Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp) for use in treatment of diseases associated with a pten deficiency

Abstract

A compound having the structure set forth in Formula (I) and Formula (II): wherein the substituents Y, Z, A, B, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions associated with a PTEN deficiency that are ameliorated by the inhibition of PARP activity.

1 - 22 . (canceled) 
     
     
         23 . A method of treating a disease or condition associated with a PTEN deficiency comprising administering to the subject a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         Y is an aryl or heteroaryl group optionally substituted with at least one R 6 ; 
         Z is an aryl group optionally substituted with at least one R 6 ; 
         A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, alkoxyalkyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; and wherein B is not OH; 
         R 6  is selected from OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 2 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; 
         R 2  is selected from hydrogen, Br, Cl, I, or F; 
         R A , and R B  are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and alkylcarbonyl; or R A  and R B  taken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C 1 -C 6 alkyl)-, —NCO(C 1 -C 6 alkyl)-, —NCO(C 3 -C 8 cycloalkyl)-, —N(aryl)-, —N(aryl-C 1 -C 6 alkyl-)-, —N(substituted-aryl-C 1 -C 6 alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 alkyl-)-, —S—, and S(O) q —, wherein q is 1 or 2; and wherein the 3-10 membered heterocycle ring, the substituted-aryl, and the substituted-heteroaryl are each independently substituted with one or more substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkenyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, —NR A R B , and —(NR A R B )carbonyl; or 
         a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         24 . The method of  claim 23 , wherein R 2  is fluorine. 
     
     
         25 . The method of  claim 23 , wherein Y is heteroaryl optionally substituted with 1, 2, or 3 R 6 . 
     
     
         26 . The method of  claim 25 , wherein Y is triazole substituted with C 1 -C 6  alkyl. 
     
     
         27 . The method of  claim 23 , wherein Z is phenyl optionally substituted with 1, 2, or 3 R 6 . 
     
     
         28 . The method of  claim 27 , wherein Z is phenyl substituted with halogen. 
     
     
         29 . The method of  claim 23 , wherein Y is triazole substituted with C 1 -C 6  alkyl; and Z is phenyl substituted with fluoro. 
     
     
         30 . The method of  claim 23 , wherein the compound is:
 (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,   (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,   (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or   (8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; or   
       a pharmaceutically acceptable salt or solvate thereof. 
     
     
         31 . The method of  claim 23 , wherein the compound is:
 (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or   
       a pharmaceutically acceptable salt or solvate thereof. 
     
     
         32 . The method of  claim 31 , wherein the disease or condition associated with a PTEN deficiency is cancer selected from glioblastoma, prostate cancer, renal cancer, small cell lung carcinoma, meningioma, head and neck cancer, colorectal cancer, thyroid cancer, bladder cancer, breast cancer, or melanoma. 
     
     
         33 . The method of  claim 32 , wherein said administration is in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof. 
     
     
         34 . A method of treating small cell lung cancer comprising administering to the subject a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         Y is an aryl or heteroaryl group optionally substituted with at least one R 6 ; 
         Z is an aryl group optionally substituted with at least one R 6 ; 
         A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, alkoxyalkyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; and wherein B is not OH; 
         R 6  is selected from OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 2 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; 
         R 2  is selected from hydrogen, Br, Cl, I, or F; 
         R A , and R B  are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and alkylcarbonyl; or R A  and R B  taken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C 1 -C 6 alkyl)-, —NCO(C 1 -C 6 alkyl)-, —NCO(C 3 -C 8 cycloalkyl)-, —N(aryl)-, —N(aryl-C 1 -C 6 alkyl-)-, —N(substituted-aryl-C 1 -C 6 alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 alkyl-)-, —S—, and S(O) q —, wherein q is 1 or 2; and wherein the 3-10 membered heterocycle ring, the substituted-aryl, and the substituted-heteroaryl are each independently substituted with one or more substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkenyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, —NR A R B , and —(NR A R B )carbonyl; or 
         a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         35 . The method of  claim 34 , wherein Y is triazole substituted with C 1 -C 6  alkyl; and Z is phenyl substituted with halogen. 
     
     
         36 . A method of treating small cell lung cancer comprising administering to the subject a therapeutically effective amount of the compound:
 (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or   
       a pharmaceutically acceptable salt or solvate thereof. 
     
     
         37 . The method of  claim 34 , wherein said administration is in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof. 
     
     
         38 . The method of  claim 36 , wherein said administration is in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof. 
     
     
         39 . A method of treating head and neck cancer, meningioma, anaplastic astrocytoma, or colorectal cancer, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         Y is an aryl or heteroaryl group optionally substituted with at least one R 6 ; 
         Z is an aryl group optionally substituted with at least one R 6 ; 
         A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, alkoxyalkyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; and wherein B is not OH; 
         R 6  is selected from OH, NO 2 , CN, Br, Cl, F, I, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 2 -C 6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2 -C 6 alkynyl, aryl, arylalkyl, C 3 -C 8 cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 2 -C 8 heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )C 1 -C 6 alkylene, (NR A R B )carbonyl, (NR A R B )carbonylalkylene, (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene; 
         R 2  is selected from hydrogen, Br, Cl, I, or F; 
         R A , and R B  are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and alkylcarbonyl; or R A  and R B  taken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of —O—, —NH, —N(C 1 -C 6 alkyl)-, —NCO(C 1 -C 6 alkyl)-, —NCO(C 3 -C 8 cycloalkyl)-, —N(aryl)-, —N(aryl-C 1 -C 6 alkyl-)-, —N(substituted-aryl-C 1 -C 6 alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 alkyl-)-, —S—, and S(O) q —, wherein q is 1 or 2; and wherein the 3-10 membered heterocycle ring, the substituted-aryl, and the substituted-heteroaryl are each independently substituted with one or more substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkenyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, —NR A R B , and —(NR A R B )carbonyl; or 
         a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         40 . The method of  claim 39 , wherein Y is triazole substituted with C 1 -C 6  alkyl; and Z is phenyl substituted with halogen. 
     
     
         41 . The method of  claim 39 , wherein the compound is:
 (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or   
       a pharmaceutically acceptable salt or solvate thereof. 
     
     
         42 . The method of  claim 39 , wherein said administration is in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.