Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use

Abstract

The invention relates to compounds represented by the formula I and to prodrugs or metabolites thereof, or pharmaceutically acceptable salts or solvates of said compounds, said prodrugs, and said metabolites, wherein Z, Y, R 11 and R 14 , R 15 , R 16 , and R 17 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formula I.

1 . A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal comprising a therapeutically effective amount of a compound represented by the formula I:  
     
       
         
         
             
             
         
       
       wherein: 
 Y is —NH—, —O—, —S—, or —CH 2 —;  
 Z is —O— or —N—;  
 R 14  is a C 1 -C 6  alkyl, C 1 -C 6  alkylamino, C 1 -C 6  alkylhydroxy, C 3 -C 10  cycloalkyl, C 1 -C 6  alkyl C 3 -C 10  cycloalkyl or methylureido group;  
 R 15  and R 17  are independently H, halo, or a C 1 -C 6  alkyl group unsubstituted or substituted by one or more R 5  groups;  
 R 16  is H or a C 1 -C 6  alkyl group when Z is N, and R 16  is absent when Z is —O—;  
 R 11  is H, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, —C(O)NR 12 R 13 , —C(O)(C 6 -C 10  aryl), —(CH 2 ) t (C 6 -C 10  aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t NR 12 R 13 , —SO 2 NR 12 R 13  or —CO 2 R 12 , wherein said C 1 -C 6  alkyl, —C(O)(C 6 -C 10  aryl), —(CH 2 ) t (C 6 -C 10  aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic) moieties of the said R 11  groups are unsubstituted or substituted by one or more R 5  groups;  
 each R 5  is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , —SO 2 NR 6 R 7 , C 1 -C 6  alkyl, C 6 -C 10  cycloalkyl, C 1 -C 6  alkylamino, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(C H 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —S(O) j (C 1 -C 6  alkyl), —(CH 2 ) t (C 8 -C 10  aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (C 6 -C 10  aryl), —(CH 2 ) t O(CH 2 ) j (C 6 -C 10  aryl), —(CH 2 ) t O(CH 2 ) q (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , (CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , (CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) j NR 7 (CH 2 ) q S(O) j (C 1 -C 6  alkyl), —(CH 2 ) j NR 7 (CH 2 ) t R 6 , —SO 2 (CH 2 ) t (C 6 -C 10  aryl), and —SO 2 (CH 2 ) t (5 to 10 membered heterocyclic), the —(CH 2 ) q — and —(CH 2 ) t — moieties of the said R 5  groups optionally include a carbon-carbon double or triple bond, and the alkyl, aryl and heterocyclic moieties of the said R 5  groups are unsubstituted or substituted with one or more substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —OC(O)OR 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, —(CH 2 ) t (C 6 -C 10  aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 ;  
 each R 6  and R 7  is independently selected from H, OH, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, —(CH 2 ) t (C 6 -C 10  aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t CN(CH 2 ) t OR 9 , —(CH 2 ) t CN(CH 2 ) t R 9  and —(CH 2 ) t OR 9 , and the alkyl, aryl and heterocyclic moieties of the said R 6  and R 7  groups are unsubstituted or substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R 8 , —C(O)OR 8 , —CO(O)R 8 , —OC(O)OR 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6  alkyl, —(CH 2 ) t (C 6 -C 10  aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , where when R 6  and R are both attached to the same nitrogen, then R and R 7  are not both bonded to the nitrogen directly through an oxygen;  
 each R 8  is independently selected from H, C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, —(CH 2 ) t (C 6 -C 10  aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic);  
 t is an integer from 0 to 6; j is an integer from 0 to 2; q is an integer from 2 to 6;  
 each R 9  and R 10  is independently selected from H, —OR 6 , C 1 -C 6  alkyl, and C 3 -C 10  cycloalkyl; and  
 each R 12  and R 13  is independently selected from H, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, —(CH 2 ) t (C 3 -C 10  cycloalkyl), —(CH 2 ) t (C 6 -C 10  aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , and the alkyl, aryl and heterocyclic moieties of the said R 12  and R 13  groups are unsubstituted or substituted with one or more substituents independently selected from R 5 , or R 12  and R 13  are taken together with the nitrogen to which they are attached to form a C 5 -C 9  azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C 5 -C 9  azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl rings are unsubstituted or substituted with one or more R substituents, where R 12  and R 13  are not both bonded to the nitrogen directly through an oxygen;  
 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.  
 
     
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein said hyperproliferative disorder is cancer.  
   
   
       3 . The pharmaceutical composition of  claim 2 , wherein said cancer is brain, lung, kidney, renal, ovarian, ophthalmic, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, gynecological, prostate, colorectal or thyroid cancer.  
   
   
       4 . The pharmaceutical composition of  claim 1 , wherein said hyperproliferative disorder is noncancerous.  
   
   
       5 . The pharmaceutical composition of  claim 4 , wherein said hyperproliferative disorder is a benign hyperplasia of the skin or prostate.  
   
   
       6 . A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal comprising a therapeutically effective amount of a compound, salt or solvate of  claim 1  in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens, and a pharmaceutically acceptable carrier.  
   
   
       7 . A pharmaceutical composition for the treatment of pancreatitis or kidney disease in a mammal comprising a therapeutically effective amount of a compound, salt or solvate of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       8 . A pharmaceutical composition for the prevention of blastocyte implantation in a mammal comprising a therapeutically effective amount of a compound, salt or solvate of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       9 . A pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal comprising a therapeutically effective amount of a compound, salt or solvate of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       10 . The pharmaceutical composition of  claim 9  wherein said disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, atherosclerosis, skin diseases, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.  
   
   
       11 . A pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal comprising a therapeutically effective amount of a compound, salt or solvate of  claim 1 , a therapeutically effective amount of a compound, salt or solvate of an antihypertensive agent, and a pharmaceutically acceptable carrier.  
   
   
       12 . A method of treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound, salt or solvate of  claim 1 .  
   
   
       13 . The method of  claim 12 , wherein said hyperproliferative disorder is cancer.  
   
   
       14 . The method of  claim 13  wherein said cancer is brain, lung, ophthalmic, squamous cell, renal, kidney, ovarian, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, gynecological or thyroid cancer.  
   
   
       15 . The method of  claim 12  wherein said hyperproliferative disorder is noncancerous.  
   
   
       16 . The method of  claim 15  wherein said hyperproliferative disorder is a benign hyperplasia of the skin or prostate.  
   
   
       17 . A method for the treatment of a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound, salt or solvate of  claim 1  in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.  
   
   
       18 . A method of treating pancreatitis or kidney disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound, salt or solvate of  claim 1 .  
   
   
       19 . A method of preventing blastocyte implantation in a mammal comprising administering to said mammal a therapeutically effective amount of a compound, salt or solvate of  claim 1 .  
   
   
       20 . A method for treating a disease related to vasculogenesis or angiogenesis in a mammal comprising administering to said mammal a therapeutically effective amount of a compound, salt or solvate of  claim 1 .  
   
   
       21 . The method of  claim 20  wherein said disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, atherosclerosis, skin diseases, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.  
   
   
       22 . A method for treating a disease related to vasculogenesis or angiogenesis in a mammal comprising administering to said mammal a therapeutically effective amount of a compound, salt or solvate of  claim 1  in conjunction with a therapeutically effective amount of an anti-hypertensive agent.