Isoxazole compounds as inhibitors of heat shock proteins

1. A method of treatment of a disease, in mammals, which is responsive to inhibition of HSP90 activity wherein the disease is selected from angiogenesis-related diseases; scrapie/CJD, and Huntingdon's disease 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 phenyl or pyridinyl radical;

R 2 is

(i) a group of formula (IAa):

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

wherein in any compatible combination

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

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

Q 1 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 1 , wherein Q 1 , Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group of formula (IAa); and

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

2. A method of treatment of a disease, in mammals, which is responsive to inhibition of HSP90 activity wherein the disease is selected from angiogenesis-related diseases; scrapie/CJD, and Huntingdon's disease 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 phenyl or pyridinyl radical;

R 2 is

(i) a group of formula (IAa):

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

wherein in any compatible combination

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

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

Q 1 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 1 wherein Q 1 , Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group (IAa); 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 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 is methyl, ethyl, isopropyl, isobutyl, tertbutyl, chloro, or bromo.

11. The method 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.

12. The method as claimed in claim 11 , wherein Q is an optionally substituted phenyl ring.

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

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

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

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

17. The method as claimed in claim 16 wherein R 2 is optionally substituted 2-, 3-, or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl, or thiazolyl.

18. The method 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. The method as claimed in claim 16 wherein R 2 is phenyl substituted in the 4 position by methoxy, ethoxy, fluoro, chloro, bromo, piperazinyl, N-methylpiperazinyl, or piperidinyl.

20. 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.

21. 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 to 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. The method as claimed in claim 1 wherein R 3 is a carboxamide group —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 to 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.

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

24. 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.

25. 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, methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide, 4-hydroxyethylpiperidinyl, and 4-hydroxypiperidinyl; and

R 8 represents an optional substituent.

26. The method 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. 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-T-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.

28. The method as claimed in claim 21 wherein R A and R B taken together with the nitrogen to which they are attached to form an N-heterocyclic ring selected from morpholino, piperidinyl, piperazinyl and N-phenylpiperazinyl.

29. The method as claimed in claim 22 wherein R A and R B taken together with the nitrogen to which they are attached to form an N-heterocyclic ring selected from morpholino, piperidinyl, piperazinyl and N-phenylpiperazinyl.