Isoxazole compounds as inhibitors of heat shock proteins

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
• R1 is a group of formula (IA):
• —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q (IA)
• wherein in any compatible combination
• Ar1 is an optionally substituted aryl or heteroaryl radical,
• Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals,
• p, r and s are independently 0 or 1,
• Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—,
• —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and
• Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
• R2 is
• (i) a group of formula (IA) as defined in relation to R1;
• (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 -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA);
• and
• R3 is a carboxamide group.

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
• R1 is 2,4-dihydroxyphenyl, substituted in the 5-position by a small lipophilic substituent
• R2 is (i) a group of formula (IA):
• —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q (IA)
• wherein in any compatible combination
• Ar1 is an optionally substituted aryl or heteroaryl radical, and
• Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals,
• p, r and s are independently 0 or 1,
• Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 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 -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA);
• and
• R3 is a carboxyl, carboxamide, or carboxyl ester group.

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
• R1 is a group of formula (IB)
• wherein in any compatible combination
• R represents one or more optional substituents,
• Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals,
• p, r and s are independently 0 or 1,
• Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—,
• —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and
• Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
• R2 is (i) a group of formula (IA):
• —Ar1-Alk1)p-(Z)r-(Alk2)s-Q (IA)
• wherein in any compatible combination
• Ar1 is an optionally substituted aryl or heteroaryl radical, and
• Alk1, Alk2, p, r, s, Z, RA and Q are as defined in relation to R1;
• (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 -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA);
• and
• R3 is a carboxyl, carboxamide, or carboxyl ester group.