl, N-acetylpiperazinyl, N-methylpiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide, 4-hydroxyethylpiperidinyl, or 4-hydroxypiperidinyl); and R 8 is ethyl, isopropyl, bromo, or chloro.

27. A compound as claimed in claim 1 selected from the group consisting of:

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

4-(4-Diethylaminomethyl-phenyl)-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-ethylaminomethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-[4-(isopropylamino-methyl)-phenyl]-isoxazole-3- carboxylic acid ethylamide,

4-(4-Cyclohexylaminomethyl-phenyl)-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

4-[4-(tert-Butylamino-methyl)-phenyl]-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid isopropylamide,

5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid isopropylamide,

5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide,

5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-(4-diethylaminomethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

3-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-5-carboxylic acid ethylamide,

4-(4-Diethylaminomethyl-phenyl)-5-(4,6-dihydroxy-2′-methyl-biphenyl-3-yl)-isoxazole-3-carboxylic acid ethylamide,

4-(4-Diethylaminomethyl-phenyl)-5-(4′-fluoro-4,6-dihydroxy-biphenyl-3-yl)-isoxazole-3-carboxylic acid ethylamide,

4-(4-Diethylaminomethyl-phenyl)-5-(4,6-dihydroxy-biphenyl-3-yl)-isoxazole-3-carboxylic acid ethylamide,

5-(2′-Fluoro-4,6-dihydroxy-biphenyl-3-yl)-4-(4-pyrrolidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(4,6-Dihydroxy-biphenyl-3-yl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(2,4-Dihydroxy-5-phenethyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid isopropylamide,

4-(4-Diethylaminomethyl-phenyl)-5-(5-ethyl-2,4-dihydroxy-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(5-Lthyl-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide,

5-(5-Lthyl-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-diethylaminomethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

5-(5-Chloro-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide, and

5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide,

or a salt thereof.

28. A pharmaceutical composition comprising a compound as claimed in claim 1 , together with a pharmaceutically acceptable carrier.

29. A pharmaceutical composition as claimed in claim 28 in the form of a solution or suspension of the compound in a sterile, physiologically acceptable carrier.

30. A pharmaceutical composition as claimed in claim 28 in the form of a solution or suspension of the compound in sterile aqueous saline.

31. 5-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl) -iso- xazole-3-carboxylic acid ethylamide, or a salt thereof.

32. A pharmaceutical composition comprising a compound as claimed in claim 31 , together with a pharmaceutically acceptable carrier.

33. A pharmaceutical composition as claimed in claim 32 in the form of a solution or suspension of the compound in a sterile, physiologically acceptable carrier.

34. A pharmaceutical composition as claimed in claim 32 in the form of a solution or suspension of the compound in sterile aqueous saline.