2-Aminopurine Analogs Having HSP90-Inhibiting Activity

A compound represented by Formula II, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:

• wherein:
• R1 is halogen or lower alkyl;
• R2 is —NR8R10;
• R3 is hydrogen, halogen, or —CN;
• R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
• the aryl group is substituted with 3 to 5 substituents,
• the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,
• the alicyclic group is substituted with 3 to 5 substituents,
• the heterocyclic group is substituted with 3 to 5 substituents, and
• the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N3, —SR8, —OR8, —CN, —C(O)R9, —NO2, —NR8R10, phosphonate and phosphonic acid;
• R8 is hydrogen, lower alkyl, lower aryl, or —C(O)R9;
• R9 is lower alkyl, lower aryl, lower heteroaryl, —NR10R10 or —OR11;
• R10 is independently hydrogen or lower alkyl;
• and
• R11 is lower alkyl, lower aryl or lower heteroaryl;
• provided that
• when R5 is aryl, R5 is not an organo-metallic cyclopentadiene;
• when R5 is phenyl, the substituents are not 3,5 di-halo;
• when R5 is alicyclic, the ring system does not contain any tetra-substituted sp3 ring carbons;
• when R5 is heterocyclic, the ring system does not contain any tetra-substituted sp3 ring carbons or the ring system is not a tetra-substituted pyrrolidine.

A pharmaceutical composition comprising one or more pharmaceutical acceptable excipients and at least one compound represented by Formula I below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:

• wherein:
• R1 is halogen or lower alkyl;
• R2 is —NR8R10;
• R4 is —CHR12—;
• R3 is hydrogen, halogen, or —CN;
• R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
• the aryl group is substituted with 3 to 5 substituents,
• the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,
• the alicyclic group is substituted with 3 to 5 substituents,
• the heterocyclic group is substituted with 3 to 5 substituents, and
• the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N3, —SR8, —OR8, —CN, —C(O)R9, —NO2, —NR8R10, phosphonate and phosphonic acid;
• R8 is hydrogen, lower alkyl, lower aryl, or —C(O)R9;
• R9 is lower alkyl, lower aryl, lower heteroaryl, —NR10R10 or —OR11;
• R10 is independently hydrogen or lower alkyl;
• R11 is lower alkyl, lower aryl or lower heteroaryl;
• R12 is hydrogen or lower alkyl;
• and
• provided that
• when R5 is aryl, R5 is not an organo-metallic cyclopentadiene;
• when R5 is phenyl, the substituents are not 3,5 di-halo;
• when R5 is alicyclic, the ring system does not contain any tetra-substituted sp3 ring carbons;
• and
• when R5 is heterocyclic, the ring system does not contain any tetra-substituted sp3 ring carbons or the ring system is not a tetra-substituted pyrrolidine.

A method of treating an gingival having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I:

• or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
• R1 is halogen, —OR11, SR11, —NHR8, hydrogen, or lower alkyl;
• R2 is —NR8R10;
• R3 is hydrogen, halogen, —N3 or —CN;
• R1 is —(CHR12)n— where n=0, 1 or 2, —C(O)—, —C(S)—, or —S(O)—;
• R5 is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all optionally substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N3, —SR8, —OR8, —CN, —C(O)R9, —NO2, or —NR8R10;
• R8 is hydrogen, lower alkyl, lower aryl, or —C(O)R9;
• R9 is lower alkyl, lower aryl, lower heteroaryl, —NR10R10, or —OR11;
• R10 is independently hydrogen or lower alkyl;
• R11 is lower alkyl, lower aryl or lower heteroaryl;
• R12 is hydrogen or lower alkyl;
• and
• provided that:
• —R4R5 is not a ribose or derivative thereof, or a sugar or derivative thereof;
• —R4R5 is not a phosphonate or phosphonic acid, or substituted with phosphonate or phosphonic acid;
• and
• when R4 is —(CH2)n— where n=1 or 2, then R4 and R5 are not connected through an ether linkage.

A compound, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, prepared by the process comprising:

• reacting a compound of formula Y and a compound of formula Z, wherein:
• Y is represented by any of the following formulae, respectively:
• and
• Z is L1—R4—R5;
• wherein:
• L1 is halogen, NR8R10, triflate, tosylate, or mesylate;
• R4 is —CHR2—,
• R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
• the aryl group is substituted with 3 to 5 substituents,
• the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,
• the alicyclic group is substituted with 3 to 5 substituents,
• the heterocyclic group is substituted with 3 to 5 substituents, and
• the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N3, —SR8, —OR8, —CN, —C(O)R9, —NO2, —NR R8R10, phosphonate and phosphonic acid;
• R8 is hydrogen, lower alkyl, lower aryl, or —C(O)R9;
• R9 is lower alkyl, lower aryl, lower heteroaryl, —NR10R10 or —OR11;
• R10 is independently hydrogen or lower alkyl;
• R11 is lower alkyl, lower aryl or lower heteroaryl;
• R12 is hydrogen or lower alkyl;
• R21 is halogen, lower alkyl or —OH;
• R22 is —NR8R10;
• R23 is hydrogen, halogen, or —CN;
• R24 is —NH2, —NO2, or —NO;
• R25 is halogen or —OH;
• R26 is —C(O)NH2 or C(O)OEt;
• and
• R27 is —NH2, —OH or halogen;
• provided that:
• when R5 is aryl, R5 is not an organo-metallic cyclopentadiene;
• when R5 is phenyl, the substituents are not 3, 5 di-halo;
• when R5 is alicyclic, the ring system does not contain any tetra-substituted sp3 ring carbons;
• or
• when R5 is heterocyclic, the ring system does not contain any tetra-substituted sp3 ring carbons or the ring system is not a tetra-substituted pyrrolidine.