Hdac inhibitors

Abstract

Compounds of formula (I) inhibit HDAC activity: wherein A, B and D independently represent ═C— or ═N—; W is a divalent radical —CH═CH— or CH 2 CH 2 —; R 1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; R 2 is the side chain of a natural or non-natural alpha amino acid; z is 0 or 1; and Y, L 1 , and X 1 are as defined in the claims.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         one of A, B and D is ═N— and the others are each ═C—, and wherein the radical HONHC(═O)—W— is attached to the ring containing A, B and D in a position meta- or para- to the radical R 1 R 2 CHNHYL 1 X 1 [CH 2 ] z —; 
         W is a divalent radical —CH═CH— or —CH 2 CH 2 —; 
         R 1  is an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group, wherein the ester group is of formula —(C═O)OR 9  wherein R 9  is R 20 R 21 R 22 C wherein 
         (i) R 20  is hydrogen or optionally substituted (C 1 -C 3 )alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b — or (C 2 -C 3 )alkenyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b — wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NR C — wherein R C  is hydrogen or (C 1 -C 3 )alkyl; and R 21  and R 22  are independently hydrogen or (C 1 -C 3 )alkyl-; 
         (ii) R 20  is hydrogen or optionally substituted R 12 R 13 N—(C 1 -C 3 )alkyl- wherein R 12  is hydrogen or (C 1 -C 3 )alkyl and R 13  is hydrogen or (C 1 -C 3 )alkyl; or R 12  and R 13  together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 21  and R 22  are independently hydrogen or (C 1 -C 3 )alkyl-; or 
         (iii) R 20  and R 21  taken together with the carbon to which they are attached form an optionally substituted monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, and R 22  is hydrogen; 
         R 2  is benzyl, phenyl, cyclohexylmethyl, cyclohexyl, pyridin-3-ylmethyl, tert-butoxymethyl (—CH 2 O(t-Bu)), iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, phenylethyl, —CH 2 S(t-Bu) or —CH(CH 3 ) 2 ; 
         Y is a bond, —S(═O) 2 —, —C(═S)—NR 3 , —C(═NH)NR 3  or 
         —S(═O) 2 NR 3 — wherein R 3  is hydrogen or optionally substituted C 1 -C 6  alkyl; 
         L 1  is a divalent radical of formula -(Alk 1 ) m (Q) n (Alk 2 ) p - wherein 
         m, n and p are independently 0 or 1, 
         Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula X 2 -Q 1 - or -Q 1 -X 2 — wherein X 2  is —O—, S— or NR A — wherein R A  is hydrogen or optionally substituted C 1 -C 3  alkyl, and Q 1  is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, 
         Alk 1  and Alk 2  independently represent optionally substituted divalent C 3 -C 7 cycloalkyl radicals, or optionally substituted straight or branched, C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (—NR A —) link wherein R A  is hydrogen or optionally substituted C 1 -C 3  alkyl; 
         X 1  represents a bond; —C(═O); or —S(═O) 2 —; —NR 4 C(═O)—, —C(═O)NR 4 —, —NR 4 C(═O)NR 5 —, —NR 4 S(═O) 2 —, or —S(═O) 2 NR 4 — wherein R 4  and R 5  are independently hydrogen or optionally substituted C 1 -C 6  alkyl; and 
         z is 0 or 1; 
         wherein the term “substituted” as applied to any moiety means substituted with up to four compatible substituents, each of which is independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, halo trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, —COOH, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —NH 2 , —NHR A , —NR A R B , —OCONH 2 , —OCONHR A , —OCONR A R B , —NHCOR A , —NHCOOR A , —NR B COOR A , —NHSO 2 OR A , —NR B SO 2 OH, —NR B SO 2 OR A , —NHCONH 2 , —NR A CONH 2 , —NHCONHR B , —NR A CONHR B , —NHCONR A R B , or —NR A CONR A R B  wherein R A  and R B  are independently a (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, or R A  and R B  when attached to the same nitrogen atom form a cyclic amino group; and wherein the nitrogen of the group R 1 CH(R 2 )NH— is not directly linked to a carbonyl (—C(═O)—). 
       
     
     
         2 . A compound as claimed in  claim 1 , wherein W is —CH 2 CH 2 —. 
     
     
         3 . A compound as claimed in  claim 1  wherein, in the radical R 1 R 2 CHNHYL 1 X 1 [CH 2 ] z —, Y is a bond. 
     
     
         4 . A compound as claimed in  claim 1  wherein, in the radical R 1 R 2 CHNHYL 1 X 1 [CH 2 ] z —, X 1  is a bond. 
     
     
         5 . A compound as claimed in  claim 1  wherein the radical —YL 1 X 1 [CH 2 ] z — is —CH 2 —. 
     
     
         6 . A compound as claimed in  claim 1  wherein R 9  is methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- or 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl or methoxyethyl. 
     
     
         7 . A compound as claimed in  claim 1  wherein R 9  is cyclopentyl. 
     
     
         8 . A compound as claimed in  claim 1  wherein R 2  is phenyl, benzyl, phenylethyl, tert-butoxymethyl or iso-butyl. 
     
     
         9 . A compound as claimed in  claim 1  wherein R 2  is —CH(CH 3 ) 2 , cyclohexyl, —CH 2 O(t-Bu), —CH 2 S(t-Bu), or phenyl. 
     
     
         10 . A compound of formula (IB) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         W is a divalent radical —CH═CH— or —CH 2 CH 2 —; 
         R 1  is an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group, wherein the ester group is of formula —(C═O)OR 9  wherein R 9  is R 20 R 21 R 22 C wherein 
         (i) R 20  is hydrogen or optionally substituted (C 1 -C 3 )alkyl-(Z 1 ) a -[(C 1 -C 3 )alkyl] b — or (C 2 -C 3 )alkenyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NR C — wherein R C  is hydrogen or (C 1 -C 3 )alkyl; and R 21  and R 22  are independently hydrogen or (C 1 -C 3 )alkyl-; 
         (ii) R 20  is hydrogen or optionally substituted R 12 R 13 N—(C 1 -C 3 )alkyl- wherein R 12  is hydrogen or (C 1 -C 3 )alkyl and R 13  is hydrogen or (C 1 -C 3 )alkyl; or R 12  and R 13  together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 21  and R 22  are independently hydrogen or (C 1 -C 3 )alkyl-; or 
         (iii) R 20  and R 21  taken together with the carbon to which they are attached form an optionally substituted monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, and R 22  is hydrogen; 
         R 2  is benzyl, phenyl, cyclohexylmethyl, cyclohexyl, pyridin-3-ylmethyl, tert-butoxymethyl (—CH 2 O(t-Bu)), iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, phenylethyl, —CH 2 S(t-Bu) or —CH(CH 3 ) 2 ; 
         wherein the term “substituted” as applied to any moiety means substituted with up to four compatible substituents, each of which is independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, phenyl, halo trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, —COOH, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —NH 2 , —NHR A , —NR A R B , —OCONH 2 , —OCONHR A , —OCONR A R B , —NHCOR A , —NHCOOR A , —NR B COOR A , —NHSO 2 OR A , —NR B SO 2 OH, —NR B SO 2 OR A , —NHCONH 2 , —NR A CONH 2 , —NHCONHR B , —NR A CONHR B , —NHCONR A R B , or —NR A CONR A R B  wherein R A  and R B  are independently a (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, or R A  and R B  when attached to the same nitrogen atom form a cyclic amino group; and wherein the nitrogen of the group R 1 CH(R 2 )NH— is not directly linked to a carbonyl (—C(═O)—). 
       
     
     
         11 . A compound as claimed in  claim 1 , wherein the term ‘substituted’ as applied to any moiety means substituted with up to four (C 1 -C 6 ) alkyl groups. 
     
     
         12 . A compound as claimed in  claim 10 , wherein
 W is —CH 2 CH 2 —;   R 1  is an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group, wherein the ester group is of formula —(C═O)OR 9  wherein R 9  is R 20 R 21 R 22 C wherein   (i) R 20  is hydrogen or optionally substituted (C 1 -C 3 )alkyl-(Z 1 ) a -[(C 1 -C 3 )alkyl] b — or (C 2 -C 3 )alkenyl-(Z 1 ) a -[(C 1 -C 3 )alkyl] b — wherein a and b are independently 0 or 1 and Z 1  is —O—, —S—, or —NR C — wherein R C  is hydrogen or (C 1 -C 3 )alkyl; and R 21  and R 22  are independently hydrogen or (C 1 -C 3 )alkyl-;   (ii) R 20  is hydrogen or optionally substituted R 12 R 13 N—(C 1 -C 3 )alkyl- wherein R 12  is hydrogen or (C 1 -C 3 )alkyl and R 13  is hydrogen or (C 1 -C 3 )alkyl; or R 12  and R 13  together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 21  and R 22  are independently hydrogen or (C 1 -C 3 )alkyl-; or   (iii) R 20  and R 21  taken together with the carbon to which they are attached form an optionally substituted monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, and R 22  is hydrogen; and   R 2  is —CH(CH 3 ) 2 , cyclohexyl, —CH 2 O(t-Bu), —CH 2 S(t-Bu), or phenyl;   wherein the term ‘substituted’ as applied to any moiety means substituted with up to four (C 1 -C 6 ) alkyl groups.   
     
     
         13 . A compound as claimed in  claim 1  selected from the group consisting of:
 Cyclopentyl (2S)-cyclohexyl({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)acetate, 
 Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-L-leucinate, 
 Cyclopentyl (2S)-cyclohexyl({4-[3-(hydroxyamino)-3-oxopropyl]benzyl}amino)acetate, 
 Cyclopentyl N-{4-[3-(hydroxyamino)-3-oxopropyl]benzyl}-L-leucinate, 
 tert-Butyl N-{4-[3-(hydroxyamino)-3-oxopropyl]benzyl}-L-leucinate, 
 Cyclopentyl (2S)-cyclohexyl[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]acetate, 
 Cyclopentyl N-({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)-L-leucinate, 
 tert-Butyl N-({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)-L-leucinate, 
 Cyclopentyl (2S)-cyclohexyl[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-2-yl}methyl)amino]acetate, 
 tert-Butyl N-({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-2-yl}methyl)-L-leucinate, 
 Cyclopentyl (2S)-cyclohexyl[({5-[3-(hydroxyamino)-3-oxopropyl]pyridin-2-yl}methyl)amino]acetate, 
 tert-Butyl N-({5-[3-(hydroxyamino)-3-oxopropyl]pyridin-2-yl}methyl)-L-leucinate, 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         14 . A pharmaceutical composition comprising a compound as claimed in  claim 1 , together with a pharmaceutically acceptable carrier. 
     
     
         15 . A method for the treatment of cell-proliferation disease, polyglutamine disease, neurodegenerative disease, autoimmune disease, inflammatory disease, organ transplant rejection, diabetes, haematological disorders or infection, which comprises administering to a subject suffering from such disease an effective amount of a compound as claimed in  claim 1 . 
     
     
         16 . A method as claimed in  claim 15  wherein treatment is of cancer, psoriasis, inflammatory bowel disease, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease, systemic lupus erythematosus, or rheumatoid arthritis. 
     
     
         17 . A method as claimed in  claim 15  wherein the treatment is of cancer cell proliferation, Huntingdon disease, or Alzheimer disease. 
     
     
         18 . A method as claimed in  claim 15  wherein the treatment is of rheumatoid arthritis. 
     
     
         19 . A method for the treatment of cell-proliferation disease, polyglutamine disease, neurodegenerative disease, autoimmune disease, inflammatory disease, organ transplant rejection, diabetes, haematological disorders or infection, which comprises administering to a subject suffering from such disease an effective amount of a compound as claimed in  claim 12 . 
     
     
         20 . A method for the treatment of cancer, psoriasis, inflammatory bowel disease, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease, systemic lupus erythematosus, or rheumatoid arthritis, which comprises administering to a subject suffering from such disease an effective amount of a compound as claimed in  claim 12 . 
     
     
         21 . A pharmaceutical composition comprising a compound as claimed in  claim 10 , together with a pharmaceutically acceptable carrier. 
     
     
         22 . A method for the treatment of cell-proliferation disease, polyglutamine disease, neurodegenerative disease, autoimmune disease, inflammatory disease, organ transplant rejection, diabetes, haematological disorders or infection, which comprises administering to a subject suffering from such disease an effective amount of a compound as claimed in  claim 10 .