Tricyclic heterocycles as anticancer agents

Abstract

Tricyclic chemical modulators of FOXO transcription factor proteins are disclosed. The compounds are useful to treat cancer, age-onset proteotoxicity, stress-induced depression, inflammation, and acne. The compounds are of the following and similar genera: in which Het is an aromatic heterocyclic ring and Y is a point of attachment of various side chains and rings. An example of such a compound is 4-chloro-N-(3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propyl)benzenesulfonamide:

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         T is a benzene ring or a five or six membered heteroaromatic ring; 
         U is a benzene ring or a five or six membered heteroaromatic ring; 
         with the proviso that at least one of T and U is a five or six membered heteroaromatic ring; 
         X is selected from the group consisting of: —S—, —(CH 2 —CH 2 )—, and —CH═CH—; 
         Y is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         A is a three to six membered aliphatic carbocycle or heterocycle attached at Y as a spiro ring, and A may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy; 
         R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of: H, halo, —N 3 , —NR 6 R 7 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —OR 6 , —C(O)R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —C(O)OR 6 , —SR 6 , —SO2R 6 , and —SO2NR 6 R 7 ; 
         R 5  is —(CR 15 R 16 ) p -Q q -(CR 15 R 16 ) n-p -Z or 
       
       
         
           
           
               
               
           
         
         R 5a  is ═CR 14 (CR 15 R 16 ) p -Q q -(CR 15 R 16 ) m-p -Z; 
         Q is chosen from —O—, —NR 14 — and 
       
       
         
           
           
               
               
           
         
         each R 6  and R 7  is independently selected from the group consisting of: H and (C 1 -C 6 )alkyl; 
         R 14  is H or (C 1 -C 3 )alkyl; 
         R 15  and R 16 , in each occurrence are chosen independently from H, OH, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy, or, taken together, two of R 14,  R 15  and R 16  may form a three to seven membered heterocycle or non-aromatic carbocycle, wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy; 
         m is an integer from 1 to 3; 
         n is an integer from 2 to 4; 
         p is zero, 1 or 2; 
         q is zero or 1; 
         t is zero, 1 or 2; 
         u is zero, 1 or 2, with the proviso that when Y is 
       
       
         
           
           
               
               
           
         
       
       u is 2;
 v is 1, 2 or 3; 
 with the proviso that when q is zero and R 15  and R 16 , in all of their occurrences are H, n is not 4; 
 Z is selected from the group consisting of: —NHSO 2 R 17 , —NHC(O)NR 8 R 9 , —NHC(O)OR 8 , —S(O) 2 NR 8 R 9 , substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide and cyanoguanidine; 
 R 8  and R 9  are independently selected from H, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl and substituted or unsubstituted (C5-C 14 )aryl; and 
 R 17  is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )acylamino, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy. 
 
     
     
         2 . A compound according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein each of W 10 , W 11 , W 12  and W 13  is independently chosen from N, CH and C—R 3 . 
       
     
     
         3 . A compound according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein each of W 20 , W 21  and W 22  is independently chosen from S, O, NH, CH and C—R 3 . 
       
     
     
         4 . A compound according to  claim 1 , wherein Z is selected from the group consisting of: —NHSO 2 R 17 , —NHC(O)NR 8 R 9 , and —NHC(O)OR 8 . 
     
     
         5 . A compound according to  claim 4  wherein Z is —NHSO 2 R 17 . 
     
     
         6 . A compound according to  claim 5  of formula: 
       
         
           
           
               
               
           
         
         wherein Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl. 
       
     
     
         7 . A compound according to  claim 6  of formula: 
       
         
           
           
               
               
           
         
         wherein: 
         each of W 10 , W 11 , W 12  and W 13  is independently chosen from N, CH and C—R 3 ; 
         each of W 20 , W 21  and W 22  is independently chosen from S, O, NH, CH and C—R 3 . 
         R 1  and R 3  are independently selected from the group consisting of: H and halo; and 
         R 2  and R 4  are H. 
       
     
     
         8 . A compound according to  claim 7  wherein X is —CH═CH— or —CH 2 CH 2 —. 
     
     
         9 . A compound according to  claim 7  wherein p and q are both zero, R 15  is H and R 16  is chosen from H and OH. 
     
     
         10 . A compound according to  claim 9  of formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 3  are independently selected from the group consisting of: H and halo; and 
         R 2  and R 4  are H. 
       
     
     
         11 . A compound according to  claim 7  wherein two R 15  or R 16  taken together form a three to seven membered carbocycle or heterocycle B, wherein said three to seven membered carbocycle or heterocycle B may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy, said compound being of formula: 
       
         
           
           
               
               
           
         
         wherein 
         t is zero, 1 or 2; and 
         Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl. 
       
     
     
         12 . A compound according to  claim 11  wherein
 (a) B is a five-membered ring of formula: 
 
       
         
           
           
               
               
           
         
         wherein, in the five-membered ring: 
       
       W 1  and W 2  are both —CH 2 —; or 
       one of W 1 and W 2  is —O— and the other is —CH 2 —; or 
       one of W 1  and W 2  is —CH(OH)— and the other is —CH 2 — 
       and the arylsulfonamide replaces one hydrogen on one CH 2  group; or
 (b) B is a six-membered ring of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein, in the six-membered ring: 
       all of W 1  W 2  and W 3  are —CH 2 —; or 
       one of W 1  W 2  and W 3  is —O— and the other two are —CH 2 —; or 
       one of W 1  W 2  and W 3  is —CH(OH)— and the other two are —CH 2 — 
       and the arylsulfonamide replaces one hydrogen on one CH 2  group. 
     
     
         13 . A compound according to  claim 7  wherein two R 15  or R 16  taken together form a three to seven membered carbocycle or heterocycle B, wherein said three to seven membered carbocycle or heterocycle B may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy, said compound being of formula: 
       
         
           
           
               
               
           
         
         wherein 
         t is zero, 1 or 2; and 
         Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl. 
       
     
     
         14 . A compound according to  claim 13  wherein
 (a) B is a five-membered ring of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein, in the five-membered ring: 
       W 1  and W 2  are both —CH 2 —; or 
       one of W 1  and W 2  is —O— and the other is —CH 2 —; or 
       one of W 1  and W 2  is —CH(OH)— and the other is —CH 2 — 
       and the arylsulfonamide replaces one hydrogen on one CH 2  group; or
 (b) B is a six-membered ring of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein, in the six-membered ring: 
       all of W 1  W 2  and W 3  are —CH 2 —; or 
       one of W 1  W 2  and W 3  is —O— and the other two are —CH 2 —; or 
       one of W 1  W 2  and W 3  is —CH(OH)— and the other two are —CH 2 — 
       and the arylsulfonamide replaces one hydrogen on one CH 2  group. 
     
     
         15 . A compound according to  claim 7  wherein Ar is phenyl or thienyl, optionally substituted with one or two substituents chosen from (C 1 -C 3 )alkyl, halogen, cyano, nitro, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )haloalkoxy, and acetylamino. 
     
     
         16 .- 23 . (canceled) 
     
     
         24 . A compound according to  claim 1  wherein t is zero. 
     
     
         25 . A compound according to  claim 2  wherein one of W 10 , W 11 , W 12  and W 13  is N, and the remaining three are CH. 
     
     
         26 . A compound according to  claim 2  wherein two of W 10 , W 11 , W 12 , and W 13  are N, and the remaining two are CH. 
     
     
         27 . A compound according to  claim 3  wherein one of W 20 , W 21  and W 22  is S and the remaining two are CH. 
     
     
         28 . (canceled) 
     
     
         29 . A compound according to  claim 6  wherein
 Ar is phenyl, optionally substituted at the 3, 4 or 5 positions with one or two substituents chosen from methyl, halogen, cyano, trifluoromethyl and trifluoromethoxy; 
 R 1  and R 3  are independently selected from the group consisting of H and halo; and 
 R 2  and R 4  are H. 
 
     
     
         30 . (canceled) 
     
     
         31 . A method of treating a disease chosen from:
 (a) cancer   (b) diabetes   (c) autoimmune disease   (d) age onset proteotoxic disease   (e) mood disorder   (f) acne vulgaris   (g) solid organ transplant rejection;   (h) graft vs host disease; and   (i) cardiac hypertrophy;   said method comprising administering a therapeutically effective amount of a compound according to  claim 1 .   
     
     
         32 .- 39 . (canceled) 
     
     
         40 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to  claim 1 .