Isoxazole compounds as inhibitors of heat shock proteins

1. A method of treatment of cancer in mammals comprising administering to the mammal an amount of a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof effective to inhibit HSP90 activity:

wherein

R 1 is a group of formula (IB)

wherein in any compatible combination

R represents one or more optional substituents,

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 carbocyclic or heterocyclic 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.

2. A method of treatment of cancer in mammals comprising administering to the mammal an amount of a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof, effective to inhibit HSP90 activity:

wherein

R 1 is 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,

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 carbocyclic or heterocyclic radical;

R 2 is

(i) a group of formula (IA) 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 carboxamide group.

3. The method as claimed in claim 1 wherein the compound is one of formula (A), or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof.

4. The method as claimed in claim 2 wherein R 1 has formula (IB)

wherein Alk 1 , Alk 2 , p, r, s, Z and Q are as defined in claim 2 , and R represents one or more optional substituents.

5. The method as claimed in claim 1 wherein that the ring carbon atom adjacent the hydroxyl group in radical (IB) is unsubstituted.

6. The method as claimed in claim 1 wherein, in R 1 , each of p, r and s is 0, and Q is hydrogen.

7. The method as claimed in claim 2 wherein R 1 is optionally substituted phenyl.

8. The method as claimed in claim 6 wherein R 1 is 2-hydroxyphenyl, optionally further substituted by one or more of hydroxy, methyl, ethyl, methoxy, ethoxy, chloro, or bromo.

9. The method as claimed in claim 6 wherein R 1 is 2,4-dihydroxyphenyl, substituted in the 5-position by a small lipophilic substituent.

10. The method as claimed in claim 9 wherein the small lipophilic substituent methyl, ethyl, isopropyl, isobutyl, tert-butyl, chloro, or bromo.

11. A method of treatment of cancer in mammals comprising

administering to the mammal an amount of a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof effective to inhibit HSP90 activity:

wherein

R 1 is 2,4-dihydroxyphenyl, substituted in the 5-position by a small lipophilic substituent

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 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 carbocyclic or heterocyclic radical;

(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.

12. The method as claimed in claim 11 wherein the protecting groups are methylcarbonyloxy, or isopropylamino-carbonyloxy.

13. The method as claimed in claim 1 wherein, in R 1 , p, r and s are each 0, and Q is an optionally substituted carbocyclic or heterocyclic ring.

14. The method as claimed in claim 13 wherein Q is an optionally substituted phenyl or pyridyl ring.

15. The method as claimed in claim 1 wherein, in R 1 , p and/or s are each 1 and r is 0.

16. The method as claimed in claim 1 wherein, in R 1 , each of p, r, and s is 1.

17. The method as claimed in claim 1 wherein, in R 1 , p and s are each 0 and r is 1.

18. The method as claimed in claim 1 wherein R 2 is a group of formula (IA).

19. The method as claimed in claim 18 wherein R 2 is optionally substituted 2-, 3-, or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl, or thiazolyl.

20. The method as claimed in claim 19 wherein optional substituents present in R 2 are selected from methoxy, ethoxy, methylenedioxy, ethylenedioxy, fluoro, chloro, bromo, and trifluoromethyl.

21. The method as claimed in claim 18 wherein R 2 is phenyl substituted in the 4 position by methoxy, ethoxy, fluoro, chloro, bromo, piperazinyl, N-methylpiperazinyl, or piperidinyl.

22. The method 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.

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

Alk is a divalent alkylene, alkenylene or alkynylene radical, and the Alk radical may be optionally substituted,

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, heterocyclyl,

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, examples of such N-heterocyclic rings including morpholino, piperidinyl, piperazinyl and N-phenylpiperazinyl.

24. The method as claimed in claim 1 wherein R 3 is a carboxamide group —CONR B (Alk) n R A as defined in claim 23 .

25. The method as claimed in claim 1 wherein R 3 is ethylaminocarbonyl or isopropylaminocarbonyl.

26. The method as claimed in claim 1 wherein the compound has formula (ID) or the formula B regioisomer thereof,

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

27. The method as claimed in claim 1 wherein the compound has formula (IE) or the formula B regioisomer thereof,

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, N-methylpiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide, 4-hydroxyethylpiperidinyl, and 4-hydroxypiperidinyl; and R 8 represents an optional substituent.

28. The method as claimed in claim 27 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.

29. The method as claimed in claim 1 wherein the compound is selected from:

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

5-(5-Ethyl-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, hydrate, solvate or prodrug thereof.

30. A method of inhibiting HSP90 activity, comprising bringing into contact, in vitro, an HSP90 enzyme and a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof, for the preparation of a composition for inhibition of HSP90 activity:

wherein

R 1 is a group of formula (IB)

wherein in any compatible combination

R represents one or more optional substituents,

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 carbocyclic or heterocyclic 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.