Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders

Abstract

Disclosed are pyrrolopyridazine compounds, methods of preparing such compounds, and their use for the treatment of proliferative, inflammatory, and other disorders.

1 - 10 . (canceled)  
     
     
         11 . A pharmaceutical composition comprising a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       including enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein: 
 R 1  is selected from the group consisting of H, hydroxyl, alkyl, aralkyl, halogen, OR 1 ′, OC(O)R 1 ′, OC(O)OR 1 ′, OC(O)NR 1 ′R 1 ″, OS(O) 2 R 1 ′″, and OS(O) 2 NF 1 ′R 1 ″; wherein R 1 ′ and R 1 ″ are each independently selected from the group consisting of H, alkyl, aryl, aralkyl, heterocyclo, and cycloalkyl groups; R 1 ′ and R 1 ″ may also be taken together to form one of a cycloalkyl, an aryl, and a heterocyclic group; R 1 ′″ is selected from the group consisting of H, alkyl, aryl, aralkyl, heterocyclo, and cycloalkyl;  
 R 2  is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R 1 ′OC(O—, R 1 ′C(O)— R 1 ″R 1 ′NC(O)— R 1 ′″O(O) 2 S— R 1 ′R 1 ″N(O) 2 S— and R 1 ′″(O) n S— wherein n is the integer 1 or 2;  
 R 1  and R 2  may be taken together with the carbon atoms to which they are attached to form cycloalkene;  
 X is selected from the group consisting of a valence bond, O, S, and NR 2 ′; and R 2 ′ is selected from the group consisting of H, alkyl, aralkyl, C(O)R 1 , C(O)OR 1 , SO 2 NR 1 ′R 1 ″, C(O)NR 1 ′R 1 ″ and SO 2  R 1 ′″; with the proviso that when X is S, R 2  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl;  
 R 3  is selected from the group consisting of H, hydroxyl, alkyl, cycloalkyl, heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido, halogen, amine, substituted amine, OR 3 ′, CH 2 OR 3 ′, CH 2 NR 3 ′R 3 ″, CH 2 SR 3 ′, OC(O)R 3 ′, OC(O)OR 3 ″, OC(O)NR 3 ′R 3 ″, OS(O) 2 R 3 ′, and OS(O) 2 NR 3 ′R 3 ″; wherein R 3 ′ and R 3 ″ are each independently selected from the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl, and aryl; R 3 ′ and R 3 ″ may also be taken together with the nitrogen atom to which they are attached to form a heterocyclyl; when R 3  is a carbalkoxy, acyl, or carboxamido group, these groups are optionally substituted with one or two substituent groups, said substituent groups are independently selected from the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl, and aryl;  
 R 2  and R 3  may also be taken together to form a cycloalkyl, aryl, or heterocyclic group;  
 R 4  is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, aralkyl, R 1 ′OC(O), R 1 ′C(O), R 1 ″R 1 ′NC(O), R 1   1 ′″O(O) 2 S, R 1 ′R 1 ″N(O) 2 S and R 1 ′″(O) n S, wherein n is the integer 1 or 2;  
 Y is selected from the group consisting of a valence bond, O, S, and NR 4 ′; R 4 ′ is selected from the group consisting of H, alkyl, aralkyl, a heterocycle, C(O)R 1 , C(O)OR 1 , S(O 2 )NR 1 ′R 1 ″, C(O)NR 1 ′R 1 ″, and S(O 2 )R 1 ; with the proviso that when Y is S, R 4  is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle and aralkyl; when Y is NR 4 ′, R 4 ′ can be taken together with R 3  with the N atom and carbon atoms to which they are attached to form a heterocyclic ring system;  
 R 5  is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, a heterocycle, aryl, aralkyl, acyl, substituted alkylene group, R 1 ′OC(O), R 1 ′C(O), R 1 ″R 1 ′NC(O), R 1 ′″O(O) 2 S, R 1 ′R 1 ″N(O) 2 S and R 1 ′″(O) n S; wherein n the integer 1 or 2;  
 Z is selected from the group consisting of a valence bond, O, S, and NR 5 ′; R 5 ′ is selected from the group consisting of H, alkyl, aralkyl and a heterocycle; with the proviso that when Z is a valence bond, R 5  is selected from the group consisting of H, halogen, a substituted alkylene group and a cyano group; and, with the further proviso that when Z is S, R 5  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heterocycle and aralkyl; and,  
 R 6  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, a heterocycle, acyl, carbalkoxy, and carboxamido; said carbalkoxy, acyl, and carboxamido groups are optionally substituted with one or two substituent groups, each of which is independently selected from the group consisting of H, alkyl, aralkyl, and a heterocycle, further comprising one or more additional therapeutic agent.  
 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the additional therapeutic agent is selected from the group consisting of angiogenesis inhibitors, antiestrogens, progestogens, aromatase inhibitors, antihormones, antiprogestogens, antiandrogens, LHRH agonists and antagonists, testosterone 5α-dihydroreductase inhibitors, farnesyl transferase inhibitors, anti-invasion agents, growth factor inhibitors, antimetabolites, intercalating antitumour antibiotics, platinum derivatives, alkylating agents, antimitotic agents, topoisomerase inhibitors, cell cycle inhibitors, and biological response modifiers.  
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the additional therapeutic agent is selected from the group consisting of linomide, integrin αvβ3 function inhibitors, angiostatin, razoxin, tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, luprolide, finasteride, metalloproteinase inhibitors, urokinase plasminogen activator receptor function inhibitors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine, adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide nitrosoureas, thiotephan, vincristine, taxol, taxotere, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols.  
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the additional therapeutic agent is selected from the group consisting of taxol, Erbitux™, paraplatin and Ifex.  
     
     
         15 . A method of treating a proliferative or inflammatory disease, in a patient in need thereof, comprising administering a therapeutically effective amount of the compound of claim  1 .  
     
     
         16 . The method of  claim 15 , further comprising administering at least one additional therapeutic agent.  
     
     
         17 . The method of  claim 16 , wherein the additional therapeutic agent is selected from the group consisting of angiogenesis inhibitors, antiestrogens, progestogens, aromatase inhibitors, antihormones, antiprogestogens, antiandrogens, LHRH agonists and antagonists, testosterone 5α-dihydroreductase inhibitors, farnesyl transferase inhibitors, anti-invasion agents, growth factor inhibitors, antimetabolites, intercalating antitumour antibiotics, platinum derivatives, alkylating agents, antimitotic agents, topoisomerase inhibitors, cell cycle inhibitors, and biological response modifiers.  
     
     
         18 . The method of  claim 16 , wherein the additional therapeutic agent is selected from the group consisting of linomide, integrin αvβ3 function inhibitors, angiostatin, razoxin, tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, luprolide, finasteride, metalloproteinase inhibitors, urokinase plasminogen activator receptor function inhibitors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine, adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide nitrosoureas, thiotephan, vincristine, taxol, taxotere, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols.  
     
     
         19 . The method of  claim 16 , wherein the additional therapeutic agent is selected from the group consisting of Erbitux™, taxol, paraplatin and Ifex.  
     
     
         20 . The method of  claim 16 , wherein the at least one additional therapeutic agent is administered simultaneously, sequentially or a combination thereof, with the compound of formula I.