Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

A method of selectively inhibiting HDAC6 over other HDACs in a subject, comprising administering a compound of formula I:

• or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
• Z is N or CR*, wherein R* is an optionally substituted alkyl, an optionally substituted acyl, an optionally substituted aryl or an optionally substituted heteroaryl;
• ring A is an optionally substituted aryl or an optionally substituted heteroaryl;
• ring B is an optionally substituted aryl or an optionally substituted heteroaryl;
• R1 is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R2, C(O)O—R2, or S(O)p, each of which may be optionally substituted;
• or (ii) when Z is CR*, R1 may be optionally substituted branched alkyl, OR3, or N(R3)(R3), —CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;
• or ring B and R1 may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;
• or R* and R1 together with the atom to which each is attached, may form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl ring;
• R is H or an optionally substituted alkyl;
• or R and ring A may be joined to form a fused bicyclic ring which may be optionally substituted;
• each R2 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• each R3 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• n is 4, 5, 6, 7 or 8;
• and
• p is 0, 1,or 2.

A method of treating a disease mediated by HDAC-6 in a subject comprising administering to the subject a compound of formula I:

• or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
• Z is N or CR*, wherein R* is an optionally substituted alkyl, an optionally substituted acyl, an optionally substituted aryl or an optionally substituted heteroaryl;
• ring A is an optionally substituted aryl or an optionally substituted heteroaryl;
• ring B is an optionally substituted aryl or an optionally substituted heteroaryl;
• R1 is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R2, C(O)O—R2, or S(O)p, each of which may be optionally substituted;
• or (ii) when Z is CR*, R1 may be optionally substituted branched alkyl, OR3, or N(R3)(R3), —CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;
• or ring B and R1 may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;
• or R* and R1 together with the atom to which each is attached, may form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl ring;
• R is H or an optionally substituted alkyl;
• or R and ring A may be joined to form a fused bicyclic ring which may be optionally substituted;
• each R2 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• each R3 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• n is 4, 5, 6, 7 or 8;
• and
• p is 0, 1, or 2.

A method of treating a subject suffering from or susceptible to multiple myeloma comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
• Z is N or CR*, wherein R* is an optionally substituted alkyl, an optionally substituted acyl, an optionally substituted aryl or an optionally substituted heteroaryl;
• ring A is an optionally substituted aryl or an optionally substituted heteroaryl;
• ring B is an optionally substituted aryl or an optionally substituted heteroaryl;
• R1 is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R2, C(O)O—R2, or S(O)p, each of which may be optionally substituted;
• or (ii) when Z is CR*, R1 may be optionally substituted branched alkyl, OR3, or N(R3)(R3), —CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;
• or ring B and R1 may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;
• or R* and R1 together with the atom to which each is attached, may form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl ring;
• R is H or an optionally substituted alkyl;
• or R and ring A may be joined to form a fused bicyclic ring which may be optionally substituted;
• each R2 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• each R3 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• n is 4, 5, 6, 7 or 8;
• and
• p is 0, 1, or 2;
• to thereby treat the subject suffering from or susceptible to multiple myeloma.

A kit comprising a compound capable of inhibiting HDAC activity selected from one or more compounds of formula I:

• or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
• Z is N or CR*, wherein R* is an optionally substituted alkyl, an optionally substituted acyl, an optionally substituted aryl or an optionally substituted heteroaryl;
• ring A is an optionally substituted aryl or an optionally substituted heteroaryl;
• ring B is an optionally substituted aryl or an optionally substituted heteroaryl;
• R1 is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R2, C(O)O—R2, or S(O)p, each of which may be optionally substituted;
• or (ii) when Z is CR*, R1 may be optionally substituted branched alkyl, OR3, or N(R3)(R3), —CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;
• or ring B and R1 may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;
• or R* and R1 together with the atom to which each is attached, may form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl ring;
• R is H or an optionally substituted alkyl;
• or R and ring A may be joined to form a fused bicyclic ring which may be optionally substituted;
• each R2 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• each R3 is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
• n is 4, 5, 6, 7 or 8;
• and
• p is 0, 1, or 2;
• and instructions for use in treating multiple myeloma.