Anti-tumour polycyclic carboxamides

Abstract

This invention relates to polycyclic carboxamide compounds of the formula I: with cytotoxicity, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment and/or prophylaxis of cellular proliferative disorders such as cancer.

1 . A compound of the formula IV: 
     
       
         
         
             
             
         
       
     
     in which positional numbering, where mentioned, refers to the system illustrated above, and one or more Z are attached to a ring carbon or carbons at any of positions 6 to 10, and in which:
 Q is O or S; 
 Y is: 
 i) hydrogen; 
 ii) C 1 -C 6  alkyl; or 
 iii) —(CH 2 ) n X(CH 2 ) p U;
 the indices n and p are independently integers from 0 to 6; 
 X is: 
 a) CH 2 ; 
 b) C═O; 
 c) CH═CH; 
 d) O; 
 e) S; 
 f) NR; or 
 g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 U is: 
 a) hydrogen, 
 b) CF 3 ; 
 c) halo; 
 d) NR 4 R 5 ; 
 e) cyano; 
 f) C(═O)NR 4 R 5 ; 
 g) OR 4 ; 
 h) CO 2 R 5 ; 
 i) G; 
 j) NR 4 G; 
 k) OG; 
 G is an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 
 Z is: 
 i) hydrogen; 
 ii) halo; 
 iii) OH; 
 iv) CO 2 H; 
 v) CO 2 R 4 ; 
 vi) SO 2 R 4 ; 
 vii) NR 4 R 5 ; 
 viii) nitro; 
 ix) cyano; 
 x) C 1 -C 6  alkyl; 
 xi) C 1 -C 6  haloalkyl; 
 xii) C 1 -C 6  alkoxy; 
 xiii) C 1 -C 6  haloalkoxy; 
 xiv) C 1 -C 6  aminoalkyl; 
 xv) C 1 -C 6  aminoalkoxy; 
 xvi) an aza functionality replacing a ring CH functionality; or 
 xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring;
 R 4  and R 5  are each independently hydrogen, optionally substituted C 1 -C 4  alkyl, or R 4  and R 5  can be taken together with a nitrogen atom to form an optionally 
 substituted, saturated or unsaturated heterocyclic ring; or 
 
 a pharmaceutically acceptable salt thereof. 
 
   
   
       2 . The compound according to  claim 1 , wherein Q is O. 
   
   
       3 . The compound according to  claim 1 , wherein Q is S. 
   
   
       4 . The compound according to  claim 1 , wherein Z is 6-aza or 10-aza having the formula: 
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound according to  claim 1 , wherein Z is one or more:
 i) hydrogen;   ii) C 1 -C 4  alkyl;   iii) C 1 -C 4  alkoxy; or   iv) halo.   
   
   
       6 . The compound according to  claim 1 , wherein Y is hydrogen or C 1 -C 6  alkyl. 
   
   
       7 . The compound according to  claim 1 , wherein Y has the formula:
   —(CH 2 ) n U   wherein U is:   i) OH;   ii) CF 3 ;   iii) CO 2 Et;   iv) NMe 2 ;   v) phenyl;   vi) 4-fluorophenyl;   vii) 4-boronophenyl;   viii) 3,4-dimethoxyphenyl;   xi) pyridine-2-yl;   xii) 2-oxopyrrolidin-1-yl; or   xiii) indol-3-yl; and   the indices n and p are independently integers from 0 to 3.   
   
   
       8 . The compound according to  claim 1 , chosen from: 
     6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-ethyl-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-butyl-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-(2,2,2-trifluoroethyl)-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-hydroxyethyl-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-(2-ethoxy-2-oxoethyl)-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-[2-(dimethylamino)ethyl]-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-[2-(dimethylamino)ethyl]-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]-naphthyridine-4-carboxylic acid; 
     2-phenyl-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-(4-fluorophenyl)-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-(4-boronophenyl)-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-(3,4-dimethoxyphenethyl)-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]-naphthyridine-4-carboxylic acid; 
     2-(pyridin-2-ylmethyl)-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; 
     2-[3-(2-oxopyrrolidin-1-yl)propyl]-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]-naphthyridine-4-carboxylic acid; 
     2-[2-(indolin-3-yl)ethyl]-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]-naphthyridine-4-carboxylic acid; 
     2-methyl-7-methoxy-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid; and 
     2-methyl-6-chloro-7-methoxy-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid. 
   
   
       9 . A process for the preparation of a compound having the formula: 
     
       
         
         
             
             
         
       
     
     in which positional numbering, where mentioned, refers to the system illustrated above, and one or more Z are attached to a ring carbon or carbons at any of positions 6 to 10, and in which:
 Q is O or S; 
 Y is: 
 i) hydrogen; 
 ii) C 1 -C 6  alkyl; or 
 iii)-(CH 2 ) n X(CH 2 ) p U;
 the indices n and p are independently integers from 0 to 6; 
 X is: 
 a) CH 2 ; 
 b) C═O; 
 c) CH═CH; 
 d) O; 
 e) S; 
 f) NR; or 
 g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 U is: 
 a) hydrogen, 
 b) CF 3 ; 
 c) halo; 
 d) NR 4 R 5 ; 
 e) cyano; 
 f) C(═O)NR 4 R 5 ; 
 g) OR 4 ; 
 h) CO 2 R 5 ; 
 i) G; 
 j) NR 4 G; 
 k) OG; 
 G is an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 
 Z is: 
 i) hydrogen; 
 ii) halo; 
 iii) OH; 
 iv) CO 2 H; 
 v) CO 2 R 4 ; 
 vi) SO 2 R 4 ; 
 vii) NR 4 R 5 ; 
 viii) nitro; 
 ix) cyano; 
 x) C 1 -C 6  alkyl; 
 xi) C 1 -C 6  haloalkyl; 
 xii) C 1 -C 6  alkoxy; 
 xiii) C 1 -C 6  haloalkoxy; 
 xiv) C 1 -C 6  aminoalkyl; 
 xv) C 1 -C 6  aminoalkoxy; 
 xvi) an aza functionality replacing a ring CH functionality; or 
 xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring;
 R 4  and R 5  are each independently hydrogen, optionally substituted C 1 -C 4  alkyl, or R 4  and R 5  can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring; or 
 
 a pharmaceutically acceptable salt thereof, comprising: 
 reacting a compound having the formula: 
 
     
       
         
         
             
             
         
       
     
     with a compound having the formula YNH 2 , wherein Q, Z, and Y are the same as defined herein above. 
   
   
       10 . The process according to  claim 9 , wherein Q is O. 
   
   
       11 . The process according to  claim 9 , wherein Q is S. 
   
   
       12 . The process according to  claim 9 , wherein Z is one or more:
 i) hydrogen;   ii) C 1 -C 4  alkyl;   iii) C 1 -C 4  alkoxy; or   iv) halo.   
   
   
       13 . The process according to  claim 9 , wherein Y is hydrogen or C 1 -C 6  alkyl. 
   
   
       14 . The process according to  claim 9 , wherein Y has the formula:
   —(CH 2 ) n U   wherein U is:   i) OH;   ii) CF 3 ;   iii) CO 2 Et;   iv) NMe 2 ;   v) phenyl;   vi) 4-fluorophenyl;   vii) 4-boronophenyl;   viii) 3,4-dimethoxyphenyl;   xi) pyridine-2-yl;   xii) 2-oxopyrrolidin-1-yl; or   xiii) indol-3-yl; and   the indices n and p are independently integers from 0 to 3.   
   
   
       15 . A compound of the formula II or III 
     
       
         
         
             
             
         
       
     
     in which one or more W and one or more Z in formula II, and one or more Z and C(═O) NR in formula III are attached to a ring carbon or carbons at any of positions 3, 4 and 6 to 10 and in which:
 Q is O or S; 
 W is C(=Q)NR-M-(CH 2 ) m R 1 , in which 
 M is CHJ or G, 
 R is H or a substituted or unsubstituted C 1 -C 4  alkyl group, 
 J is H or a substituted or unsubstituted C 1 -C 6  alkyl group, 
 G is a substituted or unsubstituted fully saturated, or partially unsaturated, or aromatic, carbocycle or heterocycle, 
 R 1  is C(NR 2 )NH 2 , NHC(═NR 3 )NH 2  or NR 4 R 5 , in which 
 each of R 2  and R 3  are independently H or a substituted or unsubstituted C 1 -C 4  alkyl group, 
 R 4  and R 5  are independently H or a substituted or unsubstituted C 1 -C 4  alkyl group or R 4  and R 5  together with the nitrogen atom to which they are attached form a substituted or unsubstituted C 1 -C 4  alkyl group, saturated or unsaturated heterocyclic group, and m is an integer from 0 to 6; 
 Y is: 
 i) hydrogen; 
 ii) C 1 -C 6  alkyl; or 
 iii) —(CH 2 ) n X(CH 2 ) p U;
 the indices n and p are independently integers from 0 to 6; 
 X is: 
 a) CH 2 ; 
 b) C═O; 
 c) CH═CH; 
 d) O; 
 e) S; 
 f) NR; or 
 g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 U is: 
 a) hydrogen, 
 b) CF 3 ; 
 c) halo; 
 d) NR 4 R 5 ; 
 e) cyano; 
 f) C(═O)NR 4 R 5 ; 
 g) OR 4 ; 
 h) CO 2 R 5 ; 
 i) G; 
 j) NR 4 G; 
 k) OG; 
 
 Z is: 
 i) hydrogen; 
 ii) halo; 
 iii) OH; 
 iv) CO 2 H; 
 v) CO 2 R 4 ; 
 vi) SO 2 R 4 ; 
 vii) NR 4 R 5 ; 
 viii) nitro; 
 ix) cyano; 
 x) C 1 -C 6  alkyl; 
 xi) C 1 -C 6  haloalkyl; 
 xii) C 1 -C 6  alkoxy; 
 xiii) C 1 -C 6  haloalkoxy; 
 xiv) C 1 -C 6  aminoalkyl; 
 xv) C 1 -C 6  aminoalkoxy; 
 xvi) an aza functionality replacing a ring CH functionality; or 
 xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring; 
 R 4  and R 5  are each independently hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, or R 4  and R 5  can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring; 
 x is an integer from 2 to 4; and 
 L is a linker group of valency x; or 
 a pharmaceutically-acceptable salt thereof. 
 
   
   
       16 . The compound according to  claim 15 , wherein x is 2. 
   
   
       17 . The compound according to  claim 15 , wherein L is O, S, a substituted or unsubstituted C 1 -C 20  alkylene, alkenylene or alkynylene chain which can be interspersed with one or more substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic groups and/or one or more O, S or N atoms; or a substituted or unsubstituted saturated or unsaturated aryl or heterocyclic group. 
   
   
       18 . The compound according to  claim 15 , wherein L comprises a nitrogen atom. 
   
   
       19 . The compound according to  claim 15 , wherein L has the formula:
   V 1 -[(CHR) q NR 4 ] r (CHR) q —V 2      V 1  and V 2  are each independently oxygen, NR 4  or CHR;   each q is independently an integer from 0 to 5;   r is an integer from 0 to 2;   R is H or an substituted or unsubstituted C 1 -C 4  alkyl, group;   R 4  is H or substituted or unsubstituted C 1 -C 4  alkyl, or when r is greater than 0, R and R 4  may together form an optionally substituted branched or straight chained alkylene.   
   
   
       20 . The compound according to  claim 19 , wherein R and R 4  are each independently H, CH 3 , or C 2 H 5 , or if r is greater than 0, R and R 4  are each —CH 2 CH 2 CH 2 —. 
   
   
       21 . The compound according to  claim 15 , wherein L is selected from:
 —(CH 2 ) 2 NH(CH 2 ) 2 —   —(CH 2 ) 3 —NMe-(CH 2 ) 3 —   —(CH 2 ) 2 NH(CH 2 ) 2 NH(CH 2 ) 2 —   —(CH 2 ) 2 NH(CH 2 ) 3 NH(CH 2 ) 2 —   —(CH 2 ) 2 NMe(CH 2 ) 2 NMe(CH 2 ) 2 —   —(CH 2 ) 2 NMe(CH 2 ) 3 NMe(CH 2 ) 2 —   —N,N′-Bis(ethylene)piperazine-   —N,N′-Bis (propylene)piperazine-,   —(CH 2 ) S NH(CH 2 ) t —   —(CH 2 ) S NAlkyl(CH 2 ) t —   —(CH 2 ) S NH(CH 2 ) t NH(CH 2 ) u —, and   —(CH 2 ) S NAlkyl(CH 2 )tNAlkyl(CH 2 ) u —,   wherein the indices s, t and u are each independently integers from 2 to 6.   
   
   
       22 . A pharmaceutical or veterinary composition comprising:
 a) a compound of the formula II or III   
     
       
         
         
             
             
         
       
       
         in which one or more W and one or more Z in formula II, and one or more Z and C(=Q)NR in formula III are attached to a ring carbon or carbons at any of positions 3, 4 and 6 to 10 and in which: 
         Q is O or S; 
         W is C(=Q)NR-M-(CH 2 ) m R 1 , in which 
         M is CHJ or G, 
         R is H or a substituted or unsubstituted C 1 -C 4  alkyl group, 
         J is H or a substituted or unsubstituted C 1 -C 6  alkyl group, 
         G is a substituted or unsubstituted fully saturated, or partially unsaturated, or aromatic, carbocycle or heterocycle, 
         R 1  is C(NR 2 )NH 2 , NHC(═NR 3 )NH 2  or NR 4 R 5 , in which 
         each of R 2  and R 3  are independently H or a substituted or unsubstituted C 1 -C 4  alkyl group, 
         R 4  and R 5  are independently H or a substituted or unsubstituted C 1 -C 4  alkyl group or R 4  and R 5  together with the nitrogen atom to which they are attached form a substituted or unsubstituted C 1 -C 4  alkyl group, saturated or unsaturated heterocyclic group, and 
         m is an integer from 0 to 6; 
         Y is: 
         i) hydrogen; 
         ii) C 1 -C 6  alkyl; or 
         iii) —(CH 2 ) n X(CH 2 ) p U;
 the indices n and p are independently integers from 0 to 6; 
 X is: 
 a) CH 2 ; 
 b) C═O; 
 c) CH═CH; 
 d) O; 
 e) S; 
 f) NR; or 
 g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 U is: 
 a) hydrogen, 
 b) CF 3 ; 
 c) halo; 
 d) NR 4 R 5 ; 
 e) cyano; 
 f) C(═O)NR 4 R 5 ; 
 g) OR 4 ; 
 h) CO 2 R 5 ; 
 i) G; 
 j) NR 4 G; 
 k) OG; 
 
         Z is: 
         i) hydrogen; 
         ii) halo; 
         iii) OH; 
         iv) CO 2 H; 
         v) CO 2 R 4 ; 
         vi) SO 2 R 4 ; 
         vii) NR 4 R 5 ; 
         viii) nitro; 
         ix) cyano; 
         x) C 1 -C 6  alkyl; 
         xi) C 1 -C 6  haloalkyl; 
         xii) C 1 -C 6  alkoxy; 
         xiii) C 1 -C 6  haloalkoxy; 
         xiv) C 1 -C 6  aminoalkyl; 
         xv) C 1 -C 6  aminoalkoxy; 
         xvi) an aza functionality replacing a ring CH functionality; or 
         xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring; 
         R 4  and R 5  are each independently hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, or R 4  and R 5  can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring; 
         x is an integer from 2 to 4; and 
         L is a linker group of valency x; or 
         a pharmaceutically-acceptable salt thereof, and 
       
       b) a pharmaceutically or veterinarily acceptable carrier. 
     
   
   
       23 . A method of treatment and/or prophylaxis of a cellular proliferative disorder, comprising administering a therapeutically effective amount of a compound of the formula II or III 
     
       
         
         
             
             
         
       
     
     in which one or more W and one or more Z in formula II, and one or more Z and C(═O) NR in formula III are attached to a ring carbon or carbons at any of positions 3, 4 and 6 to 10 and in which:
 Q is O or S; 
 W is C(=Q)NR-M-(CH 2 ) m R 1 , in which 
 M is CHJ or G, 
 R is H or a substituted or unsubstituted C 1 -C 4  alkyl group, 
 J is H or a substituted or unsubstituted C 1 -C 6  alkyl group, 
 G is a substituted or unsubstituted fully saturated, or partially unsaturated, or aromatic, carbocycle or heterocycle, 
 R 1  is C(NR 2 )NH 2 , NHC(═NR 3 )NH 2  or NR 4 R 5 , in which 
 each of R 2  and R 3  are independently H or a substituted or unsubstituted C 1 -C 4  alkyl group, 
 R 4  and R 5  are independently H or a substituted or unsubstituted C 1 -C 4  alkyl group or R 4  and R 5  together with the nitrogen atom to which they are attached form a substituted or unsubstituted C 1 -C 4  alkyl group, saturated or unsaturated heterocyclic group, and 
 m is an integer from 0 to 6; 
 Y is: 
 i) hydrogen; 
 ii) C 1 -C 6  alkyl; or 
 iii)-(CH 2 ) n X(CH 2 ) p U;
 the indices n and p are independently integers from 0 to 6; 
 X is: 
 a) CH 2 ; 
 b) C═O; 
 c) CH═CH; 
 d) O 
 e) S; 
 f) NR; or 
 g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle; 
 U is: 
 a) hydrogen, 
 b) CF 3 ; 
 c) halo; 
 d) NR 4 R 5 ; 
 e) cyano; 
 f) C(═O)NR 4 R 5 ; 
 g) OR 4 ; 
 h) CO 2 R 5 ; 
 i) G; 
 j) NR 4 G; 
 k) OG; 
 
 Z is: 
 i) hydrogen; 
 ii) halo; 
 iii) OH; 
 iv) CO 2 H; 
 v) CO 2 R 4 ; 
 vi) SO 2 R 4 ; 
 vii) NR 4 R 5 ; 
 viii) nitro; 
 ix) cyano; 
 x) C 1 -C 6  alkyl; 
 xi) C 1 -C 6  haloalkyl; 
 xii) C 1 -C 6  alkoxy; 
 xiii) C 1 -C 6  haloalkoxy; 
 xiv) C 1 -C 6  aminoalkyl; 
 xv) C 1 -C 6  aminoalkoxy; 
 xvi) an aza functionality replacing a ring CH functionality; or 
 xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring; 
 R 4  and R 5  are each independently hydrogen, substituted or unsubstituted C 1 -C 4  alkyl, or 
 R 4  and R 5  can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring; 
 x is an integer from 2 to 4; and 
 L is a linker group of valency x; or 
 a pharmaceutically-acceptable salt thereof, to a subject in need thereof. 
 
   
   
       24 . A method according to  claim 23 , in which cellular proliferative disorder is a neoplasm, tumour, or a cancer. 
   
   
       25 . A method according to  claim 23 , in which the cellular proliferative disorder is a cancer of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, intestinal, exocrine, endocrine, lymphatic, haematopoietic system, and/or head and neck tissue. 
   
   
       26 . A method according to  claim 23 , in which the cellular proliferative disorder is leukemia, lymphoma, multiple myeloma, sarcoma, a brain tumour, or a cancer of the lung, breast, ovary, testes, and/or colon. 
   
   
       27 . A method according to  claim 23 , in which the compound is administered separately, sequentially, or simultaneously with another medicament. 
   
   
       28 . Original) A method according to  claim 23 , in which the compound is administered in the form of a tumour-activated prodrug in which the compound is linked to a trigger domain.