NOVEL PHOSPHODIESTERASE INHIBITORS AND USES THEREOF

摘要

The invention provides for novel benzonaphthyridine derivatives and compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the compounds are phosphodiesterase inhibitors. The invention further provides for methods for inhibition of phosphodiesterase comprising contacting phosphodiesterase with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. The invention further provides for methods for treatment of neurodegenerative diseases, increasing memory or long term potentiation with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the phosphodiesterase is PDE5.

主权项

1. A compound of formula (I), wherein A is O or NR4; B is CR16 or N; V is a bond or C(O); W is a bond or NR13; X is —(C1-C3)-alkyl, —(C1C3)-alkyl substituted with at least one D, C(O), S, S(O), or S(O)2; Y is NR5, O or S; Z is C or N; R1 is hydrogen, halogen or —(C1-C6)-haloalkyl; R2 is hydrogen or —OR6; R3 is hydrogen, —OMe, —CF3, —CN or halogen; R4 is hydrogen or —(C1-C3)-alkyl; R5 is hydrogen, —(C1-C3)-alkyl, —(C3-C5)-cycloalkyl, —C(O)R7, —C(O)OR7, —C(O)N(R7)2, —S(O)2R7; R6 is hydrogen, —(C1-C6)-alkyl, —(C1-C6)-haloalkyl, or —(C3-C8)-cycloalkyl; R7 is independently hydrogen, —(C1-C6)-alkyl, —(C1-C6)-haloalkyl, or aryl; R8 is hydrogen, —(C1-C6)-alkyl, —(C1-C6)-haloalkyl, —(C3-C8)-cycloalkyl, —NR9R1, —S(O)2R11, or heterocyclyl; R9 and R10 are each independently hydrogen, —(C1-C6)-alkyl, —(C3-C8)-cycloalkyl, or —C(O)R11, wherein the —(C1-C6)-alkyl or —(C3-C8)-cycloalkyl are optionally substituted with —(C1-C6)-alkyl, —(C3-C8)-cycloalkyl, —NR11R12, —SR11, or heterocyclyl; or, R9 and R10 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with —(C1-C6)-alkyl; R11 and R12 are each independently hydrogen, —(C1-C6)-alkyl, or —(C3-C8)-cycloalkyl; R13 is hydrogen, —(C1-C6)-alkyl, —(C3-C5)-cycloalkyl, —C(O)R7, —C(O)OR7, —C(O)N(R7)2, or —S(O)2R7; R14 is hydrogen, halogen or —(C1-C6)-haloalkyl; R15 is hydrogen, —OR17, —OH or halogen; R16 is hydrogen, —OR17, —OH or halogen; R17 hydrogen, —(C1-C6)-alkyl, —(C1-C6)-haloalkyl, or —(C3-C8)-cycloalkyl; m and n are each 0, 1, 2, or 3, provided that the sum of m+n is an integer from 1-4; or a pharmaceutically acceptable salt or tautomer thereof; with the proviso that R1 and R2 are not both hydrogen when V and W are each a bond, Y is NR5, A is NR4, X is CO, n=2 and m=1.