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1. (WO2011091213) REVERSE AMIDE COMPOUNDS AS PROTEIN DEACETYLASE INHIBITORS AND METHODS OF USE THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED:

1. 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;

Ri is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, C(0)0-R2, or S(0)p, each of which may be optionally substituted; or (ii) when Z is CR*, Ri may be optionally substituted branched alkyl, OR3, or N(R3)(R3)-CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;

or ring B and Ri may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;

or R* and Ri 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.

2. The compound of claim 1, wherein ring A is phenyl, naphthyl, anthracenyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, furyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, or 5,6,7,8-tetrahydroisoquinoline; each of which may be optionally substituted.

3. The compound of claim 1, wherein ring B is phenyl, naphthyl, anthracenyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, furyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, or 5,6,7,8-tetrahydroisoquinoline; each of which may be optionally substituted.

4. The compound of claim 1, wherein Ri is H, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or Ri is OH or alkoxy.

5. The compound of claim 4, wherein Ri is H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, phenyl, naphthyl, pyridinyl, OH or OCH3; each of which may be optionally substituted.

6. The compound of claim 1, wherein Ri is OH, alkoxy, NH2, NH(alkyl), N(alkyl)(alkyl), NH-aryl, NH-hetroaryl, N(aryl)(aryl), N(aryl)(heteroaryl), or

N(hetero aryl) (hetero aryl) .

7. The compound of claim 1, wherein the carbonyl and the Z group attached to ring A are disposed para to each other.

8. The compound of claim 1, wherein the carbonyl and Z group attached to ring A are disposed meta to each other.

9. The compound of claim 1, wherein the carbonyl and the Z group attached to ring A are disposed ortho to each other.

The compound of claim 1, of formula II:


or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

each of Xi, X2, X3, or X4 is independently N, CR', O, S, NCR', CR'CR', OCR', SCR', or absent, or Xi or X4 may be joined with R to form a bicyclic ring; wherein up to three of Xl5 X2, X3, or X4 may be N;

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

Ri is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, or C(0)0-R2, each of which may be optionally substituted;

R is H or an optionally substituted alkyl; or R and Xi or X4 may be joined to form a fused bicyclic ring which may be optionally substituted;

each R' is independently H, optionally substituted alkyl, halo, OH, NH2, NHR", haloalkyl, CN, N3, N02;

R" is H or alkyl; and

R2 is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted.

11. The compound of claim 10, wherein Xl5 X2, X3, and X4 are all CR' .

12. The compound of claim 10, wherein X2 and X3, are N and Xi and X4 are CR'.

13. The compound of claim 10, wherein X2 and X3, are CR' and Xi and X4 are N.

14. The compound of claim 10, wherein X2, is N; X3 is S, N or O; Xi is CR' and X4 is absent.

15. The compound of claim 10, wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted.

16. The compound of claim 15, wherein ring B is substituted by alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, haloalkyl, hal, OH, NH2, NHR", CN, N3, or N02.

17. The compound of claim 10, wherein Ri is H, alkyl, aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted.

The compound of claim 1, of formula III:


or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

Ri is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, or C(0)0-R2, each of which may be optionally substituted;

R2 is optionally substituted heteroaryl, and

R is H or an optionally substituted alkyl; or R and the phenyl ring may be joined to form a fused [6,5] bicyclic ring which may be optionally substituted.

19. The compound of claim 18, wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted.

20. The compound of claim 19, wherein ring B is substituted by alkyl, aryl, aralkyl, haloalkyl, hal, OH, NH2, CN, or N02.

21. The compound of claim 18, wherein Ri is H, alkyl, aryl, arylalkyl, heteroaryl, C(0)-R2, or C(0)0-R2, each of which may be optionally substituted.

22. The compound of claim 21, wherein R2 is optionally substituted pyridinyl.

23. The compound of claim 1, of formula IV:


(IV); or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

Ri is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;

or ring B and Ri may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl, and

R is H or an optionally substituted alkyl; or R and the 1,3-pyrimidinyl ring may be joined to form a fused bicyclic ring which may be optionally substituted.

24. The compound of claim 23, wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted.

25. The compound of claim 24, wherein ring B is substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH2, CN, or N02.

26. The compound of claim 23, wherein Ri is H, alkyl, aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted.

27. The compound of claim 26, wherein Ri is substituted by OH, halo,

28. The compound of claim 23, wherein the ring formed by ring B and Ri is piperidine, pyrrolidine, tetrahydroquinoline, morpholine, piperazine, tetrahydro-triazolo pyrazine, diazepane, each of which is optionally substituted.

29. The compound of claim 1, of formula V:


or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

each of Xi, X2, or X3 is independently N or CR' ;

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

Ri is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;

each RA and RB is independently H, NH(RC), N(Rc)(Rc), N(Rc)CO(Rc), C02H, C(0)Rc, C(0)ORc, C(0)NH2, C(0)NH(Rc), C(0)N(Rc)(Rc), S02Rc, SORc, SRC, alkyl, ar arylalkyl, alkoxy, heteroaryl, heterocyclic, and carbocyclic, each of which may be further substituted; or RA and RB together with the carbon to which they are attached form a carbonyl;

each Rc is independently H, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclic, each of which may be further substituted;

R' is H, optionally substituted alkyl, halo, OH, NH2, NHR", haloalkyl, CN, N3, N02 R" is H or alkyl; and

m is 1 or 2.

The compound of claim 1, of formula Va:


or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

each of Xl5 X2, or X3 is independently N or CR' ;

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

Ri is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;

each RA and RB is independently H, NH(RC), N(RC)(RC), N(Rc)CO(Rc), C02H, C(0)Rc, C(0)ORc, C(0)NH2, C(0)NH(Rc), C(0)N(Rc)(Rc), S02Rc, SORc, SRC, alkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, and carbocyclic, each of which may be further substituted; or RA and RB together with the carbon to which they are attached form a carbonyl;

each Rc is independently H, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or

heterocyclic, each of which may be further substituted;

R' is H, optionally substituted alkyl, halo, OH, NH2, NHR", haloalkyl, CN, N3, N02;

R" is H or alkyl; and

m is 1 or 2.

31. The compound of claim 29 or claim 30, wherein Xi, X2, and X3, are all independently CR' .

32. The compound of claim 29 or claim 30, wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted.

33. The compound of claim 32, wherein ring B is substituted by alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, haloalkyl, halo, OH, NH2, NHR", CN, N3, or N02.

34. The compound of claim 29 or claim 30, wherein Ri is H, alkyl, aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted.

The compound of claim 1, of formula VI:


(VI); or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring B is an optionally substituted aryl or an optionally substituted heteroaryl;

R* is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl;

Ri is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, OH, alkoxy, NH2, NH(alkyl), or N(alkyl)(alkyl);

or R* and Ri 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; and

R is H or an optionally substituted alkyl.

36. The compound of claim 35, wherein ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or thiazole; each of which may be optionally substituted.

37. The compound of claim 35, wherein R* is methyl, trifluoromethyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or thiazole; each of which may be optionally substituted.

38. The compound of claim 35, wherein Ri is OH, methoxy, or ethoxy.

39. The compound of claim 35, wherein ring B and R* are each independently substituted with one or more of alkyl, halogen, or C(0)NRxRy, wherein Rx is H or alkyl, and RY is H or alkyl.

40. The compound of claim 39, wherein ring B and R* are each independently substituted with one or more of methyl, F, or C(0)N(Me)2.

41. The compound of claim 1, selected from the following:

4-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(dipyrimidin-2-ylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(bis(4-methoxyphenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-((2,6-dichlorophenyl)(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(dipyrimidin-2-ylamino)-N-(8-(hydroxyamino)-8-oxooctyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methyl(2-(trifluoromethyl)phenyl) amino)benzamide; 4-((2,6-diisopropylphenyl)(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(methyl(phenyl)amino)pyrimidine-5-carboxamide; 4-(2,6-diisopropylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-((2-isopropylphenyl)(methyl)amino)pyrimidine-5-carboxamide;

4-(2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(ethyl(2-(trifluoromethyl)phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide; 4-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(dipyrimidin-2-ylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-((2,6-dichlorophenyl)(ethyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(2,6-dichlorophenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenyl(pyrimidin-2-yl)amino)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-((2-isopropylphenyl)(methyl)amino)-N-methylpyrimidine-5-carboxamide;

4-((2-chloro-6-methylphenyl)(methyl) amino)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide;

4-((2,6-difluorophenyl)(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide;

4-(ethyl(2-(trifluoromethyl)phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(2,6-difluorophenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(bis(3-chlorophenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

7-(4-((2,6-difluorophenyl)(methyl) amino)benzylamino)-N-hydroxy heptanamide;

2-(2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(methyl(pyrazin-2-yl)amino)pyrimidine-5-carboxamide;

4-(2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide 4-(ethyl(pyrazin-2-yl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(l -methyl- lH-benzo[d]imidazol-2-ylamino)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenyl(pyrimidin-5-yl)amino)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(N-phenylacetamido)benzamide;

4-(benzo[d]oxazol-2-ylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenyl(pyrazin-2-yl)amino)benzamide;

2-(2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylpyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenyl(pyridin-2-yl)amino)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(N-phenylphenylsulfonamido)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenyl(pyridin-3-yl)amino)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-((3-methylpyridin-2-yl)(phenyl)amino) benzamide; 4-(benzo[d]oxazol-2-yl(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide ;

4-(benzo[d]oxazol-2-yl(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-((2-cyanophenyl)(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(benzo[d]thiazol-2-ylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(N-(2,6-dimethylphenyl)acetamido)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(phenyl(pyridin-3-yl)amino) benzamide;

4-((2-cyanophenyl)(methyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenylamino)benzamide;

4-(2,6-dimethylphenylamino)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide;

4-((2,6-dimethylphenyl)(methyl)amino)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(phenylamino)benzamide;

4-((2,6-dimethylphenyl)(methyl)amino)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(N-phenylacetamido)benzamide;

4-(N-(2,6-dimethylphenyl)acetamido)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(N-phenylisobutyramido) benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(phenyl(pyridin-2-yl)amino) benzamide;

4-(N-(2,6-dimethylphenyl)isobutyramido)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(2,6-dimethylphenylamino)-3-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(benzo[d]thiazol-2-ylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide; 4-(N-(2,6-dimethylphenyl)-3-methylbutanamido)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(2,6-dimethylphenylamino)-3-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide ;

3-(2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

3- (2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide; 4-(2,6-diisopropylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-((3-methylpyridin-2-yl)(phenyl)amino) benzamide;

2-(2,6-dimethylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-4-(mesitylamino)-N-methylbenzamide;

4-(2-chloro-6-methylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4- ((2,6-dimethylphenyl)(pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(phenyl(pyrimidin-2-yl)amino)benzamide; 4-(2,6-dimethylphenylamino)-N-(6-(hydroxyamino)-6-oxohexyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(phenyl(o-tolyl)amino)pyrimidine-5-carboxamide; N-(7-(hydroxyamino)-7-oxoheptyl)-2-(mesitylamino)-N-methylpyrimidine-5-carboxamide; 4-((2,6-dimethylphenyl)(pyrimidin-2-yl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

2-(2,6-diisopropylphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylpyrimidine-5-carboxamide;

4-(2,6-dimethylphenylamino)-N-(5-(hydroxyamino)-5-oxopentyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(hydroxydiphenylmethyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxydiphenylmethyl)benzamide;

4-(hydroxy(phenyl)(pyridin-4-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl-4-(N-phenylbenzamido)benzamide;

N-(4-(7-(hydroxyamino)-7-oxoheptylcarbamoyl)phenyl)-N-phenylbenzamide;

4-(bis(4-fluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(bis(4-fluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxy(phenyl)(pyridin-3-yl)methyl)benzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxy(phenyl)(pyridin-3-yl)methyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxy(phenyl)(pyridin-2-yl)methyl) benzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-4-(hydroxydipyridin-2-ylmethyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(hydroxydipyridin-2-ylmethyl)-N-methyl benzamide; 2-(di-o-tolylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-((2,6-dimethylphenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

7-(5-(2,6-dimethylphenylamino)-l-oxoisoindolin-2-yl)-N-hydroxyheptanamide;

7-(5-(2,6-dimethylphenylamino)-l,3-dioxoisoindolin-2-yl)-N-hydroxyheptanamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxydipyridin-2-ylmethyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxydipyridin-2-ylmethyl)-N-methylbenzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-2-(pyridin-2-yl(o-tolyl)amino)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(pyridin-4-yl(o-tolyl)amino)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(methoxy(phenyl)(pyridin-4-yl)methyl)benzamide; 4-(hydroxy(phenyl)(pyridin-4-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

N-(4-(7-(hydroxyamino)-7-oxoheptyl carbamoyl )phenyl)-N-phenylpicolinamide;

4-(ethoxydiphenylmethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(bis(3-f uorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(3-f uorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(bis(3-f uorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(l-(4-fluorophenyl)-l-hydroxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

N-(4-(7-(hydroxyamino)-7-oxoheptyl carbamoyl )phenyl)-N-phenylpicolinamide;

4-(ethoxydiphenylmethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(ethoxydiphenylmethyl)-N-(7-(hydroxy amino)-7-oxoheptyl)-N-methylbenzamide;

4-(ethoxydipyridin-2-ylmethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(ethoxydipyridin-2-ylmethyl)-N-(7-(hydroxy amino)-7-oxoheptyl)-N-methylbenzamide;

4-(bis(3-f uorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(3-fluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

4-(bis(3-fluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(3-fluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

4-(l-(4-fluorophenyl)-l-hydroxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(l-(4-fluorophenyl)-l-hydroxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(l-(4-fluorophenyl)-l-hydroxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(l-(4-fluorophenyl)-l-hydroxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

4-(l-(4-fluorophenyl)-l-methoxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(l-(4-fluorophenyl)-l-methoxyethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

4-(l -hydroxy- l-(pyridin-2-yl)ethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(l -hydroxy- l-(pyridin-2-yl)ethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(l-methoxy-l-(pyridin-2-yl)ethyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(l-methoxy-l-(pyridin-2-yl)ethyl)-N-methylbenzamide;

4-(bis(2-f uorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(2-f uorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

4-(bis(2-f uorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(2-f uorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methyl benzamide;

4-(bis(2,4-difluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(bis(2,4-difluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(bis(2,4-difluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(2,4-difluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(bis(3,5-difluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(3,5-difluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide ;

4-(bis(3,5-difluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 4-(bis(3,5-difluorophenyl)(methoxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-(bis(4-fluoro-2-methylphenyl) (hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-(bis(4-fluoro-2-methylphenyl)(methoxy) methyl)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide;

4-((4-fluorophenyl)(hydroxy)(pyridin-2-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-((4-fluorophenyl)(hydroxy)(pyridin-2-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

4-((4-fluorophenyl)(methoxy)(pyridin-2-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide;

4-((4-fluorophenyl)(methoxy)(pyridin-2-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(hydroxydithiazol-2-ylmethyl)benzamide;

3- (bis(4-fluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide; 3-(bis(4-fluorophenyl)(hydroxy)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylbenzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(2,2,2-trifluoro-l-(4-fluorophenyl)-l-hydroxyethyl) benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(2,2,2-trifluoro-l-(4-fluorophenyl)-l-methoxyethyl) benzamide;

4- (2-(4-fluorophenyl)tetrahydrofuran-2-yl)-N-(7-(hydroxyamino)-7-oxoheptyl) benzamide; N-(7-(hydroxyamino)-7-oxoheptyl)-2-((2-hydroxyethyl)(phenyl)amino)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-3-(hydroxydipyridin-2-ylmethyl)benzamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-3-(methoxydipyridin-2-ylmethyl)benzamide;

4-(hydroxy(4-(7-(hydroxyamino)-7-oxoheptylcarbamoyl)phenyl)(phenyl)methyl)-N,N-dimethylbenzamide;

3-(hydroxy(4-(7-(hydroxyamino)-7-oxoheptylcarbamoyl)phenyl)(phenyl)methyl)-N,N-dimethylbenzamide ;

2- (bis(4-fluorophenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide; N-(7-amino-7-oxoheptyl)-2-(diphenylamino)pyrimidine-5-carboxamide;

4-((4-(7-(hydroxyamino)-7-oxoheptylcarbamoyl)phenyl)(methoxy)(phenyl)methyl)-N,N-dimethylbenzamide;

3- ((4-(7-(hydroxyamino)-7-oxoheptylcarbamoyl)phenyl)(methoxy)(phenyl)methyl)-N,N-dimethylbenzamide;

7-(2-(diphenylamino)pyrimidine-5-carboxamido)heptanoic acid;

N-(7-(hydroxyamino)-7-oxoheptyl)-4-(3-oxo-l-phenyl-l,3-dihydroisobenzofuran-l-yl)benzamide;

2-(bis(4-fluorophenyl)methylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-(3,4-dihydroquinolin-l(2H)-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-(3,4-dihydroisoquinolin-2(lH)-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-((2,2-bis(4-fluorophenyl)ethyl)(2-hydroxyethyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-((2-(lH-indol-3-yl)ethyl)(2-hydroxyethyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-morpholinopyrimidine-5-carboxamide;

2-((2S,6R)-2,6-dimethylmorpholino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(piperazin-l-yl)pyrimidine-5-carboxamide;

2-(4-benzylpiperazin-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-(2-hydroxyethyl)piperazin-l-yl)pyrimidine-5-carboxamide;

2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine- 5 -carboxamide ;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(3-(trif uoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-phenylpiperazin-l-yl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-(4-methoxyphenyl)piperazin-l-yl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-(2-methoxyethyl)piperazin-l-yl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-(4-(trifluoro

yl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(2-(hydroxymethyl)morpholino)pyrimidine-5-carboxamide;

(R)-N-(7-(hydroxyamino)-7-oxoheptyl)-2-(3-hydroxypiperidin-l-yl)pyrimidine-5-carboxamide;

2-(4-carbamoylpiperidin-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-(4-hydroxy-4-phenylpiperidin-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-(4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

(R)-2-(3-(dimethylamino)pyrrolidin-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrim carboxamide;

(S)-N-(7-(hydroxyamino)-7-oxoheptyl)-2-(2-(hydroxymethyl)pyrrolidin-l-yl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-methyl-2-phenylpiperazin-l-yl)pyrimidine-5-carboxamide;

2-(4-(4-fluorophenyl)piperazin-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

2-(l,4-diazepan-l-yl)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide;

N-(7-(hydroxyamino)-7-oxoheptyl)-2-(piperidin-l-yl)pyrimidine-5-carboxamide; and N-(7-(hydroxyamino)-7-oxoheptyl)-2-(4-methylpiperazin-l-yl)pyrimidine-5-carboxamide.

42. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.

43. 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;

Ri is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, C(0)0-R2, or S(0)p, each of which may be optionally substituted; or (ii) when Z is CR*, Ri may be optionally substituted branched alkyl, OR3, or N(R3)(R3), -CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;

or ring B and Ri may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;

or R* and Ri 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.

44. The method of claim 43, wherein the compound of formula I has a selectivity for HDAC6 of 5 to 1000 fold.

45. The method of claim 43, wherein the compound of formula I has a selectivity for HDAC6 when tested in a HDAC enzyme assay of about 5 to 1000 fold.

46. 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;

Ri is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, C(0)0-R2, or S(0)p, each of which may be optionally substituted; or (ii) when Z is CR*, Ri may be optionally substituted branched alkyl, OR3, or N(R3)(R3), -CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;

or ring B and Ri may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;

or R* and Ri 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.

47. The method of claim 46, wherein the disease is cancer or a proliferation disease.

48. The method of claim 47, wherein the disease is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, gliobastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, and solid tumors.

49. The method of claim 47, wherein the cancer is multiple myeloma.

50. The method of claim 46, wherein the disease is Wilson's disease,

spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, amyloidosis, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's Disease, spinal muscular dystrophy or Lewy body dementia.

51. The method of claim 46, wherein the disease is rheumatoid arthritis, osteoarthritis; rheumatoid spondylitis; psoriasis; post ischemic perfusion injury; inflammatory bowel disease; chronic inflammatory pulmonary disease, eczema, asthma, psoriasis, ischemia/reperfusion injury, ulcerative colitis, acute respiratory distress syndrome, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis, hemolytic anemia, aplasic anemia, idiopathic

thrombocytopenia, neutropenia, ulcerative colitis, Crohn's disease, host versus graft disease, allograft rejection, chronic thyroiditis, Graves' disease, schleroderma, diabetes, active hepatitis, primary binary cirrhosis, myasthenia gravis, multiple sclerosis (MS), systemic lupus erythematosus, atopic dermatitis, contact dermatitis, skin sunburns, chronic renal

insufficiency, Stevens-Johnson syndrome, idiopathic sprue, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, or chronic inflammatory pulmonary disease.

52. 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 o


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;

Ri is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, C(0)0-R2, or S(0)p, each of which may be optionally substituted; or (ii) when Z is CR*, Ri may be optionally substituted branched alkyl, OR3, or N(R3)(R3), -CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;

or ring B and Ri may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;

or R* and Ri 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.

53. The method of claim 46, further comprising co-administering one or more of a chemotherapeutic agent, radiation agent, hormonal agent, biological agent or an antiinflammatory agent to the subject.

54. The method of claim 53, wherein the chemotherapeutic agent is tamoxifen, trastuzamab, raloxifene, doxorubicin, fluorouracil/5-fu, pamidronate disodium, anastrozole, exemestane, cyclophosphamide, epirubicin, letrozole, toremifene, fulvestrant, fluoxymester-one, trastuzumab, methotrexate, megastrol acetate, docetaxel, paclitaxel, testolactone, aziridine, vinblastine, capecitabine, goselerin acetate, zoledronic acid, taxol, vinblastine, or vincristine.

55. The method of any one of claims 46-54, wherein the subject is a human.

56. A kit comprising a compound capable of inhibiting HDAC activity selected 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;

Ri is (i) H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(0)-R2, C(0)0-R2, or S(0)p, each of which may be optionally substituted; or (ii) when Z is CR*, Ri may be optionally substituted branched alkyl, OR3, or N(R3)(R3), -CH2CH2OH, OCH2CH2OH, SH, or thio alkoxy;

or ring B and Ri may together with the atom to which each is attached, form an optionally substituted heterocyclic, or an optionally substituted heteroaryl;

or R* and Ri 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.